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The longer the neutropenia, the greater the risk of a fungal infection.The duration of the neutropenia affects the infection risk of the patient.Side effects common to aminoglycosides include nephrotoxicity and ototoxicity; side effects common to cephalosporins include rashes, fever and pruritus.Additionally, cultures of sputum, throat, lesions, wounds, urine and faeces are essential in the surveillance of the patient. It may also be necessary to do a tracheal aspiration, bronchoscopy with bronchial brushings or lung biopsy to diagnose the cause of pneumonic infiltrates. However, invasive diagnostic studies are often contraindicated due to the concern of introducing infection and the fact that patients are also often thrombocytopenic. Despite these many tests, the causative organism is identified in only approximately half of neutropenic patients. When a febrile episode occurs in a neutropenic patient, antibiotic therapy must be initiated immediately (within 1 hour) even before the determination of a specific causative organism by culture. Administration of broad-spectrum antibiotics is usually by the IV route because of the rapidly lethal effects of infection. However, some oral antibiotics are highly effective and routinely used for prophylaxis against infection in some neutropenic patients. The use of a third- or fourth-generation cephalosporin (e.g. cefepime, ceftazidime), a carbapenem (e.g. imipenem/cilastatin) or a combination of an aminoglycoside plus an antipseudomonal offers broad-spectrum coverage for initial management.43 Regardless of the combination, the nurse must initiate therapy promptly and observe the patient for side effects of antimicrobial agents. Side effects common to aminoglycosides include nephrotoxicity and ototoxicity; side effects common to cephalosporins include rashes, fever and pruritus. The duration of the neutropenia affects the infection risk of the patient. The longer the neutropenia, the greater the risk of a fungal infection.G-CSF (filgrastim and pegfilgrastim) can be used to treat a neutropenic patient.G-CSF stimulates the production and function of neutrophils.GM-CSF stimulates the production and function of neutrophils and monocytes.These agents can be given IV or SC.The nurse can teach the patient and family how to administer the SC medication. | en | apollo | train |
Similarly, the newer HCV agents are also substrates and inhibitors or inducers of various P450 enzymes and transporters. The NS5A inhibitor ledipasvir (which is coformulated with sofosbuvir) is a substrate and weak inhibitor of Pglycoprotein (P-gp). It is also a weak inhibitor of transporters including BCRP (breast cancer resistance protein) and OATP (organic anion transporter protein) 1B1/1B3.
Ledipasvir/sofosbuvir may be coadministered with most antiretrovirals, but special attention is required for tenofovircontaining regimens. Tenofovir exposures are increased 40-98% in the presence of ledipasvir/sofosbuvir, regardless of the type of antiretroviral combination used. This effect is postulated to be secondary to inhibition of P-gp and BCRPmediated efflux of tenofovir by ledipasvir. There is no evidence to suggest that clinical relevant negative consequences result from this interaction. Nonetheless, patients continuing on tenofovir treatment during ledipasvir/sofosbuvir therapy should be monitored for tenofovir-associated adverse events. Use of an alternate NRTI backbone may be considered, particularly in patients with additional risk factors for renal dysfunction including use of other potentially nephrotoxic agents (including NSAID use), or when prolonged ledipasvir/sofosbuvir treatment (i.e., greater than 12 weeks) is required. | en | apollo | train |
Testicular pain following initiation of elexacaftor/tezacaftor/ivacaftor in males with cystic fibrosis.
Elexacaftor/tezacaftor/ivacaftor (Trikafta) was approved by the Food and Drug Administration in October 2019 for treatment of cystic fibrosis (CF) in patients 12 years and older with at least one F508del mutation in the CFTR protein. There were no documented reports of testicular pain during clinical trials. In this case series, we discuss 7 males between 17 and 39 years of age who reported testicular pain or discomfort within the first two weeks of starting therapy. The precise mechanism of this side effect is unknown, but it may be related to restoration of CFTR function in the male reproductive tract. All patients experienced resolution of this side effect within a week after onset, regardless of the management, except for one. Further research is needed to determine short- and long-term impact of this drug on male fertility. Until more data is available, the authors recommend counseling patients on contraceptive options. | en | apollo | train |
Downregulation of tumor suppressor QKI in gastric cancer and its implication in cancer prognosis.
Gastric cancer (GC) is the fourth most common cancer and second leading cause of cancer-related death worldwide. RNA-binding protein Quaking (QKI) is a newly identified tumor suppressor in multiple cancers, while its role in GC is largely unknown. Our study here aimed to clarify the relationship between QKI expression with the clinicopathologic characteristics and the prognosis of GC. In the 222 GC patients' specimens, QKI expression was found to be significantly decreased in most of the GC tissues, which was largely due to promoter hypermethylation. QKI overexpression reduced the proliferation ability of GC cell line in vitro study. In addition, the reduced QKI expression correlated well with poor differentiation status, depth of invasion, gastric lymph node metastasis, distant metastasis, advanced TNM stage, and poor survival. Multivariate analysis showed QKI expression was an independent prognostic factor for patient survival. | en | apollo | train |
RGS4 inhibits Gq-mediated activation of mitogen-activated protein kinase and phosphoinositide synthesis.
Recombinant regulators of G protein-signaling (RGS) proteins stimulate hydrolysis of GTP by alpha subunits of the Gi family but have not been reported to regulate other G protein alpha subunits. Expression of recombinant RGS proteins in cultured cells inhibits Gi-mediated hormonal signals probably by acting as GTPase-activating proteins for Galphai subunits. To ask whether an RGS protein can also regulate cellular responses mediated by G proteins in the Gq/11 family, we compared activation of mitogen-activated protein kinase (MAPK) by a Gq/11-coupled receptor, the bombesin receptor (BR), and a Gi-coupled receptor, the D2 dopamine receptor, transiently co-expressed with or without recombinant RGS4 in COS-7 cells. Pertussis toxin, which uncouples Gi from receptors, blocked MAPK activation by the D2 dopamine receptor but not by the BR. Co-expression of RGS4, however, inhibited activation of MAPK by both receptors causing a rightward shift of the concentration-effect curve for both receptor agonists. RGS4 also inhibited BR-stimulated synthesis of inositol phosphates by an effector target of Gq/11, phospholipase C. Moreover, RGS4 inhibited inositol phosphate synthesis activated by addition of AlF4- to cells overexpressing recombinant alphaq, probably by binding to alphaq.GDP.AlF4-. These results demonstrate that RGS4 can regulate Gq/11-mediated cellular signals by competing for effector binding as well as by acting as a GTPase-activating protein. | en | apollo | train |
Play a sport or join a social group that incorporates exercise.Swim, do yoga or aerobics every couple of days and don't be afraid to buy barbells to use once in a while.Take the stairs instead of the elevator, go for walks, jogs, bicycle rides.Here is what I would recommend you do, based on the research, to minimize your risk of osteoporosis:
• Stay physically active.In practical terms, this means that if you have a low BMD, you are at a higher risk for a fracture. But there are some devilishly contradictory and confusing details in this great circus of osteoporosis research. To name a few:
• A high BMD increases the risk of osteoarthritis. • A high BMD has been linked to a higher risk of breast cancer. • Although high BMD is linked both to increased breast cancer risk and decreased osteoporotic risk, breast cancer and osteoporosis nonetheless cluster together in the same areas of the world and even in the same individuals. • Rate of bone loss matters just as much as overall BMD. • There are places where overall bone mass, bone mineral density or bone mineral content measurements are lower than they are in "Western" countries, but the fracture rate also is lower, defying accepted logic of how we define "big, strong bones." • Being fat is linked to greater BMD, even though areas of the world that have higher rates of obesity also have higher rates of osteoporosis. Something is wrong with the idea that BMD reliably represents osteoporosis and, by inference, indicates the kind of diet that would lower fracture rates. In contrast, an alternative, but much better, predictor of osteoporosis is the dietary ratio of animal-to-plant protein.. The higher the ratio, the higher the risk of disease. And guess what? BMD is not significantly associated with this ratio. Clearly the conventional recommendations regarding animal foods, dairy and bone mineral density, which are influenced and advertised by the dairy industry, are besieged by serious doubts in the literature. Here is what I would recommend you do, based on the research, to minimize your risk of osteoporosis:
• Stay physically active. Take the stairs instead of the elevator, go for walks, jogs, bicycle rides. Swim, do yoga or aerobics every couple of days and don't be afraid to buy barbells to use once in a while. Play a sport or join a social group that incorporates exercise.You'll feel better, and your bones will be much healthier for the effort.• Eat a variety of whole plant foods, and avoid animal foods, including dairy.Plenty of calcium is available in a wide range of plant foods, including beans and leafy vegetables. | en | apollo | train |
RXi Pharmaceuticals is working on improving cancer immunotherapy by editing T-cells with RNA interference.
he experimental drug has startling powers: It can turn down a mutant gene in a patient’s body, stopping the production of proteins that cause a terribly painful rare disease.
The news has thrilled both patients and scientists, who have been working for decades on the technology to mute misbehaving genes, known as RNA interference, or RNAi. They’ve understood for two decades how the biology works. But it’s been a long, slow slog to figure out how to deliver RNAi therapies to the right cells safely and effectively. Alnylam alone has spent 15 years, and more than $1 billion, on the effort.
So does the company’s recent success herald an explosion of new drugs that can shut down troublesome genes?
The RNAi delivery systems remain highly complex — and the most effective technologies are still protected by patents that make it difficult for startups to get into the field. Safety concerns persist with other RNAi drugs in development: Last year, for instance, Alnylam had to scrap revusiran, one of its most advanced drugs. Rather than alleviating it, the drug exacerbated pain in a rare nerve disease called transthyretin amyloidosis. And several patients died in the clinical trial, though it’s still not clear exactly why. Alnylam’s stock plummeted by half on that news.
The issue of safety has haunted the RNAi field for many years now: Although it’s possible to silence the impact of genes, early work has resulted in several off-target effects that create unforeseen toxicities. So the major focus of RNAi research in recent years has been drug delivery: how to safely deposit the RNAi load to the right tissues, minimizing the impact on other bodily functions. And that’s proven challenging. While it’s working, for now, in diseases of the liver, the field still needs to validate whether RNAi can work in other organs.
Alnylam is testing seven RNAi drugs in the clinic, for conditions ranging from hepatitis B to high cholesterol. A handful of other companies are also in the field, working on therapies that treat diseases of the central nervous system or enhance cancer immunotherapy. But we’re unlikely to see a flood of startups suddenly raising tens of millions to pursue RNAi.
“I don’t think you’ll see new companies popping up in RNA interference. The intellectual property around the field is too constraining,” said Doug Fambrough, CEO of RNAi competitor Dicerna Pharmaceuticals.
Still, the field does have enormous promise — and market potential.
Most drugs work by targeting ill-formed or malfunctioning proteins and trying to excise them from the body. RNAi, by contrast, goes after the genetic source of the faulty protein production and shuts that system down.
When it works, it can ease symptoms in patients with no other options.
Alnylam’s lead RNAi drug patisiran, aimed at treating a rare nerve disorder called familial amyloid polyneuropathy, is projected to ultimately exceed $1 billion in worldwide sales at its peak, which is expected in 2023. The drug, which is being developed in conjunction with Sanofi, should be up for review by the Food and Drug Administration in a couple months, and will be up for European regulatory approval next year.
Alnylam’s stock shot up so much on the news, its market capitalization now exceeds $11 billion.
The phenomenon of RNA interference was first observed in the 1990s in nematodes, and in 1998 scientists Andrew Fire and Craig Mello published a seminal paper in Nature that demonstrated these roundworm genes could be silenced. The duo won the Nobel Prize in 2006 for their work. By that point, several companies had already launched to try to develop new RNAi-based therapeutics — including Alnylam.
Expectations were high — and so was the pressure to create a groundbreaking medicine.
Then came the roadblocks. Scientists hit hurdle after hurdle. And many companies began to crumble: While gene silencing was simple in worms, mammals proved to be far more complex — and safe drug delivery emerged as a major problem. When RNAi therapies weren’t delivered to the right tissues, dangerous side effects showed up in humans that weren’t predicted through animal models. The drugs just weren’t working.
The most dogged RNAi companies — Alnylam among them — began to study better methods to deliver these therapeutics to the right tissues. And a few different techniques have since emerged to improve drug delivery, and, by extension, safety — such as Alnylam’s approach of binding the RNAi therapeutic to a lipid nanoparticle, or fat, to help it settle in the liver. Another method used broadly by RNAi companies is “GalNAc” — a sugar derivative that’s attached to RNAi drugs to help it safely work in the liver.
Both have shown preclinical promise, and the lipid nanoparticle approach was used with patisiran to great effect in Alnylam’s positive trial. So the initial hurdles of safe RNAi delivery finally seem surmountable.
The closest approximation to another RNAi success comes from Ionis Pharmaceuticals and Biogen, which last year received approval for Spinraza, a drug aimed at spinal muscular atrophy. Children with the disease don’t produce enough of a protein called SMN, and the drug works by amplifying the gene that produces the protein — allowing the body to create more of it. It is, in a sense, the opposite of gene silencing, but it’s another proof point that validates the general concept of creating drugs that mute or amplify defective genes.
It’s also proof of concept that a successful RNAi therapy can be quite lucrative.
Meanwhile, other biotechs working on RNAi continue to churn along. Arbutus Therapeutics just landed a $116 million investment from Roivant Sciences to speed development of its RNAi tech as well as other therapeutic platforms in development.
RXi Pharmaceuticals is pursuing RNAi therapeutics in a broad array of diseases, from warts to cancer. Arrowhead Pharmaceuticals and Wave Life Sciences have a number of preclinical programs in play, though none have advanced nearly as far as Alnylam.
Dicerna Pharmaceuticals, meanwhile, is preparing to enter the clinic with an RNAi drug that treats primary hyperoxaluria — a rare genetic disease that causes the overproduction and buildup of substances called oxalates in the urine. The company’s therapeutic aims to turn off the enzyme that creates all the excess oxalate.
Alynlam’s success boosted the stock of many of these biotechs; Dicerna’s share price jumped 21 percent immediately after Alynlam released its data on Sept. 20 and has increased steadily ever since.
The bull case for RNAi draws from biotech history. As many in the industry point out, monoclonal antibodies have become a hugely lucrative and important therapeutic class — but their development was just as fraught, with just as many hurdles, as RNAi. Scientists finally solved the biggest problems, and by 2024, the market is expected to top $130 billion globally.
RNAi could hit great heights, too, if it can be made to work outside the liver.
Gene Yeo, an RNA researcher at University of California, San Diego, thinks he can break that liver barrier. He’s building on the ideas of RNAi to form his own startup, Locana Therapeutics. The company aims to use CRISPR gene-editing to craft RNA therapeutics that can be delivered into the central nervous system — clearly a daunting task for most drug makers.
By editing the RNA, the company hopes to find therapies for neurodegenerative diseases like Huntington’s and ALS.
Madhu Lal-Nag, a researcher at the National Institutes of Health who coordinates RNAi research, said she’s starting to see a surge of interest in the field among academics who want to unravel more of the basic science, especially as it becomes clear that other hot fields of research, such as CRISPR gene-editing, face their own series of hurdles. | en | apollo | train |
Brainstem Monitoring in the Neurocritical Care Unit: A Rationale for Real-Time, Automated Neurophysiological Monitoring.
Patients with severe traumatic brain injury or large intracranial space-occupying lesions (spontaneous cerebral hemorrhage, infarction, or tumor) commonly present to the neurocritical care unit with an altered mental status. Many experience progressive stupor and coma from mass effects and transtentorial brain herniation compromising the ascending arousal (reticular activating) system. Yet, little progress has been made in the practicality of bedside, noninvasive, real-time, automated, neurophysiological brainstem, or cerebral hemispheric monitoring. In this critical review, we discuss the ascending arousal system, brain herniation, and shortcomings of our current management including the neurological exam, intracranial pressure monitoring, and neuroimaging. We present a rationale for the development of nurse-friendly-continuous, automated, and alarmed-evoked potential monitoring, based upon the clinical and experimental literature, advances in the prognostication of cerebral anoxia, and intraoperative neurophysiological monitoring. | en | apollo | train |
Alpha viruses, such as Sindbis virus, carry their genetic information on a single strand of RNA. On infection they use a protein, replicase, to produce double stranded RNA (dsRNA) which is used as genetic material to make more viruses. However the body recognizes dsRNA as foreign, and infected cells initiate an immune response.
New research published in BioMed Central's open access journal BMC Cancer demonstrates that an artificial plasmid coding for the replicase genes of Sindbis virus causes regression and destruction of lung cancer, or melanoma, cells in mice.
Previous attempts to use synthetic dsRNA to destroy tumor cells have met with problems, including side effects at an effective dose, but there are also concerns about using attenuated viruses, to deliver dsRNA inside cells.
Researchers from the University of Texas at Austin have instead used a plasmid containing Sindbis replicase genes (nsp1-4) to force cells to produce dsRNA themselves.
For ten days mice were given daily injections of plasmid into the site of a tumor. After another 15 days most of the tumors had begun to regress, and by day 37 all of the tumors had either regressed or been destroyed. Professor Cui said, "The anti-cancer action of the plasmid seemed to be two-fold. Firstly accumulation of dsRNA resulted in cell death and secondly the presence of dsRNA, and the foreign, unmethylated, plasmid DNA, inside a cell activated both innate and adaptive immune responses."
Professor Cui continued, "In our study both highly immunogenic and poorly immunogenic tumors were receptive to treatment with an RNA replicase based plasmid. Our results suggested a novel approach to cancer molecular therapy." | en | apollo | train |
Processing of concanavalin A-receptor complexes by rat osteoclasts in vitro.
The osteoclast is a large multinucleate cell that is widely accepted as the primary effector cell responsible for normal bone resorption. In a previous study, we demonstrated that concanavalin A (con A) has a dose-dependent biphasic effect on the bone-resorbing capacity of osteoclasts, using a 45Ca bone-organ culture system; bone resorption was stimulated at low concentrations and inhibited at high concentrations. The mitogenic property of con A in lymphocyte cultures is well documented; therefore con A has been used extensively to study the manner in which lymphocytes and other mononuclear cells process the cell-bound lectin. In this study, we have investigated the processing of con A-receptor complexes by osteoclasts in culture, using con A-FITC to evaluate the redistribution of cell-bound con A via epifluorescence microscopy and using con A-ferritin to determine whether the lectin receptor complexes are internalized. The osteoclasts were obtained from the long bones of newborn rats and allowed to attach to glass coverslips at 37 degrees C. Following attachment, the nonadherent cells were removed by rinsing. The adherent osteoclasts were preincubated in 50 micrograms/ml con A-FITC or con A-ferritin at 4 degrees C for 10 min, washed to remove unbound con A, and incubated at 37 degrees C for 15 or 30 min in the absence of con A. Positive controls were fixed immediately after preincubation at 4 degrees C; negative controls were preincubated in con A-FITC and alpha-methyl mannoside, the haptenic inhibitor of con A binding. The results demonstrate that redistribution and endocytosis of con A-receptor complexes occurs within 30 min. These findings confirm the hypothesis that cell-bound con A can alter the structure and activity of osteoclast membrane components in a manner similar to that observed in mononuclear cell cultures. The internalization of con A may be important in altering osteoclastic activity by mediating intracellular mechanisms involved in the bone-resorbing process. | en | apollo | train |
An extrarenal source of "renin-like" activity in anephric man.
To examine extrarenal sources of "renin-like" activity plasma was obtained from 19 anephric males. Plasma renin activity (PRA), concentration (PRC) (obtained after addition of exogenous renin substrate) and total renin concentration (TRC) (obtained after acid-activation of plasma and subsequent incubation with exogenous renin substrate) demonstrated values for several anephric patients comparable or above those seen in plasma from 10 normal subjects. Incubation of untreated plasma (PRA and PRC) and acid-dialyzed plasma (TRC) for angiotensin I generation was performed at pH 7.5, at 37 degrees C with EDTA, dimercaprol, and 8-OH-quinoline as angiotensinase and converting enzyme inhibitors. The pH optimum for acid-activation of TRC in anephric plasma was the same as that in normal plasma (pH 3.3). Molecular weight determinations following Sephadex gel chromatography demonstrated that the renin-like enzyme in normal plasma had a molecular weight of about 42,000 before and after acid-activation, while that in anephric plasma had a molecular weight of approximately 61,000. A saliva sample from one anephric subject with the highest levels of PRA, PRC, and TRC in plasma also demonstrated measurable amounts of PRA, PRC, and TRC. The molecular weight of this salivary "renin-like" activity also was 61,000. These observations suggest a possible extrarenal source of "renin-like" activity in anephric man. The physiological significance of these studies remains to be clarified. | en | apollo | train |
α-Lactose Improves the Survival of Septic Mice by Blockade of TIM-3 Signaling to Prevent NKT Cell Apoptosis and Attenuate Cytokine Storm.
Sepsis is the leading cause of death among critically ill patients and natural killer T (NKT) cell activation is essential to induce inflammatory cytokine cascade in sepsis. However, little is known about what regulates the NKT cell function during sepsis. Herein, we showed that T-cell immunoglobulin and mucin domain 3 (Tim-3) expression in NKT cells is elevated in experimental mice during sepsis. Tim-3 expression was positively correlated with NKT cell activation and apoptosis. In sepsis, interleukin (IL)-12 secreted by dendritic cell exposure to lipopolysaccharide increased the expression of Tim-3 in NKT cells. Administration of α-lactose to block Tim-3 signaling pathway significantly improved the survival of septic mice, concomitant with reduced IL-12 production by dendritic cells, reduced Tim-3 expression, prevented NKT cell apoptosis, and attenuated production of inflammatory cytokines. Collectively, Tim-3 signaling in NKT cells plays a critical role in the immunopathogenesis of sepsis. Thus, α-lactose could be a promising immunomodulatory agent in the treatment of sepsis. | en | apollo | train |
Remissions of diabetes mellitus after weight reduction by jejunoileal bypass.
Limited weight loss following jejunoileal bypass in 24 diabetic persons who were still distinctly overweight five to ten months after a mean weight decrease of 78 lbs. was accompanied by a return of normal fasting glucose and insulin levels, normal insulin responses, and a decrease in glucose intolerance. The glucose disappearance rate had improved in the majority of the subjects, but only three had attained values in the normal range. Concomitants of the undue hyperglycemia and/or obesity included labile and, rarely, sustained hypertension and/or cardiomegaly. The blood pressure returned to normal but heart size did not change. Electrocardiographic abnormalities noted in about one-half of the patients persisted after the operation. Triglyceride and cholesterol levels decreased. No patients had diabetic retinopathy visible on funduscopy. Proteinuria did not change in three patients. Neuropathy consisting of absent ankle reflexes and/or decreased vibration perception noted in one-half of the subjects persisted despite the improvement in carbohydrate metabolism. | en | apollo | train |
Pleural effusion, ascites, pathological fracture, and spinal compression can occur with advanced disease.Prognosis dims markedly as the number of involved lymph nodes increases.Pain, tenderness, changes in breast shape, dimpling, and nipple retraction rarely occur until the disease reaches an advanced stage.Chemotherapeutic agents frequently administered in various combinations are cyclophosphamide, methotrexate, 5-fluorouracil, phenylalanine mustard (L-PAM), thiotepa, DOXOrubicin, vinCRIStine, paclitaxel, methotrexate, and predniSONE. The presence of estrogen receptors in breast tumors is considered an indication for hormonal manipulation such as the administration of antiestrogens. Implantation of a prosthesis after mastectomy is optional and does not appear to decrease survival probability. Reconstructive surgery is common, with few complications. Males account for 17% of all breast cancer cases; those with Klinefelter's syndrome are at much greater risk than other men. See also **lumpectomy,** **mastectomy,** **scirrhous carcinoma**. OBSERVATIONS: Increasing numbers of breast cancers are found on mammogram. The most common presenting sign is a lump in the breast. About 50% of all lumps are found in the upper outer quadrant. Nipple discharge may also be present. A mass detected by breast self-examination, clinical breast examination, or mammogram requires follow-up. Ultrasonography helps distinguish cysts from a solid mass. Definitive diagnosis is made by incisional, excisional, fine needle, or stereotactic core biopsy of the mass. Pain, tenderness, changes in breast shape, dimpling, and nipple retraction rarely occur until the disease reaches an advanced stage. Prognosis dims markedly as the number of involved lymph nodes increases. Pleural effusion, ascites, pathological fracture, and spinal compression can occur with advanced disease.Adjunct systemic multidrug chemotherapy is used primarily for premenopausal node-positive women.Adjunct hormone therapy (estrogens, androgens, and progestins) is used primarily for postmenopausal node-positive or receptor-positive women. | en | apollo | train |
of the CaSR can cause hypomagnesemia as well as hypocalcemia.Abbreviations: ATN, acute tubular necrosis; SIADH, syndrome of inappropriate antidiuretic hormone.Pancreatitis, burns, excessive sweating 2.C. Other 1.Treatment of vitamin D deficiency 3.2.Accelerated bone formation 1.B.Correction of respiratory acidosis 4.3.2.1.A.IV.8.7.6.5.4.3.2.D. Other 1.Aminoglycosides, amphotericin B 7.6.Proton pump inhibitors (omeprazole and others) may produce hypomagnesemia by an unknown mechanism that does not involve renal wasting of magnesium. Several genetic magnesium-wasting syndromes have been described, including inactivating mutations of genes encoding the DCT NaCl co-transporter (Gitelman’s syndrome), proteins required for cTAL Na-K-2Cl transport (Bartter’s syndrome), claudin 16 or claudin 19 (autosomal recessive renal hypomagnesemia with hypercalciuria), a DCT Na+,K+-ATPase γ-subunit (autosomal dominant renal hypomagnesemia with hypocalciuria), DCT K+ channels (Kv1.1, Kir4.1), and a mitochondrial gene encoding a tRNA. Activating mutations
CAuSES of HyPomAgnESEmiA
I. Impaired intestinal absorption
A. Hypomagnesemia with secondary hypocalcemia (TRPM6 mutations)
B. Malabsorption syndromes
C. Vitamin D deficiency
D. Proton pump inhibitors
II. A. B.
Intestinal drainage, fistulas
III. A. 1. 2. 3. 4. Potassium channel mutations (Kv1.1, Kir4.1) 5. Na+,K+-ATPase γ-subunit mutations (FXYD2)
B. Acquired renal disease 1. 2. Postobstruction, ATN (diuretic phase) 3. C. Drugs and toxins 1. 2. Diuretics (loop, thiazide, osmotic) 3. 4. Pentamidine, foscarnet 5. 6. Aminoglycosides, amphotericin B 7. D. Other 1. 2. 3. 4. 5. 6. 7. 8. IV. A. 1. 2. 3. Correction of respiratory acidosis 4. B. Accelerated bone formation 1. 2. Treatment of vitamin D deficiency 3. C. Other 1. Pancreatitis, burns, excessive sweating 2. Abbreviations: ATN, acute tubular necrosis; SIADH, syndrome of inappropriate antidiuretic hormone. of the CaSR can cause hypomagnesemia as well as hypocalcemia.A rising blood concentration of ethanol directly impairs tubular magnesium reabsorption, and persistent glycosuria with osmotic diuresis leads to magnesium wasting and probably contributes to the high frequency of hypomagnesemia in poorly controlled diabetic patients.Magnesium depletion is aggravated by metabolic acidosis, which causes intracellular losses as well. | en | apollo | train |
Neurohospitialist evaluation is associated with faster DNT in patients with ischemic stroke. Neurohospitalist evaluation could be a part of a multidimensional initiative to improve the timeliness of tPA administration. | en | apollo | train |
There are many common uses for yarrow, but I find the most intriguing uses for this plant are also the least talked about.It is an excellent diaphoretic.I like to use yarrow to temper fever.In the urinary tract it is a nice diuretic, addressing such issues as nephritis, cystitis, bloating, incontinence, arthritis, gout, high blood pressure and rheumatism.Yarrow ( _Achillea millefolium_ )
Diaphoretic, hypotensive, astringent, diuretic, antiseptic
Harvest notes: Everything above ground, yes, even the flowers can be harvested from yarrow. It is a perennial and is harvested as the plant just starts to flower anytime from midsummer to early fall. Yarrow is a mover. It tends to help move fluid in the body, so it has applications in bloating, inflammation and swelling. I once prevented some pretty nasty swelling after spraining both my ankles simply by placing the herb on my skin as a quick poultice. This ability to move fluid also makes the herb successful with headache, stroke, vertigo and earache that is due to inflammation in the ear canal or sinuses. In the respiratory system yarrow can be used for stuffy sinuses (applied both internally and externally), bronchitis, pleurisy, pneumonia and allergies. In digestion it excels in aiding with digestive cramping, colitis, diverticulitus and hemorrhoids. The female reproductive system can benefit from yarrow's ability to address missing periods, menorrhagia, cramping, endometriosis, uterine fibroids, uterine prolapse and menopausal night sweats. _With a fascinating history and impressive medicinal qualities, the feathery leaves of yarrow will easily make it one of your favorite herbs to grow._
Yarrow's astringency can help with bleeding both internal and external. It is good topically for bee sting, wrinkles, psoriasis, varicose veins, nosebleed, bruises and cuts. In the mouth it has been used successfully for toothache and gingivitis. In the urinary tract it is a nice diuretic, addressing such issues as nephritis, cystitis, bloating, incontinence, arthritis, gout, high blood pressure and rheumatism. I like to use yarrow to temper fever. It is an excellent diaphoretic. There are many common uses for yarrow, but I find the most intriguing uses for this plant are also the least talked about.In the case of radiation, the plant can be used in whole plant applications or as a flower essence as part of a comprehensive plan to move toxicity out of the body.Yarrow is an important piece of history to add to your garden.Spend some time getting to know this very storied herb throughout literature and mythology.You won't regret having this one in your medicine cabinet. | en | apollo | train |
Chemoselective Hydrogenation of 6-Alkynyl-3-fluoro-2-pyridinaldoximes: Access to First-in-Class 6-Alkyl-3-Fluoro-2-pyridinaldoxime Scaffolds as New Reactivators of Sarin-Inhibited Human Acetylcholinesterase with Increased Blood-Brain Barrier Permeability.
Novel 6-alkyl- and 6-alkenyl-3-fluoro-2-pyridinaldoximes have been synthesised by using a mild and efficient chemoselective hydrogenation of 6-alkynyl-3-fluoro-2-pyridinaldoxime scaffolds, without altering the reducible, unprotected, sensitive oxime functionality and the C-F bond. These novel 6-alkyl-3-fluoro-2-pyridinaldoximes may find medicinal application as antidotes to organophosphate poisoning. Indeed, one low-molecular-weight compound exhibited increased affinity for sarin-inhibited acetylcholinesterase (hAChE) and greater reactivation efficiency or resurrection for sarin-inhibited hAChE, compared with those of 2-pyridinaldoxime (2-PAM) and 1-({[4-(aminocarbonyl)pyridinio]methoxy}methyl)-2-[(hydroxyimino)methyl]pyridinium chloride (HI-6), two pyridinium salts currently used as antidote by several countries. In addition, the uncharged 3-fluorinated bifunctional hybrid showed increased in vitro blood-brain barrier permeability compared with those of 2-PAM, HI-6 and obidoxime. These promising features of novel low-molecular-weight alkylfluoropyridinaldoxime open up a new era for the design, synthesis and discovery of central non-quaternary broad spectrum reactivators for organophosphate-inhibited cholinesterases. | en | apollo | train |
BM-T is a surgery to treat children who have otitis media (oh-TITE-us MEE-dee-ya) or middle ear infections that won’t go away with medication; middle ear fluid that won’t go away; or hearing loss or speech delays caused by frequent ear infections.
In a BM-T, the surgeon will put small tubes in your child’s eardrums to allow air to get inside. When air is able to get behind the eardrum, the fluid inside the ear can flow out or dry up, taking away the pain or pressure your child may have been feeling and making future infections less likely.
An ear tube is made of plastic and looks like a tiny spool. More than 25 of them could fit on the face of a dime. They are so small that you usually cannot see the tubes just by looking into your child’s ear.
In most cases, ear tubes do not need to be removed and usually are pushed out on their own after about 6 to 18 months, as the eardrum heals. If a tube remains in the eardrum for more than 2 or 3 years, however, it may need to be removed by your doctor.
Tympanoplasty is an operation to repair the ear drum when it is not working correctly or when there is a perforation (hole) in it, usually from infection, a ventilation tube, or sometimes from trauma. This may also include repair of the tiny bones in the middle ear, called ossicles (the hammer, anvil, and stirrup). The operation is performed at the Shea Ear Clinic Surgery Center as an outpatient with the patient under anesthesia. It may be performed completely through the ear canal, with no external incision, or through an incision in the crease behind the ear. Which route is used will depend on the size and shape of the ear canal and location and size of the perforation. Sometimes mastoidectomy (removal of the bone and air cells behind the air which may harbor infection) is performed at the same time as tympanoplasty. Either way, the goal is to leave the patient with a “safe” ear, if possible (one that does not drain and is impervious to water) and to hopefully restore hearing as much as possible. Recovery takes a few days to a week in some cases and most patients can return to school or work within this time frame. Results are generally good, with at least 80-90% success in most cases.
The mastoid refers to the bony air cells that are behind the ear canal. Their role is not completely understood, though they may help keep the middle ear space filled with air, and act as a resonance chamber to help us hear. In some, these air cells can develop an infection, mastoiditis, which does not respond to antibiotics, and surgery is necessary to address the infection. In other cases, a mastoidectomy is performed in order to place hearing devices such as a cochlear implant. The surgery that is performed to open and remove those air cells is called a mastoidectomy.
During an operation, the surgeon uses a drill to remove the bone and underlying air cells to remove infection or disease, or provide access to the inner ear in order to place a cochlear implant. In some cases of infection or cholesteatoma (abnormal cyst of trapped skin cells), it is necessary to remove the posterior ear canal wall, which will combine the ear canal and mastoid into a mastoid “cavity”. This is known as a “canal wall down mastoidectomy”. The mastoid cavity helps reduce the likelihood of recurrent infection and cholesteatoma, and frequently the middle ear bones can be reconstructed to improve hearing as well. In some cases, the patient will require periodic visits to an otologist to clean debris from this cavity, which can be done during a clinic visit.
The middle ear houses three very small bones, or ossicles, called the malleus (hammer), the incus (anvil), and the stapes (stirrup). These bones conduct sound from the tympanic membrane (ear drum) to the inner ear, amplifying it at the same time. Sometimes the ossicles do not work properly, because of disease or trauma, which leads to a “conductive” hearing loss, or loss of hearing due to lack of effective sound transmission into the inner ear. This type of hearing loss can often be improved through surgery, as opposed to sensorineural hearing loss (nerve deafness), which usually cannot. When a hearing loss occurs, a procedure called an “ossicular chain reconstruction” can help restore some or most of the hearing.
Ossicular chain reconstruction refers to the rebuilding of the connection from the tympanic membrane (ear drum) to the stapes bone. This can be done as a single procedure, or can be combined with a tympanoplasty and mastoidectomy. By using a prosthesis (artificial ear bone), the connections are restored in a manner to mimic the original mechanism. The prosthesis can be made of ceramic, metal, plastic, or several different materials combined together, depending on the extent of reconstruction needed.
In some cases of infection or cholesteatoma, the ossicular reconstruction is delayed, and a “second look” surgery is done at a later point in time to determine if the ear is healthy enough for ossicular chain reconstruction.
Some patients, both children and adults, have hearing loss in both ears that is too severe to be helped by hearing aids. Many of these patients can benefit from a cochlear implant. A cochlear implant consists of two parts, an internal component and an external component. The internal component is surgically implanted and has an electrode that is placed into the inner ear (cochlea) and a receiver that is placed into a pocket under the skin behind the ear. The external component is the processor, and it is worn on the back of the external ear. The external component picks up sound and converts it into signals that are then sent across the skin to the internal component, which sends them through a wire into the inner ear (cochlea). The hearing nerves are connected to the cochlea, and they pick up these signals and relay them to the brain, where they are perceived as sound. While a cochlear implant does not restore normal hearing, patients who have been implanted can, with time and practice, understand spoken word, follow conversation, and hear music.
During the outpatient operation for cochlear implantation, the surgeon makes an incision behind the ear, uses a drill to remove the mastoid bone, and enters the middle ear through an area called the facial recess. The electrode is placed through the facial recess into an opening created in the cochlea, and the receiver is then placed into a pocket under the skin on the skull behind the ear. Following surgery there is a waiting period while the incision heals and swelling goes down. After a few weeks, the patient is seen by an audiologist who activates the cochlear implant, at which time the patient will be able to hear with it. Some patients hear remarkably well, even on a telephone, as soon as their implant is activated. Others may need longer to get used to the new sound patterns they are hearing. Over the next few weeks to months following activation, the patient goes back to see the audiologist for additional programming sessions that will fine-tune the performance of the implant. Eventually, the patient learns to associate the sounds with words, which with time and practice will lead to natural sounding and functional speech recognition and word understanding.
Cochlear implantation is a true “miracle of modern medicine” and has profoundly changed the lives of hundreds of thousands of patients all over the world who are deaf and were formerly able to communicate only through lip reading or sign language. It is approved for use in children down to one year of age in the United States and has allowed children born deaf to develop completely normal speech and language so that they are able to enter a mainstream school environment. Its importance and significance in modern otology cannot be overstated. The physicians at the Shea Ear Clinic will used specialized tests to determine whether you or your family member are a candidate for a cochlear implant.
Some patients, both children and adults, have a hearing loss that is difficult to help with hearing aids because of changes to the inner ear, middle ear, middle ear bones, ear drum or ear canal. A bone anchored hearing aid (BAHA) can help by bypassing the normal hearing mechanism, and send the sound through the bone of the head directly to the cochlea (inner ear). A BAHA consists of a titanium post that is surgically placed into the bone behind the ear, to which a specially designed hearing aid is attached. While a BAHA does not restore normal hearing, patients with a BAHA can have the benefit of hearing aids, even if their inner ear, middle ear, middle ear bones, tympanic membrane or ear canal has changed.
During the outpatient operation, the surgeon uses a drill to place the post into the bone behind the ear through a skin incision. Often some of the soft tissue under the skin is also removed to reduce problems from the post irritating the skin. Following the healing process, the user snaps the specially designed hearing aid onto the post, and the sound travels from the hearing aid, through the post and the bone, into the inner ear, allowing the person to hear. The person can easily remove the BAHA from the post any time they like, and the post can be partially covered by hair, making it less noticeable. | en | apollo | train |
Following questions needs to be answered.
This calculator assess the exact surgery as a part of risk assessment. So, it may be a best calculator for this reason.
NSQIP is limited on its cardiac complication assessment, RCRI is better in that way.
RCRI predicts cardiac complications but NSQIP does not. Hence, probably, RCRI is better. Use lab.
Score of 3 or more . But not all patients with score > 3 have post-op complications.
Treat patients with OSA or suspected patients like OSA until confirmed.
If previously on it, then monitor for HR and BB. Most complication due to Hypotension, and Bradycardia. Hypotension often lead to stroke.
Target Blood Pressure (<130) and HR (60-75). Some clinicians follow more on heart rate than BB. More sensitive BB dosing change. In terms of BB, try to compare it to the baseline BP to decide on hypotension.
Perioperative BB started within 1 day decreases preoperative MI, but causes more harm with increased sepsis.
Continue BB for appropriate indication if patient has been on it before.
Cimzia: Hold 6 weeks Preop.
Continue it. Appropriate DVT prophylaxis.
Opiates: Affects REM sleep . REM sleep is suppressed.
Shoulder surgery are painful. Ongoing postoperative pain control is important.
Compression Stockings: Intermittent Pneumatic Compression. They do not always wear it.
No recommendation on when should IVC filter be placed prior to surgery. No literature on this are available.
Extended prophylaxis for 30 days after Abdominal and Pelvic Surgery in oncologic patients with some risk of increased bleeding.
California study ; JAMA 2014: 0.81 % of patients had A fib when it was non-cardiac surgery.
When to stop the anti-coagulation medication? Below is the Manufacturer label. Depends on half life, and the risk of bleeding during the surgery?
Do they need Bridging (based on risk of VTE risk - moderate or high risk, and risk of bleeding risk during surgery if moderate risk), and if they are bridged when should birding anti-coagulation be stopped prior to surgery?
Assess the thrombotic risk, and find if it is low, moderate or high risk?
Based on the risk decide on BT. Also, based on when bridging therapy decide on the timing to discontinue bridging therapy prior to surgery?
If moderate risk, assess the risk of bleeding to decide bridging or not?
How do you decide on the risk of bleeding?
When to restart the anti-coagulation?
Underestimates the risk in Sickle Cell disease.
> 8, its a arbitrary number, some patients has to be in this range.
Yes for high risk. No for low risk.
If suspected, get an ECHO.
Fix hip in 48 hr. If delayed by 48-72 hr, leads to increased mortality, pneumonia, pressure sores. | en | apollo | train |
Identification of a novel, fast-acting GABAergic antidepressant.
Current pharmacotherapies for depression exhibit slow onset, side effects and limited efficacy. Therefore, identification of novel fast-onset antidepressants is desirable. GLO1 is a ubiquitous cellular enzyme responsible for the detoxification of the glycolytic byproduct methylglyoxal (MG). We have previously shown that MG is a competitive partial agonist at GABA-A receptors. We examined the effects of genetic and pharmacological inhibition of GLO1 in two antidepressant assay models: the tail suspension test (TST) and the forced swim test (FST). We also examined the effects of GLO1 inhibition in three models of antidepressant onset: the chronic FST (cFST), chronic mild stress (CMS) paradigm and olfactory bulbectomy (OBX). Genetic knockdown of Glo1 or pharmacological inhibition using two structurally distinct GLO1 inhibitors (S-bromobenzylglutathione cyclopentyl diester (pBBG) or methyl-gerfelin (MeGFN)) reduced immobility in the TST and acute FST. Both GLO1 inhibitors also reduced immobility in the cFST after 5 days of treatment. In contrast, the serotonin reuptake inhibitor fluoxetine (FLX) reduced immobility after 14, but not 5 days of treatment. Furthermore, 5 days of treatment with either GLO1 inhibitor blocked the depression-like effects induced by CMS on the FST and coat state, and attenuated OBX-induced locomotor hyperactivity. Finally, 5 days of treatment with a GLO1 inhibitor (pBBG), but not FLX, induced molecular markers of the antidepressant response including brain-derived neurotrophic factor (BDNF) induction and increased phosphorylated cyclic-AMP response-binding protein (pCREB) to CREB ratio in the hippocampus and medial prefrontal cortex (mPFC). Our findings indicate that GLO1 inhibitors may provide a novel and fast-acting pharmacotherapy for depression. | en | apollo | train |
Cats are prone to sustain wounds from fighting due to their territorial nature.
Neosporin is an ointment used by humans to clear slight infections and provide pain relief to the affected area.
It is not against the rules to apply Neosporin to a cat’s bruise, but owners should proceed with caution.
Excessive bleeding and red coloration coupled with swelling are signs of either deep puncturing or severe infection. Neosporin should not be used in these instances.
You should proceed with caution when applying Neosporin since the product is not meant for ingestion and cats often lick themselves for cleaning purposes.
There are two types of cat infections: abscess and cellulitis.
There are serious consequences that come with denying your cat proper treatment for a bruise. These include septic arthritis, osteomyelitis, and pyothorax.
Cat owners should only stick with the regular formula for Neosporin and avoid anything that alludes to pain relief when treating their felines’ ailments.
A veterinarian’s services are necessary if the wound is too deep or infected.
The central purpose of treatment for a cat wound should be to rid the animal of infection pus.
It is important to ask your veterinarian what form of treatment is best for your furry friend after he is injured in a fight.
You love your cat with everything that you are, which is why it hurts you to see her in pain.
The first thing that you may want to do is put your feline out of her misery after she has been in a fight with another cat for territory.
It may not be the best idea to treat that open wound with Neosporin, though.
There are certainly benefits to using Neosporin on cat wounds. You reduce the risk of the injury becoming infected when you act fast.
It is possible, though, to do more harm than good as Neosporin can become toxicity to cats.
You should do a few things before applying Neosporin to your cat’s wound. Read on to find out when the ointments such as Neosporin work for your feline and when they should be avoided.
It is not uncommon for cats to sustain injuries that lead to infection. As territorial animals, felines often get into fights when outdoors that lead to scratching, biting, and ultimately wounds.
Even indoor cats stand to sustain wounds as they explore themselves and puncture the skin.
Just as it is common nature for cats to have wounds during their lifetime, so it is second nature for these injuries to become infected.
Cats are known to carry a lot of bacteria in their mouths. Any biting, therefore, leads to such germs passing to the affected area.
Some cat owners do not take puncture wounds seriously because they are small in nature. It is important to note, however, that small does not always equal superficial.
In fact, the deepness of a typical cat wound is what makes them so dangerous and prone to infection.
It is better to take action the moment that you spot a scar by analyzing the injury and determining the best course of action.
Some pet owners take their cats to the veterinarian regardless of whether or not the wound is serious.
You may decide to try home remedies first if the health of your cat is not at risk.
A cat with an infected scar either suffers from an abscess or cellulitis infection. An abscess infection is usually classified by loose skin that covers what would be an open wound.
Puss usually begins to form underneath the layer of skin and must be drained to rid the cat of infection.
A cellulitis infection is one that forms where the skin is not loose. A cat’s tail or foot is typically where this sort of bacteria festers.
What are signs that a cat’s wound has become infected?
The central sign of your cat being in intense pain possibly caused by an infected wound is the feline crying or growling when you touch the injured area.
Your cat may be in so much pain that she refuses to get up and move around.
Such lack of motivation should be taken as a sign that the injury may be worse than you thought.
What are the consequences of neglecting your cat’s injuries?
It is not common for a simple puncture wound to turn into something monstrous, but anything is possible in the feline world.
You do your cat a great injustice to ignore his pain after he has been in the fight of his life and sustained noticeable injuries.
Some felines develop septic arthritis, which is an infection of the joints, as the result of neglected care for wounds.
Osteomyelitis, infection of the bones, is another condition that can come with an abscess.
In some instances, felines can develop a condition known as pyothorax when proper care for wounds is not administered. This build-up of puss threatens the chest cavity and could be life-threatening.
The potential threat to your feline’s life may be your reasoning behind using Neosporin first and doing research on the matter later.
You should, however, proceed with caution when applying an ointment meant for humans to your cat’s skin.
Neosporin – also known as BACITRACIN, NEOMYCIN, and POLYMYXIN – is a topical medicine meant to reduce inflammation and treat bruised skin.
The over-the-counter product especially works well to combat infections caused by bacteria.
Neosporin is typically the go-to remedy for parents with active children. The ointment also comes in a formula meant to provide pain relief to the ailing patient.
Neosporin is, by definition, an ointment. The product works to clear skin infections regardless of whether the patient is a human being or animal.
There is, technically, nothing wrong with administering Neosporin to a superficial cat wound to prevent the condition from becoming worse.
Some feline owners find ointments such as Neosporin to be the perfect home remedies for minor cat wounds.
The formula is especially helpful in cases where your feline is responsible for injuring himself.
A little observation beforehand can tell you if Neosporin can help the wounded area or if you need to take more drastic steps for treatment. You can check here the Top Facts You Should Know About Cat Wound Healing Stages.
Some wounds that appear superficial actually have deeper roots. Puncture marks, regardless of how small they are, cannot be healed with one application of Neosporin.
If anything, you stand to expose your cat to even more toxins by applying a gel formula to an area that is already bleeding out.
Likewise, serious abscesses such as those sustained in fights with other outdoor cats are also wounds that require more attention than a simple ointment application.
You may end up doing more harm than good by acting hastily and, in the end, exposing your cat to certain ingredients found in regular Neosporin not meant to be ingested or administered to an open wound.
Another instance where applying the antibiotic ointment could prove detrimental is when you use the wrong type of Neosporin.
The original formula of the topical treatment works best for both pets and humans.
Neosporin that offers pain relief is ideal for you but not so much for your cat.
You run the risk of poisoning your precious feline by trying to rid his wound of infection while also giving a bit of pain relief.
Remember that, although cats can sometimes use the same products as humans, the effects are not always the same.
Ingredients that lead to pain relief for you may actually cause your feline more agony.
How can you tell of Neosporin can be used for a cat wound?
The best way to determine if Neosporin is a viable form of treatment for your cat’s wound is by simply looking at the injury.
Instead of getting up in arms over the fact that your feline is hurt, take time to calm down and assess the situation.
The average surface wound does not have a lot of blood. Your cat’s small “scratch” may actually be a full-on puncture if the fluid is gushing out from the open spot.
Another thing to assess is the level of infection. Surface wounds that are bright red with remnants of swelling have already surpassed the beginning stages of infection.
It is unlikely that administering Neosporin to a wound that is already severely infected will do much to help the situation.
Of course, you should not apply Neosporin to an open wound. Adding ointment to puss is the equivalent of pouring gas into an already blazing fire. The results of such mixtures will not be pretty.
What should you do if Neosporin cannot be used?
You should take action if your cat has a wound that requires more than antibiotic ointment. A severely infected surface wound or deep puncture requires veterinary attention.
It is essential to note that Neosporin is not meant to treat the steep punctures that cats sometimes sustain during outdoor fights.
You need to take your feline to a professional so that he can render proper care to your furry friend.
How does a veterinarian treat severe cat wounds?
The central purpose of treating cat wounds at the veterinarian’s office is to rid the feline of infection.
The doctor will typically begin proceedings with general anesthesia that is meant to calm the animal and numb the injured spot.
After applying anesthesia, the veterinarian will typically shave the area to start the disinfection process.
Some animal lovers may object to shaving a patch of the animal’s hair. It is important to note, however, that trying to work around fur is a good way to make complicate the problem.
The surface of the infected area needs to be clear for the most effective form of treatment to take root.
Those cats with abscess infections may need to have their wounds lanced for removal of pus buildup.
Veterinarians will ordinarily flush the area after initial draining the toxic fluids from the bruise. Sterile saline is often the best solution for purifying a once-infected space.
There are times when an abscessed wound becomes severe to the extent of spreading.
It may be necessary for the veterinarian to break down the “pockets” of infections so that all of the pus is drained from the site.
Also, some doctors may require your cat to wear an Elizabethan collar so that she does not expose the wound to bacteria again by licking herself.
Neosporin is a go-to ointment for parents and adults in general. Over the years, the product has proven itself to be efficient in providing relief from pain as well as reducing the likelihood of infection.
Despite your love for Neosporin, it may not always be safe to use on your beloved feline.
Cats are known to sustain piercing wounds that often require more than at-home remedies such as ointment application.
Still, Neosporin is not an option that is off limits when you want to treat superficial wounds sustained by your feline.
Observation is critical when determining if Neosporin is the right form of care to give your furry friend.
Areas with substantial bleeding or red coloration coupled with swelling should not be treated with Neosporin.
It is never a bad idea to check with your veterinarian before deciding to administer at-home remedies such as Neosporin to cat wounds.
You could save yourself much heartache in the near future by simply observing and proceeding with caution.
There is nothing generally wrong with applying Neosporin to your cat’s wound.
You should be careful, though, to only use the ointment in instances where the injury is minor. | en | apollo | train |
Wall stiffness suppresses Akt/eNOS and cytoprotection in pulse-perfused endothelium.
Increased steady shear stress stimulates nitric oxide synthase (eNOS) in part by Akt-dependent phosphorylation. Arteries in vivo are exposed to pulse perfusion (PP) combining phasic shear with stretch. In compliant vessels, enhancing PP lowers vascular tone by stimulating eNOS; whereas in aged, stiff arteries, flow-mediated dilation declines and PP is a prominent risk factor. Here, we tested the hypothesis that reduced wall distensibility alters PP-induced eNOS/Akt mechano-signaling. Bovine aortic endothelial cells cultured within distensible tubes were exposed to physiological nonreversing steady or PP (7 dynes/cm(2) mean shear, pulse pressure 0 or 90 mm Hgx2 hours) in a custom servo-system. In compliant tubes, PP doubled Akt phosphorylation above nonpulsatile flow levels, whereas P-Akt declined to static levels from PP in stiffer tubes. eNOS phosphorylation (S-1179) similarly increased with PP in compliant tubes but was nearly undetectable with increased PP in stiffer tubes. After PP, brief exposure of cells to ultraviolet irradiation (oxidant stress) and subsequent culture revealed cytoprotection in compliant tubes but diffuse cytotoxicity and cell detachment in stiffer tubes. NOS inhibition by L-NAME converted compliant-tube post-UV behavior to that of stiffer tubes. These data provide novel evidence that wall compliance can directionally mediate endothelial Akt/eNOS phosphorylation and mechano-signaling. This may help explain increased vascular risks resulting from artery stiffening. | en | apollo | train |
Effects of CdCl2 and Cd-metallothionein on cultured mesangial cells.
Cadmium is a potent nephrotoxin known to cause damage to the proximal tubular epithelium in vivo. The renal glomerulus is less frequently a target and is sensitive to Cd in vitro. We have previously presented evidence that the mesangial cell is a major target for Cd2+ toxicity in the isolated glomerulus (D. M. Templeton and N. Chaitu, Toxicology 61, 119-133, 1990). The present study was undertaken to investigate the sensitivity to Cd of rat mesangial cells grown in homogeneous culture. At a concentration of 1 microM, Cd2+ was a potent inducer of its binding protein metallothionein (MT). Cd2+ inhibited DNA synthesis in these cells with an EC50 of 5.4 +/- 0.4 microM, while preinduction of MT with Zn2+ was protective, raising the EC50 to 17.6 +/- 0.7 microM Cd2+. DNA synthesis in these cells is especially sensitive to Cd2+; only at concentrations of 20 microM Cd2+ and higher were significant effects on cell viability, attachment, and protein synthesis observed. Renal function depends in part on synthesis of specialized matrices by glomerular cells. Synthesis of both matrix and secreted proteoglycans was specifically affected by Cd2+ with an EC50 of about 10 microM for proteoglycan sulfation. We also investigated the effects of Cd-MT on these parameters. Contrary to observations that extracellular Cd-MT is a potent nephrotoxin in vivo, we were unable to demonstrate any effects of Cd-MT on DNA and protein synthesis at Cd concentrations below 60 microM in the cultured cells. Nor did Cd-MT at these concentrations affect DNA or protein synthesis in LLC-PK1 cells, a proximal tubule cell line. This was not due to failure of the cells to take up Cd because they accumulated comparable amounts of Cd whether it was provided as CdCl2 or Cd-MT. We conclude that ionic Cd2+ is the most toxic form of this metal to cultured mesangial cells. While these cells respond to micromolar concentrations of Cd2+ by increasing their content of metallothionein, presumably a protective response, only slightly higher levels may impair the regenerative capacity of mesangial cells, in addition to interfering with the specialized function of matrix synthesis. | en | apollo | train |
Voltage-dependent anion-selective channel protein 3 (VDAC3) is a protein that in humans is encoded by the VDAC3 gene on chromosome 8.
The protein encoded by this gene is a voltage-dependent anion channel and shares high structural homology with the other VDAC isoforms. Nonetheless, VDAC3 demonstrates limited pore-forming ability and, instead, interacts with other proteins to perform its biological functions, including sperm flagella assembly and centriole assembly. Mutations in VDAC3 have been linked to male infertility, as well as Parkinson’s disease.
Structure
The three VDAC isoforms in human are highly conserved, particularly with respect to their 3D structure. VDACs form a wide β-barrel structure, inside of which the N-terminal resides to partially close the pore. The sequence of the VDAC3 isoform contains an abundance of cysteines, which allow for the formation of disulfide bridges and, ultimately, affect the flexibility of the β-barrel. VDACs also contain a mitochondrial targeting sequence for the protein's translocation to the outer mitochondrial membrane. VDAC3 still yet possesses multiple isoforms, including a full-length form and shorter form termed VDAC3b. This shorter form is predominantly expressed over the full-length form at cell centrosomes.
Function
VDAC3 belongs to the mitochondrial porin family and is expected to share similar biological functions to the other VDAC isoforms. VDACs are involved in cell metabolism by transporting ATP and other small metabolites across the outer mitochondrial membrane. In addition, VDACs form part of the mitochondrial permeability transition pore (MPTP) and, thus, facilitate cytochrome C release, leading to apoptosis. VDACs have also been observed to interact with pro- or antiapoptotic proteins, such as Bcl-2 family proteins and kinases, and so may contribute to apoptosis independently from the MPTP. Nonetheless, experiments reveal a lack of pore-forming ability in the VDAC3 isoform, suggesting that it may perform different biological functions. Notably, though all VDAC isoforms are ubiquitously expressed, VDAC3 is majorly found in the sperm outer dense fiber (ODF), where it is hypothesized to promote proper assembly and maintenance of sperm flagella. Because the ODF membranes are not likely to support pore formation, VDAC3 may interact with protein partners to carry out other functions in the ODF. For instance, within cells, VDAC3 predominantly localizes to the centrosome and recruits Mps1 to regulate centriole assembly. In the case of localization to the mitochondria, VDAC3 interaction with Mps1 instead leads to ciliary disassembly.
Clinical significance
VDAC3 belongs to a group of mitochondrial membrane channels involved in translocation of adenine nucleotides through the outer membrane. These channels may also function as a mitochondrial binding site for hexokinase and glycerol kinase. The VDAC is an important constituent in apoptotic signaling and oxidative stress, most notably as part of the mitochondrial death pathway and cardiac myocyte apoptosis signaling. Programmed cell death is a distinct genetic and biochemical pathway essential to metazoans. An intact death pathway is required for successful embryonic development and the maintenance of normal tissue homeostasis. Apoptosis has proven to be tightly interwoven with other essential cell pathways. The identification of critical control points in the cell death pathway has yielded fundamental insights for basic biology, as well as provided rational targets for new therapeutics a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response. It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.
In addition, VDAC3 has been implicated in cardioprotection against ischemia-reperfusion injury, such as during ischemic preconditioning of the heart. Although a large burst of reactive oxygen species is known to lead to cell damage, a moderate release of ROS from the mitochondria, which occurs during nonlethal short episodes of ischemia, can play a significant triggering role in the signal transduction pathways of ischemic preconditioning leading to reduction of cell damage. It has even been observed that during this release of reactive oxygen species, VDAC3 plays an important role in the mitochondrial cell death pathway transduction hereby regulating apoptotic signaling and cell death.
As VDAC3 is a regulator of sperm motility, male mice missing VDAC3 result in infertility. Mutations in VDAC3 are also associated with Parkinson’s disease, as VDAC3 has been observed to target Parkin to defective mitochondria to eliminate them by mitophagy. Failure to eliminate these mitochondria result in the accumulation of reactive oxygen species, the commonly attributed cause of Parkinson’s disease. In addition, it has been found that VDAC3-null mice were born at the expected mendelian ratio. Mutant females were fertile, but males were not due to markedly reduced sperm motility. The majority of epididymal axonemes showed structural defects, most commonly loss of a single microtubule doublet at a conserved position within the axoneme. In testicular sperm, the defect was only rarely observed, suggesting that instability of a normally formed axoneme occurred during sperm maturation. In contrast, tracheal epithelial cilia showed no structural abnormalities, but there was a reduced number of ciliated cells. In skeletal muscle, mitochondria were abnormally shaped, and the activities of respiratory chain complex enzymes were reduced. Citrate synthase activity was unchanged, suggesting an absence of mitochondrial proliferation that commonly occurs in response to respiratory chain defects.
Interactions
VDAC3 has been shown to interact with:
Mps1
Parkin
See also
Voltage-dependent anion channel
References
Further reading
External links
Ion channels | en | apollo | train |
2.Branchial anomalies comprise 20% of pediatric congenital head and neck masses, with 95% of branchial anomalies involving the second branchial cleft.### Key Points
1.Recurrence of the cyst as an abscess or mass should alert the surgeon to the possibility of a pharyngeal fistula, and imaging should be obtained to confirm that finding prior to re-excision of the tract.Treatment consists of exploration of the surgical wound to decompress and evacuate the hematoma, and to identify and ligate any sources of active bleeding. 2. **Seroma formation** : May occur if a large dead space is present after surgical excision. Managed with needle aspiration, the placement of a closed-suction drain, drainage through the wound, or management with observation as gradual resorption of a seroma is expected. 3. **Wound infection** : Occurs more frequently if the branchial cleft cyst has been previously infected or is infected at the time of surgery, if a large amount of dead space is left after excision, or if there is a break in sterile technique. 4. **Salivary fistula** : May occur if the pharynx is entered and there is a persistent gap within the pharyngeal suture line or incomplete imbrication of the mucosal lining. Minimized with layered wound closure technique. Initial treatment is conservative with a pressure dressing and limiting oral intake. Wound exploration and fistulectomy are necessary if a chronic fistula develops. 5. **Recurrence of the branchial cleft cyst either as a mass or as a deep neck abscess** : There is an increased risk of recurrence if there is a history of prior infection requiring incision and drainage, current infection, or a failure to completely identify a tract that enters the pharynx. Recurrence of the cyst as an abscess or mass should alert the surgeon to the possibility of a pharyngeal fistula, and imaging should be obtained to confirm that finding prior to re-excision of the tract. ### Key Points
1. Branchial anomalies comprise 20% of pediatric congenital head and neck masses, with 95% of branchial anomalies involving the second branchial cleft. 2.3.Fine-needle aspiration cytology is an accurate, sensitive, inexpensive, and rapid technique that aids in the evaluation and diagnosis of central and lateral neck masses and adenopathy.### References
1.Chandler, J.R. and Mitchell, B., 1981.Branchial cleft cysts, sinuses, and fistulas._Otolaryngology Clinics of North America_ , 14, 175–86. | en | apollo | train |
Specific inhibition by hGRB10zeta of insulin-induced glycogen synthase activation: evidence for a novel signaling pathway.
Grb10 is a member of a family of adapter proteins that binds to tyrosine-phosphorylated receptors including the insulin receptor kinase (IRK). In this study recombinant adenovirus was used to over-express hGrb10zeta, a new Grb10 isoform, in primary rat hepatocytes and the consequences for insulin signaling were evaluated. Over-expression of hGrb10zeta resulted in 50% inhibition of insulin-stimulated IRK autophosphorylation and activation. Analysis of downstream events showed that hGrb10zeta over-expression specifically inhibits insulin-stimulated glycogen synthase (GS) activity and glycogen synthesis without affecting insulin-induced IRS1/2 phosphorylation, PI3-kinase activation, insulin like growth factor binding protein-1 (IGFBP-1) mRNA expression, and ERK1/2 MAP kinase activity. The classical pathway from PI3-kinase through Akt-PKB/GSK-3 leading to GS activation by insulin was also not affected by hGrb10zeta over-expression. These results indicate that hGrb10zeta inhibits a novel and presently unidentified insulin signaling pathway leading to GS activation in liver. | en | apollo | train |
NSAIDs
Symptomatic relief without slowing underlying disease
Glucocorticoids
Consider intraarticular injection if a single joint is inflammed
Systemic steroids reserved for moderate-severe flairs
Opioids have a limited role
Disease-modifying antirheumatic drug (DMARD)
Can be started by primary care provider or rheumatologist after ER visit
Symptomatic relief without slowing underlying disease
Consider intraarticular injection if a single joint is inflammed
Systemic steroids reserved for moderate-severe flairs
Can be started by primary care provider or rheumatologist after ER visit | en | apollo | train |
Is this patient pregnant? Can you reliably rule in or rule out early pregnancy by clinical examination? .
This review addresses a common problem facing the clinician: "When treating or evaluating a woman of childbearing years, what is the value of historical or physical examination features in determining the probability of early pregnancy?" We focus on the clinical examination findings that may help the clinician rule in or rule out early pregnancy. Generally accepted indicators of pregnancy include amenorrhea, morning sickness, tender or tingling breasts, and, after 8 weeks' gestational age, an enlarged uterus with a soft cervix. We reviewed the value (ie, sensitivity and specificity) of these indicators, as well as home pregnancy test results, as predictors of the diagnosis of early pregnancy. The available evidence suggests that some historical features, when absent, are fair but not reliable for ruling out pregnancy. When diagnosing early pregnancy, the clinician should not rely on the clinical examination or a home pregnancy test-a laboratory test should be requested. | en | apollo | train |
Inhibition of SKP2 Activity Impaired ATM-Mediated DNA Repair and Enhanced Sensitivity of Cisplatin-Resistant Mantle Cell Lymphoma Cells.
<b><i>Background:</i></b> Mantle cell lymphoma (MCL) is associated with poor patient prognosis mainly due to incomplete response to chemotherapy. S-phase kinase-related protein 2 (SKP2) is an oncoprotein that promotes cell cycle progression and proliferation. A recent study revealed that SKP2 is also involved in DNA damage response mechanisms. SKP2 induces activation of the Ataxia-telangiectasia-mutated (ATM) protein kinase by regulating NBS1 ubiquitination. The authors thus hypothesized that SKP2-mediated ATM activation is associated with MCL resistance to cisplatin (DDP). <b><i>Materials and Methods:</i></b> DDP-resistant MCL cell lines JeKo-1/DDP and Mino/DDP were established by culturing JeKo-1 and Mino cells, respectively, with increasing concentrations of DDP. Protein expression levels of SKP2, ATM, and phosphorylated ATM (p-ATM) in the cell lines were assessed using western blotting. The extent of NBS1 ubiquitination was determined with immunoprecipitation assays. Cell viability, apoptosis, and DNA damage were analyzed using specific detection kits. <b><i>Results:</i></b> JeKo-1/DDP and Mino/DDP cells showed higher levels of SKP2 and p-ATM proteins than JeKo-1 and Mino cells, respectively. SKP2 knockdown resulted in a reduced NBS1 ubiquitination and p-ATM protein level in JeKo-1/DDP cells. Both SKP2 knockdown and treatment with an ATM inhibitor enhanced DDP-induced DNA damage in JeKo-1/DDP cells by decreasing amounts of RAD51 and FANCD2, which are factors responsible for DNA repair. Consequently, both SKP2 knockdown and ATM inhibition increased the sensitivity of JeKo-1/DDP cells to DDP treatment, with a more pronounced effect observed by SKP2 depletion. <b><i>Conclusion:</i></b> These results suggest that SKP2 is likely to be a more promising target than ATM in the treatment of DDP-resistant MCL. | en | apollo | train |
An anxiotropic () agent is one that modifies anxiety, a human emotion that has homologous processes in animals. In psychopharmacology anxiotropic agents consist of two categories of psychoactive drugs: anxiolytics that reduce anxiety and may be used therapeutically, and anxiogenic compounds that increase anxiety.
Most anxiolytic agents are minor tranquilizers, the founding compound of which was meprobamate, marketed in the United States as Miltown. Meprobamate was eventually eclipsed by the benzodiazepines. The target of both categories of anxiotropic compounds is the GABAA receptor.
Globally, the two most widely used psychoactive drugs are anxiotropic agents: ethanol, an anxiolytic, and caffeine, an anxiogenic. While intake of both ethanol and caffeine has been shown to exert an anxiolytic effect, their withdrawal is associated with anxiogenic effects.
Uses in psychiatry
Anxiotropic agents are commonly used in the treatment of a variety of mental conditions, such as anxiety, insomnia, and panic disorder. Some common anxiolytics include lorazepam (Ativan), clonazepam (Klonopin), and diazepam (Valium). Benzodiazepines are generally preferred to barbiturates, as there is a wider therapeutic index, meaning there is a greater distance between therapeutic and toxic dosage levels. Anxiolytics can be prescribed on a daily basis or to be taken as needed.
See also
Anxiety
Benzodiazepines
References
Anxiety
Psychoactive drugs | en | apollo | train |
The acoustic stimulation test in the anencephalus: preliminary results.
It is not yet clear whether the acoustic stimulus influences the fetus by auditory or vibrational pathways. The anencephalic fetus is an interesting model for the study of the pathway for receipt of acoustic stimulation because of the near absence of cerebral hemispheres. After the traditional nonstress test (NST), the response to acoustic stimulation was assessed in eight fetal heart rate (FHR) recordings of six anencephalic fetuses of gestational age between 18 and 39 weeks. Although four preterm fetuses demonstrated nonreactive results in the NST, two term fetuses revealed reactive NSTs. However, none of these six anencephalic fetuses responded to acoustic stimulation. These data suggest that the cerebral cortex is the origin or transmission route of the FHR response to acoustic stimulation. We hypothesize that the normal fetus might receive externally applied sounds via auditory pathways rather than vibratory pathways, at least in term pregnancy. | en | apollo | train |
The individual's own pattern of normal cycles is typically established by the sixth gynecologic year.Menstrual bleeding generally lasts for 2 to 7 days.Occasionally, cycles may be shorter or longer than this with no pathology.Menstrual cycles are typically variable for the first 2 to 3 years after menarche, but most cycles range from 21 to 45 days even in the first year of menstruation.Initial hair growth is only slightly pigmented, sparse, and fine, appearing on the labia majora. With maturation, the volume of hair growth increases and spreads to cover the mons pubis. The hair becomes more darkly pigmented, coarser, and less straight. After approximately 2 years, at which time axillary hair growth begins, the genital pubic hair achieves its characteristic curly appearance and is distributed triangularly with a horizontal border at the level of the pubic bone. Androgens are primarily responsible for hair growth. During these stages, vaginal acidity is increasing and there is an increase in the number of normal vaginal flora. Menarche, the onset of menstruation, is the final stage in the process of puberty and occurs at a mean age in the United States of 12.2 years for African Americans and 12.8 years for Anglo-Americans. Menarche typically occurs 1 to 3 years after the onset of breast development. Initial menstrual cycles are anovulatory, with anovulatory periods lasting from 12 to 18 months. Fifty percent of girls with early onset of menarche typically have established ovulatory cycles after 1 year, whereas girls with late onset ovulation often take 8 to 12 years for all cycles to become ovulatory. Menstrual cycles are typically variable for the first 2 to 3 years after menarche, but most cycles range from 21 to 45 days even in the first year of menstruation. Occasionally, cycles may be shorter or longer than this with no pathology. Menstrual bleeding generally lasts for 2 to 7 days. The individual's own pattern of normal cycles is typically established by the sixth gynecologic year.Emotional and behavioral challenges usually taper off once the process of sexual maturation is completed and hormonal regulation is achieved.## Significance of Age at Menarche and Patterns of Early Menstrual Cycles on Long-Term Health
There has been media attention and concern given to the idea that girls appear to be entering puberty at earlier ages than has been the case historically. | en | apollo | train |
RAGE (receptor for advanced glycation endproducts), also called AGER, is a 35 kilodalton transmembrane receptor of the immunoglobulin super family which was first characterized in 1992 by Neeper et al. Its name comes from its ability to bind advanced glycation endproducts (AGE), which include chiefly glycoproteins, the glycans of which have been modified non-enzymatically through the Maillard reaction. In view of its inflammatory function in innate immunity and its ability to detect a class of ligands through a common structural motif, RAGE is often referred to as a pattern recognition receptor. RAGE also has at least one other agonistic ligand: high mobility group protein B1 (HMGB1). HMGB1 is an intracellular DNA-binding protein important in chromatin remodeling which can be released by necrotic cells passively, and by active secretion from macrophages, natural killer cells, and dendritic cells.
The interaction between RAGE and its ligands is thought to result in pro-inflammatory gene activation. Due to an enhanced level of RAGE ligands in diabetes or other chronic disorders, this receptor is hypothesised to have a causative effect in a range of inflammatory diseases such as diabetic complications, Alzheimer's disease and even some tumors.
Isoforms of the RAGE protein, which lack the transmembrane and the signaling domain (commonly referred to as soluble RAGE or sRAGE) are hypothesized to counteract the detrimental action of the full-length receptor and are hoped to provide a means to develop a cure against RAGE-associated diseases.
Gene and polymorphisms
The RAGE gene lies within the major histocompatibility complex (MHC class III region) on chromosome 6 and comprises 11 exons interlaced by 10 introns. Total length of the gene is about 1400 base pairs (bp) including the promoter region, which partly overlaps with the PBX2 gene. About 30 polymorphisms are known most of which are single-nucleotide polymorphisms.
RNA and alternative splicing
The primary transcript of the human RAGE gene (pre-mRNA) is thought to be alternatively spliced. So far about 6 isoforms including the full length transmembrane receptor have been found in different tissues such as lung, kidney, brain etc. Five of these 6 isoforms lack the transmembrane domain and are thus believed to be secreted from cells. Generally these isoforms are referred to as sRAGE (soluble RAGE) or esRAGE (endogenous secretory RAGE). One of the isoforms lacks the V-domain and is thus believed not to be able to bind RAGE ligands.
Structure
RAGE exists in the body in two forms: a membrane-bound form known as mRAGE, and a soluble form, known as sRAGE. mRAGE has three domains, and sRAGE has only the extracellular domain. sRAGE is either the product of alternative splicing or the product of proteolytic cleavage of mRAGE.
The full receptor consists of the following domains: The cytosolic domain, which is responsible for signal transduction, the transmembrane domain which anchors the receptor in the cell membrane, the variable domain which binds the RAGE ligands, and two constant domains.
Ligands
RAGE is able to bind several ligands and therefore is referred to as a pattern-recognition receptor. Ligands which have so far been found to bind RAGE are:
AGE
HMGB1 (Amphoterin)
S100A12 (EN-RAGE)
S100B
S100A7 (psoriasin) but not highly homologous S100A15 (koebnerisin)
S100P
S100A8/A9 complex referred to as calprotectin
Amyloid-β-protein
Mac-1
Phosphatidylserine.
S100A4
RAGE and disease
RAGE has been linked to several chronic diseases, which are thought to result from vascular damage. The pathogenesis is hypothesized to include ligand binding, upon which RAGE signals activation of nuclear factor kappa B (NF-κB). NF-κB controls several genes involved in inflammation. RAGE itself is upregulated by NF-κB. Given a condition in which there is a large amount of RAGE ligands (e.g. AGE in diabetes or amyloid-β-protein in Alzheimer's disease) this establishes a positive feed-back cycle, which leads to chronic inflammation. This chronic condition is then believed to alter the micro- and macrovasculature, resulting in organ damage or even organ failure. However, whilst RAGE is up-regulated in inflammatory conditions, it is down-regulated in lung cancer and pulmonary fibrosis. Diseases that have been linked to RAGE are:
Alzheimer's disease
Arthritis
Atherosclerosis
Congestive heart failure
Congenital diaphragmatic hernia
Diabetes
Myocardial infarction
Peripheral vascular disease
Psoriasis
Rheumatoid arthritis
Takayasu's arteritis
RAGE is expressed at the highest levels in the lung compared to other tissues, in particular in alveolar type I cells, and is lost in idiopathic pulmonary fibrosis (IPF) indicating that expression and regulation of RAGE in the pulmonary system differs from that in the vascular system. Blockade/knockdown of RAGE resulted in impaired cell adhesion, and increased cell proliferation and migration
Inhibitors
A number of small molecule RAGE inhibitors or antagonists have been reported.
Azeliragon vTv Therapeutics (formerly TransTech Pharma) sponsored a Phase 3 clinical trial of their RAGE inhibitor Azeliragon (TTP488) for mild Alzheimer's disease. These trials were halted in 2018.
AGE receptors
Besides RAGE there are other receptors which are believed to bind advanced glycation endproducts. However, these receptors could play a role in the removal of AGE rather than in signal transduction as is the case for RAGE. Other AGE receptors are:
SR-A (Macrophage scavenger receptor Type I and II)
OST-48 (Oligosaccharyl transferase-4) (AGE-R1)
80 K-H phosphoprotein (Proteinkinase C substrate) (AGE-R2)
Galectin-3 (AGE-R3)
LOX-1 (Lectin-like oxidized low density lipoprotein receptor-1)
CD36
References
Further reading
External links
AGER on the Atlas of Genetics and Oncology
Receptors | en | apollo | train |
At 3 years, women in the intervention group had a lower BMI and better nutrition but similar rates of physical activity. However, engaging women to adopt health behaviours may be challenging soon after delivery. More studies are needed to explore interventions that may help this population reduce their risk.
Long-term metabolic impact of fetal exposure to maternal GDM. Observational studies have linked maternal GDM with poor metabolic outcomes in offspring (451). However, 3 systematic reviews (452)(453)(454) have concluded that maternal GDM is inconsistently or minimally associated with offspring obesity and overweight and this relationship is substantially attenuated or eliminated when adjusted for confounders. The HAPO offspring study extended their follow up to 5-to 7-year-olds and found that after adjustment for maternal BMI, higher maternal plasma glucose (PG) concentrations during pregnancy were not a risk for childhood obesity (455). In contrast, a recent cohort found an association between maternal FPG and offspring BMI at 7 years of age that persisted after adjustment for birth weight, socioeconomic status and maternal pre-pregnancy BMI (456). Current evidence fails to support the hypothesis that treatment of GDM reduces obesity and diabetes in offspring. Three follow-up studies of offspring whose mothers were in randomized controlled trials of GDM management found that treatment of GDM did not affect obesity at 4 to 5 years, 5 to 10 years or a mean age of 9 years (457)(458)(459). | en | apollo | train |
A struma ovarii (literally: goitre of the ovary) is a rare form of monodermal teratoma that contains mostly thyroid tissue, which may cause hyperthyroidism.
Despite its name, struma ovarii is not restricted to the ovary.
The vast majority of struma ovarii are benign tumours; however, malignant tumours of this type are found in a small percentage of cases.
Radiologic findings
The ultrasound (US) features of struma ovarii are nonspecific, but a heterogeneous, predominantly solid mass may be seen. US demonstrates a complex appearance with multiple cystic and solid areas, findings that reflect the gross pathologic appearance of the tumor.
Magnetic resonance imaging findings may be more characteristic: The cystic spaces demonstrate both high and low signal intensity on T1- and T2-weighted images. Some of the cystic spaces may demonstrate low signal intensity on both T1- and T2-weighted images due to the thick, gelatinous colloid of the struma. No fat is evident in these lesions.
Additional images
See also
Strumal carcinoid
Teratoma
References
External links
Germ cell neoplasia | en | apollo | train |
The backup of blood (congestion) in the hepatic veins causes blood pressure in the portal vein to increase.The spleen may also enlarge.Because blood flow out of the liver is impeded, blood accumulates in the liver, causing it to enlarge.Budd-Chiari syndrome usually occurs when a clot narrows or blocks the hepatic veins.Better definition often requires magnetic resonance imaging of the bile ducts (a procedure called magnetic resonance cholangiopancreatography or MRCP) or endoscopic retrograde cholangiopancreatography (ERCP—see Understanding Endoscopic Retrograde Cholangiopancreatography). ERCP involves inserting a flexible viewing tube (endoscope) through the mouth and into the small intestine and injecting dye into the bile duct system. Treatment
In addition to detecting narrowing of the bile ducts, ERCP can be used in treatment. A wire with a deflated balloon at its end is introduced through the endoscope. Doctors inflate the balloon to widen (dilate) the narrowing. A mesh tube (stent) is then inserted to keep the duct open. Some people who have had a liver transplant require another transplant. Budd-Chiari Syndrome
Budd-Chiari syndrome is caused by blood clots that completely or partially block the large veins that carry blood from the liver (hepatic veins) into the inferior vena cava. Some people have no symptoms, but others experience fatigue, abdominal pain, nausea, and jaundice. Fluid may accumulate in the abdomen, the spleen may enlarge, and sometimes severe bleeding occurs in the esophagus. Doppler ultrasonography can detect narrowed or blocked veins. Drugs may be used to dissolve or decrease the size of the clot, or a connection may be made between veins to allow blood to bypass the liver. Budd-Chiari syndrome usually occurs when a clot narrows or blocks the hepatic veins. Because blood flow out of the liver is impeded, blood accumulates in the liver, causing it to enlarge. The spleen may also enlarge. The backup of blood (congestion) in the hepatic veins causes blood pressure in the portal vein to increase.Portal hypertension, plus the engorged and damaged liver, leads to fluid accumulating in the abdomen, a condition termed ascites.The kidneys contribute to the problem by causing salt and water to be retained.The clot may extend to also block the inferior vena cava (the large vein that carries blood from the lower parts of the body, including the liver, to the heart). | en | apollo | train |
Benzene, a cause of leukemia, is found in tires, gasoline, paint strippers, and varnishes.It can also cause asthma, respiratory allergies, and skin disease.Formaldehyde (found in thousands of building and consumer products) and benzene are toxic to the nervous system when breathed or absorbed through the skin.I won't enumerate all the potential toxicities of each of these pollutants, but the more I know about them, the more I wish to remove myself from them. Contaminants in our food are also a great concern. (I hope you're not reading this just after eating a meal.) Pesticides may stay on washed fruit even after it's peeled. The California Safe Drinking Water Initiative is trying to prohibit fluoridation, which may be linked to bone pathology, neurologic impairment, lowered IQ in children, hypothyroidism and even cancers. Tap water may also contain lead and mercury. Fungicides, which may contain mercury, are used on seeds and grains and may get into our bread. Canned tuna can contain small amounts of lead, but there's more in the can, especially if it's been soldered. Grapefruit skin can contain lead. Even some popular hair coloring products contain lead. Consider what we add to food: artificial sweeteners, cold tars with arsenic, benzoic acid, preservatives, chemical coloring agents, and dye. These ingredients are not innocuous. Think about what we cook it in: aluminum cookware can contaminate food (a concern in the search for the cause of Alzheimer's) and can destroy vitamin C. Heated plastics cause respiratory dysfunction when the fumes are breathed. Packaged meat like hot dogs and bacon contain nitrates and nitrites. Charcoal grilling produces nitrosamine and other carcinogenic compounds that accumulate over time. Be aware that household products and appliances can make you sick. Forget the microscopic spores that lurk everywhere—that innocuous container in the basement could contain antifreeze, which is poisonous to breathe as well as to drink. Formaldehyde (found in thousands of building and consumer products) and benzene are toxic to the nervous system when breathed or absorbed through the skin. It can also cause asthma, respiratory allergies, and skin disease. Benzene, a cause of leukemia, is found in tires, gasoline, paint strippers, and varnishes.Poorly ventilated buildings do not allow VOCs or other toxins to be expelled.It's no coincidence that sick-building syndrome—a condition characterized by fatigue, confusion, and respiratory problems—arose at the same time as the architectural fad of hermetically sealed buildings that allow no outdoor ventilation. | en | apollo | train |
What other imaging findings are commonly associated with celiac disease? Features of small bowel barium studies are not sensitive enough for definite diagnosis, but the following changes may be seen: Small intestinal dilatation due to excess fluid, dilution of contrast, multiple non-obstructing intussusceptions, jejunoileal fold pattern reversal, moulage sign, mosaic pattern, flocculation, and segmentation. | en | apollo | train |
This biological process has been happening since the beginning of time.As dawn begins to break, melatonin is suppressed, your body temperature starts to rise and you awaken.In response, your body temperature begins to fall and you start to feel sleepy.At sunset, your body's internal clock sounds the alarm, telling the pineal gland to secrete melatonin, signaling the body that it is dark.DRUG INTERACTIONS: Taking glucosamine and chondroitin with blood thinners, such as warfarin (Coumadin), _may_ increase the risk of bleeding, so make sure you talk to your health-care provider _before_ taking the supplement. SAFETY: Glucosamine sulfate is found in the shells of shellfish (such as shrimp, lobster, and crab), which are commonly used as a source for dietary glucosamine supplements. Although it is unlikely that someone would be allergic to glucosamine, as it is the shell that is used, not the meat protein, those with severe allergic reactions to shellfish should still exercise caution. Chondroitin is manufactured principally from bovine cartilage. For those who are vegetarian, some GH products in the marketplace are derived from corn, but I am not currently aware of any vegetarian chondroitin supplements. MELATONIN
Melatonin is a hormone secreted by the brain's pineal gland as well as by cells in the GI tract. While much of the focus has been on the role melatonin plays in maintaining our sleep-wake cycle, it also acts as an antioxidant, anti-inflammatory, pain reliever, and antidepressant. In addition, melatonin protects the GI tract and nervous system and assists in the regulation of blood sugar. It may even help protect us against certain cancers. WHAT IT DOES: One of the primary roles for melatonin is maintaining our 24-hour circadian rhythm. At sunset, your body's internal clock sounds the alarm, telling the pineal gland to secrete melatonin, signaling the body that it is dark. In response, your body temperature begins to fall and you start to feel sleepy. As dawn begins to break, melatonin is suppressed, your body temperature starts to rise and you awaken. This biological process has been happening since the beginning of time.These light sources had very little impact on our circadian rhythm.That's because not all wavelengths of light have the same impact on melatonin.Blue light, such as that from the sun and many artificial lights, is the strongest inhibitor of melatonin.You want melatonin to be suppressed during the daytime, and in fact, spending time outdoors during the day often helps people sleep better at night. | en | apollo | train |
These findings may explain the beneficial effect of arginase inhibition and L-arginine supplement on endothelial dysfunction under redox imbalance-dependent pathophysiological conditions. | en | apollo | train |
Immunomodulatory activity of triphala on neutrophil functions.
Immune activation is an effective as well as protective approach against emerging infectious diseases. The immunomodulatory activities of Triphala (Terminalia chebula, Terminalia belerica and Emblica officinalis) were assessed by testing the various neutrophil functions like adherence, phagocytosis (phagocytic index (P.I) and avidity index (A.I)) and nitro blue tetrazolium (NBT) reduction in albino rats. In recent years much attention is being focused on the immunological changes occur during stress. Noise (100 dB) stress for 4 h/d for 15 d, was employed to alter the neutrophil functions. The neutrophil function tests and corticosterone levels were carried out in eight different groups of animals, namely control, Triphala, noise-stress, Triphala noise-stress, and corresponding immunized groups were used. Sheep red blood cells (SRBC 5 x 10(9) cells per ml) were used for immunizing the animals that belongs to immunized groups. In Triphala administration (1 g/kg/d for 48 d), A.I was found to be significantly enhanced in the Triphala group, while the remaining neutrophil functions and steroid levels were not altered significantly. However the neutrophil functions were significantly enhanced in the Triphala immunized group with a significant decrease in corticosterone level was observed. Upon exposure to the noise-stress, the neutrophil functions were significantly suppressed and followed by a significant increase in the corticosterone levels were observed in both the noise-stress and the noise-stress immunized groups. These noise-stress-induced changes were significantly prevented by Triphala administration in both the Triphala noise-stress and the Triphala noise-stress immunized groups. Hence our study has divulged that oral administration of Triphala appears to stimulate the neutrophil functions in the immunized rats and stress induced suppression in the neutrophil functions were significantly prevented by Triphala. | en | apollo | train |
Peripheral involvement of the seventh cranial nerve
2.Characteristics
1.Distortion of one side of face
2.Loss of taste
5.Speech difficulty
4.Increased lacrimation
3.Inability of eye to close
2.Assessment
1.Bell's palsy (facial paralysis)
1.Nursing management
1. Reduce frustration
2. Special educational intervention; small class size
3. Provide safety and security
4. Administer medications, e.g., methylphenidate hydrochloride, dextroamphetamine sulfate
5. Refer to appropriate resources—special education, parent support groups
6. Cranial nerve disorders
1. Trigeminal neuralgia (tic douloureux)
1. Assessment
1. Stabbing or burning facial pain—excruciating, unpredictable, and paroxysmal
2. Twitching, grimacing of facial muscles
3. Social isolation
2. Characteristics
1. Type of neuralgia involving one or more branches of the fifth cranial nerve (trigeminal)
2. Causes—unknown; infections of sinuses, teeth, and mouth, irritation of nerve due to pressure are aggravating factors
3. Nursing management
1. Identify and avoid stimuli that exacerbate the attacks (light touch)
2. Administer medications—carbamazepine and pain relievers when prescribed
3. Administer appropriate diet
4. Treatment—carbamazepine, alcohol injection to nerve, resection of the nerve, microvascular decompression
2. Bell's palsy (facial paralysis)
1. Assessment
1. Inability of eye to close
2. Increased lacrimation
3. Speech difficulty
4. Loss of taste
5. Distortion of one side of face
2. Characteristics
1. Peripheral involvement of the seventh cranial nerve
2.Nursing management
1.Comfort measures—protect head from cold or drafts, administer analgesics and appropriate diet
2.Improve facial muscle tone—assist with electric stimulation, teach isometric exercises of face
3.Provide emotional support for altered body image
4.Prevent corneal abrasions
5. | en | apollo | train |
MedWire News: High-dose erythropoietin (EPO) has no effect on myocardial infarct (MI) size when administered as an adjunct to primary percutaneous coronary intervention (PCI) and may even be detrimental, results of a randomized controlled trial show.
It represents the latest in a line of "discordant findings between preclinical animal studies and the clinical translation of novel cardioprotective strategies," note co-author Derek Yellon (University College London, UK) and colleagues, who caution against further human studies.
Despite recent advances in PPCI, the morbidity and mortality of ST-elevation myocardial infarction (STEMI) patients remain significant.
This may be due, in part, to the presence of myocardial reperfusion injury, a phenomenon which induces further cardiomyocyte death.
"Therefore, novel cardioprotective agents capable of reducing lethal myocardial reperfusion injury are required to limit myocardial infarct (MI) size, preserve cardiac function and improve clinical outcomes," Yellon et al explain in the journal Heart.
One such potential agent, EPO, appears to exert pleiotropic effects beyond that of hematopoiesis, which include both neuroprotection and cardioprotection. Indeed, acute administration of high-dose EPO at the time of reperfusion has been reported in animal models to reduce MI size by approximately 50%.
To test whether this translates into the human setting, the researchers performed a double-blinded, randomized, placebo-controlled trial in 51 STEMI patients undergoing primary PCI.
Patients were randomly assigned to receive either a single intravenous bolus of EPO (50,000 IU) prior to PCI with a further bolus given 24 hours later (n=26) or placebo (n=25).
The size of MI was measured by calculating 24-hour area under the curve of troponin T and with cardiac magnetic resonance imaging (CMR) on day 2 and at 4 months.
Yellon et al report that EPO treatment failed to reduce MI size with a troponin T area under the curve of 114.7 mg/ml for EPO versus 100.9 mg/ml for placebo and infarct mass by CMR of 33,616 g for EPO vs 25,616 g for placebo.
Unexpectedly, EPO treatment doubled the incidence of microvascular obstruction (82% EPO vs 47% placebo) and significantly increased indexed left ventricular (LV) end-diastolic volumes (84,610 ml/m2 EPO vs 73,613 ml/m2 placebo). At 4 months, there were no significant differences between groups.
The researchers suggest that the discordance between clinical and pre-clinical trials could be explained by proinflammatory and prothrombotic states associated with an MI in middle-aged patients with comorbidities such as diabetes, dyslipidemia, and hypertension. These are not easily reproduced by experimental coronary artery occlusion in disease-free juvenile small-to-medium-size animal models.
They say further work should try and elucidate the protective pathways of EPO in the preclinical setting in an effort to find EPO analogues which may provide protective benefits without the apparent associated side effects. | en | apollo | train |
Is obesity a new risk factor for gastritis?
Obesity has become a major concern among gastroenterologists due to its large influence on gastrointestinal and hepatic diseases: reflux esophagitis, pancreatitis, gallstone disease, liver fibrosis, and neoplastic tumors of the esophagus, pancreas, and colon. Studies of morbid obese subjects undergoing bariatric surgery have revealed that obesity is related with an increased prevalence of endoscopic and histologic gastritis. A recent study of health check-up subjects demonstrated an association of obesity with endoscopic gastritis and gastric ulcers. We recently investigated the underlying mechanisms of the effects of obesity on endoscopic gastritis in subjects undergoing health check-up examination, and demonstrated that adiponectin, a bioactive molecule released from visceral fat, could be a protective factor of endoscopic gastritis. We would like to propose a new category of gastritis, obesity-related gastritis, which could become dominant in the near future. | en | apollo | train |
The global spread of (highly pathogenic) H5N1 in birds is considered a significant pandemic threat.
While prior H5N1 strains have been known, they were significantly different from the current H5N1 strain on a genetic level, making the global spread of this new strain unprecedented. The current H5N1 strain is a fast-mutating, highly pathogenic avian influenza virus (HPAI) found in multiple bird species. It is both epizootic (an epidemic in non-humans) and panzootic (a disease affecting animals of many species especially over a wide area). Unless otherwise indicated, "H5N1" in this article refers to the recent highly pathogenic strain of H5N1.
In January, Japan, Hungary, Russia, and the United Kingdom joined the list of nations seeing a resurgence of bird deaths due to H5N1. In February, Pakistan, Turkey, Afghanistan, and Myanmar joined the list and Kuwait saw its first major outbreak of H5N1 avian influenza.
In March, Bangladesh and Saudi Arabia each saw their first major outbreak of H5N1 avian influenza and Ghana in May.
As H5N1 continued killing many birds and a few people throughout the spring in countries where it is now endemic, in June Malaysia and Germany saw a resurgence of bird deaths due to H5N1, while the Czech Republic and Togo experienced their first major outbreak of H5N1 avian influenza.
In July, France and India also saw a resurgence of bird deaths due to H5N1.
January
January 11, 2007: "South Korean officials say the bird flu virus had been transmitted to a human during a recent outbreak among poultry, but the person showed no symptoms of disease."
January 11, 2007: "Bird flu reaches another province in southern Vietnam, spreading to flocks in two new areas in as many days. Some 20 unvaccinated chicks died suddenly over the weekend at a farm in Vinh Long province, and test results came back positive for the lethal H5N1 strain."
January 12, 2007: "In Nigeria, a new outbreak of the H5N1 virus is reported in birds in Sokoto and Katsina states."
January 14, 2007: "Japanese agricultural officials confirmed yesterday that the virulent H5N1 bird flu virus caused the deaths of thousands of chickens at a poultry farm in southern Japan this week [...] Japan's most recent [prior] outbreak occurred in Kyoto in 2004.".
January 16, 2007: "A new outbreak of virulent bird flu is confirmed in ducks in northern Thailand -- the first such case in six months. About 100 ducks were reported dead and tested in Phitsanulok province. Wild and free-range ducks within a 3-miles radius are being culled as a precaution."
January 17, 2007: Indonesia Works to Stem Bird Flu Cases - Indonesia plans to slaughter hundreds of thousands of backyard chickens over the next few weeks in a bid to stem a surge in human deaths from the H5N1 virus. Indonesia has recorded 61 deaths from bird flu, including four in the last week.
January 18, 2007: "Mutations in the bird flu virus have been found in two infected people in Egypt, in a form that might be resistant to the medication most commonly used to treat the deadly disease, the WHO said. The mutations in the H5N1 virus strain were not drastic enough to make the virus infectious enough to spark a pandemic, but officials said more such mutations could prompt scientists to rethink current treatment strategies."
January 20, 2007: "South Korea prepares to slaughter 273,000 poultry after an H5N1 outbreak at a chicken farm."
January 25, 2007: "The European Commission has confirmed the presence of H5N1 in a farm in the southeastern Hungary."
January 29, 2007:There was an outbreak of H5N1 at three farms or households in the Krasnodar territory, an agricultural region in the southern part of European Russia on the Black Sea, Russian officials said on January 29, 2007.
February
February 3, 2007: In late January 2007 there was an outbreak of avian influenza, caused by H5N1, at one of Bernard Matthews' farms in Holton in Suffolk. This infection, the second in the United Kingdom, was confirmed on 3 February 2007. A 3 km protection zone, 10 km surveillance zone and a restricted zone encompassing 2000 km² were set up and 159,000 turkeys were slaughtered with the cull being completed on 5 February. Around 320 workers at the plant were given anti-viral drugs. The plant was thoroughly disinfected. with cleaning complete on February 12 and permission being given for production to resume. Neither causation, nor a link with the Bernard Matthews plant in Hungary, has been established but the H5N1 bird flu strains found in geese in Hungary and the turkeys in Britain are 99.96% genetically identical, and almost certainly linked, according to an analysis of the viruses by the Veterinary Laboratories Agency in Weybridge, Surrey.
February 6, 2007: H5N1 was found in a flock of 40 chickens near Islamabad, Pakistan and all the chickens are now dead from the disease bird flu or culling to prevent its spread.
February 9, 2007: H5N1 killed 170 chickens in Bogazkoy village, in southeastern Turkey. Nearly 1,000 birds have been culled in Bogazkoy and two nearby villages."
February 19–20, 2007: "An outbreak of H5N1 detected at two farms near the Laotian capital Vientiane on Feb. 7 was reported."
February 22, 2007: "H5N1 is been confirmed in eight suburban Moscow districts, a top Russian veterinary official said, as experts enforced a quarantine in several villages and sought to keep the disease from spreading. The virus, which began killing domestic birds in the Moscow suburbs on Feb. 9, has been traced to a single animal market just outside the capital."
February 22, 2007:"Afghan authorities were culling poultry after an outbreak of the deadly H5N1 strain of bird flu in chicken in an eastern Afghan city, a U.N. official said Wednesday."
February 25, 2007:Kuwait saw its first major outbreak of H5N1 avian influenza.
February 28, 2007:"Myanmar reported that the H5N1 virus killed poultry at a farm about 5 miles from Rangoon, the country's largest city [...] The outbreak began 2 days ago, killing 68 of 1,360 layer chickens, ducks, and pullets, and officials attributed the outbreak to poor biosecurity on the farm, the report said. The remaining birds were destroyed, and authorities instituted several control measures including limiting poultry movement within the country, screening poultry, and disinfecting the affected area. Myanmar's last poultry outbreak was reported in April 2006."
March
March 5–6, 2007: "China reports bird flu struck a poultry market in the Tibetan capital of Lhasa, prompting the culling of nearly 7,000 birds. The outbreak began March 1."
March 22, 2007: Bangladesh saw its first major outbreak of H5N1 avian influenza. "The virus was found in the birds from a poultry firm run by Bangladesh's National Airlines Biman, which has already culled 30,000 birds over the last few days."
March 23, 2007: "Saudi Arabia's agriculture ministry has said the deadly H5N1 strain of bird flu had been discovered in [...] peacocks, turkeys, ostriches and parrots [and all] birds in the area had been culled. [...] The last reported cases of bird flu in Saudi Arabia involved 37 falcons in 2006. Last month, Saudi Arabia lifted bans going back to 2004 on poultry imports from 42 countries."
April
April 6, 2007: "A 13-year-old Cambodian girl dies from bird flu, bringing the country's death toll from the H5N1 virus to seven."
May
May 3, 2007:"Ghana's first case of the highly pathogenic H5N1 bird flu has been confirmed in sick chickens by local laboratories and a US naval laboratory in Egypt, a World Health Organization official said overnight. Some 1600 birds had already been incinerated as part of efforts to control the outbreak on a farm 20km east of Ghana's capital Accra, near the port of Tema".
June
June 5, 2007:" As Bangladesh battles to root out the lethal strain of bird flu known as H5N1 that has spread among its poultry flocks, the ability of the virus to thrive could be aided by the millions of ducks in that country."
June 6, 2007: Malaysia joined the list of nations seeing a resurgence of bird deaths due to H5N1.
June 12, 2007: "Indonesia finds traces of H5N1 in apparently healthy-looking poultry, making it tougher to detect the disease in the country hardest hit by the virus, officials said. Sick or dead chickens are used as a sign of H5N1 infection, but the appearance of "asymptomatic" chickens means humans could become more easily infected with bird flu."
June 21, 2007: The Czech Republic saw its first major outbreak of H5N1 avian influenza.
June 23, 2007: Togo saw its first major outbreak of H5N1 avian influenza. In Germany seven dead wild birds (five swans, one duck, one goose) tested positive for H5N1, the first such cases reported in Germany this year.
July
July 6, 2007: "German authorities discover H5N1 in domestic poultry for the first time this year. Officials say a goose in the town of Wickersdorf in the state of Thuringia was found to be infected."
July 5, 2007:In July France joined the list of nations seeing a resurgence of bird deaths due to H5N1. Three dead swans in France were found to have the deadly form of H5N1.
July 26, 2007:In July India joined the list of nations seeing a resurgence of bird deaths due to H5N1. The outbreak was reported in Manipur which borders the country of Myanmar. 132 chickens out of 144 died over a period of six days starting July 7. Over 150,000 birds within a five-km radius of the infected farm "will be culled in the next 10 days."
August
August 22, 2007: On August 22, 2007, an Indonesian woman, 28, chicken trader, was the 2nd person to die of bird flu in Bali, raising the death toll in the nation due to the disease to 84 (after 4 days of hospitalization). Tests in 2 local laboratories was positive for the H5N1 strain of the disease. 194 people — the majority of them in Indonesia died since 2003, according to the World Health Organization.
September
September 17, 2007: "In its first H5N1 bird flu outbreak since May, China's Ministry of Agriculture confirmed on its Web site that 36,130 ducks had been culled following the outbreak in Panyu district of the southern metropolis of Guangzhou, not far from Hong Kong."
October
October 8, 2007: ";An Indonesian Health Ministry official says a 44-year-old woman has died from bird flu after buying chickens at a local market, lifting the national death toll from the disease to 87."
October 25, 2007: "Vietnam reports its third outbreak among poultry this month, this time in the village of Lung Na near the Chinese border. The virus has already struck duck farms in the central province of Quang Tri and Tra Vinh."
November
November 12, 2007: "An outbreak of bird flu in eastern England is the deadly H5N1 strain of the disease. The source of the outbreak had not yet been identified, acting chief veterinarian official Fred Landeg said. Officials said earlier that about 5,000 free-range turkeys, 1,000 ducks and 500 geese on the affected farm would be killed."
November 29, 2007: "Authorities continue to conduct tests for bird flu in Romania's eastern Danube Delta, a day after they confirmed an outbreak of the virus in hens and ducks on a small farm in the village of Murighiol, a delta village 155 miles northeast of the capital, Bucharest."
December
December 1, 2007: "Three poultry farms northwest of Warsaw, Poland were cordoned off after the deadly H5N1 strain of bird flu was found in turkeys, officials said on Saturday. The cases were found at farms around the village of Brudzen near the city of Plock. Officials say the virus was most likely brought to Poland by migrating ducks, geese or swans."
December 10, 2007: "Chinese health authorities said they were hunting for the causal link between a son and his father both struck by bird flu, but have found no evidence that the virus has mutated into a new strain. The 52-year old father was diagnosed with the H5N1 strain of bird flu late last week in the eastern province of Jiangsu, days after his 24-year old son died from the disease."
References
Influenza A virus subtype H5N1
2007 health disasters
2000s disease outbreaks | en | apollo | train |
Prognostic significance of pre-treatment ALBI grade in advanced non-small cell lung cancer receiving immune checkpoint therapy.
The liver is an essential organ for regulating innate and acquired immunity. We hypothesized that the pre-treatment hepatic function affects the clinical outcome of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC). We analyzed 140 patients with NSCLC who received ICIs. We investigated the association between pre-treatment liver function, assessed using the albumin-bilirubin (ALBI) grade, and clinical outcomes in univariate, multivariate, and propensity score matching analyses. Patients were divided into four grades according to pre-treatment liver function. Eighty-eight patients had good hepatic reserve (ALBI grade 1 or 2a), whereas 52 patients had poor hepatic reserve (ALBI grade 2b or 3). In the univariate Kaplan-Meier analysis, the ALBI grade 1, 2a group had a significantly prolonged progression-free survival (PFS, 5.3 versus 2.5 months, p = 0.0019) and overall survival (OS, 19.6 vs. 6.2 months, p = 0.0002). These results were consistent, regardless of whether the analysis was performed in patients with a performance status of 0 or 1 at pre-treatment (N = 124) or in those selected using propensity score matching (N = 76). In the multivariate analysis, pre-treatment ALBI grade was an independent prognostic factor for both PFS (hazard ratio [HR] 0.57, 95% confidence interval [95% CI] 0.38-0.86, p = 0.007) and OS (HR 0.45, 95% CI 0.29-0.72, p = 0.001). Our results suggest that pre-treatment hepatic function assessed by ALBI grade could be an essential biomarker for predicting the efficacy of treatment with ICIs in NSCLC. | en | apollo | train |
Convoluted lymphocytic lymphoma in adults: a clinicopathologic entity.
Twelve adults had a distinct clinicopathologic type of malignant lymphoma that closely resembles the mediastinal lymphomas of childhood. Nine patients presented with mediastinal masses, and seven had symptoms related to intrathoracic compression. Seven patients presented with or developed leukemia, and in four of these patients the central nervous system (CNS) became involved. Structurally, the tumor cells had a distinctive stippled chromatin pattern, in addition to the characteristic nuclear convolutions. Tumor cells from five patients were studied immunologically, and, in each case, the tumor cells formed rosettes with sheep erythrocytes. The response to combination chemotherapy was rapid and dramatic, but usually transient, with relapse in the CNS or previously involved sites. The above data strongly suggest that these cases represent a distinct clinicopathologic entity that should be treated similarly to childhood leukemia and lymphoma, with intensive multiple agent induction, CNS prophylaxis, possibly radiation therapy to initially involved sites, and prolonged maintenance. | en | apollo | train |
HIV related pericarditis can be classified by possible complications. since there is always another organism or pathology underlying the disease, it is usually classified by its underlying cause. | en | apollo | train |
Multidrug and toxin extrusion protein 1-mediated interaction of metformin and Scutellariae radix in rats.
1. The metformin and Scutellariae radix extract (SB) combination has been previously reported to enhance anti-diabetic activity. Considering that organic cation transporters (OCTs) and multi-drug and toxin extrusion proteins (MATEs) in the liver and kidney are determinant factors on hepatic distribution and renal clearance of metformin, the effects of SB on OCT or MATE-mediated systemic exposure of metformin as well as on glucose tolerance and hypoglycemia were examined. 2. Although SB inhibited metformin uptake through human transporters OCT1 and MATE1 in vitro, the systemic exposures of metformin in vivo rats were not altered after metformin treatment with and without SB due to unchanged renal excretion of metformin. 3. However, 28-day metformin treatment with SB decreased the mRNA level of hepatic MATE1 in rats, resulting in reduced biliary excretion of metformin and thereby higher concentration of metformin in the liver. In addition, in rats with 28-day metformin treatment with SB, glucose tolerance and plasma lactate level were enhanced, while hypoglycemia was not detected. 4. Thus in rats, intervention of SB on transporter-mediated metformin transportation partially improves glucose tolerance without hypoglycemia and increases hepatic distribution of metformin. Also the further investigations in humans are required to clarify the relevance of these findings to the clinical significance. | en | apollo | train |
Song S, MD, Handwerker J, MD. Song S, MD, Handwerker J, MD Song, Samuel, MD, and Jason Handwerker, MD.Spine MRI. In: Tehranzadeh J, MD. Tehranzadeh J, MD Ed. Jamshid Tehranzadeh, MD.eds. Basic Musculoskeletal Imaging New York, NY: McGraw-Hill; . http://accessphysiotherapy.mhmedical.com/content.aspx?bookid=1788§ionid=123772720. Accessed April 21, 2019.
Song S, MD, Handwerker J, MD. Song S, MD, Handwerker J, MD Song, Samuel, MD, and Jason Handwerker, MD.. "Spine MRI." Basic Musculoskeletal Imaging Tehranzadeh J, MD. Tehranzadeh J, MD Ed. Jamshid Tehranzadeh, MD. New York, NY: McGraw-Hill, , http://accessphysiotherapy.mhmedical.com/content.aspx?bookid=1788§ionid=123772720.
Magnetic resonance imaging (MRI) has become the examination of choice for imaging the spine and its contents. Although diseases of the spine are very common, clinical syndromes may mimic each other, necessitating imaging such as MRI for diagnosis and patient management. When considering performing and interpreting imaging of the spine, it is important to first understand the clinical context. The most common symptom is back pain. While back pain is epidemic and associated with great disability, back pain without neurologic compromise is usually not an emergency. Fever or history of malignancy should raise suspicion and urgency. Patients with spine disorders may also present with radiculopathy and myelopathy. Radiculopathy results from mechanical compression or irritation of a spinal nerve, often within a lateral recess or neural foramina. This results in specific sensory deficits and muscle group weakness. However, myelopathy is caused by mechanical spinal cord compression or by intrinsic lesions of the spinal cord. Classic symptoms of myelopathy include bladder and bowel incontinence, spasticity, weakness, and ataxia. As the spinal cord has limited healing ability, an acute myelopathy is an emergency and should prompt urgent imaging, preferably with MRI given its superior evaluation of the spinal cord and canal.
Given its complex anatomy and length, the spine remains one of the most difficult parts of the skeletal system to evaluate. The spine is composed of multiple vertebrae, which protect the spinal cord and proximal spinal nerves. The spine is composed of seven cervical, twelve thoracic, and five lumbar vertebrae as well as the fused sacrum and coccyx vertebral elements. Except for the first and the second cervical vertebrae, the vertebrae share a similar structure including a vertebral body containing trabecular bone. The posterior elements include the articulating processes, lamina, and spinous process. Intervertebral discs separate the vertebrae and serve as shock absorbers.
The standard spine MRI protocol includes imaging in the sagittal and axial planes using T1- and T2-weighted sequences (Figures 14-1 and 14-2). Additional coronal images may be helpful especially in the setting of scoliosis. Short tau inversion recovery (STIR) or fat-saturated T2-weighted sequences are also invaluable for increased sensitivity of marrow edema. In the adult, the normal vertebral marrow generally has intermediate to high signal intensity on the T1-weighted images and low signal intensity on T2-weighted images. The intervertebral disc is normally high signal intensity on T2-weighted images because of its high water content but frequently loses signal over time with loss of water content. Contrast-enhanced T1-weighted sequences are helpful for evaluation of suspected neoplasm, infection, and inflammatory diseases. Proton density (PD) sequences may be useful in detecting cord signal abnormalities associated with demyelinating diseases such as multiple sclerosis (MS). Gradient-recalled echo (GRE) sequences are helpful for detecting blood products associated with cord hemorrhage in the setting of trauma. | en | apollo | train |
A clinical trial involves the testing of a new medicine (or other therapy) to evaluate whether it is effective and safe. Clinical trials of drugs can be divided into those assessing the treatment of a disease (e.g. asthma) or those assessing treatments to prevent the occurrence of significant healthcare events in the future (e.g. stroke). Clinical trials provide the quantitative information about the benefits, adverse effects and possible uses of new drugs that allows prescribers and patients to make rational decisions in relation to drug therapy. The information will provide the relative risk reduction (RRR), absolute risk reduction (ARR), the numbers needed to treat (NNT) for one to be better off on treatment than comparator.
Preclinical research answers basic questions about a drug’s safety, and require substantial in vitro and in vivo laboratory investigations, performed under good laboratory practice (GLP: FDA GLP guidance can be found in their Electronic Code of Federal Regulations), which ultimately provide detailed information on dosing and toxicity levels.
This is a narrated slide-set comprehensively covering drug development and regulation, presented at a level for first year medical students. Authored by Prof. Simon Maxwell, University of Edinburgh (s.maxwell@ed.ac.uk).
Each national agency will have its own procedures and terminology, but will essentially require some process of approval for each trial protocol. In the United States the FDA require submission of an investigational new drug (IND) application for approval by a specialist review team, before any clinical trial is allowed to begin.
Adherence to the principles of good clinical practices (GCPs), including adequate human subject protection (HSP) is universally recognised as a critical requirement to the conduct of research involving human subjects. An essential component of HSP is ensuring informed consent is sought from every trial participant. Many countries have enshrined GCP principles as laws and/or regulations.
Clinical trials that form part of the drug development process are conducted in progressive phases which are designed to assess a new medicine for safety and effectiveness. Each phase must be successfully completed before the next can begin.
Phase 0 trials are small (10-15 subjects) first-in-human trials. Typically a suboptimal drug dose is tested to generate preliminary data on a drug’s pharmacodynamics and pharmacokinetics.
Phase 1 trials are slightly larger studies (20-100 subjects) spanning several months, with the aim of evaluating the safety and tolerability of the new drug, and determine dosage ranges. These studies can also begin to identify early side effects. Some phase 1 trials are carried out in healthy subjects, others in patients with specific health conditions who are willing to try an experimental treatment. Around 70% of phase 1 trials progress to phase 2.
Phase 2 trials (several hundred subjects) spanning several months to two years, are designed to evaluate the efficacy of a drug in the target patient group. This level of trial is usually randomised, double-blinded and placebo controlled and would be expected to identify further side effects. Approximately 33% of phase 2 trials progress to phase 3.
Phase 3 trials (300-3000 subjects) taking 1-4 years, are designed to confirm the effectiveness of a drug observed in a phase 2 trial. Larger subject numbers increases the statistical veracity of the results. Phase 3 trials will often compare the new drug to existing therapies (active comparators), and will potentially identify rarer side effects. Although effectiveness of a trial drug is best assessed in a large trial, in the case of rare diseases, by definition the available patient cohort limits the size of the trial.
Phase 4 of the clinical trials take place after a drug has been marketed and typically involve post-marketing safety monitoring following use in the general population. This level of investigation provides additional information in respect of the treatment’s risks and benefits, informs its optimal use, and can identify any side effects resulting from long-term use.
This is a 30 minute narrated slide-set comprehensively describing the clinical trial process, including discussion of crucial requirements for good trial design, execution, and anaysis. The presentation is at a level for first year medical students. Authored by Prof. Simon Maxwell, University of Edinburgh (s.maxwell@ed.ac.uk).
Clinical trials are strictly regulated, to ensure they are run ethically (with the full consent of everyone taking part) and that they are safe. These conditions are achieved by having the trial protocol reviewed scientifically, in a process of independent scientific (peer) review to assess the potential risk/benefit ratio of the proposed therapy, and review by an independent ethics committee. Each centre taking part in a clinical trial must be assessed to ensure it has the staff, equipment and expertise to carry out the trial according to the precise study plan detailed in the trial’s protocol. Every trial has a ‘sponsor’ who is responsible for the conduct of the trial, this may or may not be the organisation funding the trial. Funding bodies can include government organisations, charities, universities, pharmaceutical, biotechnology or medical device companies. Management of trials, monitoring and required lab work is often outsourced to contract research organisations (CROs).
The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH.org) issues standardised guidance describing a level of Good Clinical Practice that is adhered to by trial sponsors from many countries including the United States, the European Union, Japan, Canada and Australia.
This webpage provides access to all of the guidelines recommended to achieve greater international harmonisation of technical requirements which aim to ensure that safe, effective, and high quality medicines are developed and registered in the most efficient and cost-effective manner. The main goals of the harmonisation process are to prevent unnecessary duplication of clinical trials in humans, and minimize the use of animal testing without compromising safety and effectiveness.
Centerwatch.com , clinicaltrials.gov and the ISRCTN registry are a few of the online resources providing access to registries of approved clinical trials. These resources include details of proposed, ongoing, completed or terminated trials and may provide access to trial results data. They are essential in ensuring that any trial that has been started is listed, even if it is never completed or published.
The Pharmacology Education Project (PEP) is being developed by The International Union of Basic and Clinical Pharmacology (IUPHAR), with support from sponsors, as a service to the international pharmacology community. | en | apollo | train |
At Nvision, we are committed to delivering spinal solutions that help patients get back to their quality of life.
Nvision Biomedical Technologies, a San Antonio-based medical device and biologics manufacturer, has received clearance from the U.S. Food and Drug Administration (FDA) for its focus® Pedicle Screw System.
The Nvision focus Pedicle Screw System keeps patient safety in mind by concentrating on ease and flexibility of use by surgeons. The system offers both minimally invasive and open surgery options with standard double lead thread and midline cortical thread options.
The midline cortical thread has a fast-starting initial thread, which allows the surgeon to move faster in surgery and saves turns of the wrist. Additionally, the cortical option provides surgeons the flexibility to utilize a midline approach and not just a pedicle approach. For minimally invasive surgeries, there is an extended tulip design which provides a break-away tab that eliminates unwanted tower disconnects.
The focus Pedicle Screw System is Nvision’s latest product to receive FDA clearance. The company has developed and manufactured several products that received FDA clearance, including four interbody fusion systems – the nv line, one anterior cervical plate system – the tangis® line, and a buttress plate system – the boundary® line. The interbody devices have multiple footprints to adapt to the general shape of the vertebral endplates. Each set is available in a variety of heights to accommodate patient variability. Additionally, Nvision offers products with Structural Encoding®, the industry’s most innovative solution for medical device identification with permanent direct part marking, as well as a portfolio of human tissue allograft products including celera patches, fluids, and forma demineralized bone, and sport medicine grafts.
©2019, Nvision Biomedical Technologies, LLC. All Rights Reserved. | en | apollo | train |
Albumin binding in uraemia: quantitative assessment of inhibition by endogenous ligands and carbamylation of albumin.
The binding capacity of human serum albumin (HSA) for small acidic molecules is known to be reduced in chronic renal failure (CRF). The contribution of competitive inhibition by accumulated endogenous ligands and of structural changes in HSA has now been evaluated. In a fluorimetric in vitro assay using HSA and two dansylated amino acids the inhibitory properties of various endogenous ligands were determined in concentration-effect studies. The effect of carbamylation of HSA on binding was also examined. The mode of inhibition, including binding parameters n and Ka, was determined. Finally, HSA binding in sera from controls and dialysis patients was compared in a modified assay. Thirty three substances were tested and were placed in 3 groups: strong inhibitors (IC50 < 3*10(-5) mol.l-1, e.g. indolyl acids, furanoic acids), medium inhibitors (IC50 > 3*10(-5), eg. vanillic acid), and no inhibition (e.g. urea, creatinine, guanidino compounds). Complete (> 80%) carbamylation of HSA reduced binding by 67% in a non-competitive mode. There was a significant reduction in the binding capacity of HSA from the dialysis patients (approximately 24%), irrespective of medication. It is concluded that the uraemic binding defect of HSA is caused by competitive inhibition by the many physiological ligands accumulated in CRF and structural modifications of HSA. The assay presented proved useful for the rapid analysis of possible HSA binding inhibitors and for testing large groups of patients, e.g. comparison of dialysis treatments, and pharmacological binding studies. | en | apollo | train |
31-12).The main components of the umbilical cord are the fetal umbilical vessels, two umbilical arteries and a vein, surrounded by a gelatinous, shock-absorbing substance known as Wharton's jelly (see Fig.### Umbilical Cord
The umbilical cord is the conduit for the fetal vasculature between the placenta and the fetus.(H&E, 20×.)However, histologically, there is no distinct difference [3]. The decidua of the membranes is the only vascularized tissue of the membranes and has both a superficial and deep vascular component. The maternal vasculature in the decidua parietalis does not undergo invasion and remodeling by extravillous trophoblast cells. Therefore, parietal decidual vessels can and frequently do contain smooth muscle (see Fig. 31-10). However, excessive mural thickening/hypertrophy of these membranous maternal vessels, defined as mean wall diameter more than 30% of mean circumference, is considered one of the pathologic features of maternal vascular underperfusion [5]. Other changes such as fibrinoid necrosis, acute atherosis, and thrombosis should not be considered normal within the parietal decidual vessels. Lastly, inflammatory cells are also seen in the decidua with occasional macrophages and foci of lymphocytes as normal components of the decidua (see Fig. 31-11). However, plasma cells are not a normal component of the decidua. Figure 31-10. Decidua parietalis at term. Note the muscularized decidual vessels present (arrows). Because these vessels are not normally remodeled by trophoblast, they frequently retain a thin coat of smooth muscle. (H&E, 10×.) Figure 31-11. Decidua parietalis at term. Medium-power view of the decidua in the membranes. Note the fairly thin-walled vessels both in the superficial and deep layers of the decidua. Also note the scattered lymphocytes that are a normal component of the decidua. The lower edge of the image contains a few adherent myometrial fibers. (H&E, 20×.) ### Umbilical Cord
The umbilical cord is the conduit for the fetal vasculature between the placenta and the fetus. The main components of the umbilical cord are the fetal umbilical vessels, two umbilical arteries and a vein, surrounded by a gelatinous, shock-absorbing substance known as Wharton's jelly (see Fig. 31-12).31-13).However, squamous metaplasia of the umbilical cord epithelium is considered normal (see Fig.31-14), and is especially common near the fetal body wall.The Wharton's jelly (see Figs.31-13 and 31-14) consists of mucopolysaccharides, such as hyaluronic acid and chondroitin sulfate, which give a slightly basophilic appearance to the jelly on H&E-stained sections. | en | apollo | train |
Confirm tube placement with auscultation and end tidal CO2
Secure tube
Place OG to decompress stomach
Provide sedation and analgesia
Head of bed to at least 30°
Obtain CXR
Tube should be 3-5 cm from the carina
Check ABG ~30 minutes after intubation
Check cuff pressures - should be between 20-30 cm H2O
Check plateau pressure using "inspiratory hold" - should be less than 30 cm H2O
Tube should be 3-5 cm from the carina
^Ideal body weight | en | apollo | train |
Intravenous diazepam and aspirin are used in the treatment for cocaine-induced coronary vasospasm
**Note:** If a patient has cocaine-induced chest pain and a normal cardiac enzyme profile, it is best to give a calcium channel blocker if one needs to control blood pressure and elevated heart rate.## 3 What is the correct treatment for cocaine-induced coronary vasospasm?He appears to be sweating profusely. On examination of the head, you notice some dried blood around one of his nostrils and see that his pupils are dilated. Once he settles down and begins talking with you, he complains that he feels light-headed and his chest hurts. ## 1 Abuse involving what class of drugs should be expected in this man? This patient is suffering from intoxication of a stimulant, in this case cocaine. Tactile hallucinations, impaired judgment, transient psychosis, and agitation are commonly seen in stimulant intoxication. Other characteristic symptoms include tachycardia or bradycardia, dilated pupils, hyper- or hypotension, chills or fever, nausea and emesis, and confusion. Amphetamine intoxication could present in a similar fashion. **Note:** Formication (bugs crawling on skin) is often called "cocaine bugs" because it so often is due to cocaine intoxication. However, it is also seen in DTs and in amphetamine psychosis. ## 2 Would you be surprised if this man's electrocardiogram revealed myocardial ischemia? It should not be surprising if this man's cardiac tissue has become ischemic. The cocaine he has been using can cause vasospasm, which can reduce cardiac perfusion leading to ischemia. Other drugs that can cause vasospasm include amphetamine and sumatriptan. ## 3 What is the correct treatment for cocaine-induced coronary vasospasm? Intravenous diazepam and aspirin are used in the treatment for cocaine-induced coronary vasospasm
**Note:** If a patient has cocaine-induced chest pain and a normal cardiac enzyme profile, it is best to give a calcium channel blocker if one needs to control blood pressure and elevated heart rate.## 4 Why does this man have blood around his nostril?The effect of cocaine on the nasal epithelium is vasoconstriction.This vasoconstriction can lead to infarction of the nasal septum and subsequent perforation.This is exacerbated by the sympathomimetic effects of cocaine, leading to increased blood pressure that increases the epistaxis. | en | apollo | train |
What is Primsol (trimethoprim) and how does it work?
What are the uses for Primsol (trimethoprim)?
What are the side effects of Primsol (trimethoprim)?
What is the dosage for Primsol (trimethoprim)?
Which drugs or supplements interact with Primsol (trimethoprim)?
Is Primsol (trimethoprim) safe to use during pregnancy or while breastfeeding?
What else should I know about Primsol (trimethoprim)?
Primsol is a synthetic (man-made) antibiotic that interferes with the production of tetrahydrofolic acid, a chemical that is necessary in order for bacteria and human cells to produce proteins. Trimethoprim inhibits production of tetrahydrofolic acid by inhibiting the enzyme responsible for making tetrahydrofolic acid from dihydrofolic acid. Primsol inhibits the bacterial enzyme more than the human enzyme. Therefore, Primsol has less effect on the production of tetrahydrofolic acid by humans. Because of the frequent development of resistance to Primsol, it is more effective when combined with another antibiotic, sulfamethoxazole (Azo-Gantanol), and is rarely used alone.
What brand names are available for trimethoprim?
Primsol is the brand name for trimethoprim available in the US.
Trimpex and Proloprim are brand names that have been discontinued in the US.
Is Primsol (trimethoprim) available as a generic drug?
Do I need a prescription for Primsol (trimethoprim)?
Primsol is used for the treatment of uncomplicated urinary tract infections (UTI) due to susceptible bacteria such as Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Enterobacter species, and coagulase-negative Staphylococcus species, including S. saprophyticus.
Rarely, the skin rash can progress to peeling or blistering. Some patients have photosensitivity reactions, that is, they develop skin rashes on parts of their body that are exposed to the sun.
Primsol may cause anemia due to a deficiency of folic acid. The anemia usually is mild and resolves when the Primsol is stopped. Patients who are folate-deficient, such as malnourished, alcoholic, geriatric, or pregnant females, may be at greater risk for developing anemia with Primsol. Warning signs of anemia include white or bluish fingernails and unusual tiredness and weakness. Prolonged therapy can result in low platelet counts, low white blood cell counts, and other toxic effects on the blood cells.
The usual dose is 100 mg every 12 hours or 200 mg every 24 hours for 10 days.
As with all antibiotics, it is important to complete the entire course of Primsol even if symptoms improve early during therapy.
Persons with kidney diseases may need to receive lower doses since diseased kidneys may not eliminate Primsol adequately from the body, and levels of Primsol may increase in the body and lead to side effects.
Changes in one patient's mental status occurred when a combination of trimethoprim and sulfamethoxazole was given with amantadine (Symmetrel).
Blood levels of phenytoin (Dilantin) may be increased by treatment with trimethoprim. This may lead to side effects of phenytoin such as dizziness, and reduced attention.
Trimethoprim also may increase blood levels of digoxin (Lanoxin) and warfarin (Coumadin, Jantoven) and lead to serious toxic effects.
The combination of trimethoprim and cyclosporine can increase the risk of kidney damage from cyclosporine. When trimethoprim and dapsone are used together, increased blood concentrations of both drugs can occur, sometimes with side effects that include a toxic condition of the blood called methemoglobinemia.
Rifampin can increase the elimination of trimethoprim by the kidneys and may reduce the effectiveness of trimethoprim.
Although there are no human studies that have examined the effects of trimethoprim on the fetus, animal studies have shown adverse effects. Therefore, the physician must weigh the potential risks to the fetus against the potential benefits to the mother when considering trimethoprim therapy for pregnant women.
Trimethoprim is secreted into breast milk in high concentrations. Use of trimethoprim by mothers who are breast-feeding should be avoided.
What preparations of Primsol (trimethoprim) are available?
Tablets: 100 and 200 mg.
How should I keep Primsol (trimethoprim) stored?
When was Primsol (trimethoprim) approved by the FDA?
Trimethoprim was first approved by the FDA in combination with sulfamethoxazole (for example, Bactrim, Septra) in 1973.
Trimethorpim was approved as a stand-alone drug in 1980.
Primsol (trimethoprim) is a drug prescribed for the treatment of uncomplicated urinary tract infections. Side effects include diarrhea, abdominal pain, abnormal taste, swelling of the tongue. Drug interactions, warnings and precautions, and pregnancy and breastfeeding safety information should be reviewed prior to taking any medication. | en | apollo | train |
In 2009, Walker Jackson, then a postdoc in Susan Lindquist’s lab at MIT’s Whitehead Institute (now a group leader at DZNE) published his creation of fatal familial insomnia knock-in mice [Jackson 2009]. As Prion Alliance has recently decided to make testing candidate therapeutic molecules in these mice one of its research priorities, I’ve spent a lot of time educating myself on this mouse model and am going to document the key points in this post.
First, some background. Dr. Jackson’s primary purpose in creating these mice was to demonstrate experimentally what most prion scientists had already believed for decades: that prion infectivity is encoded in the conformation of misfolded PrP, and therefore can be generated spontaneously from genetic mutations. Lindquist’s lab had studied scrapie and CJD for years, so to demonstrate conclusively that prion infectivity could arise spontaneously from a genetic mutation, Jackson needed to be able to rule out the possibility that any mice in the experiment had simply acquired prion disease from prions left in the mouse cages from other experiments. That need motivated two decisions about the mouse model he generated: first, he chose FFI as the disease to study because FFI (in humans) was known to have phenotypes distinct from CJD and other prion diseases: insomnia, hyper- or hypothermia, astrogliosis and neuronal loss localized in the thalamus. Skeptics wouldn’t be able to argue that mice with these phenotypes had simply acquired prion disease from other mice or laboratory contaminants. Second, he engineered an additional change to the mice’s Prnp DNA sequence to introduce a species barrier between his mice and previous mice studied in the lab. He did so by introducing two humanizing mutations: L109M and V112M, thus completing the 3F4 epitope. That’s an antibody binding site on HuPrP believed to consist of the KTNMKHM at codons 106-112 inclusive [Lund 2007], of which the Ms at 109 and 112 are thought to be crucial. Jackson correctly suspected that introducing this epitope would make it more difficult for these mice to infect other mice or to become infected with rodent strains of scrapie.
The mouse line Jackson created is known as ki-3F4-FFI. ki stands for knock-in: these mice carry the 3F4 epitope and FFI mutation as engineered changes to what is otherwise mouse PrP. He also created control ki-3F4-WT mice as a control: mice with the 3F4 knock-in but no FFI mutation.
The frustrating thing about being a postdoc doing mouse experiments—or a rare disease advocate hoping for progress in drug testing—is that it takes years to get any results. To speed up results from the mouse model, Dr. Jackson bred the mice to be homozygous for the knock-in disease gene. To our knowledge, there’s never been a homozygous human with FFI, but there have been a handful of homozygous E200K CJD cases suggesting that homozygous mutations lead to an earlier age of onset [Simon 2000]. Jackson also experimented with different genetic backgrounds of mice. A mouse is not a mouse is not a mouse. Laboratory mice come in a variety of strains with names like “129/Ola” and “Black-6″. Those two strains both make appearances in today’s story, and are also pretty famous. Slate has published an awesome pop science article about the importance and pitfalls of Black-6 mice in research. 129/Ola mice have some history in prion research and among other things were used to create the first PrP knockout mice [Manson 1994].
These strains (like most of the mouse lines used in research) are highly inbred, which means exactly what it sounds like. Inbred lab mice are designed to be as genetically identical as possible so that experiments are more tightly controlled. Most inbred lines are at least 99% homozygous, with genomes often available for download—for most purposes you don’t need to sequence them yourself.
Breeding is necessary not only to perpetuate your mouse line but even just to get a knock-in (or transgenic) mutant in the first place. When you mutate embryonic stem cells to create a mouse model, you don’t get a purely mutant animal right away. You inject the mutated cells into a blastocyst and as it develops, parts of the mouse carry the mutation and parts don’t. This mouse is called a chimera. If the mutation winds up in the germline, you can breed the mouse and get offspring which carry the mutation in every cell in their bodies. Then you have to start crossing these mice to the genetic background that you want the mutation on, at a cost of about 9 or 10 weeks per generation at best. Below is a nice illustration of the general idea. In the illustration the cells are transgenic rather than knock-in but to my understanding the part of the process depicted in the diagram is the same either way.
For more background on this process, don’t miss this Flash animation by Jax. This especially helped me understand the nomenclature: when backcrossing to an inbred breed to get the new mutation onto a well-characterized background strain, the generations are termed N1, N2, … while when outcrossing to a different breed the generations are termed F1, F2, etc.
When Dr. Jackson first created the ki-3F4-FFI mice, he did so in embryonic stem cells from 129/Ola mice. The resulting chimeras were bred to C57Bl/6N-Tac aka Black-6 mice. The first generation of mice born with the mutation are referred to as F1. He then backcrossed the F1s to Black-6 mice again for an N1. Next he crossed the (heterozygous for the FFI gene) N1s with each other, resulting in N2s that were 25% 129/Ola and 75% Black-6 and homozygous for the knock-in gene. These N2s were then bred to each other to produce the mice analyzed in the 2009 Neuron paper.
As time went on, Dr. Jackson also tried further backcrossing these ki-3F4-FFI mice with the Black-6 background, but discovered that after a few more generations the phenotype became very difficult to discern. The mice got sick late and mildly or not at all, and it was difficult to detect reactive gliosis in the histological sections.
So, starting from an earlier generation with less Black-6 in it, he started breeding the mice over to the 129/SvJae strain (see Jax’s 129 mice; apparently this strain is actually pretty different from 129/Ola). He’s done a good deal of analysis on the N2 mice from this line (so ~75% 129/SvJae) and they appear to get FFI symptoms earlier, more robustly and more reliably. Reactive gliosis is so visible that their brain sections can practically be genotyped at a glance.
Though less study has been done on the later generations which are as much as 96% 129/SvJae, it appears that they also have an earlier and more reliable phenotype. At Prion Alliance we are working on reaching out to other scientists interested in testing candidate therapeutics in these mice—particularly therapeutics that have already shown a significant effect in scrapie mice.
While the mice have a phenotype recognizable as FFI and distinct from other prion diseases, more work needs to be done to determine exactly how best to measure and characterize this phenotype. In the 2009 study, Jackson used three different phenotyping approaches. First, he set up cameras in the home cages of 22 FFI mice and 14 control mice and used Automated Mouse Behavioral Analysis (AMBA) to measure the time the mouse spent in various behaviors: sleeping, rearing, hanging from a bar, twitching, etc. Second, he monitored the core temperature of five FFI and five control mice using iButtons surgically embedded inside the mouse (core temperature was necessary because surface temperature fluctuates naturally and doesn’t indicate disease). Third, after the mice had died, he examined hematoxylin and eosin-stained sagittal sections to identify reactive gliosis, neuronal loss and vacuoles. These approaches were perfectly serviceable for his purposes at the time, showing that most mice exhibited hyper- or hypothermia, slept less and moved restlessly more often, and had neurodegeneration concentrated in the thalamus with some mice showing significant effects in the cerebellum and some elsewhere as well. All of these features conclusively identified the phenotype as belonging to FFI and not CJD or scrapie.
Despite all these phenotypic features, it is not clear that the mice actually die of FFI, and their lifespans are not especially shorter than wild-type mice. So age at death will not be a viable readout for a therapeutic study, and not just for this reason. Other reasons include: not wanting to wait ~two years to get results, and wanting to limit positive results to molecules that delay disease rather than extending disease.
When I spoke with Dr. Jackson recently, he noted the phenotypes he measured for the 2009 paper would not necessarily be suitable as readouts for a study of candidate therapeutics. The AMBA data were interesting but showed a number of false positive significant differences between the control (ki-3F4-WT) and true wild-type mice (see Supplemental Figure 5). They might still work as a readout but Dr. Jackson doesn’t feel he has done enough analysis on this to be able to say for certain. In particular, he hasn’t done AMBA analysis on the more recent generations of primarily 129/SvJae mice. The iButtons stored temperature data locally and it could not be accessed until after the mice had died. Newer telematic models are available to provide real-time core temperature data. Real-time core temperature data could be one valuable source of phenotypic information for FFI mice in a therapeutic study, but given that the previous study only looked at temperatures for five mice, the mean and variance of the age of onset for temperature dysregulation are not well-established yet.
By far the most robust phenotype observable in the ki-3F4-FFI mice is reactive gliosis. Reactive gliosis in FFI is the hypertrophy (i.e. enlargement) and/or proliferation of astrocytes, which are glial cells (hence “gliosis”) in response to disease stress (hence “reactive”). Reactive gliosis is readily identifiable in histological sections of FFI mouse brains, particularly in the thalamus. But again, therapeutic studies will require a real-time readout while the mice are alive. Dr. Jackson suggested that the best readout for reactive gliosis would be live animal imaging of luciferase under the GFAP promoter.
What does that mean? GFAP, or glial fibrillary acidic protein, is a protein which is uniquely expressed in glial cells and not in neurons. During prion disease, not only do astrocytes multiply in number, GFAP is also transcriptionally upregulated. For both of these reasons, the amount of GFAP in a mouse brain is a very reliable indicator of prion disease phenotype. Traditionally, post-mortem histological samples are stained with a fluorescent antibody for GFAP. But live animal imaging is now possible as well. Others have already engineered mice expressing firefly luciferase (a protein which catalyzes a bioluminescent reaction and is widely used in assays) under the GFAP promoter (you can buy these mice from JAX). So when GFAP expression increases, more luciferase is produced. Some of the wavelengths of light emitted by the reaction that luciferase catalyzes are infrared and so pass through the mouse’s tissues and can be viewed in the live mouse using infrared cameras. (For a review of several published studies using this technology, see Dothager 2009) So basically, put on your infrared goggles, and you’ll see glowing FFI mice and not-so-glowing control mice. The luciferase-under-GFAP mice are already available (for sale online from JAX) and would just need to be bred to the ki-3F4-FFI mice. Of course, as Mendel knows, it will take two generations to get mice homozygous for both luciferase-under-GFAP and ki-3F4-FFI. This cross-breeding could be hired out to companies if desired.
Live animal imaging of reactive gliosis promises to probably be the best phenotypic readout for a therapeutic study on FFI mice. But since it hasn’t been done yet, we don’t yet have solid data on the mean and variance in age of onset of this phenotype. These are important numbers for anyone designing a mouse study: you need to know going in that you’ve got enough mice to get a statistically significant result for the effect size you expect. I asked Dr. Jackson for his subjective assessment of the age of onset and its variability. He said that in the current 129/SvJae background, about half the mice seem to show reactive gliosis by 12 months, with most occurring within a range of a couple of months around that. He said 60 weeks would probably be enough time to allot for a study to run to conclusion. He pointed out to me, which I hadn’t realized before, that intracerebral injections of scrapie (which are the leading brand of prion mouse model, used in nearly all of the studies I’ve reviewed on this blog) represent not only the best (fastest, least variable, most phenotypically reliable) mouse model of prion disease, but possibly the best mouse model of any neurological disease (possibly second to stroke and just ahead of R6/2 for Huntington’s). The studies of therapeutics in scrapie mice that I’ve reviewed on this blog have used 6, 10 or 15 mice per treatment group (see Scutellaria lateriflora, statins and styryls/tricyclics respectively); whereas for the FFI mice, given the greater variance in age of onset, 20 mice per treatment group will probably be necessary. 20 (or more) mice per group would be consistent with the numbers from the only other therapeutic study in a genetic model that we are aware of— Mastrianni’s work with rapamycin in transgenic GSS mice.
Dr. Jackson was also kind enough to share with me some unpublished data on reactive gliosis in the mice so that I could draw my own conclusions about phenotypic variability. I’ll be taking a closer look at that data in a shortly forthcoming power analysis post. | en | apollo | train |
A formal analysis of cytokine networks in chronic fatigue syndrome.
Chronic Fatigue Syndrome (CFS) is a complex illness affecting 4 million Americans for which no characteristic lesion has been identified. Instead of searching for a deficiency in any single marker, we propose that CFS is associated with a profound imbalance in the regulation of immune function forcing a departure from standard pre-programmed responses. To identify these imbalances we apply network analysis to the co-expression of 16 cytokines in CFS subjects and healthy controls. Concentrations of IL-1a, 1b, 2, 4, 5, 6, 8, 10, 12, 13, 15, 17 and 23, IFN-γ, lymphotoxin-α (LT-α) and TNF-α were measured in the plasma of 40 female CFS and 59 case-matched controls. Cytokine co-expression networks were constructed from the pair-wise mutual information (MI) patterns found within each subject group. These networks differed in topology significantly more than expected by chance with the CFS network being more hub-like in design. Analysis of local modularity isolated statistically distinct cytokine communities recognizable as pre-programmed immune functional components. These showed highly attenuated Th1 and Th17 immune responses in CFS. High Th2 marker expression but weak interaction patterns pointed to an established Th2 inflammatory milieu. Similarly, altered associations in CFS provided indirect evidence of diminished NK cell responsiveness to IL-12 and LT-α stimulus. These observations are consistent with several processes active in latent viral infection and would not have been uncovered by assessing marker expression alone. Furthermore this analysis identifies key sub-networks such as IL-2:IFN-γ:TNF-α that might be targeted in restoring normal immune function. | en | apollo | train |
The reversal of diabetes, which I'll discuss in chapter 3 (see "Ketogenic Diets and Calorie Restriction" on page 170), is our generation's best example of how focusing on mitochondrial function and health can have tremendous benefits to what was previously thought to be an irreversible disorder.One domino knocking down the next, it all starts with mitochondrial dysfunction. Type 2 Diabetes
Commonly referred to as just diabetes, this metabolic disorder is characterized by high blood sugar over a prolonged period of time. Previously, a diagnosis of diabetes meant a death sentence, but with advancing medical research, it's no longer the scary disease it used to be. Yet it's important to remember that if left untreated, diabetes can lead to many complications, including cardiovascular diseases, neurological disorders, stroke, kidney failure, and even coma. There are two main types of diabetes, type 1 and type 2. Type 1 occurs when the body's immune system inappropriately attacks and destroys the insulin-producing cells in the pancreas. Type 1 is an autoimmune disease, and as a result of this destruction, the lack of insulin can no longer keep blood sugar levels in check. Type 2, on the other hand, occurs when the body can't effectively utilize the insulin that is produced and released. Most of our discussion here will focus on type 2, which also happens to account for about 95 percent of the cases of diabetes. While the management of diabetes has come a long way, recent evidence suggesting mitochondrial dysfunction lies at the heart of this disorder has given us insight into how to stop its progression, and even reverse it! The reversal of diabetes, which I'll discuss in chapter 3 (see "Ketogenic Diets and Calorie Restriction" on page 170), is our generation's best example of how focusing on mitochondrial function and health can have tremendous benefits to what was previously thought to be an irreversible disorder.Evidence suggests that mitochondria play a role in both processes, and defects are evident early in the course of the disorder.On the flip side, type 1 diabetes results mainly from the autoimmune destruction of beta cells in the pancreas. | en | apollo | train |
Elastic Band Exercises for Patients with Intensive Care Unit-Acquired Weakness: A Case Report.
Intensive care unit-acquired weakness is characterised by severe impairment of muscle function that often arises after prolonged mechanical ventilation, difficult weaning, and severe sepsis. Elastic band exercises constitute an inexpensive and simple technique that is quite appealing for implementation in a "protected environment" such as the intensive care unit; however, elastic band application in the intensive care unit and in critical patients has not yet been described. A 72-year-old male was referred to the respiratory intensive care unit for hypoxemic respiratory failure due to acute respiratory distress syndrome. Upper limb active exercises were performed using an elastic band exploring three main movement rays: abduction, forward flexion, and external rotation. At discharge, major improvements were observed for upper limb activities. The patient was also able to maintain a sitting position at the edge of the bed starting from day 27. We found that an elastic band exercise program in a critical ill patient recovering from intensive care unit-acquired weakness was a suitable, safe, viable, and inexpensive therapeutic option to preserve residual upper limb motor activities and improve trunk control. | en | apollo | train |
Phenobarbital increases the theophylline requirement of premature infants being treated for apnea.
To determine the effect of phenobarbital sodium therapy and subependymal intraventricular hemorrhage (SEp-IVH) on the theophylline requirement of premature infants suffering with apnea and seizure activity, we compared three groups of patients as follows: group 1, those with apnea of prematurity (ten patients); group 2, those with apnea and SEp-IVH (ten patients); and group 3, those with apnea, SEp-IVH, and seizure activity for which they were receiving phenobarbital therapy (nine patients). Patients in groups 1 and 2 required lower dosages and blood levels of theophylline to control their apnea than did those in group 3, who required higher dosages and blood levels of methylxanthines. Theophylline dosages and blood levels did not significantly differ between groups 1 and 2. In group 3, the theophylline requirement for control of apnea was significantly increased after initiation of phenobarbital therapy. There seems to be a direct correlation between the increased requirement for theophylline and concomitant phenobarbital administration. The data suggest that phenobarbital increases theophylline requirement when treating neonatal apnea. | en | apollo | train |
Heart failure patients who had beads of gel injected into their beating hearts continue to show improvement in their health a year after undergoing the procedure, researchers report.
About 85 percent of patients who received the gel implants displayed only slight or no limitations in physical activity during a one-year follow-up, compared with only 25 percent of patients in a comparable control group.
Blood oxygen levels also continue to improve in these patients, and they are able to walk hundreds of feet farther, said lead researcher Dr. Douglas Mann, chief of the cardiovascular division at Washington University School of Medicine and a cardiologist-in-chief at Barnes Jewish Hospital in St. Louis.
The findings from a clinical trial update were published recently in the European Journal of Heart Failure.
Based on these results, the U.S. Food and Drug Administration has authorized a larger-scale clinical trial of Algisyl-LVR. It will involve 240 patients with advanced heart failure, Mann announced last week at the American Heart Association meeting in Orlando, Fla.
Heart experts at the meeting said the initial results appear impressive, but they also expressed concern over the death rate among patients who received the gel implants.
""We really need to iron out the mortality risk associated with this device,"" said Dr. Lori Mosca, director of preventive cardiology at New York-Presbyterian Hospital and medical director of the Columbia University Center for Heart Disease Prevention in New York City.
Of the 5.7 million Americans living with heart failure, about 10 percent have advanced heart failure, according to the American Heart Association. Heart failure means the heart isn't pumping blood as well as it should. The condition is considered advanced when conventional treatments no longer work, and patients feel shortness of breath and other symptoms even when resting.
Algisyl-LVR is intended to shore up weakened heart walls, which are a major contributor to severe heart failure, Mann said.
As heart walls weaken, the heart's chambers balloon out, which compromises the heart's efficiency and increases the risk of congestive heart failure, irregular heart rhythms, strokes and heart attacks, Mann said.
""By injecting this gel into the wall and thickening it, one will reduce wall stress because you're increasing wall thickness,"" Mann said. The goal is to return the heart to a more naturally healthy shape.
The gel is described as an ""injectable proprietary biopolymer"" by its maker, Texas-based LoneStar Heart Inc., which funded the clinical trial.
In this trial, 35 patients with advanced heart failure received the gel implant while 38 received the standard medical therapy. The procedure can be performed in a beating heart and does not require bypass surgery.
It took about 80 minutes to implant an average of 15 gel beads into each patient's heart wall. The patients spent about two days in intensive care recuperating after the surgery, Mann said.
During the subsequent year, blood oxygen levels have steadily risen in the gel implant patients, while decreasing in the control group, the researchers reported.
Patients treated with Algisyl were nearly 32 times more likely to have experienced significant improvement in their functional ability, compared to the control group, the investigators found.
The implant patients also were able to walk 330 feet farther than the other patients in a six-minute walk test, according to the study.
However, more patients died in the implant group than the control group. There were four deaths (11 percent) in the control group, compared with 9 deaths (22.5 percent) in the Algisyl group.
Although the death-rate numbers are troubling, Mann and other experts at the heart association meeting said that it's hard to assess mortality rates in small-scale trials. The larger FDA-approved trial will provide a clearer picture of the risks associated with the gel implants, he said.
Mann said researchers also are investigating improvements to the procedure, mainly by figuring out a way to inject the beads using a catheter snaked through the blood vessels and into the heart. Currently, surgeons have to crack open the chest to inject the gel.
""This is now a fairly invasive procedure, and I think it would be much more palatable to patients if it can be performed endoscopically,"" Mosca said.
For more on advanced heart failure, visit the American Heart Association. | en | apollo | train |
T3 is best reserved for short-term TSH suppression.Using the more expensive thyroxine and liothyronine fixed-dose combination (liotrix) and desiccated thyroid has not been shown to be more effective than T4 administration alone.T3 should also be avoided in patients with cardiac disease due to significant elevations in peak levels and a greater risk of cardiotoxicity.Inhibition of TRH or TSH secretion without induction of Bexarotene, dopamine, bromocriptine, cabergoline, levodopa, corticosteroids, hypothyroidism or hyperthyroidism somatostatin, octreotide, metformin, interleukin-6, heroin
Inhibition of thyroid hormone synthesis or release Iodides (including amiodarone), lithium, aminoglutethimide, thioamides, ethionamide, with the induction of hypothyroidism (or occasionally tyrosine kinase inhibitors (eg, sunitinib, sorafenib, imatinib), HIV protease inhibitors hyperthyroidism)
Alteration of thyroid hormone transport and serum total T3 and T4 levels, but usually no modification of FT4 or TSH
Increased TBG Estrogens, tamoxifen, raloxifene, heroin, methadone, mitotane, 5-fluorouracil, perphenazine
Decreased TBG Androgens, anabolic steroids, glucocorticoids, danazol, L-asparaginase, nicotinic acid
Displacement of T3 and T4 from TBG with transient Salicylates, fenclofenac, mefenamic acid, intravenous furosemide, heparin
Alteration of T4 and T3 metabolism with modified serum T3 and T4 levels but not TSH levels (unless receiving thyroxine replacement therapy)
Increased hepatic metabolism, enhanced degradation Nicardipine, phenytoin, carbamazepine, primidone, phenobarbital, rifampin, rifabutin, of thyroid hormone tyrosine kinase inhibitors (eg, sunitinib, sorafenib, imatinib), sertraline, quetiapine replacement by conventional laboratory tests. T3 should also be avoided in patients with cardiac disease due to significant elevations in peak levels and a greater risk of cardiotoxicity. Using the more expensive thyroxine and liothyronine fixed-dose combination (liotrix) and desiccated thyroid has not been shown to be more effective than T4 administration alone. T3 is best reserved for short-term TSH suppression.The use of desiccated thyroid rather than synthetic preparations is never justified, since the disadvantages of protein antigenicity, product instability, variable hormone concentrations, and difficulty in laboratory monitoring far outweigh the advantage of lower cost.Significant amounts of T3 found in some thyroid extracts may produce significant elevations in T3 levels and toxicity. | en | apollo | train |
CIP4 targeted to recruit GTP-Cdc42 involving in invadopodia formation via NF-κB signaling pathway promotes invasion and metastasis of CRC.
Cdc42-interacting protein 4 (CIP4), a member of the F-BAR family, which plays an important role in regulating cell membrane and actin, has been reported to interact with Cdc42 and be closely associated with tumor invadopodia formation. In this study, we found that CIP4 expression was significantly higher in human CRC tissues and correlated with the CRC infiltrating depth and metastasis, as well as the lower survival rate in patients. In cultured CRC cells, knockdown of CIP4 inhibited cell migration and invasion ability <i>in vitro</i> and tumor metastasis <i>in vivo</i>, while the overexpression of CIP4 promoted invadopodia formation and matrix degradation ability. We then identified GTP-Cdc42 as a directly interactive protein of CIP4, which was upregulated and recruited by CIP4. Furthermore, activated NF-κB signaling pathway was found in CIP4 overexpression of CRC cells contributing to invadopodia formation, while the inhibition of either CIP4 or Cdc42 led to the suppression of the NF-κB pathway and resulted in a decreased quantity of invadopodia. Our findings suggested that CIP4 targets to recruit GTP-Cdc42 and directly combines with it to accelerate invadopodia formation and function by activating NF-κB signaling pathway, thus promoting CRC infiltration and metastasis. | en | apollo | train |
Scissor gait is a form of gait abnormality primarily associated with spastic cerebral palsy. That condition and others like it are associated with an upper motor neuron lesion.
Presentation
This gait pattern is reminiscent of a marionette. Hypertonia in the legs, hips and pelvis means these areas become flexed to various degrees, giving the appearance of crouching, while tight adductors produce extreme adduction, presented by knees and thighs hitting, or sometimes even crossing, in a scissors-like movement while the opposing muscles, the abductors, become comparatively weak from lack of use. Most common in patients with spastic cerebral palsy, the individual is often also forced to walk on tiptoe unless the plantarflexor muscles are released by an orthaepedic surgical procedure.
These features are most typical with the scissors gait and usually result in some form and to some degree regardless of the mildness or severity of the spastic CP condition:
rigidity and excessive adduction of the leg in swing
plantar flexion of the ankle
flexion at the knee
adduction and internal rotation at the hip
progressive contractures of all spastic muscles
complicated assisting movements of the upper limbs when walking.
Conditions associated with a scissor gait
Arthrogryposis
Spastic diplegia
Pernicious anemia
Cerebrovascular accident
Cervical spondylosis with myelopathy (a problem with the vertebrae in the neck)
Liver failure
Multiple sclerosis
Spinal cord trauma
Spinal cord tumor
Syphilitic meningomyelitis
Syringomyelia
other forms of Cerebral palsy
References
Cerebral palsy types
Gait abnormalities | en | apollo | train |
Partially overlapping distribution of epsin1 and HIP1 at the synapse: analysis by immunoelectron microscopy.
Synapses of neurons use clathrin-mediated endocytic pathways for recycling of synaptic vesicles and trafficking of neurotransmitter receptors. Epsin 1 and huntingtin-interacting protein 1 (HIP1) are endocytic accessory proteins. Both proteins interact with clathrin and the AP2 adaptor complex and also bind to the phosphoinositide-containing plasma membrane via an epsin/AP180 N-terminal homology (ENTH/ANTH) domain. Epsin1 and HIP1 are found in neurons; however, their precise roles in synapses remain largely unknown. Using immunogold electron microscopy, we examine and compare the synaptic distribution of epsin1 and HIP1 in rat CA1 hippocampal synapse. We find that epsin1 is located across both sides of the synapse, whereas HIP1 displays a preference for the postsynaptic compartment. Within the synaptic compartments, espin1 is distributed similarly throughout, whereas postsynaptic HIP1 is concentrated near the plasma membrane. Our results suggest a dual role for epsin1 and HIP1 in the synapse: as broadly required factors for promoting clathrin assembly and as adaptors for specific endocytic pathways. | en | apollo | train |
## Crd diagnosis
CRD diagnosis can be confused with other genetic hypocholesterolemias characterized by decreased LDLcholesterol (LDL-C), such as ABL or homozygous HBL, or with acquired disorders associated with low highdensity lipoprotein-cholesterol (HDL)-C. [fig_ref] Figure 1: Etiology of familial hypocholesterolemia in childhood depending on lipid profile [/fig_ref] summarizes the differences in familial hypocholesterolemia with low LDL-C. The major clinical and biological manifestations as well as complications are summarized in [fig_ref] Table 1: Clinical and Biological Expressions of Chylomicron Retention Disease in Studies with Genotyping [/fig_ref] and steps to diagnose CRD are presented in [fig_ref] Table 2: Chylomicron Retention Disease Diagnosis [/fig_ref].
## Clinical signs
In CRD, consanguinity is frequent but there is usually no noted intrauterine growth retardation. Digestive symptoms are most prominent at the beginning of life. Nonspecific malabsorptive diarrhea is constant and begins in infants shortly after birth. Other digestive symptoms, such as vomiting or abdominal swelling, are often present. They get better within a few days or weeks with a low-fat diet. The long-term evolution of digestive symptoms is variable. The intensity of symptoms decreased over time independent of the level of fat in the diet in some previously reported patients [bib_ref] Studies on lipoprotein metabolism in a family with jejunal chylomicron retention, Nemeth [/bib_ref]. | en | apollo | train |
Leveraging of open EMR architecture for clinical trial accrual.
Accrual to clinical trials is a major bottleneck in scientific progress in clinical medicine. Many methods for identifying potential subjects and improving accrual have been pursued; few have succeeded, and none have proven generally reproducible or scalable. We leveraged the open architecture of the core clinical data repository of our electronic medical record system to prototype a solution for this problem in a manner consistent with contemporary regulations and research ethics. We piloted the solution with a local investigator-initiated trial for which candidate identification was expected to be difficult. Key results in the eleven months of experience to date include automated screening of 7,296,708 lab results from 69,288 patients, detection of 1,768 screening tests of interest, identification of 70 potential candidates who met all further automated criteria, and accrual of three candidates to the trial. Hypotheses for this disappointing impact on accrual, and directions for future research, are discussed. | en | apollo | train |
Delineation of a conserved B cell epitope on bonnet monkey (Macaca radiata) and human zona pellucida glycoprotein-B by monoclonal antibodies demonstrating inhibition of sperm-egg binding.
To circumvent autoimmune oophoritis after immunization with zona pellucida (ZP) glycoproteins, synthetic peptides encompassing B cell epitope(s) and devoid of oophoritogenic T cell epitopes as immunogens have been proposed. In this study, bonnet monkey (Macaca radiata) ZP glycoprotein-B (bmZPB) was expressed as polyhistidine fusion protein in Escherichia coli. Rabbit polyclonal antibodies against recombinant bmZPB (r-bmZPB) significantly inhibited human sperm-oocyte binding. To map B cell epitopes on ZPB, a panel of 7 murine monoclonal antibodies (mAbs) was generated against r-bmZPB. All 7 mAbs, when tested in an indirect immunofluorescence assay, reacted with bonnet monkey ZP, and only 6 recognized human zonae. Monoclonal antibodies MA-809, -811, -813, and -825 showed significant inhibition in the binding of human spermatozoa to human ZP in a hemizona assay. Epitope-mapping studies using multipin peptide synthesis strategy revealed that these 4 mAbs recognized a common epitope corresponding to amino acids (aa) 136-147 (DAPDTDWCDSIP). Competitive binding studies revealed that the synthetic peptide corresponding to the identified epitope (aa 136-147) inhibited the binding of MA-809, -811, -813, and -825 to r-bmZPB in an ELISA and to bonnet monkey ZP in an indirect immunofluorescence assay. The epitopic domain corresponding to aa 136-147 of bmZPB was completely conserved in human ZPB. These studies will further help in designing ZP-based synthetic peptide immunogens incorporating relevant B cell epitope for fertility regulation in humans. | en | apollo | train |
Osmotic dilators are medical implements used to dilate the uterine cervix by swelling as they absorb fluid from surrounding tissue. They may be composed of natural or synthetic materials. A laminaria stick or tent is a thin rod made of the stems of dried Laminaria, a genus of kelp. Laminaria sticks can be generated from Laminaria japonica and Laminaria digitata. Synthetic osmotic dilators are commonly referred to by their brand names, such as Dilapan. Dilapan-S are composed of polyacrylonitrile, a plastic polymer. The hygroscopic nature of the polymer causes the dilator to absorb fluid and expand.
Use in obstetrics and gynecology
Osmotic dilators are most commonly used to slowly dilate and soften the cervix prior to surgical abortion, a process referred to as cervical preparation. Adequate cervical preparation is important prior to surgical abortions because it helps to prevent complications of dilation and evacuation (D&E), such as laceration of the cervix. Cervical preparation can be accomplished with osmotic dilators, with medications such as prostaglandins and/or mifepristone, or with a combination of these. However, there is no consensus as to which cervical preparation method is superior in terms of safety and efficacy.
At later gestational ages, osmotic dilators, including laminaria, may be used to assist in dilating the cervix. Most abortion providers use laminaria, Dilapan, or both for osmotic dilation prior to surgical abortion after 16–18 weeks gestation.
Osmotic dilators may also be used to achieve cervical dilation prior to gynecology procedures, such as hysteroscopy or dilation and curettage of the non-pregnant uterus, although this is uncommon.
Placement
Prior to a planned surgical abortion, osmotic dilator(s) may be inserted into a woman's cervix. A speculum is placed in the vagina to allow the provider to see the uterine cervix. A tenaculum may be placed on the anterior lip of the cervix to straighten the cervical canal and hold the cervix steady. Pain medications may be administered via a paracervical block. The dilator is then grasped with a ring forceps and is placed into the cervix so that it spans both the internal cervical os and external cervical os. Over time, the osmotic dilator absorbs fluid and swells to 3-4 times the initial diameter. Most of the increase in size occurs within 6 hours after the dilator are placed in the cervix, though further expansion will continue over 12–24 hours. The number of osmotic dilators placed depends on the degree of cervical dilation that is sought. This may be affected by the gestational age of the pregnancy and history of prior vaginal deliveries. More dilators are generally used with advancing gestational age.
Laminaria tents are usually left in place overnight.
Mechanism of action
Laminaria function by absorbing fluid from the surrounding tissue and expanding. Thus exerts radial pressure on the cervix. They also cause the release of prostaglandins.
Removal
Laminaria are removed prior to initiating the D&E, after they have started the process of dilating the cervix. They are removed by grasping the strings of the dilator and applying gentle traction. The cervix may be dilated further using rigid cervical dilators which serially increase in diameter.
Effectiveness
There is no evidence regarding the risk of not achieving vaginal delivery within 24 hours with laminaria compared to prostaglandin E2 but there may be a lower risk of uterine hyperstimulation with laminaria. It is not certain whether the risks of caesarian section, perinatal death or maternal death are reduced or increased with laminaria compared with vaginal or cervical prostaglandin E2.
Risks
The incidence of complications related to osmotic dilator use prior to abortion has not been systematically studied and reported, but serious complications appear to be very rare. Risks of osmotic dilator insertion include pain, rupture of amniotic membranes, initiation of labor, cervical or uterine perforation, retention of the dilator, and infection.
Original Dilapan dilators were prone to fracturing under tension during removal which sometimes led to retention of dilator fragments within the uterus. Dilapan was subsequently removed from the market and replaced with Dilapan-S which is less prone to fragmentation. Dilapan may expand unevenly within the cervix and develop a dumbbell shape which can result in difficult removal.
References
Obstetrics | en | apollo | train |
Aerobic kinetoplastid flagellate Phytomonas does not require heme for viability.
Heme is an iron-coordinated porphyrin that is universally essential as a protein cofactor for fundamental cellular processes, such as electron transport in the respiratory chain, oxidative stress response, or redox reactions in various metabolic pathways. Parasitic kinetoplastid flagellates represent a rare example of organisms that depend on oxidative metabolism but are heme auxotrophs. Here, we show that heme is fully dispensable for the survival of Phytomonas serpens, a plant parasite. Seeking to understand the metabolism of this heme-free eukaryote, we searched for heme-containing proteins in its de novo sequenced genome and examined several cellular processes for which heme has so far been considered indispensable. We found that P. serpens lacks most of the known hemoproteins and does not require heme for electron transport in the respiratory chain, protection against oxidative stress, or desaturation of fatty acids. Although heme is still required for the synthesis of ergosterol, its precursor, lanosterol, is instead incorporated into the membranes of P. serpens grown in the absence of heme. In conclusion, P. serpens is a flagellate with unique metabolic adaptations that allow it to bypass all requirements for heme. | en | apollo | train |
TS-1 as first-line therapy for gastric linitis plastica: historical control study.
Gastric linitis plastica (LP) is usually found as an advanced gastric cancer and has a poor prognosis. No sufficiently effective chemotherapy has been reported. In recent years, TS-1 has yielded a high response rate for advanced gastric cancers and favorable treatment results have also been suggested for gastric LP. We retrospectively compared and discussed anti-tumor effects and survival time for 62 consecutive patients with unresectable gastric LP who underwent chemotherapy at Kitasato University East Hospital between November 1995 and December 2002. They were divided into two groups: 19 patients given chemotherapy including TS-1 as first-line therapy (TS-1 group), and 43 patients given chemotherapy mainly with 5-fluorouracil, cisplatin, methotrexate and mitomycin C (non-TS-1 group). The overall response was 57.9% [95% confidence interval (CI) 35.7-80.1%] in the TS-1 group, which was significantly greater than the 27.9% (95% CI 14.5-41.3%) of the non-TS-1 group (P < 0.01). The median survival time was 402 days (95% CI 251-553 days) in the TS-1 group, which was also significantly longer than the non-TS-1 group (213 days, 95% CI 165-261 days, P < 0.01). Neutropenia and febrile neutropenia of grade 3 or higher were observed in 21.1 and 5.2%, respectively, in the TS-1 group, which were lower than the values of 37.2 and 20.9% in the non-TS-1 group. We conclude that greater anti-tumor effects and longer survival time can be expected from chemotherapy including TS-1 for gastric LP compared with conventional chemotherapy. | en | apollo | train |
For example, a low-salt (low-sodium) diet and diuretics help keep fluid from accumulating in the abdomen.Problems resulting from the blocked vessels are treated.Ursodeoxycholic acid helps prevent veno-occlusive disease from developing after bone marrow or stem cell transplantation.If possible, the cause should be eliminated.Treatment
There is no specific treatment for the blockage.Other people develop cirrhosis with time, usually over months, depending on the cause and repeated exposure to toxic agents. Diagnosis
Doctors suspect veno-occlusive disease based on symptoms or blood test results that suggest liver dysfunction, particularly if people have ingested substances or have conditions (particularly following bone marrow transplantation) that may cause the disease. Blood tests evaluate the liver and blood clotting. Doppler ultrasonography often confirms the diagnosis. Occasionally, invasive tests may be necessary. Liver biopsy or blood pressure measurements of the hepatic veins and portal veins rarely are necessary. These measurements are done by inserting a catheter into a vein in the neck (jugular vein) and threading it to the hepatic veins. A biopsy of the liver can be taken at the same time. Prognosis
The prognosis depends on how extensive the damage is and whether the condition causing it recurs or continues—for example, when people continue to drink senecio tea. Overall, about one fourth of people with veno-occlusive disease die of liver or other organ failure within 3 months. When the cause is graft-versus-host disease after bone marrow transplantation, veno-occlusive disease often resolves on its own within a few weeks. Increasing the dose of drugs used to suppress the immune system can also cause graft-versus-host disease to resolve. If the cause is an ingested substance, stopping its use helps prevent further liver damage. Treatment
There is no specific treatment for the blockage. If possible, the cause should be eliminated. Ursodeoxycholic acid helps prevent veno-occlusive disease from developing after bone marrow or stem cell transplantation. Problems resulting from the blocked vessels are treated. For example, a low-salt (low-sodium) diet and diuretics help keep fluid from accumulating in the abdomen.A catheter is inserted in a neck vein (jugular vein), threaded to the portal vein, and used to make this connection (shunt).Then a wire mesh tube (called a transjugular intrahepatic stent) is inserted to keep the shunt open.The effectiveness of such shunts is unclear.Liver transplantation may be necessary in extreme cases. | en | apollo | train |
An herbal colon cleanse is an alternative complimentary therapy that can help improve digestion, enhance energy, improve your digestive system and remove toxins from the colon and gastrointestinal tract. The natural herbs used to make colon cleansing products have laxative properties and can help reduce inflammation. Herbal colon cleanse products are available over the counter without a doctor’s prescription and contain some of the following ingredients.
Flaxseed is one of the most popular herbal, natural healing products used by adults and children. Flaxseed is not a vitamin or mineral. It contains soluble fiber – the part of plant-based foods that cannot be digested – which aids in stimulating your digestive tract and promoting bowel movements. Flaxseed also helps relieve symptoms associated with constipation and is also commonly used as a remedy for menopause symptoms. Flaxseed is well tolerated and has few, if any, side effects.
Psyllium husk is a natural herb that is commonly used by adults in the United States. Psyllium helps relieve irritation in the bowel and soothes intestinal discomfort. Psyllium husk has an oily texture that softens the stool and relieves symptoms associated with constipation. Along with other natural herbs, psyllium reduces bloating in the abdomen and relieves pain and discomfort caused by irritable bowel syndrome.
Chamomile is one of the most popular herbs used in complimentary therapeutic treatments. Chamomile is helpful for relieving stomach cramps, nausea, diarrhea, and flatulence in children and adults. Chamomile is also used to treat gastrointestinal disorders and digestive irritation.
The National Center for Complementary Alternative Medicine explains that aloe vera is a tropical plant that has been used as an oral laxative for several centuries. Aloe vera is a safe, natural herb that when used in colon cleansing products, reduces pain and bloating associated with irritable bowl syndrome for most patients. The laxative characteristics of aloe vera come from aloe latex, a bitter liquid in the leaf of the plant.
Cascara sagrada is an herb derived from the bark of a tree. Cascara sagrada, used in herbal colon cleanse products, is a natural herb that works like a powerful laxative by promoting regular bowel movements. Cascara sagrada is also known for lowering potassium and sodium levels.
Tumeric is a member of the ginger family. Tumeric is used in herbal colon cleanse products to ward off abdominal pain caused by inflammation, spasms or an obstruction in the bowels or gastrointestinal tract. Magnesium oxide is an important ingredient in colon cleansing products because it can introduce good bacteria into your system. Hydrochloric acid is used for reducing constipation. Hydrochloric acid contains peptides that work by breaking down proteins in the colon and may eliminate dangerous toxins. | en | apollo | train |
NMES therapy may enhance the hyperemic arterial response and endothelium-dependent dilation in skin vasculature in the paretic upper extremities of patients with stroke. | en | apollo | train |
This study evaluates the safety and efficacy of administering sorafenib concurrent with yttrium-90 radioembolization to patients with advanced hepatocellular cancer.
Studies in Asia of unresectable hepatocellular cancer (HCC) demonstrated that sorafenib could be administered safely at 400mg BID when initiated 14 days following radioembolization (RE). However, the ideal sequence of RE and sorafenib may not be completely elucidated, the two treatments given concurrently may be more effective than the sequential approach studied in the Asian trials. Preclinical models have demonstrated that sorafenib acts synergistically with radiation, increasing apoptosis. Furthermore, case reports suggest profound responses in patients who have received sorafenib concurrent with TARE as evidenced by improvement in symptoms, >80% decrease in alpha fetoprotein (AFP), and conversion from unresectable to resectable. Sorafenib concurrent with TARE may take advantage of the synergistic relationship between the two therapies and prove to be a more effective treatment strategy than sequential administration of TARE and sorafenib.
- Barcelona Clinic Liver Cancer Stage B or C. Segmental and subsegmental portal vein thrombosis is allowed.
- Have at least one tumor lesion that can be accurately measured according to Response Evaluation Criteria in Solid Tumor (RECIST v1.1).
- Consultation with interventional radiologist and deemed an appropriate candidate for TARE.
- Prior local therapy, such as surgery, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection or cryoablation is allowed if the index lesion(s) remains outside of the treatment field or has progressed since prior treatment. Local therapy must have been completed at least 4 weeks prior to the baseline scan.
- Patient must be informed of the investigational nature of this study, sign and give written informed consent in accordance with institutional and federal guidelines.
- ECOG performance status ≤ 1.
- Have adequate hematologic function as documented by ANC ≥ 1000/ul, platelet count ≥ 60,000/ul, and hemoglobin ≥ 8.5 mg/dl obtained within 28 days prior to registration.
- Have adequate hepatic function, as determined by the following tests measured within 28 days prior to registration: serum bilirubin ≤ 2 x upper limit of normal (ULN); SGOT (AST) or SGPT (ALT) ≤ 5 x the IULN.
- Have adequate renal function, as determined by the following tests measured within 28 days prior to registration: serum creatinine ≤ 1.5 x ULN OR a measured creatinine clearance or calculated creatinine clearance ≥ 50 mL/min.
- Must be able to swallow oral medications.
- Negative pregnancy test done ≤7 days prior to registration, for women of childbearing potential only.
- Known or suspected allergy or hypersensitivity to sorafenib.
- Must not have known brain metastases.
- No concurrent anticancer chemotherapy or local therapy.
- Inability to perform y90 TARE due to: (1) inability to catheterize the hepatic artery, (2) portal vein thrombosis/occlusion without the ability to perform selective infusion, (3) Tc-99m MAA hepatic artery perfusion scintigraphy shows unfavorable shunt fraction between the liver and the pulmonary parenchyma as determined by the interventional radiologist, or (4) other contraindication to TARE identified by interventional radiologist.
- No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for 3 years.
- History of myocardial infarction, stroke, ventricular arrhythmia, or symptomatic conduction abnormality within 6 months.
- Concurrent severe or uncontrolled medical disease (i.e., active systemic infection, diabetes, coronary artery disease, congestive heart failure) that, in the opinion of the Investigator, would compromise the safety of the patient or compromise the ability of the patient to complete the study. | en | apollo | train |
13.10) are not absolutely essential if the clinical picture is sufficiently characteristic, but they should be performed if there is any doubt as to the etiology of radiculopathy or if surgery is needed.13.9; **MRI** , ▶ Fig.13.8 and ▶ Fig.**Imaging studies** ( **CT** , ▶ Fig.The normal lumbar lordosis is no longer present, and scoliosis is seen.13.7** **A patient with lumbar disk herniation**.* **Conus medullaris syndrome** (damage to the conus medullaris at level L1). * **Cauda equina syndrome** (compression of the nerve roots in the lumbar spinal canal below the L1 level). **Diagnostic evaluation** Often, the **posture** of the standing patient already displays the typical appearance of a lumbar disk herniation ( ▶ Fig. 13.7). As in cervical disk herniation, the level of the affected nerve root can generally be determined from the pattern of referred pain and any motor, sensory, and reflex deficits that may be present. The peripheral nerve trunk containing the axons derived from the affected root is often sensitive to **pressure** ( **at the Valleix's pressure points** ), and **stretching** of the nerve is often **painful**. The latter can be tested by passive raising of the supine patient's extended leg (the **Lasègue test** ). Pain caused by elevation of the leg on the side opposite the sciatica (the **crossed Lasègue sign** ) usually indicates a large, sequestrated disk herniation. If a higher lumbar root (L3 or L4) is affected, one should look for the **reverse Lasègue sign** , that is, test for pain on _extension_ of the leg in the _prone_ patient, which stretches the femoral nerve rather than the sciatic nerve. If the herniation is lateral or extraforaminal, pain may also be inducible by lateral bending of the trunk. **Fig. 13.7** **A patient with lumbar disk herniation**. The normal lumbar lordosis is no longer present, and scoliosis is seen. **Imaging studies** ( **CT** , ▶ Fig. 13.8 and ▶ Fig. 13.9; **MRI** , ▶ Fig. 13.10) are not absolutely essential if the clinical picture is sufficiently characteristic, but they should be performed if there is any doubt as to the etiology of radiculopathy or if surgery is needed.13.8).**Fig.13.8** **Lateral L3/L4 disk herniation** (arrowheads), CT image.The normal spinal ganglion on the right side is visible in the intervertebral foramen (arrow).**Fig.13.9** **Left S1 radicular compression** in a 40-year-old man.**a** Myelography reveals a broadened and shortened left S1 nerve root (arrowhead) and an indentation of the dural sack from the right at this level. | en | apollo | train |
Amniotic sac rupture can result in prolapse of the umbil-ical cord with fetal compromise.Vaginal bleeding can signal early cervical dilation and labor, abruptio placentae, or placenta previa.Additional hematologic changes include a moderate leukocytosis (up to 20,000 mm3) and a rela-tive hypercoagulable state due to increased levels of factors VII, VIII, IX, X, and XII and decreased fibrinolytic activity.During evaluation in the ED, the primary and secondary surveys commence, with mindfulness that the mother always receives priority while conditions are still optimized for the fetus.148 This management includes provision of supplemental oxygen (to prevent maternal and fetal hypoxia), fluid resuscita-tion (the hypervolemia of pregnancy may mask signs of shock), and placement of the patient in the left lateral decubitus posi-tion (or tilting of the backboard to the left) to avoid caval com-pression. Assessment of the fetal heart rate is the most valuable information regarding fetal viability. Fetal monitoring should initially be assessed with bedside FAST ultrasound to document the heart rate of the fetus; subsequent monitoring should be per-formed with a cardiotocographic device that measures both con-tractions and fetal heart tones (FHTs). Because change in heart rate is the primary response of the fetus to hypoxia or hypo-tension, anything above an FHT of 160 is a concern, whereas bradycardia (FHT of <120) is considered fetal distress. Indica-tions for emergent cesarean section include: (a) severe mater-nal shock or impending death (if the fetus is delivered within 5 minutes, survival is estimated at 70%), (b) uterine injury or significant fetal distress (anticipated survival rates of >70% if FHTs are present and fetal gestational age is >28 weeks).149If possible, a member of the obstetrics team should be present during initial evaluation. Vaginal bleeding can signal early cervical dilation and labor, abruptio placentae, or placenta previa. Amniotic sac rupture can result in prolapse of the umbil-ical cord with fetal compromise.Focused prenatal history-taking should elicit a history of pregnancy-induced hypertension, ges-tational diabetes, congenital heart disease, preterm labor, or placental abnormalities.Asking the patient when the baby first moved and if she is currently experiencing movement of the fetus is important.Determining fetal age is key for consider-ations of viability. | en | apollo | train |
Kinetic analysis of the AH8165-receptor interaction at the mammalian neuromuscular junction.
The effect of a new neuromuscular blocking agent, AH8165, on carbachol-induced end-plate depolarization was measured in isolated guinea pig lumbrical muscles. The results showed that the kinetics were competitive (parallel shift of dose-response curves to the right and a slope of Schild plot of 1.09 +/- 0.07) and the AH8165-receptor dissociation constant was estimated as 0.337 +/- 0.008 muM. Once the dissociation constant was known, the fraction of receptors occupied by any given concentration of AH8165 could be determined. This fractional receptor occupancy was then compared with the indirect twitch response in an isolated guinea pig nerve-lumbrical muscle preparation. These measurements of the effect of AH8165 on the margin of safety of neuromuscular transmission gave values comparable to those obtained with d-tubocurarine, i.e., the twitch remained normal until 75-80 per cent of the receptors were blocked and was abolished when 90-95 per cent of the receptors were occluded. Thus, the neuromuscular blocking action of AH8165 appears to be consistent with a simple postsynaptic competitive interaction with the transmitter. | en | apollo | train |
A paradoxical embolism refers to an embolus that is carried from the venous side of circulation to the arterial side or vice versa. It is a kind of stroke or another form of arterial thrombosis caused by embolism of a thrombus (blood clot), air, tumor, fat, or amniotic fluid of venous origin, which travels to the arterial side through a lateral opening in the heart, such as a patent foramen ovale, or arteriovenous shunts in the lungs.
The opening is typically an atrial septal defect, but can also be a ventricular septal defect. Other conditions that can cause paradoxical embolism includes pulmonary arteriovenous malformations, and patent foramen ovale.
Paradoxical embolisms represent two per cent of arterial emboli.
Pathophysiology
Passage of a clot (thrombus) from a systemic vein to a systemic artery. When clots in systemic veins break off (embolize), they travel first to the right side of the heart and, normally, then to the lungs where they lodge, causing pulmonary embolism. On the other hand, when there is a hole at the septum, either upper chambers of the heart (an atrial septal defect) or lower chambers of the heart (ventricular septal defects), a clot can cross from the right to the left side of the heart, then pass into the systemic arteries as a paradoxical embolism. Once in the arterial circulation, a clot can travel to the brain, block a vessel there, and cause a stroke (cerebrovascular accident).
Diagnosis
CT angiography; bubble echocardiography may also be used to detect a patent foramen ovale.
Treatment
Therapeutic preventional anticoagulation is the first line if correction of the underlying anatomical pathology is not already done, by using Heparin or other anticoagulative agents. This approach is also used in the treatment of a present embolism, albeit at higher doses. Once these are exhausted or the use of therapeutic anticoagulation is contraindicated (for example, in a co-occurring traumatic hemorrhage), mechanical thrombectomy may be used to physically remove the embolism from the blocked artery.
References
External links
Vascular diseases
Neurological disorders
Stroke | en | apollo | train |
Forensic matters include anything related to the application and enforcement of the law as well as the prosecution of those who violate the law.**Forensic** —The word forensic refers to the legal system.**Forebrain** —The part of the neural tube that develops into the evolutionarily newest parts of the brain, such as the neocortex and the limbic system.**Evolution** —The modern scientific theory about how species develop over time into their present forms. **Evolutionary fitness** —The ability to pass on one's genes to the next generation. If there is a larger proportion of gene A in the present generation than in the previous one, then the organism with gene A has demonstrated evolutionary fitness. **Executive functions** —A set of mental abilities, associated with the frontal lobes, which include planning, analyzing, considering alternative actions, abstraction, and changing sets. **Extinction** —The unlearning of a behavior. When the association between the stimulus and the response (in classical conditioning) or between the behavior and the reinforcement (in operant conditioning) starts to erode, the conditioned behavior gets extinguished. **Extroversion** —A personality trait derived from Jungian theory. The extrovert attends primarily to external reality, to other people and objects. Extroverts are typically outgoing and gregarious. **Factor analysis** —A statistical technique that shows how different items group together into distinct clusters. **Fluid intelligence** —Immediate information processing skills, such as memory, processing speed, and the amount of information that can be processed at a time. Fluid intelligence reduces with age and is sensitive to illness and injury. **fMRI** —Functional Magnetic Resonance Imaging. This technology allows us to get a picture of the brain's activity over time. **Forebrain** —The part of the neural tube that develops into the evolutionarily newest parts of the brain, such as the neocortex and the limbic system. **Forensic** —The word forensic refers to the legal system. Forensic matters include anything related to the application and enforcement of the law as well as the prosecution of those who violate the law.**Frontal lobe** —The frontal lobe is a brain region which comprises the front half of the cortex.It extends from the central sulcus forward.**Functionalism** —A school of psychology, pioneered by William James, that focused on the way the mind functions.It arose in reaction to Wilhelm Wundt's structuralism.**GABA** —An inhibitory neurotransmitter; it calms the nervous system. | en | apollo | train |
This report describes two novel findings: (1) injury to SMCs in vitro induces the conversion of biologically latent TGF-beta to active TGF-beta; and (2) the therapeutic PDT dose interferes with this injury activation process. This study substantiates the concept of local cytokine inhibition by PDT in a biologic system and provides new insights into the mechanisms of PDT-mediated inhibition of experimental IH. | en | apollo | train |
Neuroprotective effect of Amaranthus lividus and Amaranthus tricolor and their effects on gene expression of RAGE during oxidative stress in SH-SY5Y cells.
Amaranthus plants, or spinach, are used as food sources worldwide. Amaranthus leaves are rich in antioxidant compounds, which act as free radical scavengers. Oxidative stress caused by the aberrant production of reactive oxygen species (ROS) represents an important mechanism for neuronal dysfunction and cell loss in different neurodegenerative disorders. The neuroprotective effects of antioxidant-containing plants have been extensively demonstrated in different models of neurotoxicity. However, few studies have investigated the antioxidant properties of Amaranthus extracts and their effect on the nervous system. In the present study, the leaves of Amaranthus lividus and Amaranthus tricolor were extracted using petroleum ether, dichloromethane, and methanol. Results indicated that antioxidant activities were the highest in methanol extracts from both kinds of Amaranthus leaves. In addition, oxidative stress was induced in human neuroblastoma cell lines (SH-SY5Y) by using H2O2. Intracellular oxidative stress, cytotoxicity, and gene expression of RAGE were then determined. In vitro results demonstrated that pretreatment with A. lividus and A. tricolor extracts can significantly decrease cell toxicity and intracellular ROS production in SH-SY5Y cells. Interestingly, the extracts also significantly downregulated the expression of oxidative stress genes such as HMOX-1, RAGE, and RelA/ NF-κB. Our results suggested that Amaranthus leaves may be useful for reducing oxidative stress and may be beneficial for age-related diseases and neurodegenerative disorders. | en | apollo | train |
Intro: For over 50 years, supplement K antagonists such as for example warfarin (Aldocumar?) and acenocoumarol (Sintrom?) have already been the gold regular for reducing the chance of cerebrovascular occasions. margin. These medications are expensive, nevertheless, and some absence a particular antidote, while some must be implemented twice per day. Regarding the dental care of patients getting these drugs, suspension system or adjustment of the backdrop medication is not needed when performing intrusive dental techniques, except where indicated from the prescribing doctor. Conclusions: The brand new dental anticoagulants usually do not cause significantly greater dangers than conventional dental anticoagulants when offering invasive dental care, and their suspension system is not firmly needed in such circumstances. Key phrases:Dabigatran, rivaroxaban, apixaban, dental care, hemostasis. Introduction Due to the ageing Aliskiren of the populace and the upsurge in life span, the prevalence of chronic illnesses, including center disorders and cerebrovascular occasions, keeps growing (1). To be able to prevent thromboembolic complications and infarction, these individuals frequently receive anticoagulant treatment C the cement indications which consist of Aliskiren atrial fibrillation and additional center arrhythmias; venous thromboembolism (deep venous thrombosis, pulmonary embolism); severe coronary symptoms and myocardial infarction; pulmonary hypertension; and center valve disease and valve prostheses (1,2). Generally terms, dental anticoagulants work and reliable, providing great tolerance, and fast absorption after Aliskiren dental administration, with maximum plasma concentrations becoming reached after 1 hour (3,4). In britain, it’s been approximated that about 300,000 people receive treatment with dental anticoagulants C the proportional quantity in Spain becoming around 250,000 individuals. For many years, the drugs found in dental anticoagulation therapy have already been the supplement K antagonists (VKAs) [acenocoumarol (Sintrom?) and warfarin (Aldocumar?)], and in individuals with special dangers or contraindications to VKAs, antiplatelet medicine has been utilized alternatively (5). Nevertheless, these anticoagulants can provide rise to undesireable effects and relationships with different medicines and foods. Furthermore, even though the antithrombotic effects express after 48-72 hours, a reduction in coagulation elements is only noticed after 5 times of therapy (6). The medical management of the medication substances is consequently complicated by the necessity for close monitoring of their activity. These and additional elements have limited the usage of such medications in routine medical practice, and there’s been a dependence on fresh dental anticoagulant drugs providing easier handling features, a better protection profile, and fewer medication relationships (7). With this framework, Haremberg et al. in the entire year 2008 (8) described the perfect anticoagulant like a medication offering rapid starting point of actions and a brief half-life (easy managing performance in case of blood loss, with no need to add various other anticoagulants); predictable pharmacokinetics (less complicated dosing); a predictable anticoagulant impact (fixed dose, with no need for monitoring); administration via the dental route (thus facilitating this is of brand-new indications); metabolism not really mediated by isoenzyme CYP2C9 or VCOR1 (i.e., without medication or food connections); option of an antidote (basic safety in case of blood loss); and a satisfactory cost (thus facilitating clinical advancement). Furthermore, the introduction of brand-new anticoagulants should look for to offer a little molecular weight artificial medication specifically and straight acting upon an individual coagulation aspect (Xa/IIa), with Aliskiren non-e from the known undesired ramifications Aliskiren of the current medications, like the coumarin derivatives (7,9,10). Appropriately, within the last 5 years, choice anticoagulants (dabigatran, rivaroxaban and apixaban) have already been evaluated that action straight upon a concrete focus on inside the coagulation cascade, thus affording a far more predictable anticoagulant impact. The present research offers an revise on the brand new dental anticoagulants and testimonials the implications described the dental hygiene of patients implemented these substances. Materials and strategies An exhaustive PubMed-Medline and Cochrane Library search was manufactured from the primary alternatives to typical dental anticoagulation. The main element words used Mouse monoclonal to Alkaline Phosphatase had been dabigatran, rivaroxaban and apixaban, using the boolean operator ?AND?. We included research published in British and Spanish during the last a decade. Specialized books and pharmaceutical catalogs had been also consulted. A complete of 184 content were identified, which 76 (68 books testimonials, 4 metaanalyses and organized testimonials, and 7 scientific trials) fulfilled the inclusion requirements. It ought to be noted which the search yielded just three research on the brand new dental anticoagulants released in the oral books. Coagulation cascade The coagulation cascade was initially defined in the middle-1960s, based.
Previously, we reported that cancerous inhibitor of protein phosphatase 2A (CIP2A) mediates the apoptotic aftereffect of bortezomib in hepatocellular carcinoma (HCC). CIP2A, P-Akt and P-4EBP1, recommending that the result of bortezomib on autophagy is definitely self-employed of proteasome inhibition. Furthermore, our data demonstrated that both bortezomib and Btz inhibited tumor development, downregulated CIP2A, P-Akt and induced autophagy in Huh-7 tumors. To conclude, bortezomib induces autophagy in HCC through a CIP2A-PP2A-Akt-4EBP1 pathway. Intro Hepatocellular carcinoma (HCC) may be the 5th most common solid tumor world-wide . Advanced HCC is definitely characterized by regular resistance to standard chemotherapeutic providers and radiation. There is certainly thus obviously a have to develop fresh therapeutic focuses on and approaches for HCC therapy. Lately, the autophagy pathway offers emerged like a encouraging fresh target in malignancy BMN-673 8R,9S manufacture treatment. Autophagy is actually a homeostatic system for maintaining mobile integrity and it is a catabolic procedure which involves degradation of cytoplasmic elements via the lysosomal equipment . Autophagy has multiple assignments in cancers: it could promote cancers cell loss of life or survival with regards to the complicated connections among metabolic tension, pathways of apoptosis and autophagy , , ; and perturbation of autophagy may also donate to tumorigenesis , . An improved BMN-673 8R,9S manufacture knowledge of autophagy legislation may facilitate breakthrough of brand-new potential therapeutic goals in HCC. Bortezomib may be the initial in-class dipeptide boronate proteasome inhibitor particularly designated to focus on the 26S proteasome , . Bortezomib continues to be accepted for treatment of multiple myeloma and mantle cell non-Hodgkin’s lymphoma (NHL) and it is under clinical analysis for make use of in other malignancies , . Furthermore to its results on apoptosis induction, cell-cycle inhibition (G2-M stage arrest) and several other cellular systems connected with proteasome inhibition , , , bortezomib has been proven to induce autophagy in hypoxic HeLa cervical carcinoma cells in response to turned on endoplasmic reticulum (ER) tension , in individual prostate cancers cells through EIF-2 phosphorylation , and in individual head and throat squamous cell carcinoma cells in BMN-673 8R,9S manufacture colaboration with proteasome-dependent JNK activation and Bcl-2 phosphorylation . Although these research commonly recommend bortezomib-induced autophagy correlates using its proteasome inhibition , , , the precise system of bortezomib-induced autophagy isn’t fully understood. It really is popular that mammalian BMN-673 8R,9S manufacture focus on of rapamycin (mTOR) is definitely an integral regulator of cell development and autophagy . Furthermore, triggered mTOR complicated 1 (mTORC1), among the two main mTOR parts, activates S6K and phosphorylates 4EBP-1 (therefore liberating 4EBP-1 from eIF4E) advertising mRNA translation . Furthermore, mTORC1 straight interacts with and inhibits the ULK1 complicated, an essential element in autophagy initiation BMN-673 8R,9S manufacture . Mediation of development element signaling by mTOR is definitely mainly in response towards the phosphatidylinositol 3-kinase (PI3K)/Akt pathway . Akt includes a important role in tumor cell success and apoptosis rules, and recent research show that inhibition of Akt also promotes autophagy , , . In HCC, the Akt pathway offers been shown to become constitutively triggered and correlated with a worse prognosis . Our earlier study also shown that downregulation of p-Akt is definitely a significant molecular determinant of bortezomib-induced apoptosis in HCC cells . It really is noteworthy that bad rules of Akt signaling may be accomplished by phosphatases, such as for example phosphatase and tensin homologue erased on chromosome ten (PTEN) and proteins phosphatase 2A (PP2A). PTEN is definitely a dual proteins/lipid phosphatase that counteracts PI3K/Akt signaling by dephosphorylating phosphatidylinositol-3,4,5-trisphosphate (PIP3) in the 3-placement . On the other hand, PP2A is definitely a serine/threonine proteins phosphatase that may straight dephosphorylate p-Akt and p-ERK . PP2A comprises catalytic C subunit (PP2Ac), scaffolding A subunit (PR65) and regulatory B subunits . PP2A continues to be suggested to be always a tumor suppressor . For instance, improved PP2A activity can induce apoptosis through inactivation of Bcl-2 or activation of Poor . PP2A also regulates the cell routine, cell success and proliferation by either straight or indirectly inhibiting cdc2, MAPK and Akt kinases . Our latest data also indicated that bortezomib enhances PP2A activity therefore downregulating p-Akt and inducing apoptosis in HCC Diras1 cells . Furthermore, several mobile inhibitors of PP2A, such as for example Collection and CIP2A have already been determined . CIP2A offers emerged like a book oncoprotein and an increasing number of reviews show that it’s overexpressed in lots of human being malignancies, including HCC , , , , , , , . CIP2A offers been proven to stabilize c-Myc oncoprotein by inhibiting PP2A activity toward c-Myc, therefore promoting anchorage-independent.
Scorpions are among the oldest terrestrial arthropods plus they have got passed through little morphological changes throughout their evolutionary background on property. about digestive enzymes in scorpions possess referred to the characterization of the amylase , a lipase and a chymotrypsin from . Because of all the shown features, scorpions are especially attractive pets for physiological and evolutionary research, resulting in the understanding of evolutionary areas of the nourishing system in Arachnida and Arthropoda and allowing the introduction of scorpion control strategies. On the onset of the research, neither DNA or full proteins series nor advanced methods such as following era sequencing and shotgun proteomics have been utilized to the analysis of scorpion digestive tract (Fig 1). Within this function, we looked into the molecular physiology of digestive function in the scorpion with a mix of transcriptomic, proteomic and enzymological techniques, mainly concentrating on proteins digestion. A combined mix of transcriptomics and proteomics methods together provides previously been referred to as a strong strategy to be able to identify also to series DNA and proteins from non-sequenced microorganisms [14,15]. Open up in another home window Fig 1 General morphology of scorpion digestive tract and its area.Schematic ventral (A) and lateral (B) views of scorpion digestive tract and its own divisions. Best picture (A) represents ventral look at of MMG. PMG, prosomal midgut. Fig 1B was altered from . We right here report a big dataset of transcribed and translated proteins sequences in the midgut and midgut glands which we from a scorpion. Quantitative proteomics and proteolytical data exhibited comparative quantities and pH optima of different hydrolases. The primary digestive peptidases had been isolated and kinetically characterized. Subsequently, a phylogenetic evaluation of cathepsin L and legumain was performed. For the very first time, a far more elucidative model for the digestive procedure in scorpions was suggested with evolutionary factors about the nourishing system in Arachnida. Components and Methods Pets and test obtaining Adult females had been from the lab of arthropods at Instituto Butantan (S?o Paulo, Brazil). The pets had been starved for at least 8 times and then given with set up was done from the applications Velvet/Oases incorporated towards OSI-906 manufacture the Agalma pipeline [16,17]. Four assemblies had been done to all or any examples with kmers of 31, 41, 51 and 61 that thereafter had been merged as well as the redundant contigs taken out. A GREAT TIME (basic local position search device- ) was utilized to recognize and annotate set up sequences using the UniProt being a data source with an e-value threshold of 10-10. Fasta data files had been filtered by removal of transcripts smaller sized than 150 bp, splice variants and low self-confidence contigs. The ultimate assembly OSI-906 manufacture of every physiological condition comes in S1 Dataset. Furthermore, this transcriptome shotgun set up project continues OSI-906 manufacture to be transferred at DDBL/EMBL/GenBank beneath the accession “type”:”entrez-nucleotide”,”attrs”:”text message”:”GBZU00000000″,”term_id”:”815933442″,”term_text message”:”GBZU00000000″GBZU00000000. The edition described within this paper may be the first edition “type”:”entrez-nucleotide”,”attrs”:”text message”:”GBZU01000000″,”term_id”:”815933442″,”term_text message”:”gb||GBZU01000000″GBZU01000000. The gene ontology was attained using this program Blast2Move using the nonredundant NCBI data source. The e-value and annotation cutoff had been respectively 10-6 and 45. Subcellular area was forecasted using the program WoLF PSORT . The contig translation predicated on the DNA coding locations was performed using the program FrameDP v 1.2.0 . After using the BLASTX device against the UniProt data source the program made a training established to predict the much more likely coding DNA series (CDS) predicated on the interpolated Markov versions (IMMs). Contigs with significantly less than 50 proteins had been taken out. The directories from given and fasting pets had been mixed for the MASCOT queries (below) however the redundancy from the feasible digestive enzymes had been manually taken out by evaluating the sequences. The data source used for proteins identification comes in data established S2. For all of those other sequences the redundancy was taken out using this program BLASTClust with series length insurance of 90% and a percent identification threshold of 97% OSI-906 manufacture following the MASCOT queries with the partly Rabbit Polyclonal to JAK2 redundant data source. This avoided discarding isoforms and incomplete sequences which contain an overlapping area but also various areas of the protein. Proteomics techniques The MMG homogenates of 1 specimen had been posted to three freeze and thaw cycles and centrifuged for 20 min at 1,000 x g. Supernatants had been collected and employed for proteome analyses. Three distinctive biological samples had been independently separated by SDS-PAGE on the 10 well Web page Novex 4C12% Bis-Tris Gel (Invitrogen, Bleiswijk, NL) for 30 min at a continuing voltage of 200 V using MES-SDS as working buffer. Each gel street was chopped up in 32 equivalent pieces. Proteins had been in-gel digested (trypsin) after decrease and alkylation, tryptic proteins fragments had been extracted from your gel with OSI-906 manufacture acetonitrile, vacuum dried out and resuspended in 0.1 M acetic acidity ahead of analysis by nanoLC-MS/MS.
History & Aims Esophageal squamous cell carcinoma (ESCC) may be considered a highly angiogenic tumor. demonstrates the fundamental part of fibroblasts in the ESCC angiogenic-induced response and shows that the pharmacological focusing on from CD248 the TGF- signaling axis could possibly be of therapeutic advantage with this fatal disease. Intro The tumor body organ includes a dynamic combination of tumor cells, fibroblasts, endothelial cells and immune system cells that work together to operate a vehicle tumor development 1. Activated fibroblasts, also called carcinoma-associated fibroblasts (CAFs)2, have already been identified in the leading sides of several solid tumors, including breasts, digestive tract and melanoma 3C5. The current presence of CAFs inside the tumor microenvironment is definitely preceded from the chemoattraction and migration of precursor cells, that may either occur from the encompassing sponsor fibroblasts or from circulating mesenchymal precursors/stem cells 6, 7. Once recruited, paracrine tumor-derived development elements activate the CAFs which go through a myofibroblastic transdifferentiation, described by an elongated spindle form, as well as the manifestation of contractile -clean muscle mass actin and vimentin 8. CAFs are hypothesized to operate a vehicle tumor development through the deposition of extracellular BIIE 0246 supplier matrix (ECM) protein, the secretion of development factors as well as the BIIE 0246 supplier activation of invasion 9. One region that is little explored may be the potential part of CAFs in tumor angiogenesis. A lot of the development of solid tumors depends upon the prepared supply of nutrition and air from an area blood circulation. As tumors develop beyond several millimeters in proportions they easily outstrip the neighborhood supply of nutrition available through basic diffusion and stimulate the forming of their personal tumor BIIE 0246 supplier vasculature. Though it has been proven that stromal fibroblasts are a significant way to obtain the pro-angiogenic element vascular endothelial cell development element (VEGF) 10, it’s been difficult to review the connection of carcinoma cells, fibroblasts and endothelial cells inside a physiologically relevant model. In today’s study we’ve used a book 3D model where in fact the connection of esophageal squamous cell carcinoma cells (ESCC) with fibroblasts drives vascular network development inside a 3D collagen gel. We display that ESCCs need the current presence of stromal fibroblasts to stimulate vascular network development, thereby recommending that fibroblasts will be the essential mediators of angiogenesis in this technique. Mechanistic studies expose that paracrine TGF- from your ESCC prospects to activation from the fibroblasts which pharmacological inhibitors of TGF- signaling can invert both fibroblast activation and vascular network development. Materials and strategies Cell Lines Esophageal malignancy cells, TE cell lines (TE1, -8, -10, -11, -12) had been cultured as previously explained 11. Human being esophageal keratinocytes EPC2 have already been explained previously 11, 12. Human being microvascular endothelial cells HMVEC can be BIIE 0246 supplier found commercially through Cascade Biologics, Inc. (Portland, OR) 13. Main human being esophageal fibroblasts specified as FEF3 had been isolated from human being fetal esophagus as explained previously 11. FEF3 cells had been stably transduced using ViraPower Lentiviral manifestation system comprising the gene for GFP. GFP lentivirus grew up in our lab as well as the FEF3 cells had been transduced in the current presence of 6g/ml polybrene. Forty-eight hours BIIE 0246 supplier after transduction cells had been selected in the current presence of 10g/ml blasticidin for two weeks. Antibodies and Reagents The next antibodies had been found in this research: anti-human Compact disc31 (Dako, Carpinteria, CA), anti–smooth muscles actin (Sigma-Aldrich, St. Louis, MO), anti-Von Willebrand Aspect (Neomarkers, Fremont, CA), anti-fibroblast activation proteins.
The look of novel -helix mimetic inhibitors of protein-protein interactions is of interest to pharmaceuticals and chemical genetics researchers as these inhibitors give a chemical scaffold presenting side chains in the same geometry as an -helix. the examined the demonstrated that arylamide substances can become low M inhibitors from the described the formation of a collection comprising a diverse group of these arylamide substances . A restricted docking research was performed by Shaginian determining configurations showing the arylamide part chains coincident using the locations from the p53 Phe-Trp-Leu part chains. In the task by Plante six arylamides had been synthesized and screened against the determined problems with effectively sampling particular arylamide backbone conformations using regular molecular dynamics techniques and used a sophisticated sampling strategy to attempt to conquer the issues . Vemparala and co-workers mentioned that changing the thioether for an ether group is definitely one manner in which the flexibility from the compound could KRT17 possibly be controlled, because the bigger thioether group would decrease backbone versatility . Work COMPLETED in this Research As you can find no published constructions of any (released following the computations with this research had been performed) validates the decision of these revised guidelines for the ArNH relationship (CSCH3 comprising model arylamide substances) for the ArNH dihedral for the arylamide substance in this research (COCH3 useful group) . Liu demonstrated which the potential energy profile from the ArNH dihedral comes after the same dihedral design for model substances filled with the COCH3 and CSCH3 useful groups bonded towards the benzamide band, with barrier levels within 1 kcal mol?1 for both substances . MD Simulations of p53 and Small-molecule Inhibitors of HDM2 To be able to determine whether our molecular dynamics process is suitable for simulating the (where p1 may be the stage described by C Met 62), as well as the range described by (p2Cp0)(where p2 may be the stage described by C Val 93). Cluster Evaluation of Arylamide Conformations The Gromacs 4.0.4 system g_cluster was used to create clusters with the very least RMSD of just one 1.5 ?. The clustering technique takes a arbitrary structure through the pool of constructions and recognizes all structures inside the RMSD threshold, determining a cluster. The framework with neighbors from the biggest cluster can be chosen as the group middle, and this framework and most of its cluster people ML 786 dihydrochloride are taken off the pool. The task can be repeated before pool of constructions can be empty and ML 786 dihydrochloride everything structures are designated to clusters . Cluster size (amount of people of every cluster), and cluster regular membership was generated for the pooled conformations used at 10 ps intervals between 3 ns and 20 ns from 5 anti-parallel (1, 2, 3, 7, 8) beginning conformations. 3 ns can be chosen as the stage where temp, pressure and additional brief timescale fluctuations got equilibrated. The same was repeated for the 4 parallel (4, 9, 10, 11) beginning conformations. Outcomes and Dialogue We 1st address the suitability from the MMFF94, Autodock and GAFF push areas for modeling arylamide substances and using molecular docking to create and Prabhakaran by Vemparala Furthermore, QM computations showed how the torsion angle is approximately 6 kcal/mol higher in energy than its most steady energy minimum, therefore an improbable conformation . Using the guidelines through the thioether substance previously researched by Vemparala the ArNH and ArCO torsion conformational choices are described a lot more accurately. Certainly, the ML 786 dihydrochloride usage of these thioether guidelines instead of ether guidelines continues to be validated by a report published. | en | apollo | train |
###### **_T REATMENT_**
Exogenous surfactant administration.**Differential diagnosis:** Transient tachypnea of the newborn (TTN—self-resolving, relatively benign respiratory distress associated with pulmonary edema), bacterial pneumonia, congenital heart disease.Hyaline membranes are also seen (note that neonatal RDS was formerly called hyaline membrane disease).###### **N EONATAL (INFANT) RESPIRATORY DISTRESS SYNDROME**
Neonatal respiratory distress syndrome (RDS) is the most common cause of respiratory failure in newborns and the most common cause of death in premature infants. It results from a deficiency of surfactant in immature lungs, leading to atelectasis due to increased surface tension in the air-liquid interface, mismatch, and shunting. Predisposing factors include prematurity, maternal diabetes mellitus, and delivery by cesarean section. Incidence and mortality decrease dramatically with gestational age, with the most severe disease seen prior to the alveolar stage of lung development. ###### **_P RESENTATION_**
Dyspnea and tachypnea. ###### **_D IAGNOSIS_**
**Physical exam:** Infants may appear cyanotic, and crackles can be heard on auscultation. Fetal pulmonary maturity can be assessed by measuring the **ratio of surfactant lecithin to sphingomyelin in the amniotic fluid. ** A ratio of 2:1 or greater indicates lung maturity. **Chest film:** Low lung volumes, diffuse ground-glass appearance with air bronchograms. **Arterial blood gas testing:** Hypoxemia, hypocapnia, with a large A-a gradient. Hypoxemia that is refractory to supplemental O2 due to shunting. **Pathology:** Lungs are heavier than normal, with alternating atelectatic areas and dilated alveoli. The pulmonary vessels are engorged, with leakage of fluid into the alveoli. Hyaline membranes are also seen (note that neonatal RDS was formerly called hyaline membrane disease). **Differential diagnosis:** Transient tachypnea of the newborn (TTN—self-resolving, relatively benign respiratory distress associated with pulmonary edema), bacterial pneumonia, congenital heart disease. ###### **_T REATMENT_**
Exogenous surfactant administration.Inhaled nitric oxide.Antenatal maternal corticosteroid therapy to promote surfactant production.###### **_P ROGNOSIS_**
Mortality rates have improved dramatically with the use of exogenous surfactant but remain over 10%.Bronchopulmonary dysplasia may develop due to treatment with high-concentration O2 and mechanical ventilation. | en | apollo | train |
Pseudomonas aeruginosa deficient in 8-oxodeoxyguanine repair system shows a high frequency of resistance to ciprofloxacin.
The 8-oxodeoxyguanine (8-oxodG) repair system participates in the prevention and correction of mutations generated by oxidative DNA damage in prokaryotes and eukaryotes. In this study, we report that Pseudomonas aeruginosa strains deficient in this repair mechanism by inactivation of the mutT, mutM and mutY genes generate a high frequency of cells resistant to the antibiotic ciprofloxacin. In the mutT strain, the increase in ciprofloxacin resistance achieved at threefold minimal inhibitory concentration was about 1600-fold over the wild-type (WT) level, similar to the frequency achieved by the mismatch repair-deficient mutS strain. Molecular analysis of WT, mutT and mutY clones resistant to ciprofloxacin indicated that the nfxB gene was mutated in the majority of the cases, while mutS-derived resistant clones were mainly mutated in gyrA and parC genes. Cell viability analysis after treatment with paraquat or hydrogen peroxide indicated that 8-oxodG repair-deficient strains were considerably more susceptible to oxidative stress than the parental strain. Finally, it is shown that the ciprofloxacin resistance frequency of WT and repair-deficient strains increased significantly after cell exposure to paraquat. Thus, oxidative stress is strongly implicated in the emergence of ciprofloxacin-resistant mutants in P. aeruginosa, and the 8-oxodG repair pathway plays an important role in the prevention of these mutations. | en | apollo | train |
If you become infected with the flu after getting vaccinated, your body activates an immune response that stops you from becoming ill. Although, this can trigger the virus to change into a slightly different form - one that may be more infectious.
A novel investigation from MIT reveals the mechanism responsible for this phenomenon, known as antigenic drift. The study was funded by the National Institutes of Health and the Singapore-MIT Alliance for Research and Technology and appears in the December 19 online edition of Scientific Reports, an open-access journal published by Nature.
The chain of amino acids that create viral protein hemagglutinin was examined by the researchers, led by Ram Sasisekharan. The team identified which amino acids are most likely to encounter mutations that enhance the virus' ability to infect novel hosts.
"This knowledge could help flu-vaccine designers produce vaccines that don't induce the evolution of fitter viruses", explained Sasisekharan, The Edward Hood Taplin Professor of Health Sciences and Technology and Biological Engineering at MIT, director of the Harvard-MIT Division of Health Sciences and Technology and senior author of the report.
As novel strains of influenza arise constantly throughout the world, the World Health Organization finds novel strains that should be included in the seasonal influenza vaccine, which is reformulated each year.
Influenza vaccines provoke creation of antibodies that target a part of the hemagglutinin (HA) protein known as the antigenic site. In 2009, Sasisekharan and investigators at the National Institute of Allergy and Infectious Diseases (NIAID) revealed that viruses can evolve into a slightly changed strain when it comes across such antibodies. This novel strain can then spread to non-vaccinated individuals.
Some novel strains are more infectious because they attach stronger to receptors found on the surfaces of cells in the respiratory tract of potential flu victims. This discovery baffled investigators as the antigenic site, where the mutations took place, is a long way from the HA site where the receptor attachment occurs.
The team decided to solve the mystery by examining the interactions between the amino acids that create viral hemagglutinin.
Like all proteins, HA is constructed by a long network of amino acids. These networks mutate into complex structures determined by the interactions between amino acids. The researchers used a method called network analysis in order to analyze how each amino acid interacts with every other amino acid in the protein, which is determined by electric charges as well we additional properties of atoms within the amino acids.
The resulting model provided data on how powerfully each amino acid is connected to other amino acids in the protein. Focusing on amino acids in the antigenic site, the team discovered that the more strongly they were connected to amino acids in the receptor-binding region, the more likely the amino acids were to change receptor-binding affinity upon mutating. In addition they found that amino acids that were weakly connected in the antigen region did not change receptor-binding upon mutation. These findings offer new insight into the mechanism of how selection pressure as a result of vaccination could contribute to the virus evolving into a more infectious strain by generating better-binding HA proteins.
"Incomplete vaccination could be causing a lot of these problems and therefore effective vaccinations are key to limiting drift.
Now that there is a way to predict which amino acids are most likely to mutate into a more infectious form, vaccine designers could create vaccines that don't provoke such mutations. This understanding of the relationship between the antigenic site and the receptor-binding site could be added to the current methods of vaccine selection and vaccine designs to limit drift."
Further examinations of circulating influenza HA sequences can possibly speed up and assist in the design of ideal vaccines for each flu season.
Rattue, Grace. "How Influenza Evolves - And How To Stop It From Doing So." Medical News Today. MediLexicon, Intl., 20 Dec. 2011. Web. | en | apollo | train |
ME is an illness and stands for Myalgic Encephalopathy – which is a bit of a mouthful, but basically means muscle (myalgic) and brain (encephalitic) symptoms. ME is also known as Chronic Fatigue Syndrome (CFS), and also Post-Viral Fatigue Syndrome (PVFS) because it often follows on from a viral infection. Doctors prefer to call it CFS, patients prefer ME, so to please both sides we call it ME/CFS.
Often it will start after an ordinary viral infection, such as flu, chicken-pox, glandular fever. It is possible for an apparently healthy person to come down with a viral infection and develop full-blown ME immediately. In other cases, there may be no obvious viral ‘trigger’ at all, and the person may ‘slide’ into the illness over a period of months or even years. Older people tend to develop ME in this way.
It is not known exactly what causes ME, but research has revealed a number of abnormalities in ME sufferers. Findings include evidence of persisting viral infection, abnormalities in skeletal and cardiac muscle structure and function, and evidence of damage to nervous tissue.
As its name suggests, ME mainly affects the muscles and the head; muscle symptoms include severe fatigue on exercise, muscle pain and spasms. It’s important to appreciate that the kind of fatigue experienced by many ME sufferers is quite different from the straightforward ‘tiredness’ most normal people experience. ME sufferers have likened the fatigue to being ‘totally drained’ of energy, and unlike many other illnesses, exercise may make things worse. Any physical activity - such as walking up or down the stairs – may cause pain and discomfort, and even cause a major relapse. Sometimes, you will see ME sufferers apparently able to do quite normal things physically, yet complaining of terrible fatigue and muscle problems. What you haven’t seen is the price they pay afterwards for their physical exertion – perhaps days in bed recovering. Some sufferers have learnt how to ‘save up’ energy to enable them to do things, and they know exactly how much they can do, and what price they may have to pay afterwards. It is as though their muscles have a limited ‘energy supply’. When this runs out, the muscles stop functioning and need time to ’recharge’. The head symptoms experienced by ME sufferers include: headaches, dizziness, ‘swimmy’ feelings and perhaps most difficult of all to handle, loss of concentration and short-term memory. ME sufferers will often forget things you have just told them, and will find it hard to take in new information – especially if it’s complicated. These problems will tend to be worse when fatigued, and mental exertion as well as physical may be exhausting for people with ME. These are not the only symptoms experienced in ME - sufferers will often feel ‘ill all over’ and therefore experience many flu-like symptoms; nausea, shivering, fever and aching joints. They may over-react to heat and cold. Digestive problems are also common, such as constipation, diarrhoea, gas, bloating and pain.
Many people have allergies or intolerances to food or substances in the environment - you may have come across people who are on restricted diets (such as gluten-free). Similarly, some people with ME find that things like exhaust fumes, perfume or ordinary household chemicals affect them very badly.
Is this a ‘new’ disease?
ME has been around, under different names, for at least a century. It was probably seen before then, but in far fewer people. So it isn’t a ‘new’ disease, but rather a newly recognised disease. There are around 250,000 people in the UK with this illness, so it is fairly common.
How many people have ME/CFS?
Population prevalence is 0.4% (250,000 nationally—12,000 in the Northern region).
What kind of people have ME/CFS?
ME strikes people of all ages (including very young children and very old people), and all social classes. There do seem to be more women than men with ME (for women it's twice as common), and the reasons for this are not known. Most of them had an active, healthy lifestyle before becoming ill, and would like nothing more than to return to it.
Many people experience a period of what is known as ‘post-viral debility’ - after having flu for instance. This post-viral fatigue may feature many of the symptoms of ME, but rarely lasts more than a few weeks. In a minority of cases, it may last longer, and it is generally agreed that if it lasts longer than four months, and the symptoms correspond, then it may be considered to be ME.
How do you forecast the outcome?
Prognosis is extremely variable - early intervention and positive clinical input is likely to improve the outcome.
What specialist help is there for ME/CFS?
Some local specialist teams are available and referral can be made for benefits assessment, therapy services, or to confirm a diagnosis. Guidelines recommend referral at 4 months since on-set of symptoms. Diagnosis should be considered after 4-6 weeks of onset of abnormal fatigue (please note that seeing a GP may come significantly later than symptom onset).
How do people get a referral?
Referrals are made through your GP following strict referral criteria. All GPs have received information about the clinical teams, but should anyone have any problems, contact ME North East.
How ill is a person with ME/CFS?
Like any other illness, ME affects everyone differently, and some are more affected than others. The most severely affected sufferers are completely bedridden, in constant pain and unable to attend to normal bodily functions. Others may be in wheelchairs much of the time to allow them to get out and about and do normal things like shopping and visiting friends. Those who are quite mildly affected may still be working or going to school full time – and appear OK - but may be having to rest every evening and weekend just to maintain their energy levels at work or school. Even quite severely affected sufferers may look healthy – be assured, they’re not. The same applies in other illnesses such as Multiple Sclerosis. ME is a very variable illness – it does tend to following a course of ‘relapse and remit’, and it may vary from week to week, day to day, or even hour to hour.
How should I deal with a person with ME/CFS?
The most important thing to remember, is that ME sufferers get very tired, and it may be disastrous for them not to rest when they need to, and for as long as they need to. Also, ‘normal’ activities like conversation, which require very little energy from a healthy person, may be very exhausting for someone with ME. If an ME sufferer tells you they have to rest, or they cannot carry on talking to you, or they want you to leave, respect their need. It may seem selfish, but be assured, it is absolutely necessary. Similarly, if a sufferer tells you they are not physically capable of doing something (e.g. walking to the corner shop) - believe them. What they may mean is that they might be able to do whatever it is, but know that they will suffer for it afterwards.. Sometimes, an ME sufferer may appear not to be taking in what you are saying to them. These problems of concentration and memory are symptoms of the illness, and will vary according to how ill the person is feeling, and how exhausted they are. Slow down your conversation, and if necessary say or explain things to the sufferer a second time, without being patronising.
The best you can do is be there for the person you care for. Give plenty of TLC, but most important — be patient! | en | apollo | train |
Cd(2+)-induced cytochrome c release in apoptotic proximal tubule cells: role of mitochondrial permeability transition pore and Ca(2+) uniporter.
Cd(2+) induces apoptosis of kidney proximal tubule (PT) cells. Mitochondria play a pivotal role in toxic compound-induced apoptosis by releasing cytochrome c. Our objective was to investigate the mechanisms underlying Cd(2+)-induced cytochrome c release from mitochondria in rat PT cells. Using Hoechst 33342 or MTT assay, 10 muM Cd(2+) induced approximately 5-10% apoptosis in PT cells at 6 and 24 h, which was associated with cytochrome c and apoptosis-inducing factor release at 24 h only. This correlated with previously described maximal intracellular Cd(2+) concentrations at 24 h, suggesting that elevated Cd(2+) may directly induce mitochondrial liberation of proapoptotic factors. Indeed, Cd(2+) caused swelling of energized isolated kidney cortex mitochondria (EC(50) approximately 9 muM) and cytochrome c release, which were independent of permeability transition pore (PTP) opening since PTP inhibitors cyclosporin A or bongkrekic acid had no effect. On the contrary, Cd(2+) inhibited swelling and cytochrome c release induced by PTP openers (PO(4)(3-) or H(2)O(2)+Ca(2+)). The mitochondrial Ca(2+) uniporter (MCU) played a key role in mitochondrial damage: 1) MCU inhibitors (La(3+), ruthenium red, Ru360) prevented swelling and cytochrome c release; and 2) ruthenium red attenuated Cd(2+) inhibition of PO(4)(3-)-induced swelling. Using the Cd(2+)-sensitive fluorescent indicator FluoZin-1, Cd(2+) was also taken up by mitoplasts. The aquaporin inhibitor AgNO(3) abolished Cd(2+)-induced swelling of mitoplasts. This could be partially mediated by activation of the mitoplast-enriched water channel aquaporin-8. Thus cytosolic Cd(2+) concentrations exceeding a certain threshold may directly cause mitochondrial damage and apoptotic development by interacting with MCU and water channels in the inner mitochondrial membrane. | en | apollo | train |
Unilateral ureteral obstruction causes gut microbial dysbiosis and metabolome disorders contributing to tubulointerstitial fibrosis.
Chronic kidney disease (CKD) increases the risk and prevalence of cardiovascular disease (CVD) morbidity and mortality. Recent studies have revealed marked changes in the composition of the microbiome and the metabolome and their potential influence in renal disease and CVD via the accumulation of microbial-derived uremic toxins. However, the effect of unilateral ureteral obstruction (UUO) on the gut microbiome and circulating metabolites is unknown. Male Sprague-Dawley rats were randomized to UUO and sham-operated control groups. Renal histology, colonic microbiota, and plasma metabolites were examined two weeks later. We employed 16S rRNA sequence and untargeted metabolomic analyses to explore the changes in colonic microbiota and plasma metabolites and their relationship with tubulointerstitial fibrosis (TIF). The UUO rats exhibited tubular atrophy and dilatation, interstitial fibrosis and inflammatory cell infiltration in the obstructed kidney. UUO rats showed significant colonic enrichment and depletion of genera. Significant differences were identified in 219 plasma metabolites involved in lipid, amino acid, and bile acid metabolism, which were consistent with gut microbiota-related metabolism. Interestingly, tryptophan and its metabolites kynurenine, 5-hydroxytryptophan and 5-hydroxytryptamine levels, which were linked with TIF, correlated with nine specific genera. Plasma tryptophan level was positively correlated with Clostridium IV, Turicibacter, Pseudomonas and Lactobacillales, and negatively correlated with Oscillibacter, Blautia, and Intestinimonas, which possess the genes encoding tryptophan synthase (K16187), indoleamine 2,3-dioxygenase (K00463) and tryptophan 2,3-dioxygenase (K00453) and their corresponding enzymes (EC:1.13.11.52 and EC:1.13.11.11) that exacerbate TIF. In conclusion, UUO results in profound changes in the gut microbiome and circulating metabolites, events that contribute to the pathogenesis of inflammation and TIF. | en | apollo | train |
PVP formulated fullerene (C60) increases Rho-kinase dependent vascular tissue contractility in pregnant Sprague Dawley rats.
Pregnancy is a unique physiological state, in which C60 fullerene is reported to be distributed in both maternal and fetal tissues. Tissue distribution of C60 differs between pregnant and non-pregnant states, presumably due to functional changes in vasculature during pregnancy. We hypothesized that polyvinylpyrrolidone (PVP) formulated C60 (C60/PVP) increases vascular tissue contractility during pregnancy by increasing Rho-kinase activity. C60/PVP was administered intravenously to pregnant and non-pregnant female Sprague Dawley rats. Vascular responses were assessed using wire myography 24h post-exposure. Increased stress generation was observed in uterine artery, thoracic aorta and umbilical vein. Rho-Rho-kinase mediated force maintenance was increased in arterial segments from C60/PVP exposed pregnant rats when compared to PVP exposed rats. Our findings suggest that intravenous exposure to C60/PVP during pregnancy increases vascular tissue contractility of the uterine artery through elements of Rho-Rho-kinase signaling during late stages of pregnancy. | en | apollo | train |
First-dose ChAdOx1 and BNT162b2 COVID-19 vaccines and thrombocytopenic, thromboembolic and hemorrhagic events in Scotland.
Reports of ChAdOx1 vaccine-associated thrombocytopenia and vascular adverse events have led to some countries restricting its use. Using a national prospective cohort, we estimated associations between exposure to first-dose ChAdOx1 or BNT162b2 vaccination and hematological and vascular adverse events using a nested incident-matched case-control study and a confirmatory self-controlled case series (SCCS) analysis. An association was found between ChAdOx1 vaccination and idiopathic thrombocytopenic purpura (ITP) (0-27 d after vaccination; adjusted rate ratio (aRR) = 5.77, 95% confidence interval (CI), 2.41-13.83), with an estimated incidence of 1.13 (0.62-1.63) cases per 100,000 doses. An SCCS analysis confirmed that this was unlikely due to bias (RR = 1.98 (1.29-3.02)). There was also an increased risk for arterial thromboembolic events (aRR = 1.22, 1.12-1.34) 0-27 d after vaccination, with an SCCS RR of 0.97 (0.93-1.02). For hemorrhagic events 0-27 d after vaccination, the aRR was 1.48 (1.12-1.96), with an SCCS RR of 0.95 (0.82-1.11). A first dose of ChAdOx1 was found to be associated with small increased risks of ITP, with suggestive evidence of an increased risk of arterial thromboembolic and hemorrhagic events. The attenuation of effect found in the SCCS analysis means that there is the potential for overestimation of the reported results, which might indicate the presence of some residual confounding or confounding by indication. Public health authorities should inform their jurisdictions of these relatively small increased risks associated with ChAdOx1. No positive associations were seen between BNT162b2 and thrombocytopenic, thromboembolic and hemorrhagic events. | en | apollo | train |
Without treatment, the diarrhea can last for months.**Giardia:** A small parasite that causes diarrhea.Surgery is necessary only if they become very large or painful.Most eventually disappear.These outpouchings of the joint capsule probably result from trauma.**Ganglion:** A cyst (smooth circular swelling filled with thick fluid) usually occurring on the back of the wrist.Usually clears in 1 to 4 weeks. Early treatment with steroids may be helpful. **Bronchiolitis:** An infection of the bronchioles (small air passages) occurring in the first 2 years of life. The main symptoms are wheezing, rapid breathing, cough, runny nose, and fever. Caused by the respiratory syncytial virus. **Cat scratch fever:** A swollen lymph node caused by the scratch of a young cat. Usually lasts several months. A bacterium called _Bartonella henselae_ has been identified as the infectious agent. **Chlamydia:** A germ that causes urethral or vaginal infections. Spread by sexual contact. Can also cause eye infections or pneumonia in newborns by contact at birth. **Chondromalacia of the patella:** A roughening of the underside of the kneecap causing knee pain in adolescents. Often due to excessive deep knee bends or running upstairs. Helped by rest and quadriceps-strengthening exercises. **Cold panniculitis:** A lump of frozen fat tissue. Usually occurs in the fatty cheeks of infants less than 1 year of age. Due to prolonged contact with ice, Popsicles, cold metal, or cold weather. The lump can last 2 weeks, and occasionally the overlying skin turns red. **Creeping eruption:** A localized itchy rash consisting of a wavy red line. Caused by a tunneling young hookworm, from skin contact with dog or cat excrement. Common along the Atlantic coast. Lasts 1 to 2 months without treatment. **Ganglion:** A cyst (smooth circular swelling filled with thick fluid) usually occurring on the back of the wrist. These outpouchings of the joint capsule probably result from trauma. Most eventually disappear. Surgery is necessary only if they become very large or painful. **Giardia:** A small parasite that causes diarrhea. Without treatment, the diarrhea can last for months.The causes are many.**Gonorrhea:** A bacterium that can cause genital infections.Spread by sexual contact.Eye infections of newborns are usually prevented by routine application of silver nitrate or antibiotic eyedrops.**Granuloma annulare:** Rings of little bumps, usually found at the ankle.The overlying skin looks normal.The cause is unknown.Clears spontaneously in 2 years. | en | apollo | train |
Conditional Demyelination and Remyelination in a Transgenic Xenopus laevis.
Multiple sclerosis (MS) is the first cause of acquired disability progression in the young adult. Pathology of MS associates inflammation, demyelination, and neurodegeneration. The development of immunotherapies, by reducing the relapse rate, has profoundly impacted short-term prognosis and patients' quality of life. These anti-inflammatory medications, however, have not proven to be sufficient to prevent long-term disability progression, resulting from axonal transection and neuronal damage, consequences of prolonged demyelination. Promoting remyelination is therefore a key therapeutic strategy to limit handicap progression, and represent the major therapeutic challenge in MS. Here we present a simple, rapid, and cost-effective experimental model developed in Xenopus laevis to screen in vivo molecules promoting remyelination. | en | apollo | train |
Effect of Dopamine D<sub>2</sub> Receptor Antagonists on [<sup>18</sup>F]-FEOBV Binding.
The interaction of dopaminergic and cholinergic neurotransmission in, e.g., Parkinson's disease has been well established. Here, D<sub>2</sub> receptor antagonists were used to assess changes in [<sup>18</sup>F]-FEOBV binding to the vesicular acetylcholine transporter (VAChT) in rodents using positron emission tomography (PET). After pretreatment with either 10 mg/kg haloperidol, 1 mg/kg raclopride, or vehicle, 90 min dynamic PET scans were performed with arterial blood sampling. The net influx rate (<i>K</i><sub>i</sub>) was obtained from Patlak graphical analysis, using a metabolite-corrected plasma input function and dynamic PET data. [<sup>18</sup>F]-FEOBV concentration in whole-blood or plasma and the metabolite-corrected plasma input function were not significantly changed by the pretreatments (adjusted <i>p</i> > 0.07, Cohen's <i>d</i> 0.28-1.89) while the area-under-the-curve (AUC) of the parent fraction of [<sup>18</sup>F]-FEOBV was significantly higher after haloperidol treatment (adjusted <i>p</i> = 0.022, Cohen's <i>d</i> = 2.51) than in controls. Compared to controls, the AUC of [<sup>18</sup>F]-FEOBV, normalized for injected dose and body weight, was nonsignificantly increased in the striatum after haloperidol (adjusted <i>p</i> = 0.4, Cohen's <i>d</i> = 1.77) and raclopride (adjusted <i>p</i> = 0.052, Cohen's <i>d</i> = 1.49) treatment, respectively. No changes in the AUC of [<sup>18</sup>F]-FEOBV were found in the cerebellum (Cohen's <i>d</i> 0.63-0.74). Raclopride treatment nonsignificantly increased <i>K</i><sub>i</sub> in the striatum 1.3-fold compared to control rats (adjusted <i>p</i> = 0.1, Cohen's <i>d</i> = 1.1) while it reduced <i>K</i><sub>i</sub> in the cerebellum by 28% (adjusted <i>p</i> = 0.0004, Cohen's <i>d</i> = 2.2) compared to control rats. Pretreatment with haloperidol led to a nonsignificant reduction in <i>K</i><sub>i</sub> in the striatum (10%, adjusted <i>p</i> = 1, Cohen's <i>d</i> = 0.44) and a 40-50% lower <i>K</i><sub>i</sub> than controls in all other brain regions (adjusted <i>p</i> < 0.0005, Cohen's <i>d</i> = 3.3-4.7). The changes in <i>K</i><sub>i</sub> induced by the selective D<sub>2</sub> receptor antagonist raclopride can in part be quantified using [<sup>18</sup>F]-FEOBV PET imaging. Haloperidol, a nonselective D<sub>2</sub>/σ receptor antagonist, either paradoxically decreased cholinergic activity or blocked off-target [<sup>18</sup>F]-FEOBV binding to σ receptors. Hence, further studies evaluating the binding of [<sup>18</sup>F]-FEOBV to σ receptors using selective σ receptor ligands are necessary. | en | apollo | train |
Oedema does not usually occur because the rate of sodium excretion increases, which prevents more severe sodium retention.Sodium retention leads to hypernatraemia, hypertension and headache.## CLINICAL MANIFESTATIONS
Elevated levels of aldosterone are associated with sodium retention and elimination of potassium.Notify the healthcare provider if experiencing postprandial heartburn or epigastric pain that is not relieved by antacids. 7. See an eye specialist yearly to assess possible development of cataracts. 8. Use safety measures, such as getting up slowly from the bed or a chair, and use good lighting to avoid accidental injury. 9. Maintain good hygiene practices and avoid contact with people with colds or other contagious illnesses to avoid infection. 10. Inform all healthcare providers about long-term corticosteroid use. 11. May need increased doses of corticosteroids in times of physical and emotional stress. 12. Never abruptly stop the corticosteroids as this could lead to Addisonian crisis and possible death. # Hyperaldosteronism
## AETIOLOGY AND PATHOPHYSIOLOGY
**Hyperaldosteronism** is characterised by excessive aldosterone secretion. The main effects of aldosterone are sodium retention and potassium and hydrogen ion excretion. Thus, the hallmark of this disease is hypertension with hypokalaemic alkalosis. _Primary hyperaldosteronism (PA)_ is most commonly caused by a small solitary adrenocortical adenoma. Occasionally, multiple lesions are involved and are associated with bilateral adrenal hyperplasia. PA affects both sexes equally and occurs most frequently between 30 and 49 years of age. It is estimated that approximately 1% of cases of hypertension are caused by PA. _Secondary hyperaldosteronism_ occurs in response to a non-adrenal cause of elevated aldosterone levels, such as renal artery stenosis, renin-secreting tumours and chronic kidney disease. ## CLINICAL MANIFESTATIONS
Elevated levels of aldosterone are associated with sodium retention and elimination of potassium. Sodium retention leads to hypernatraemia, hypertension and headache. Oedema does not usually occur because the rate of sodium excretion increases, which prevents more severe sodium retention.## DIAGNOSTIC STUDIES
The diagnosis of hyperaldosteronism should be suspected in all hypertensive patients with hypokalaemia who are not being treated with diuretics.PA is associated with elevated plasma aldosterone levels, elevated sodium levels, decreased serum potassium levels and decreased plasma renin activity.Adenomas are localised by means of a CT scan or MRI. | en | apollo | train |
Identification of Patients Affected by Mitral Valve Prolapse with Severe Regurgitation: A Multivariable Regression Model.
<i>Background</i>. Mitral valve prolapse (MVP) is the most common cause of severe mitral regurgitation. Besides echocardiography, up to now there are no reliable biomarkers available for the identification of this pathology. We aim to generate a predictive model, based on circulating biomarkers, able to identify MVP patients with the highest accuracy. <i>Methods</i>. We analysed 43 patients who underwent mitral valve repair due to MVP and compared to 29 matched controls. We assessed the oxidative stress status measuring the oxidized and the reduced form of glutathione by liquid chromatography-tandem mass spectrometry method. Osteoprotegerin (OPG) plasma levels were measured by an enzyme-linked immunosorbent assay. The combination of these biochemical variables was used to implement several logistic regression models. <i>Results</i>. Oxidative stress levels and OPG concentrations were significantly higher in patients compared to control subjects (0.116 ± 0.007 versus 0.053 ± 0.013 and 1748 ± 100.2 versus 1109 ± 45.3 pg/mL, respectively; <i>p</i> < 0.0001). The best regression model was able to correctly classify 62 samples out of 72 with accuracy in terms of area under the curve of 0.92. <i>Conclusions</i>. To the best of our knowledge, this is the first study to show a strong association between OPG and oxidative stress status in patients affected by MVP with severe regurgitation. | en | apollo | train |
It is usually sexually transmitted, although contact with an infected ulcer (e.g., by a doctor not wearing gloves) can cause spread._**Treponema pallidum**_ causes **syphilis**.##### Treponema
Rash on the palms and soles: think syphilis, Rocky Mountain spotted fever, or hand-foot-and-mouth disease (Coxsackie A virus).Both _Bartonella_ species can also cause bacteremia, endocarditis, and an AIDS-related condition known as bacillary angiomatosis in which small blood vessels proliferate and look like red raised lesions on the skin (can be confused with Kaposi sarcoma). _**Coxiella burnetii**_ causes **Q fever**. The bacteria are unique from other rickettsial diseases in that they form endospores, conferring several unique properties: ability to survive (though not replicate) outside a host cell; resistance to heat and drying; and transmission by aerosolized tic/cow feces rather than needing an arthropod vector. Because of this method of infection, _C. burnetii_ causes a mild atypical pneumonia along with fever and sweats 2 to 3 weeks after infection (the only rickettsial infection to cause pneumonia). _C. burnetii_ can also cause granulomatous hepatitis and culture-negative endocarditis. _**Ehrlichia chaffeensis**_ is transmitted by dog ticks and causes **ehrlichiosis** , which is similar to Rocky Mountain spotted fever but without rash. Two other species can cause ehrlichiosis ( _E. ewingii_ and _Anaplasma phagocytophilum_ ). #### Gram-Negative Spirals
_Treponema pallidum_
Subspecies _endemicum_
Subspecies _carateum_
_Borrelia burgdorferi_
_Leptospira interrogans_
Spirochetes are very small, spiral-shaped bacteria that spin to achieve propulsion. Because they are so small, special techniques are used to view them (i.e., dark-field microscopy). ##### Treponema
Rash on the palms and soles: think syphilis, Rocky Mountain spotted fever, or hand-foot-and-mouth disease (Coxsackie A virus). _**Treponema pallidum**_ causes **syphilis**. It is usually sexually transmitted, although contact with an infected ulcer (e.g., by a doctor not wearing gloves) can cause spread.5-25).In **primary** syphilis, a painless chancre develops 3 to 6 weeks after initial contact at the site of infection (a painless ulcer with a punched-out base) along with regional lymphadenopathy.This resolves over 4 to 6 weeks (but this doesn't mean it's cured!). | en | apollo | train |