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Macroscopic Models for Human Circadian Rhythms. Mathematical models have a long and influential history in the study of human circadian rhythms. Accurate predictive models for the human circadian light response have been used to study the impact of a host of light exposures on the circadian system. However, generally, these models do not account for the physiological basis of these rhythms. We illustrate a new paradigm for deriving models of the human circadian light response. Beginning from a high-dimensional model of the circadian neural network, we systematically derive low-dimensional models using an approach motivated by experimental measurements of circadian neurons. This systematic reduction allows for the variables and parameters of the derived model to be interpreted in a physiological context. We fit and validate the resulting models to a library of experimental measurements. Finally, we compare model predictions for experimental measurements of light levels and discuss the differences between our model's predictions and previous models. Our modeling paradigm allows for the integration of experimental measurements across the single-cell, tissue, and behavioral scales, thereby enabling the development of accurate low-dimensional models for human circadian rhythms.

Dengue virus type 2 vaccine: reactogenicity and immunogenicity in soldiers. A live dengue virus type 2 (dengue-2) vaccine (PR-159/S-1) was tested for reactogenicity and immunogenicity in a placebo-controlled, double-blind clinical trial involving 98 soldiers. Seroconversion rates based on the development of neutralizing antibody to dengue-2 were 90% in 70 recipients with immunity to yellow fever and 61% in 28 vaccinees without such immunity (P less than .01). Peak titers of neutralizing antibody were three times higher in recipients with antibody to yellow fever virus and persisted in most for at least 18 months. Individuals seroconverting to the vaccine virus more frequently experienced systemic symptoms than those who received placebo (P less than .02). Future users of this dengue-2 vaccine may wish to employ immunization schedules that include preliminary immunization against yellow fever and must be prepared to accept mild vaccine-related symptoms in some recipients.

Protein tyrosine kinase-mediated pathways in G protein-coupled receptor signaling. Abundant evidence has indicated that protein tyrosine kinases (PTKs) convey signals from G protein-coupled receptors (GPCRs) to regulate cell proliferation, migration, adhesion, and potentially cellular transformation. Molecular mechanisms by which PTKs regulate such diverse effects in GPCR signaling are not well understood. Recently, an unifying theme has emerged where both growth factors and GPCRs utilize protein tyrosine kinase activity and the highly conserved Ras/MAP kinase pathway to control mitogenic signals. Additionally, PTKs are also involved in the regulation of signal transmission from GPCRs to activation of the JNK/SAPK kinase pathway. Furthermore novel insights in chemokine receptor-activated PTKs and their role in mediating cell functions are discussed in this review.

Intramolecular DNA Coiling Mediated by a Metallo-Supramolecular Cylinder. In the groove! A tetracationic supramolecular cylinder, [Fe2 L3 ]4+ (L=C25 H20 N4 ), with a triple-helical architecture is just the right size to fit into the major groove of DNA and too big to fit into the minor groove. NMR spectroscopic data confirm that the cylinder binds in the major groove. Linear dichroism shows that very low loadings of [Fe2 L3 ]4+ have a dramatic bending effect on the DNA and atomic force microscopy images show that this is an intramolecular effect resulting in coils of DNA.

[Serious video games in pediatrics]. Playing video games has been associated with several negative effects in children. However, serious games, which are video games designed for a primary purpose other than pure entertainment, should not be neglected by pediatricians. In the field of public health, some serious games are a means to decrease drug consumption and improve sexual health behavior in adolescents. In schools, serious games can be used to change students' perception of the disease of one of their classmates, or to train students on basic life support. Serious games are also used with patients: they can distract them from a painful procedure, increase their compliance to treatments, or participate in their rehabilitation. Finally, serious games allow healthcare professionals to train on the management of various medical situations without risk. For every field of application, this review presents the rationale of the use of video games, followed by concrete examples of video games and the results of their scientific evaluation.

Anti-interleukin-9 antibody treatment inhibits airway inflammation and hyperreactivity in mouse asthma model. Numerous in vitro and in vivo studies in both animals and patients with asthma have shown that interleukin (IL)-9 is an important inflammatory mediator in asthma. To examine the effects of IL-9 antagonism on airway inflammation, ovalbumin-sensitized BALB/c mice were intravenously given anti-IL-9 antibody or an isotype-matched control antibody 30 minutes before challenge with aerosolized ovalbumin. Airway response to methacholine was measured, and samples of bronchoalveolar lavage fluid (BALF) were obtained 24 hours after the last antigen challenge. Lung tissue was harvested and examined histopathologically. After ovalbumin challenge, there were significant increases in airway hyperreactivity, the numbers of inflammatory cells in lung, and IL-4, IL-5, and IL-13 production in BALF. Treatment with anti-IL-9 antibody significantly prevented airway hyperreactivity in response to methacholine inhalation. Blockade of IL-9 reduced the numbers of eosinophils (0.3 +/- 0.1 x 10(5) and 23.6 +/- 0.5 x 10(5)/ml, anti-IL-9 antibody/control immunoglobulin G) and lymphocytes (0.2 +/- 0.2 x 10(5) and 0.8 +/- 0.1 x 10(5)/ml) in BALF. Anti-IL-9 antibody treatment also reduced the concentrations of IL-4 (from 70.6 +/- 4.6 to 30.8 +/- 5.2 pg/ml), IL-5 (from 106.4 +/- 12 to 54.4 +/- 6.6 pg/ml), and IL-13 (from 44.2 +/- 7.6 to 30.1 +/- 5.5 pg/ml) in BALF. Macrophage-derived cytokine expression in the airways was also decreased by IL-9 blockade. Taken together, our findings emphasize the importance of IL-9 in the pathogenesis of asthma and suggest that blockade of IL-9 may be a new therapeutic strategy for bronchial asthma.

The quantified process approach: an emerging methodology to neuropsychological assessment. An important development in the field of neuropsychological assessment is the quantification of the process by which individuals solve common neuropsychological tasks. The present article outlines the history leading to this development, the Quantified Process Approach, and suggests that this line of applied research bridges the gap between the clinical and statistical approaches to neuropsychological assessment. It is argued that the enterprise of quantifying the process approach proceeds via three major methodologies: (1) the "Satellite" Testing Paradigm: an approach by which new tasks are developed to complement existing tests so as to clarify a given test performance; (2) the Composition Paradigm: an approach by which data on a given test that have been largely overlooked are compiled and subsequently analyzed, resulting in new indices that are believed to reflect underlying constructs accounting for test performance; and (3) the Decomposition Paradigm: an approach which investigates the relationship between test items of a given measure according to underlying facets, resulting in the development of new subscores. The article illustrates each of the above paradigms, offers a critique of this new field according to prevailing professional standards for psychological measures, and provides suggestions for future research.

Increases in glutamate release and phosphoinositide metabolism associated with long-term potentiation and classical conditioning. Long-term potentiation (LTP) is a widely studied model of the kind of activity-dependent modulation of synaptic efficacy which is assumed to provide the physical basis for learning. Whether LTP, in the hippocampus or elsewhere in the brain, does in fact serve such a role is still a matter for debate. One approach to answering this question is to identify physiological or biochemical changes which are common to both learning and LTP; in the hippocampus, for example, one can ask whether the biochemical changes associated with LTP are also associated with learning. In this chapter we summarize the results which we have obtained in a study of glutamate release and phosphoinositide turnover in the dentate gyrus of rats trained in a classical conditioning task. The similarity between the changes occurring after classical conditioning and those associated with LTP is consistent with the hypothesis that LTP is one of the mechanisms by which a neural trace of the learned association is formed. We discuss this interpretation in the light of the observation that classical conditioning does not appear to affect synaptic responses in the hippocampus.

Perinatal self-report of thoughts of self-harm, depressive symptoms, and personality traits: Prospective study of Japanese community women. The aim of this study was to identify women with thoughts of self-harm preceded by suicidal ideation, during the perinatal period, on cluster analysis and to clarify their psychological correlates. A secondary analysis was conducted using the data from a longitudinal study involving 18 obstetric clinics between 2011 and 2012 in Kumamoto Prefecture (Japan). Self-administered questionnaires including demographic data, Edinburgh Postnatal Depression Scale, Temperament and Character Inventory, and the Postnatal Bonding Questionnaire were distributed during the third trimester of pregnancy (wave 1), at 5 days (wave 2), and 1 month postpartum (wave 3). On cluster analysis using the data of participants who answered all observational points, the participants were divided into two groups: cluster 1, normal (n = 201); and cluster 2, thoughts of self-harm (n = 42). Low self-directedness, low cooperativeness, higher anxiety, depression, and lack of affection and anger and rejection towards the baby were associated with cluster 2. The finding that low self-directedness and low cooperativeness were related to the cluster 2 group suggests that immature personality traits may work as a predisposing factor mediating between anxiety, depression and thoughts of self-harm.

Cardiovascular risk in women: the impact of hormone replacement therapy and prospects for new therapeutic approaches. Cardiovascular disease (CVD) is the main cause of death in women. Observational studies of hormone replacement therapy (HT) and data from women with premature ovarian failure have provided support for the principle that estrogen confers protection against the development of CVD in premenopausal women. However, randomised, controlled trials investigating HT in postmenopausal women have failed to demonstrate a benefit of HT in the primary or secondary prevention of CVD. Nevertheless, HT may be effective if targeted at younger perimenopausal women. Research aimed at investigation of the cellular mechanisms of estrogen may result in the discovery of new therapeutic targets that may be able to harness the potential beneficial effects of estrogens in the cardiovascular system. An improved understanding of the distinct processes in the clinical presentation and progress of CVD in women will help develop new targets and enhance the use of current established drugs.

Meaning and medication in the care of treatment-resistant patients. When patients fail to respond to psychopharmacologic treatment, one reason is that the meanings that treatment and/or wellness hold for them are psychologically intolerable. The result may be noncompliance with medications or the repeated emergence of intolerable side-effects, or a defensive attachment to the medications that prevents improvement. When treatment resistance emerges from the level of meaning, it may be that it can be resolved only by addressing it at that level. This paper argues for the importance of integrating psychological understanding into the pharmacologic treatment of treatment-resistant patients, and explores some factors that mitigate against integration. Several treatment vignettes are presented, suggesting ways of working with meaning in relation to pharmacology. Finally, the paper explores benefits of integration for treaters, even if integration does not result in the resolution of treatment resistance.

Endotoxaemia in racehorses following exertion. Endotoxins (lipopolysaccharides-LPS) and anti-endotoxin IgG antibodies were measured in racehorses before and after races of 1,000, 2,000 and 2,800 m. Results show that the mean plasma concentration of endotoxin increased significantly (p less than 0.02) while the anti-LPS IgG concentration decreased significantly (p less than 0.005) in all horses following the races. Pre-race and post-race anti-LPS IgG levels in racing-fit racehorses were significantly higher than in untrained horses (p less than 0.05). The possibility therefore exists that training-induced stress leads to leakage of LPS into the systemic circulation which results in self-immunisation against LPS. The effects of plasma LPS and anti-LPS IgG concentrations on performance of racehorses require further studies.

Adenoviral gene therapy with catalase suppresses experimental optic neuritis. To determine if adenoviral-mediated transfer of the gene for catalase (CAT), the reactive oxygen species scavenger, suppresses experimental optic neuritis. Gene therapy with CAT delivered by an adeno-associated viral vector was previously shown to suppress experimental optic neuritis. Because the transduction of protein expression with recombinant adeno-associated viral vector is relatively slow, taking weeks to reach full levels, we studied the effects of replication-deficient adenovirus containing CAT in suppressing experimental optic neuritis. Transduction with adenovirus occurs within days of inoculation, thus, it may be more applicable for the treatment of patients with acute optic neuritis. Replication-deficient adenovirus containing CAT was injected above the right optic nerve heads of SJL/J mice that were simultaneously sensitized for experimental allergic encephalomyelitis. For controls, the left eyes were injected with the replication-deficient adenovirus without CAT or no virus. The histological effects of CAT on the lesions of experimental allergic encephalomyelitis were measured by computerized analysis of the myelin sheath area (for demyelination), optic disc area (for optic nerve head swelling), the extent of the cellular infiltrate, extravasated serum albumin labeled with immunogold (for disruption of the blood-brain barrier), and the in vivo hydrogen peroxide reaction product. After 1 month, cell-specific catalase activity, evaluated by the quantitation of catalase immunogold, was increased about 2-fold each in endothelia, oligodendroglia, astrocytes, and axons of the CAT-inoculated right optic nerves compared with the control left optic nerves. The increased cellular levels of catalase reduced demyelination by 30%, optic nerve head swelling by 25%, cellular infiltration by 26%, disruption of the blood-brain barrier by 61%, and in vivo levels of hydrogen peroxide by 81%. Adenoviral-mediated gene transfer increased catalase levels in all optic nerve cell types, and it persisted for 1 month after inoculation. The increased cellular levels of catalase suppressed demyelination and blood-brain barrier disruption at the foci in the optic nerve where prior magnetic resonance imaging and histopathologic studies have demonstrated the demyelinating inflammation of experimental and human optic neuritis. Together, they suggest that gene therapy with CAT may be helpful in the treatment of patients with optic neuritis.

Attenuation of the degenerative effects of endothelin-1 on cartilaginous end plate cells by the endothelin receptor antagonist BQ-123 via the Wnt/β-catenin signaling pathway. Endothelin-1 (ET-1) is an inflammatory mediator associated with cartilage end plate (CEP) degeneration in the intervertebral disc (IVD). SOX9 is downregulated during CEP degeneration, along with its targets, collagen II and aggrecan. Wnt/β-catenin signaling is associated with CEP degeneration and a downstream target of SOX9; however, the precise mechanism of CEP degeneration and the role of ET-1 are largely unknown. The purpose of the study was to evaluate the influence of the endothelin-A receptor antagonist, BQ-123, on ET-1-induced effects on cartilaginous end plate cells (CECs) associated with CEP degeneration via the Wnt/β-catenin signaling pathway. The influence of ET-1 on the expression levels of collagen II, aggrecan, and SOX9 in CECs and the effect of BQ-123 in this context were investigated. To establish a model for CEP degeneration, three lumbar discs (L3-L4, L4-L5, and L5-L6 levels) in New Zealand white rabbits were punctured close to the vertebral end plate using a 14G needle. Intervertebral disc degeneration was evaluated by magnetic resonance imaging 4 weeks after vertebral end plate injury. CECs were then isolated from the degenerated CEPs to allow evaluation of the role of ET-1 and BQ-123 and to investigate their effects on the Wnt/β-catenin signaling pathway. The expression of ET-1 in CECs from degenerated CEPs was analyzed by immunofluorescent staining. Changes in the levels of collagen II, aggrecan, and SOX9 were evaluated in CECs by real-time polymerase chain reaction and by Western blotting. The Wnt/β-catenin signaling pathway was also investigated by Western blotting. After 4 weeks, IVDs with vertebral end plate injury exhibited clear signs of disc degeneration. Immunofluorescent staining showed that ET-1 was expressed in the cytoplasm of CECs. Endothelin-1 stimulation significantly inhibited the expression of collagen II, aggrecan, and SOX9 in CECs, whereas BQ-123 increased the levels of these three molecules. In addition, ET-1 stimulation increased the expression of β-catenin, cyclin D1, and Dvl1 in the Wnt/β-catenin signaling pathway of CECs from degenerated discs and reduced the expression of GSK-3β, whereas BQ-123 had the opposite effect. Endothelin-1 can reduce levels of collagen II, aggrecan, and SOX9 in CECs through activation of the Wnt/β-catenin signaling pathway, whereas BQ-123 attenuates these negative effects, highlighting a new molecular mechanism with potential for exploitation for treatment of CEP degeneration.

[Dental service for nursing home residents in The Netherlands--the present situation]. In order to establish adequate dental care for nursing home residents it is important to gather information about the present situation. For that purpose a questionnaire was sent to dentists who were involved in this field of dentistry. The results indicate that dental care for nursing home residents has to be improved. In order to attain this improvement the dental service for nursing home residents should be better organized and research should be carried out with regard to the specific problems arising in treating these patients.

Effects on somatosensory and motor evoked potentials of senile patients using different doses of dexmedetomidine during spine surgery. The aim of this study was to evaluate the effects of different doses of dexmedetomidine (Dex) compounded propofol and fentanyl on intraoperative somatosensory evoked potential (SEP) and motor evoked potential (MEP) monitoring on senile patients. Forty-five patients undergoing elective spinal surgery were randomly divided into three groups: group C, group D1 (Dex, 0.3 μg kg(-1) h(-1)), and group D2 (Dex, 0.8 μg kg(-1) h(-1)). Anesthesia administration: midazolam, propofol, fentanyl, and cisatracurium. Anesthesia maintenance: propofol and fentanyl. No muscle relaxant was used throughout the operation. When muscle relaxation was T 4/T 1 > 75%, SEPs and MEPs were monitored for the baseline. In group D1, Dex (0.3 μg/kg, loading dose) was administered, followed by a 0.3 μg kg(-1) h(-1) infusion of said drug until the end of surgery. In group D2, Dex (0.8 μg/kg, loading dose) was injected, followed by a 0.8 μg kg(-1) h(-1) infusion of said drug. Compared with group C, no significant difference was observed in the amplitude and latency of SEP (P15-N20) waves in groups D1 and D2 (P > 0.05). In groups C and D1, the MEP waveform did not disappear at every stage. In group D2, three patients lost the MEP waveform after the Dex loading dose, while four patients lost it during the Dex infusion stage. A significant difference was observed between groups C and D1. The median time to recover the MEP waveform was 47 min. Dex did not affect SEPs of senile patients, but inhibited MEPs when larger doses were administered.

Heart-type fatty acid-binding protein as a prognostic factor in patients with severe sepsis and septic shock. This study was performed to evaluate whether heart-type fatty acid-binding protein (H-FABP) could predict 28-day mortality in patients with severe sepsis and septic shock. We performed a prospective observational study and included consecutive patients with severe sepsis and septic shock. Patients' demographic data, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and the blood test results including H-FABP concentrations were compared between the 28-day survivors and nonsurvivors. The association between the concentration of H-FABP and survival was analyzed with multivariate logistic regression and Cox proportional hazards regression analyses. The prognostic performance of H-FABP was compared with those of the APACHE II score and albumin using the area under the receiver operating characteristic curve. Of the 99 patients, 38 (38%) died. The mortality rate increased with increasing H-FABP concentration. In multivariate logistic regression analyses, H-FABP greater than 40 ng/mL was an independent predictor of mortality compared with H-FABP less than 7 ng/mL (odds ratios, 9.23; 95% confidence interval, 1.29-65.86). By Cox proportional hazards analysis, H-FABP greater than 40 ng/mL was associated with a 5.57-fold increased risk for death during the 28-day follow-up period (hazard ratio, 5.57; 95% confidence interval, 1.20-25.80). The area under the receiver operating characteristic curve of H-FABP was 0.739 (95% confidence interval, 0.640-0.839), which was comparable with those of the APACHE II score and albumin. The H-FABP was an independent prognostic factor and could be a useful biomarker for 28-day mortality in patients with severe sepsis and septic shock.

Purification of human protease nexin. Addition of several arginine-specific serine proteases to culture medium conditioned by fibroblasts results in the proteases being taken into sodium dodecyl sulfate-stable complexes with a secreted factor termed protease nexin (PN) (Baker, J. B., Low, D. A., Simmer, R. L., and Cunningham, D. D. (1980) Cell 21, 37-45). PN not only inhibits these degradative enzymes but also mediates their binding, internalization, and degradation by the cells (Low, D. A., Baker, J. B., Koonce, W. C., and Cunningham, D. D. (1981) Proc. Natl. Acad. Sci. U. S. A. 78, 2340-2344). Here we describe a simple procedure for purifying milligram quantities of PN from serum-free medium conditioned by human foreskin cells. Accumulation of PN in the medium is increased by using high density microcarrier cultures supplemented with epidermal growth factor and bovine serum albumin. Application of ultrafiltration-concentrated medium to a heparin-Sepharose column followed by extensive washing of the column with buffer containing 0.2 M NaCl and elution with buffer containing 1.0 M NaCl results in the recovery of 60-90% of the input PN in a form that is 90-97% pure. This preparation can be further purified by hydrophobic chromatography on octyl-agarose. Purified PN has a molecular mass of approximately 51 kilodaltons. On nonequilibrium pH gradient electrophoresis it migrates as five bands with isoelectric points between 7.5 and 7.8. Purified PN exhibits all the properties attributed to PN in culture medium. These include: 1) formation of sodium dodecyl sulfate-stable complexes with thrombin, urokinase, and plasmin; 2) inhibition of protease activity; 3) heparin-enhanced inhibition of thrombin; and 4) cellular binding of protease-PN complexes in a heparin-sensitive reaction. When thrombin-PN complexes are dissociated with 1 M hydroxylamine a smaller form of PN (approximately 46 kilodaltons) is detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, indicating that the complexed PN is proteolytically modified.

Epidemiology of esophageal cancer. The incidence of cancer of the oesophagus is high in India but not as high as the rates reported from the Caspian Littoral of Iran. Incidence data available for three places in India--Bombay, Madras, and Bangalore--show regional variations. In Bombay, the rates for males are high compared to Madras and Bangalore. A case control study of 503 oesophageal cancer cases in males and 634 controls registered at the Tata Memorial Hospital during the period 1980-84 was carried out to determine the association of oesophageal cancer with two types of dietary practices, viz., vegetarian and non-vegetarian, in addition to tobacco and alcohol habits. In the presence of an alcohol habit, the relative risk for tobacco chewing and smoking was observed to be high in the non-vegetarian group compared to the vegetarian group. A vegetarian diet was protective. Further studies are suggested to confirm this finding.

Ellagic acid rhamnosides from the stem bark of Eucalyptus globulus. Four ellagic acid rhamnosides were isolated from the stem bark of Eucalyptus globulus. Their structures have been established on the basis of the analysis of their 1H NMR, 13C NMR, HMBC, IR and MS spectral data. The HMBC data of these compounds were most useful for their structure determinations, with these bring determined to be 3-O-methylellagic acid 3'-O-alpha-rhamnopyranoside, 3-O-methylellagic acid 3'-O-alpha-3''-O-acetylrhamnopyranoside, 3-O-methylellagic acid 3'-O-alpha-2''-O-acetylrhamnopyranoside, 3-O-methylellagic acid 3'-O-alpha-4''-O-acetylrhamnopyranoside, respectively. Their antioxidant activities were evaluated by measuring the inhibition of lipid peroxidation using rat liver microsomes, with IC50 values of 10.0-14.0 microg/ml.

Improving the safety net for single mothers who face serious barriers to work. Rebecca Blank explores a weakness of the welfare reforms of the mid-1990s--the failure of the Temporary Assistance to Needy Families program to address the plight of so-called "hard to employ" single mothers and their children. TANF has moved many women on the welfare caseload into work, but the services it provides are not intensive or flexible enough to meet the needs of women with multiple disadvantages who find it difficult to get and keep full-time employment. Blank notes that many of these women have lost welfare benefits because of their failure to find work. Increasingly, studies show that the number of single mothers who are neither working nor on welfare has grown significantly over the past ten years. Such "disconnected" women now make up 20 to 25 percent of all low-income single mothers, and reported income in these families is extremely low. Disconnected women are likely to report multiple and serious barriers to work, including low education, learning disabilities, health problems, or a history of domestic violence or substance abuse. Counting both longer-term welfare recipients and women who are neither working nor on welfare, Blank estimates that about 2.2 million women who head families are not able to find jobs or, if they do, cannot keep them. And almost 4 million children are in the care of these severely challenged single mothers. Blank proposes a Temporary and Partial Work Waiver Program to provide more effective employment assistance and other supports for these women and their children. The program she proposes would recognize that some women might be able to work only part-time or be temporarily unable to work. It would supplement their earnings while also offering referral to services that both address their own work barriers and provide help for their children. The support, however, would be temporary. Women would be regularly reassessed for their readiness to return to work or work more hours. Such a program, Blank notes, would require intensive case management. Estimating the cost of such a program is difficult, she explains, because costs would depend heavily on the number of women who participate. But she offers a rough estimate of $2.8 billion, some of which is already being spent as part of the current TANF program.

Long-term outcome of hyperthyroidism diagnosed in childhood and adolescence: a single-centre experience. Background The objective of the study was to evaluate the long-term outcome of paediatric-onset hyperthyroidism with follow-up into adulthood and to identify any early predictors of a need for definitive therapy (DT). Methods In a retrospective analysis of patients diagnosed with hyperthyroidism under the age of 18 years and at follow-up, a comparison was made by categorising them into those who underwent definitive therapy (DT group), i.e. thyroidectomy/radioactive iodine (RAI), those who remained on antithyroid drugs (ATD) (CBZ group) and those who had complete remission (RE group). Results Sixty-one (49 females, 12 males) patients with a median age of 15.1 years (range: 3.6-18) at diagnosis were studied. The duration of the first course of ATD varied from <1 year (7%), 1-2 years (26%), >2 years (46%) and ATD never discontinued (21%). Disease relapsed in 69% of patients with <1 year of ATD vs. 79% with >2 years of ATD. At follow-up, the median duration since diagnosis was 8.75 years (range 2.0-20.7 years) and the median age at follow-up was 23.2 years (8-36 years). Thirty-three percent (20/61) had undergone DT (DT group) - with 16.5% (n=10) on RAI and 16.5% (n=10) on surgery, 36% (22/61) were on ATD (CBZ group), whilst 32% (19/61) had undergone full remission (RE group). The comparison did not identify any statistically significant difference for predictor factors at diagnosis including age, T4 and free T4 levels, thyroid peroxidise antibody levels (TPO) and the duration of the first course of carbimazole (CBZ) treatment. Conclusion Long-term complete remission of paediatric-onset hyperthyroidism in our study was 31%. There were no predictors identified that could help predict the long-term outcome, especially into adulthood.

A novel K+ channel expressed in carrot roots with a low susceptibility toward metal ions. Kdc1 is a novel K+-channel gene cloned from carrot roots, and which is also present in cultured carrot cells. We investigated the characteristics of the ionic current elicited in Xenopus oocytes coinjected with KDC1 (K+-Daucus carota 1) and KAT1 (from Arabidopsis thaliana) RNA. Expressed heteromeric channels displayed inward-rectifying potassium currents whose kinetics, voltage characteristics, and inhibition by metal ions depended on KDC1:KAT1 ratios. At low KDC1:KAT1 ratios, Zn2+ inhibition of heteromeric K+ current was less pronounced compared to homomeric KAT1 channels, while at higher KDC1:KAT1 ratios, the addition of Zn2+ even produced an increase in current. Under the same conditions, the Ni2+ inhibition of the current was also reduced, but no current increase was observed. These effects might be explained by the unusual amino acid composition of the KDC1 protein in terms of histidine residues that are absent in the pore region, but abundant (four per subunit) in the proximity of the pore entrance. Channels like KDC1 could be at least partially responsible for the higher resistance of carrot cells in the presence of metals.

Current therapy of HIV. Antiretroviral therapy has improved continuously. Almost every year a new drug has been approved. Nucleoside analogs still build the backbone of antiretroviral therapy. They inhibit reverse transcriptase and thus the transcription of RNA to DNA. They are combined with non-nucleoside reverse transcriptase inhibitors or protease inhibitors. New therapeutic approaches are attachment or entry inhibitors, integrase inhibitors and maturation inhibitors. Multiple prospective multicenter studies have proven the life prolonging effect of antiretroviral therapy. With the optimal therapy life expectancy of HIV patients is only slightly reduced, similar to that of those with chronic diseases such as diabetes mellitus. One result of the higher age of HIV patients is an increase in concomitant diseases and medications. Drug interactions have to be considered and avoided. There has been a long discussion about the best time point to start antiretroviral therapy. In the late 1990s, every infected patient was treated hoping to eliminate the virus, ignoring the CD4+ cell count and viral load. This caused multiple (long-term) side effects and a rising resistance problem. The guidelines now recommend starting therapy at about 350/microl CD4 lymphocytes. Due to its complexity antiretroviral therapy should be initiated and monitored in specialized centers.

Glucagon-like peptide-1 production in the GLUTag cell line is impaired by free fatty acids via endoplasmic reticulum stress. Glucagon-like peptide-1 (GLP-1) is secreted from intestinal L cells, enhances glucose-stimulated insulin secretion, and protects pancreas beta cells. However, few studies have examined hypernutrition stress in L cells and its effects on their function. Here, we demonstrated that a high-fat diet reduced glucose-stimulated secretion of GLP-1 and induced expression of an endoplasmic reticulum (ER) stress markers in the intestine of a diet-induced obesity mouse model. To clarify whether ER stress in L cells caused the attenuation of GLP-1 secretion, we treated the mouse intestinal L cell line, GLUTag cells with palmitate or oleate. Palmitate, but not oleate caused ER stress and decreased the protein levels of prohormone convertase 1/3 (PC1/3), an essential enzyme in GLP-1 production. The same phenomena were observed in GLUTag cells treated with in ER stress inducer, thapsigargin. Moreover, oleate improved palmitate-induced ER stress, reduced protein and activity levels of PC1/3, and attenuated GLP-1 secretion from GLUTag cells. These results suggest that the intake of abundant saturated fatty acids induces ER stress in the intestine and decreases GLP-1 production.

E3B1, a human homologue of the mouse gene product Abi-1, sensitizes activation of Rap1 in response to epidermal growth factor. E3B1, a human homologue of the mouse gene product Abi-1, has been implicated in growth-factor-mediated regulation of the small GTPases p21Ras and Rac. E3b1 is a regulator of Rac because it can form a complex with Sos-1 and eps8, and such a Sos-1-e3B1-eps8 complex serves as a guanine nucleotide exchange factor for Rac. In the present study, we found that overexpression of e3B1 in NIH3T3/EGFR cells sensitized EGF-induced activation of Rac1, whereas it had no impact on EGF-induced activation of p21Ras. Remarkably, we found that EGF-induced activation of the p21Ras-related GTPase Rap1 was also sensitized in NIH3T3/EGFR-e3B1 cells. Thus, in NIH3T3/EGFR-e3B1 cells, maximal EGF-induced activation of Rap1 occurs with a dose of EGF much lower than in NIH3T3/EGFR cells. We also report that overexpression of e3B1 in NIH3T3/EGFR cells renders EGF-induced activation of Rap1 completely dependent on Src tyrosine kinases but not on c-Abl. However, EGF-induced tyrosine phosphorylation of the Rap GEF C3G occurred regardless of whether e3B1 was overexpressed or not, and this did not involve Src tyrosine kinases. Accordingly, we propose that overexpression of e3B1 in NIH3T3/EGFR cells leads to mobilization of Src tyrosine kinases that participate in EGF-induced activation of Rap1 and inhibition of cell proliferation.

Modulation of adult hippocampal neurogenesis during myelin-directed autoimmune neuroinflammation. In chronic autoimmune diseases of the central nervous system (CNS) such as multiple sclerosis (MS) clinical signs of cognitive dysfunction have been associated with structural changes in the hippocampus. Moreover, experimental studies indicate that inflammatory responses within the CNS modulate the homeostasis of newborn cells in the adult dentate gyrus (DG). However, it remained open whether such changes happen regardless of the primary immunological target or whether a CNS antigen-directed T lymphocyte-mediated autoimmune response may exert a specific impact. We therefore induced experimental autoimmune encephalomyelitis (EAE), a common model of MS serving as a paradigm for a CNS-specific immune response, by immunizing C57BL/6 mice with encephalitogenic myelin oligodendrocyte glycoprotein (MOG) p35-55. In EAE animals, we found enhanced de novo generation and survival of doublecortin (DCX)-positive immature neurons when compared with controls immunized with CNS-irrelevant antigen (ovalbumine). However, despite activation of neurogenesis, we observed a reduced capacity of these cells to generate mature neurons. Moreover, the high number of newly born cells retained the expression of the glial marker GFAP. These effects were associated with downregulation of pro-neurogenic factors Neurogenin1 and Neurogenin2 and dysregulation of Notch, β-catenin, Sonic Hedgehog (Shh) signaling as suggested by altered gene expression of effector molecules. Thus, a CNS antigen-specific immune response leads to an aberrant differentiation of neural precursors associated with dysbalance of signaling pathways relevant for adult hippocampal neurogenesis. These results may further extend our understanding of disturbed regeneration in the course of chronic inflammatory CNS diseases such as MS.

Imaging of radiation dose for stereotactic radiosurgery. The distributions of radiation dose for stereotactic radiosurgery, using a modified linear accelerator (Philips SL-25 and SRS-200), have been studied by using three different dosimeters: (1) ferrous-agarose-xylenol orange (FAX) gels, (2) TLD, and (3) thick-emulsion GafChromic dye film. These dosimeters were loaded into a small volume of defect in a phantom head. A regular linac stereotactic radiosurgery treatment was then given to the phantom head for each type of dosimeter. The measured radiation dose and its distributions were found to be in good agreement with those calculated by the treatment planning computer.

Perceptual restoration of a "missing" speech sound: auditory induction or illusion? This study investigated whether the apparent completeness of the acoustic speech signal during phonemic restoration derives from a process of auditory induction (Warren, 1984) or segregation, or whether it is an auditory illusion that accompanies the completion of an abstract phonological representation. Specifically, five experiments tested the prediction of the auditory induction (segregation) hypothesis that active perceptual restoration of an [s] noise that has been replaced with an extraneous noise would use up a portion of that noise's high-frequency energy and consequently change the perceived pitch (timbre, brightness) of the extraneous noise. Listeners were required to compare the pitch of a target noise, which replaced a fricative noise in a sentence, with that of a probe noise preceding or following the speech. In the first two experiments, a significant tendency was found in favor of the auditory induction hypothesis, although the effect was small and may have been caused by variations in acoustic context. In the following three experiments, a larger variety of stimuli were used and context was controlled more carefully; this yielded negative results. Phoneme identification responses collected in the same experiments, as well as informal observations about the quality of the restored phoneme, suggested that restoration of a fricative phone distinct from the extraneous noise did not occur; rather, the spectrum of the extraneous noise itself influenced phoneme identification. These results suggest that the apparent auditory restoration which accompanies phonemic restoration is illusory, and that the schema-guided process of phoneme restoration does not interact with auditory processing.

Impact of Employee Assistance Services on Depression, Anxiety, and Risky Alcohol Use: A Quasi-Experimental Study. To test the impact of Employee Assistance Programs (EAPs) on reducing employee depression, anxiety, and risky alcohol use, and whether improvements in clinical symptoms lead to improved work outcomes. The study used a prospective, quasi-experimental design with propensity score matching. Participants (n = 344) came from 20 areas of state government. EAP (n = 156) and non-EAP (n = 188) employees were matched on baseline demographic, psychosocial, and work-related characteristics that differentiate EAP from non-EAP users. Follow-up surveys were collected 2 to 12 months later (M = 6.0). EAP significantly reduced symptoms of depression and anxiety, but not at-risk alcohol use. EAP reductions in depression and anxiety mediated EAP-based reductions in absenteeism and presenteeism. EAPs provide easy-to-access work-based services that are effective at improving employee mental health.

(E)-alkene and ethylene isosteres substantially alter the hydrogen-bonding network in class II MHC A(q)/glycopeptide complexes and affect T-cell recognition. The structural basis for antigen presentation by class II major histocompatibility complex (MHC) proteins to CD4(+) T-cells is important for understanding and possibly treating autoimmune diseases. In the work described in this paper, (E)-alkene and ethylene amide-bond isosteres were used to investigate the effect of removing hydrogen-bonding possibilities from the CII259-270 glycopeptide, which is bound by the arthritis-associated murine A(q) class II MHC protein. The isostere-modified glycopeptides showed varying and unexpectedly large losses of A(q) binding that could be linked to the dynamics of the system. Molecular dynamics (MD) simulations revealed that the backbone of CII259-270 and the A(q) protein are able to form up to 11 hydrogen bonds, but fewer than this number are present at any one time. Most of the strong hydrogen-bond interactions were formed by the N-terminal part of the glycopeptide, i.e., in the region where the isosteric replacements were made. The structural dynamics also revealed that hydrogen bonds were strongly coupled to each other; the loss of one hydrogen-bond interaction had a profound effect on the entire hydrogen-bonding network. The A(q) binding data revealed that an ethylene isostere glycopeptide unexpectedly bound more strongly to A(q) than the corresponding (E)-alkene, which is in contrast to the trend observed for the other isosteres. Analysis of the MD trajectories revealed that the complex conformation of this ethylene isostere was structurally different and had an altered molecular interaction pattern compared to the other A(q)/glycopeptide complexes. The introduced amide-bond isosteres also affected the interactions of the glycopeptide/A(q) complexes with T-cell receptors. The dynamic variation of the patterns and strengths of the hydrogen-bond interactions in the class II MHC system is of critical importance for the class II MHC/peptide/TCR signaling system.

Hematology of experimental acute Sarcocystis bovicanis infection in calves. II. Serum biochemistry and hemostasis studies. Of four Holstein-Friesian calves infected with 200,000 sporocysts of Sarcocystis bovicanis, three become ill and died on days 35, 55, and 59 of a 63-day experiment. No control calves became ill or died. Serum biochemicals and hematologic indicators of hemostasis from both groups were measured throughout the experiment. Creatine phosphokinase values for both groups increased markedly during acute infection. Lactic dehydrogenase and aspartate aminotransferase values were high in infected calves on days 25 to 35 and days 24 to 63, respectively, indicating injury of muscle, liver, or other tissues. Sorbitol dehydrogenase values were significantly higher for infected than for control calves on days 25 and 35, indicating liver injury. Serum bilirubin and blood urea nitrogen values were significantly increased in three anemic infected calves from day 25 or 26 to day 35, probably reflecting destruction of erythrocytes. The fourth infected calf was not anemic and had no hyperbilirubinemia and only minimal azotemia. Serum protein and albumin values decreased in infected calves on days 21 to 30 or 35, when, although hypoalbuminemia persisted, total protein concentration increased. Glucose, calcium, sodium, and chloride values decreased in infected calves slightly before onset of illness and remained low throughout the experiment. Potassium, magnesium, and phosphorus values did not differ between infected and control calves. Activated partial thromboplastin time and Russell's viper venom time were normal; prothrombin time was significantly higher from day 27 to day 49 in infected calves. This pattern was interpreted as evidence for acquired factor VII deficiency. Abnormal retraction of blood clots and enlarged platelets in blood smears, which indicate platelet dysfunction and increased platelet turnover, respectively, were seen on days 27 through 35 in anemic infected calves. Values for thrombin time (three calves) and fibrin degradation product concentration (one calf) increased just before death of the infected calves.

[Caplan's syndrome: rarely presenting as <<pulmorenal>> syndrome]. A 59-year-old man complained about having dry cough for months and a recent sudden onset of minor hemoptoe, asymmetric arthritis, myalgia as well as lack of appetite. He presented an occupational history of 12-year exposure to an organic dust as uranium miner in German Democratic Republic followed by 21 years as heavy construction worker in Germany and in Switzerland. Laboratory work-up tested positive for microhematuria and anti-neutrophilic cytoplasmic antibodies (ANCA). Chest X-rays and CT scan showed bilaterally scattered nodules. Thoracoscopic wedge resection was performed, histopathological analysis revealed granuloma with central necrotic area containing black coal dust and silica depositions surrounded by histiocytes. The pulmonary opacities on X-ray and the typical histology in the light of significant dust exposure allow the diagnosis of a Caplan's syndrome. The symptoms improved rapidly under steroid therapy. Further investigations revealed a clear renal cell carcinoma as a cause for the persistent microhematuria. Rheumatoid arthritis, pulmonary nodules and history of prolonged dust exposure are classical findings that define Caplan's syndrome. These patients present with different immunological phenomena - in our case ANCA-positivity without vasculitis. Interestingly, the renal cell carcinoma which led to the "pulmorenal" syndrome in our patient is another health problem overrepresented in uranium mine workers.

Behçet's disease with intestinal perforation: A case report. A 34-year-old man with an 8-year history of outbreaks of oral and genital ulcers presented with high fever and skin lesions that had developed 21 days earlier, without abdominal pain. Computed tomography revealed intestinal perforation requiring surgery. After treatment with corticosteroids and azathioprine proved to be ineffective, it was switched to adalimumab.

Carbonaceous micro-filler for cement: Effect of particle size and dosage of biochar on fresh and hardened properties of cement mortar. This study explores influence of biochar particle size and surface morphology on rheology, strength development and permeability of cement mortar, under moist and dry curing condition. Experimental results show that the flowability and viscosity of cement paste is more affected by macro-porous coarser (or 'normal') biochar particles of size 2-100 μm (NBC) compared to fine (or 'ground' biochar), which is in the size range of 0.10-2 μm (GBC). Addition of both GBC and NBC accelerated hydration kinetics and improved early (1-day) and 28-day strength by 20-25% compared to the control. Water permeability, measured by capillary absorption was reduced by about 50% compared to control mortar, due to the addition of 0.50-1% NBC and GBC respectively. GBC is found to be more effective in minimizing loss in strength and water tightness under dry curing condition compared to the control and mortar with NBC and quartz filler respectively. In summary, findings from the study show that finer biochar particles offer superior performance in improving early strength and water tightness compared to normal biochar (with macro-pores), while 28-day properties are similar for mortar with both GBC and NBC respectively.

Instant RNA isolation from virus-infected tissue culture fluid for the polymerase chain reaction. This paper describes an efficient method of RNA isolation, enabling RNA templates to be obtained for reverse transcription within 20 min. The procedure avoids the use of hazardous organic chemicals and ethanol precipitation, and does not require ultracentrifugation. Results are presented for extraction of RNA from virus-infected tissue culture fluid, infected cell sheets, vaccine bulk material and lyophilized commercial vaccines.

Binding characteristics and cross-reactivity of three different antilipid A monoclonal antibodies. A detailed characterization of binding specificity and cross-reactivity of three antilipid A murine mAb was performed. Binding characteristics of these three mAb were investigated against Ag (ReLPS, lipid A, derivatives of lipid A) in solid phase (ELISA) and in fluid phase (C consumption, inhibition studies), and upon incorporation in membranes (E: passive hemolysis assay, and liposomes: inhibition studies). Cross-reactivity with heterologous Ag was investigated in ELISA (LPS, Gram-negative bacteria) and immunoblot experiments (LPS). The binding specificity of mAb 26-5 (IgG2b), raised against synthetic lipid A, was located in the hydrophilic region of biphospholipid A and was also exposed after membrane incorporation of lipid A or after preincubation of lipid A with polymyxin B (PMX). mAb 26-20 (IgM), also raised against synthetic lipid A, showed binding specificity for the hydrophobic region of lipid A: no binding to membrane-associated lipid A could be demonstrated, and binding in ELISA could be blocked very efficiently by PMX. The reaction pattern of mAb 8-2 (IgM), raised against the heat-killed Re mutant of Salmonella typhimurium, was in part similar to that of mAb 26-20. However, inhibition of binding with PMX was less efficient and a high specificity for ReLPS, also after membrane incorporation of this Ag, was demonstrated. In contrast to mAb 26-5 and 26-20, mAb 8-2 showed extensive cross-reactivity with heterologous LPS preparations and heat-killed as well as live Gram-negative bacteria. It is concluded that each of the three mAb binds to a different antigenic epitope in lipid A and that exposure of those epitopes for antibody binding is restricted in a differential manner, depending on mode of Ag presentation. The here defined reaction patterns provide a basis for the interpretation of potential inhibitory effects on in vitro and in vivo biologic (and toxic) activities of endotoxins and Gram-negative bacteria.

[Diagnosis of muscular disease]. Diagnostic evaluation of muscle disease has gained considerably from the expanding development in molecular science in the last decade. This paper gives an overview of current diagnostic procedures in the evaluation of patients with muscle disease. The role of the clinical examination, genetic and serological tests, neurophysiological examination, muscle imaging, muscle histology and exercise tests for the diagnosis of muscle disease are discussed.

Psychotherapy of Arab patients in the West: uniqueness, empathy, and "otherness". The study of Arab patients seeking treatment for their psychological problems in the West has previously been underrepresented in mainstream American journals. Notwithstanding various attempts that deal with Arab Americans as a minority group, there has been a paucity of scholarship dealing with Arab patients' unique characteristics related to sociopolitical, cultural, and other factors that impact the therapeutic process for those individuals who are not acculturated to the American way of life. These patients present challenges to their therapists owing to the contrasting cultural understanding and conceptualization of mental illness and therapeutic process. Therapists need to fully appreciate the relationship between culture and psychotherapy. Patients' and clinicians' awareness of differences may contribute to the ability of both sides of the therapeutic dyad to overcome some of the differences encountered when Arab patients are treated outside their cultural domain. A case vignette serves to illuminate how issues of cultural transference and countertransference can be managed for the benefit of the patient and the enlightenment of the therapist.

Effects of social deprivation in prepubescent rhesus monkeys: immunohistochemical analysis of the neurofilament protein triplet in the hippocampal formation. Social deprivation during early postnatal life has profound and long-lasting effects on the behavior of primates, including prolonged and exaggerated responses to stress as well as impaired performance on a variety of learning tasks. Although the cellular changes that underlie such alterations in behavior are unknown, environmentally induced psychopathology may involve morphologic or biochemical changes in select neuronal populations. The hippocampal formation of both socially deprived and socially reared prepubescent rhesus monkeys was selected for immunocytochemical investigation because of its association with the behavioral stress response and learning. Immunocytochemical analysis using antibodies specific for the neurofilament protein triplet was performed since these proteins are modified within degenerating neurons in a variety of neurodegenerative disorders. Results from optical density measurements indicate an increase in the intensity of non-phosphorylated neurofilament protein immunoreactivity in the dentate gyrus granule cell layer of socially deprived monkeys in comparison with that of socially reared animals, suggesting that early social deprivation may result in an increase in the amount of non-phosphorylated neurofilament protein in these cells. This phenotypic difference in dentate granule cells between differentially reared monkeys supports the notion that specific subpopulations of neurons in brain regions that subserve complex behaviors may undergo long-term modifications induced by environmental conditions. Furthermore, the data suggest that constitutive chemical components related to structural integrity may be as susceptible to early environmental manipulations as the more traditionally viewed measures of cellular perturbations, such as neurotransmitter dynamics, cell density and the establishment of connectivity. The observed modifications may serve as an anatomical substrate for behavioral abnormalities that persist in later life.

Co-delivery of vincristine and quercetin by nanocarriers for lymphoma combination chemotherapy. Chemotherapy is the current standard treatment for Non-Hodgkin's lymphoma (NHL). Combination therapy is emerging as an important strategy for a better long-term prognosis with decreased side effects, maximized therapeutic effect. The aim of this study is to deliver vincristine (VCR) and quercetin (QU) with synergistic drug ratios through lipid-polymeric nanocarriers (LPNs) for the lymphoma combination chemotherapy METHODS: In this present study, we constructed VCR and QU dual-loaded LPNs (VCR/QU LPNs) and investigated their antitumor efficacy in vitro cell culture models and a tumor xenograft mouse model. The formulated VCR/QU LPNs exhibited nano-size, negative zeta potential with sustained release profile in vitro. The dual drug loaded LPNs exhibited the best antitumor efficacy in vitro and in vivo. It could be concluded that VCR/QU LPNs can combine the efficiency of these two drugs, bring about synergistic effect. Co-encapsulation of VCR and QN in the same LPNs has potential as a novel therapeutic approach to overcome chemo-resistant lymphoma.

[Growth of codoped CdWO4 crystals by Bridgman method and their optical spectra]. The CdWO4 crystals with good quality in the size of Phi25 mm x 120 mm, doped with Co in 0.5% molar fraction in the raw composition, were grown by the Bridgman method by taking -70 degrees C x cm(-1) of solid-liquid interface and -0.50 mm x h(-1) growth rate. The crystal presents transparence and deep blue. The X-ray diffraction (XRD) was used to characterize the crystals. Three absorption peaks at 518, 564 and 655 nm respectively, which are attributed to the overlapping of 4 T1 (4F) --> 4A2 (4F) and 4 T1 (4F) --> 4 T1 (4P) of Co2+ octahedrons, and a wide band centered at 1 863 nm, which is attributed to 4Ti (4F) --> 4 T2 (4F), was observed. The absorption results indicated that the Co ions presented +2 valence in crystal and located within the distorted oxygen octahedrons. The crystal-field parameter D(q) and the Racah parameter B were estimated to be 990 and 726.3 cm(-1) respectively based on the absorption spectra. A fluorescence emission at 778 nm (4T1 (4P) --> 4 T1 (4F)) for codoped CdWO4 crystals was observed under excitation by 520 nm light. It can be deduced from the changes in absorption and emission intensity of different parts of crystal that the concentration of Co2+ ion in crystal increased along growing direction and the effective distribution coefficient of Co2+ ion in CdWO4 crystal is less than 1.

No evidence of association between CAG expansions and essential tremor in a large cohort of Italian patients. Essential tremor (ET) is one of the most common movement disorders. However the pathogenesis is as yet unknown, although a genetic cause has long been recognised. Clinical and molecular evidences suggested that the ET gene might contain a CAG expanded region. In a cohort of Italian ET patients Repeat Expansion Detection (RED) approach did not demonstrate large CAG expansions. We extended the study towards specific targets: the channel proteins hSKCa3 and CACNL1A4. Direct assessment of CAG stretches within these two genes did not demonstrate any CAG expansion in affected subjects. Also a case-control analysis failed to reveal any evidence of association, thus excluding these genes as a cause of ET.

Factors affecting outcomes of liver transplantation: an analysis of OPTN/UNOS database. This was a historic cohort analysis based on 110,521 patients who underwent liver transplant between 1987 and July 2011 in the United States and were reported to the UNOS registry. In addition to univariate Kaplan-Meier survival analyses, we used cox proportional hazard analysis and multiple logistic regression analysis to evaluate hazard ratios adjusted for clinical factors. The overall 5- and 10-year patient survival rates were 81% and 72%, respectively, for 4,412 recipients of living donor livers and 73% and 59%, respectively, for 106,109 recipients of deceased donor livers. Multivariate analyses suggest that these differences are due to demographics, including patient age rather than differences due to the donor organs. Recipients of zero HLA-mismatched livers had significantly worst graft survival (HR 1.29, p = 0.02) compared with those given an HLA mismatched graft. This appears to be due in part to graft versus host disease. Among recipients who experienced GVHD, multivariate analysis revealed that zero mismatch of HLA-A (HR 2.75), zero mismatch of HLA-B (HR 4.79), recipient age > 65 (HR 2.57) and Asian recipient (HR 2.70) were significant risk factors for GVHD respectively.

Use of additives in the electrodeposition of nanostructured Eu3+/ZnO films for photoluminescent devices. Rare-earth ion-doped ZnO has been the focus of numerous investigations because of its unique optical properties and promising applications in optoelectronic devices. Here we presented a facile electrochemical deposition route for the controllable preparation of Eu3+/ZnO nanostructures on a large scale. The prepared Eu3+/ZnO deposits were characterized by scanning electron microscopy, energy dispersive spectroscopy, X-ray diffraction, selected area electron diffraction, and X-ray photoelectron spectroscopy. Herein, the growth mechanisms of Eu3+/ZnO nanosheets and nanorods were discussed. The formation process of Eu3+/ZnO foam-like nanostructures is illuminated in this paper. The room temperature photoluminescence properties of the Eu3+/ZnO foam-like nanostructures were investigated. The sharp 4f-4f transition emissions of Eu3+ can be directly observed at 593, 617, and 698 nm. An energy transfer between ZnO and Eu3+ is shown to occur under UV excitation.

Emotional status in systemic lupus erythematosus. Psychological and emotional status was assessed in 36 patients with systemic lupus erythematosus (SLE) with the General Health Questionnaire-30 (GHQ-30) and Minnesota Multiphasic Personality Inventory (MMPI) questionnaires. The two tests were found to measure different aspects of psychological functioning. More than 50% of the patients could be classified as cases with mild psychiatric disturbances, according to the GHQ, and 28% had an abnormal score > 70 on the MMPI depression subscale, indicating significant depression. Emotional disturbances such as problems with social functioning, personal discomfort in social situations, and depressive mood, were frequent and associated with skin and joint abnormalities. This suggests additional etiologies for psychological dysfunction among SLE patients other than the direct central nervous system (CNS) effect of SLE.

The Post Birth Partnership: Washington State's comprehensive approach to improve follow-up care. In 1995, a group of professionals committed to providing quality maternity care in Washington State met to discuss the proposed legislation that would mandate hours of stay after delivery. The meeting resulted in the formation of the Post Birth Partnership, whose goals were to have a role in affecting legislation, define standards of care for follow-up visits, and increase public awareness about the need for follow-up care. This article describes the formation of the Partnership and the work it has accomplished.

Coarse fibrillatory waves in atrial fibrillation predict success of electrical cardioversion. To determine whether the presence of "coarse" fibrillatory waves (Fw) seen on surface ECGs of patients with persistent atrial fibrillation (AF) predict maintenance of sinus rhythm (SR) at 6 weeks after electrical cardioversion (ECV). Preprocedure ECGs from 94 consecutive patients with persistent AF scheduled to undergo ECV at a single centre were classified as having coarse Fw (≥0.1 mV) or fine Fw (<0.1 mV) in leads II or V1 . The primary outcome was ECG rhythm at 6-week clinical follow-up. Demographic and echocardiographic data were also collected. Thirty-two patient ECGs (34%) had coarse Fw on baseline ECG in either or both leads II or V1 with no significant differences in baseline demographics compared to those patients with fine Fw. At 6 weeks post-ECV, in the coarse Fw group 72% of patients maintained SR vs. 42% in the fine Fw group (χ2 , p = .006) with the odds ratio (OR) of maintaining SR at 6 weeks in the presence of coarse Fw being 3.5 (95% CI: 1.4-8.9, p = .007). Across the overall study population, there were no other significant univariate predictors of SR at 6 weeks post-ECV. Classifying persistent AF using the maximal Fw amplitude on a surface ECG is a simple and reproducible method of predicting medium-term success of ECV, independent of traditional risk factors.

Pentoxifylline and vitamin E treatment for prevention of radiation-induced side-effects in women with breast cancer: a phase two, double-blind, placebo-controlled randomised clinical trial (Ptx-5). A previous study has shown that pentoxifylline in combination with vitamin E can reverse radiation-induced fibrosis. The aim of the present study is to investigate if the same drugs could prevent radiation-induced side-effects in women with breast cancer. A randomised, placebo-controlled, double-blind, parallel group trial was performed. Women with breast cancer were treated for 12 months with 400 mg pentoxifylline t.i.d. or placebo, in combination with 100 mg vitamin E t.i.d., starting 1-3 months after the completion of radiotherapy. The primary end-point was passive abduction of the shoulder, and the secondary end-point was difference in arm volumes. The trial is registered on the ISRCTN.org website, number ISRCTN39143623. 83 patients were included in the study; 42 in the pentoxifylline+vitamin E group and 41 in the placebo+vitamin E group. Both treatments were generally well tolerated. Seven patients were withdrawn from the treatment due to disease progression; four in the pentoxifylline group and three in the placebo group. At inclusion, patients had impaired passive abduction of the shoulder. During treatment, both the groups improved significantly. Median improvement from baseline was 3.7 degrees (p=0.0035) on pentoxifylline and was 9.4 degrees (p=0.0041) in the placebo group, but no difference between the groups was detected (p=0.20). Arm volumes increased over time in the placebo group (1.04%), but not on pentoxifylline (0.50%), and differed significantly between the groups (p=0.0172). The combination of pentoxifylline and vitamin E was safe and may be used for the prevention of some radiation-induced side-effects.

Switching cyclin D-Cdk4 kinase activity on and off. The cyclin-cdks are master regulators of cell proliferation. These serine/threonine kinases are the motors that both start and stop the cell cycle in response to proliferative or antiproliferative signals. They phosphorylate substrates required to trigger orderly cell cycle progression, and thus their activity is tightly regulated in order to prevent inappropriate activation. One of the main interfaces between the extraceullar environment and the cell cycle machinery is the interaction of the cyclin-cdks with two families of stoichiometric cyclin kinase inhibitors (CKIs), the Ink4s and the Cip/Kips. As their name suggests, the CKIs have historically been considered negative regulators of the cyclin-cdks, responsible for rapidly and effectively turning off cyclin-cdk activity. However, the interaction of cyclin D-cdk4 with the Cip/Kip family, and with p27Kip1 in particular, appeared complex. In addition to its ability to inhibit cyclin D-cdk4, p27 appeared to be a required assembly factor for the complex, binding in a non-inhibitory mode at least some of the time. Whether p27 was a cyclin D-cdk4/6 inhibitor or not was controversial, and how it might switch between these two modes was unknown. Arguing for a two state mechanism, we have recently shown that p27 can be both a cdk4 bound-inhibitor and a bound-non-inhibitor, depending on the growth state of the cell. This perspective highlights the significance of this finding in terms of normal cell cycle progression and tumor development.

Inquiry in bioethics and the philosophy of medicine: organ donation, defining death, and fairness in distribution. This issue of the Journal of Medicine and Philosophy brings together fresh essays addressing three main genres of questions: (1) questions about the nature of bioethical inquiry and the relevance of the humanities to medical practice; (2) questions regarding the ethics of organ donation; (3) questions bearing on the application of fairness to the distribution of medical resources.

Genetic evaluation of fertility traits of dairy cattle using a multiple-trait animal model. A genetic evaluation system was developed for 5 fertility traits of dairy cattle: interval from first to successful insemination and nonreturn rate to 56 d of heifers, and interval from calving to first insemination, nonreturn rate to 56 d, and interval first to successful insemination of cows. Using the 2 interval traits of cows as components, breeding values for days open were derived. A multiple-trait animal model was applied to evaluate these fertility traits. Fertility traits of later lactations of cows were treated as repeated measurements. Genetic parameters were estimated by REML. Mixed model equations of the genetic evaluation model were solved with preconditioned conjugate gradients or the Gauss-Seidel algorithm and iteration on data techniques. Reliabilities of estimated breeding values were approximated with a multi-trait effective daughter contribution method. Daughter yield deviations and associated effective daughter contributions were calculated with a multiple trait approach. The genetic evaluation software was applied to the insemination data of dairy cattle breeds in Germany, Austria, and Luxembourg, and it was validated with various statistical methods. Genetic trends were validated. Small heritability estimates were obtained for all the fertility traits, ranging from 1% for nonreturn rate of heifers to 4% for interval calving to first insemination. Genetic and environmental correlations were low to moderate among the traits. Notably, unfavorable genetic trends were obtained in all the fertility traits. Moderate to high correlations were found between daughter yield-deviations and estimated breeding values (EBV) for Holstein bulls. Because of much lower heritabilities of the fertility traits, the correlations of daughter yield deviations with EBV were significantly lower than those from production traits and lower than the correlations from type traits and longevity. Fertility EBV were correlated unfavorably with EBV of milk production traits but favorably with udder health and longevity. Integrating fertility traits into a total merit selection index can halt or reverse the decline of fertility and improve the longevity of dairy cattle.

Antifungal compounds: controversies, queries and conclusions. A new session in this Congress was the development of a discussion panel regarding controversies and queries about the main topics of treatment and prophylaxis of severe systemic mycoses. Experts presenting each side of three controversial areas provided an interchange of ideas and clarified those areas where there remain substantial disagreements. Some common recommendations have been made, and some differences persist. The contents of this session are compiled in this paper. Due to the limitations of space, this paper presents the most relevant parts of each presentation. The large and up-to-date list of references should be useful to gain a better understanding of these subjects.

Hsp104: a weapon to combat diverse neurodegenerative disorders. Many of the fatal neurodegenerative disorders that plague humankind, including Alzheimer's and Parkinson's disease, are connected with the misfolding of specific proteins into a surprisingly generic fibrous conformation termed amyloid. Prior to amyloid fiber assembly, many proteins populate a common oligomeric conformation, which may be severely cytotoxic. Therapeutic innovations are desperately sought to safely reverse this aberrant protein aggregation and return proteins to normal function. Whether mammalian cells possess any such endogenous activity remains unclear. By contrast, fungi, plants and bacteria all express Hsp104, a protein-remodeling factor, which synergizes with the Hsp70 chaperone system to resolve aggregated proteins and restore their functionality. Surprisingly, amyloids can also be adaptive. In yeast, Hsp104 directly regulates the amyloidogenesis of several prion proteins, which can confer selective advantages. Here, I review the modus operandi of Hsp104 and showcase efforts to unleash Hsp104 on the protein-misfolding events connected to disparate neurodegenerative amyloidoses.

Decomposition pathways of formamide in the presence of vanadium and titanium monoxides. Thermally feasible decomposition pathways of formamide (FM) in the presence of vanadium VO(X(4)Σ(-)) and titanium TiO(X(3)Δ) monoxides are determined using density functional theory (BP86 functional) and coupled-cluster theory (CCSD(T)) computations with large basis sets. These diatomic metal oxides have been shown to be present in the prebiotic conditions. The dehydration, decarbonylation and dehydrogenation reactions of the molecular and dissociative complexes of FM and MO (M = V, Ti) turn out to be more favourable than those of the ground state isolated FM. The effect of addition of one or two water molecules on energy barriers is also probed for these reaction pathways. In some cases, a combined catalytic effect when adding water is observed. This enhanced catalytic effect was not observed in previously reported cases of FM transformation, for example, when adding water molecules into the mineral-catalyzed isomerizations of FM. The dehydration process of MO-FM complexes without the presence of water is found to be more feasible than the decarbonylation and dehydrogenation. The overall energy barrier for the non-water VO-FM dehydration is ∼3 kcal mol(-1) lower than the reference energy of the separated systems, whereas those of the two latter reactions are higher than the reference. Although the TiO-FM dehydration has a larger overall barrier of 14 kcal mol(-1) as compared to the VO-FM counterpart, the two other decomposition pathways still have much higher energy barriers. Direct formation of urea and H2CO from a FM dimer and indirect formation of urea from FM via the intermediate HNCO are also established. Urea formation in an indirect pathway is preferred. These low-energy-barrier pathways leading to the formation of important prebiotic molecules suggest that metal monoxides MO could play an important catalytic role in the prebiotic reactions of FM.

Complications associated with warfarin prophylaxis in total knee arthroplasty. Systemic and local complications associated with the use of warfarin for deep vein thrombosis prophylaxis in total knee arthroplasty (TKA) are significant. Forty-seven patients with primary TKAs considered at high risk for developing thromboembolic disease were treated with a regimen of preoperative and postoperative warfarin. The incidence (n = 2) of systemic complications was 4%. The incidence (n = 6) of wound complications requiring specific treatment or discontinuing physiotherapy was 12%. In this series, wound complications did not jeopardize the end results of TKA. However, such wound complications as may have delayed recovery occurred with a frequency similar to that reported in other series of TKA using different antithromboembolic modalities.

Relationship between uterine secretion of prostaglandin F2 alpha induced by oxytocin and endogenous concentrations of estradiol and progesterone at three stages of the bovine estrous cycle. The purpose of this experiment was to determine whether differences among cows in the ability of oxytocin to stimulate uterine secretion of prostaglandin F2 alpha (PGF2 alpha) were related to the endogenous ovarian steroid environment. Sexually mature heifers were treated with oxytocin (.33 IU/kg BW) at three stages of the estrous cycle: early (d 3 to 5; n = 5), middle (d 10 to 11; n = 5) or late (d 16 to 17; n = 5). To assess uterine responsiveness to oxytocin, concentrations of 13,14-dihydro-15-keto-PGF2 alpha (PGFM) were quantified in jugular venous plasma samples collected at 1/2-h intervals for 8 h postinjection. The ovarian steroid environment at the time of injection was estimated by measuring the concentrations of progesterone and estradiol in jugular venous plasma samples collected at 4-h intervals for 12 h immediately prior to injection. Concentrations of PGFM increased immediately following injection of oxytocin either early or late in the estrous cycle. The response was much less during the middle of the estrous cycle. The magnitudes of response, early and late in the estrous cycle, were similar and greater than that observed during the middle of the estrous cycle (P less than .05). There was a positive relationship (R2 greater than .8; P less than .05) between magnitude of the response to oxytocin and ratio of estradiol to progesterone both early and late in the estrous cycle. Thus, individual differences in uterine secretion of PGF2 alpha in response to oxytocin were related to stage of the cycle and to differences in the endogenous ovarian steroid environment within each stage of the estrous cycle.

Fatty acids in plasma, white and red blood cells, and tissues after oral or intravenous administration of fish oil in rats. The importance of route of administration of omega-3 (n-3) polyunsaturated fatty acids (PUFA) (oral vs intravenous (iv)) is not clear. We determined the relative concentrations of fatty acids in plasma phosphatidylcholine (PC), red blood cells (RBC), white blood cells (WBC) and several tissues after short-term oral or iv administration of soybean oil (SO) or fish oil (FO). Wistar rats (n = 6/group) received saline, FO, or SO by gavage or saline, FO based-lipid emulsion (FLE), or SO based-lipid emulsion (SLE) iv. The oils were provided at 0.2 g/kg/day for three consecutive days. The animals were sacrificed 24 h after the last administration, blood was collected for plasma, WBC and RBC separation and tissues removed. Fatty acids were analysed by gas chromatography. FO resulted in higher eicosapentaenoic acid (EPA) in plasma PC and liver than the control. FLE resulted in higher EPA, docosahexaenoic acid (DHA) and total n-3 PUFA in plasma PC, WBC and liver than both the control and SLE groups. EPA, DHA and total n-3 PUFA were higher in the heart with FLE compared with SLE. Individual and total n-3 PUFA were higher in plasma PC, WBC, liver and heart with FLE than with FO given by gavage. Short-term iv administration of n-3 PUFA appears to be more effective at increasing EPA and DHA status in plasma, WBC, liver and heart than oral administration. This might be important for rapid treatment with n-3 PUFA.

Chordin-like protein 1 promotes neuronal differentiation by inhibiting bone morphogenetic protein-4 in neural stem cells. In the present study, the effects of chordin‑like protein 1 (CHRDL1) overexpression, together with bone morphogenetic protein‑4 (BMP‑4) treatment, on the differentiation of rat spinal cord‑derived neural stem cells (NSCs) was investigated. Adult rat spinal cord‑derived NSCs were cultured in serum‑free medium. The recombined eukaryotic expression vector pSecTag2/Hygro B‑CHRDL1 was transfected into adult rat spinal cord‑derived NSCs using a lipid‑based transfection reagent and protein expression was assessed by western blot analysis. Differentiation of transfected NSCs following BMP‑4 treatment was determined by immunocytochemistry. The percentage of microtubule‑associated protein‑2 (MAP‑2)‑positive cells in the BMP‑4‑treated (B) group was found to be significantly lower compared with that in the non‑transfected control (N) group. The percentage of MAP‑2‑positive cells in the pSecTag2/Hygro B‑CHRDL1‑transfected, BMP‑4‑treated group was identified to be significantly higher compared with that in group B, however, no significant difference was observed between group N and the transfected, non‑BMP‑4‑treated control group. The current study indicates that CHRDL1 protein antagonizes BMP‑4 activity and induces spinal cord‑derived NSCs to differentiate into neurons.

Three cases of atypical pneumonia caused by Chlamydophila psittaci. Psittacosis is a zoonotic disease caused by Chlamydophila psittaci. The most common presentation is atypical pneumonia. Three cases of pneumonia of varying severity due to psittacosis are described. All patients had a history of avian contact. The diagnosis was confirmed by molecular detection of Chlamydophila psittaci in respiratory specimens. The cases showed good recovery with doxycycline treatment. Increased awareness of psittacosis can shorten diagnostic delay and improve patient outcomes.

Antibodies against the beta1-adrenergic receptor induce progressive development of cardiomyopathy. Different immune disturbances have been found among patients with dilated cardiomyopathy (DCM), including antibodies directed against different cardiac antigens, such as the second extracellular loop of the beta(1)-adrenergic receptor. The aim of our study was to investigate antibodies directed against the second extracellular loop of the beta(1)-adrenergic receptor effect on cardiac functions at an early and late stage during DCM development. This was made in a mouse model, in which DCM was induced by immunization with the second extracellular loop of the beta(1)-adrenergic receptor. Mice were immunized for 14 or 25 weeks respectively with the second extracellular loop of the beta(1)-adrenergic receptor. At 14 weeks, there was no decreased heart function reviled by echocardiography at rest, but when dobutamine stress echocardiography was used, a lower cardiac reserve was shown in the mice with antibodies against the second extracellular loop of the beta(1)-adrenergic receptor. By 25 weeks, decreased heart function, dilatation of the left ventricle and thinner left ventricular posterior wall were observed. Further biochemical analyses at 25 weeks showed increased mRNA expressions for beta(1)-adrenergic receptor kinase, monocyte chemoattractant protein-1 and the brain natriuretic peptide as well as increased concentrations of complement factor 3 in sera in the immunized animals. Our data suggest a cardiotoxic effect of antibodies directed against the second extracellular loop of the beta(1)-adrenergic receptor and a capacity to induce DCM with progressive remodeling, decreased cardiac function, altered beta(1)AR signaling and upregulation of proinflammatory components.

[Treatment regulations and treatment limits: factors influencing clinical decision-making]. Providing or withholding of treatment is based on a variety of factors. We sought for criteria in clinical decision making and reviewed attitudes towards clinical intuition and the patient's will. 503 physicians (25.6 % females; mean age 36.3) in 49 departments at nine hospitals of the universities Bochum and Magdeburg filled in a validated questionnaire. The most important factors in the decision to carry out a therapy were "international standards" and "own experience". The decision to omit a therapy was mainly influenced by the "patient's wish". Physicians with a higher status judged their own experience higher than young physicians, who considered the experience of colleagues more important. "Severe accompanying illnesses" and "multimorbidity" were the most frequently named reasons to withdraw a therapy. Intuitive decision-making was rare, especially in young physicians, although these decisions were seldom risky and often successful. A patient's will plays a prominent role in clinical decision making, especially in decisions to withdraw or to withhold treatment. Cost containment and research interest have been called less important, a remarkable response from research-based university hospitals. Also remarkable is the recognition and importance of clinical intuition in situations of complex or missing information. This important aspect is rarely discussed in the literature or in medical education. The widely voiced concern that priorities in clinical care are guided by scientific interest, financial or technical possibilities could not be confirmed.

Glycoluril. The crystal structure of glycoluril [tetrahydroimidazo-[4,5-d]imidazole-2,5(1H,3H)-dione, C4H6N4O2] has been determined. The molecule has two equivalent planes containing urea moieties, and hence exhibits C2v symmetry. The dihedral angle is found to be 124.1 (4) degrees.

Structural studies on tazobactam. Tazobactam (3, C10H12N4O5S) is an effective inhibitor of bacterial beta-lactamases. It crystallizes with unit cell dimensions a = 10.230 (2) A, b = 14.396 (2) A, and c = 17.291 (2) A in space group P2(1)2(1)2(1). Compared to the related inhibitor sulbactam (2), which lacks the triazole ring, crystalline tazobactam exhibits very similar beta-lactam geometry and the same S(1) envelope conformation of the thiazolidine ring. However, in both independent molecules of 3 a triazole ring nitrogen atom accepts an intermolecular hydrogen bond; similar interaction by this moiety of 3 with a hydrogen-bond donor on the enzyme, which is impossible for 2, could account for its enhanced inhibitory power. Semiempirical molecular orbital calculations show pronounced negative potential there. Molecular mechanics supports the hypothesis that the carboxyl group can rotate freely and the triazole ring can "flip".

Mental health system reform in Moldova: Description of the program and reflections on its implementation between 2014 and 2019. In 2014, the Republic of Moldova started a systematic process of reforming its mental health system, implementing priority actions set out in the National Mental Health Programme. The reform entailed a service delivery re-design, instituting mechanisms for collaboration across health and social sectors, and revision of the policy framework. Outcomes of the first 4 years of the reform included: 1) the establishment of a network of mental health services in 4 pilot districts embedding mental health diagnosis, treatment and referral in primary and specialized mental healthcare; 2) creation of an enabling policy environment at the national and district level; and 3) strengthened community support and acceptance of mental health issues. Objectives of the first Phase were achieved and the reform is now in its second Phase (2018-2022). The implementation strategy in Phase 1 focused efforts on 4 pilot districts, whereas Phase 2 harnesses lessons learned from Phase 1 and facilitates local leaders and actors to scale-up the model to all 32 districts and municipalities in Moldova. Ownership over the reform process shifted from project-led in Phase 1 to national and local government-led in Phase 2. We reflect on the process and contents of the mental health reform, discuss lessons learned and implementation challenges encountered. We conclude with learning points for policymakers and researchers considering mental health reform in other countries.

Fibrolipomatosis of the transplanted kidney. Fibrolipomatosis of varying degree was observed in 24 transplanted kidneys. In 8 patients there was no history of urinary tract obstruction or multiple infections, leaving earlier rejection periods as the probable factor responsible for development of fibrolipomatosis after transplantation.

Late referral for end-stage renal disease: a region-wide survey in the south west of England. The proportion of patients referred for renal replacement therapy (RRT) at a late stage of disease appears to be similar to that first described nearly 20 years ago. This study investigated the current scale of the problem in a large region in England, identifying the prior health care, patient characteristics, referral pattern, and outcomes of those accepted onto RRT. Three hundred and sixty-one (88%) out of 411 patients accepted for RRT in six renal units in the South and West Region of the UK between 1 June 1996 and 31 May 1997 were studied retrospectively. We examined the history of chronic renal failure, referral path to nephrologist, management of chronic renal failure (CRF) and patient outcomes. Patients were categorized as 'late' if they were referred to the renal unit either within 4 months or within 1 month of requiring RRT. One hundred and twenty-four (35%) patients were referred within 4 months of RRT, and 84 (23%) within 1 month. The main differences between patients referred later and other patients was seen for those referred within 1 month. These patients were older and had more co-morbidity, significantly worse laboratory parameters at the start of RRT, were less likely to have received standard treatments for CRF, had less permanent dialysis access in place at the start of RRT (18% vs 47%, P=0.001), and had a significantly longer hospital stay (18 vs 10 days, P=0.001). Seventy-four (19%) patients died in the first 6 months: 27 (32%) in the 1-month group, 46 (16%) in all others (P=0.002). We found no evidence that patients referred late had defaulted from nephrology follow-up or had an excess of rapidly progressive disease. Though data were incomplete, there was evidence of prior CRF of over 1 year in all late referral groups. Nearly a quarter of patients are referred for specialist nephrology treatment at a very late stage, within 1 month of RRT. They are less likely to receive interventions that could alter the progression of CRF or reduce its associated co-morbidity, have a worse clinical state at the start of RRT, longer hospitalization and poorer survival. These differences were much less marked for those referred within 1-4 months of starting RRT, although this is an insufficient time to prepare for RRT. Further research is needed to determine the missed opportunities for more proactive diagnosis and management of CRF.

Compensation culture. Do patients justice. Complexity of cases means some negligence claims against the NHS take years to settle. Many patients or relatives want only an apology, not money. Surgery is subject to the highest number of claims, and fear of complaints can deter medics from innovating.

Efficacy and safety of combination therapy with amiodarone and type I agents for treatment of inducible ventricular tachycardia. In a prospective study the efficacy of amiodarone in combination with the three Class I drugs mexiletine, flecainide, or encainide was evaluated consecutively in 12 patients with recurrent ventricular tachycardias (VT) by programmed stimulation. None of the tested drug combinations suppressed induction of sustained VT. The combination of amiodarone with Class IC drugs flecainide and encainide prolonged the cycle length of VT significantly, whereas the combination with mexiletine did not have the same degree of slowing on the VT cycle length. Several proarrhythmic effects occurred during the combination therapy with encainide: (1) frequent, spontaneous recurrences of hemodynamically well tolerated VT in four patients; (2) enhanced inducibility of VT in three patients; (3) impaired termination of VT in three patients. Though a marked increase in QRS and QTc intervals was observed by combined treatment with encainide, no significant correlation could be established between aggravation of arrhythmia and plasma levels of encainide, degree of QRS widening, JT or QTc prolongation. The only predictor for the occurrence of proarrhythmic events was found in left ventricular ejection fraction. These findings suggest that in patients refractory to amiodarone alone or a combination with mexiletine, the combined treatment of amiodarone with other Class IC drugs prolongs the VT cycle length but does not suppress induction of VT during programmed stimulation. Combination therapy of amiodarone with encainide was associated with a high incidence of proarrhythmic effects.

Biological activities of 5-fluorouracil and its prodrug 5'-deoxy-5-fluorouridine in rats. The antitumor activity and toxicity of 5-fluorouracil (FUra) and 5'-deoxy-5-fluorouridine (dFUR) were compared in female Fischer rats bearing transplanted dimethylhydrazine-induced colon tumors. The therapeutic effects of FUra and dFUR were not affected by the initial tumor size, but were dependent on the dose and duration of treatment. The maximal response rate of 80-90% cures was obtained with 7-day infusions of 35 mg-kg-1-day-1 FUra or 500 mg-kg-1-day-1 dFUR. The host toxicity of FUra and dFUR in tumor-bearing or normal rats included gastrointestinal and central nervous system disturbances. Toxicity related death was preceded by a greater than 20% animal weight loss and other signs of gastrointestinal disturbances. The maximal therapeutic dose of FUra was identical to the toxic dose which caused 40% death in normal rats. By contrast, the maximal therapeutic dose of dFUR did not cause toxic death, and the threshold lethal dose of dFUR was 40% higher than the maximally therapeutic dose, indicating a better therapeutic index for dFUR in this rat tumor.

Topical negative pressure therapy. Topical negative pressure therapy (TNP) has been available for clinical use in wound management since the late 1990s. It has been shown to be of particular benefit for the treatment of chronic nonhealing wounds and has also recently been positively linked to wound bed preparation.

Cardiac angiosarcoma in a pregnant woman: a case report and review of the literature. Cardiac angiosarcomas, although very rare, are the most common primary malignant tumours. They are characterized by no specific clinical findings, rapid growth with frequent metastasis at the time of diagnosis and a reduced response to treatment. We describe the case of a 34-year-old pregnant woman who began to complain of dyspnoea and palpitations at 32 weeks of gestation. The echocardiogram showed a mass in the right atrial cavity and the CT scan showed extensive local invasion and hepatic metastasis. After 4 weeks, because of progressive heart failure due to obstruction of the tricuspid valve by the mass, the patient was submitted to an urgent caesarean section followed, two days later, by palliative cardiac surgery in order to alleviate the symptoms. Adjuvant chemotherapy was performed.

Management of asymptomatically/minimally symptomatic post-ERCP serum liver test elevations: first do no harm. Trauma to the major papilla and transient supraphysiologic biliary tract pressure during ERCP may produce transient serum liver test elevation. Further investigation of these abnormal serum tests may be costly, potentially hazardous, and unnecessary. Transient rises in post ERCP serum liver tests may be a common epiphenomenon that requires only careful clinical observation. Our aim was to study serum liver test results collected before and after ERCP in asymptomatic (or minimally symptomatic) patients and determine the natural clinical history of these patients, without further intervention. Data were collected prospectively as part of a larger study, and this subset of data on asymptomatic patients was then analyzed separately. All patients had serum liver tests done before ERCP, and 4 and 18-24 h after ERCP. Thirty-seven patients were evaluated. Sixteen of the 36 (43%) had an abnormal serum liver test after ERCP. Fifteen of the 36 had a biliary or pancreatic papillotomy done. Whether or not a patient had a papillotomy performed did not appear to influence the incidence of abnormal transient serum liver test rise. There were no biliary stents placed in any of the patients evaluated. There were two cases of post-ERCP pancreatitis (one mild; one moderate). There were no cases of cholangitis or persistent biliary tract obstruction. In conclusion, a transient rise in ERCP serum liver tests appears common following ERCP. In the absence of significant clinical signs or symptoms, these isolated serum laboratory test abnormalities should managed expectantly.

Expression of alphav integrin family in gastric carcinomas: increased alphavbeta6 is associated with lymph node metastasis. To investigate the alterations as to integrin expression in human gastric carcinomas, we analyzed the alphav subunit and 5 types of beta subunits using reverse transcription-polymerase chain reaction (RT-PCR) and competitive RT-PCR. The incidence of alphav, beta6 and beta8 expression was significantly higher in carcinoma tissues than in non-neoplastic gastric mucosal tissues (NGMTs). Out of 18 carcinoma cases with coexpression of alphav and beta6 subunits, which was demonstrated by RT-PCR, 17 cases (94%) showed lymph node metastasis (p = 0.0033). This tendency was confirmed by immunohistochemistry; most cases (23/28, 82%) in which alphavbeta6 integrin was immunohistochemically detected showed lymph node metastasis (p = 0.0193). RT-PCR and immunohistochemical studies showed that gastric carcinoma tissues expressed beta5 subunit in all cases. Furthermore, in a quantitative analysis using competitive RT-PCR, the mean level of beta5 expression was approximately 140 times higher in gastric carcinomas than in NGMTs. Most gastric carcinoma cases (27/38, 71%) were immunohistochemically positive for beta8 subunit. These findings suggest that some members of the alphav integrin family (alphavbeta5, alphavbeta6, alphavbeta8) are up-regulated, and that alphavbeta6 integrin may be involved in the lymphatic metastasis of gastric carcinomas.

miR-142-3p inhibits aerobic glycolysis and cell proliferation in hepatocellular carcinoma via targeting LDHA. Cancer cells are addictively dependent on glycolysis even in an oxygen-rich condition. However, the mechanism underlying micro (mi)RNA regulation of aerobic glycolysis in cancer cells has not been fully understood. Here, we demonstrated that the expression of miR-142-3p was lower in hepatocellular carcinoma (HCC) as compared to adjacent non-tumor samples, which was confirmed in The Cancer Genome Atlas (TCGA) HCC cohorts and Gene Expression Omnibus (GEO) datasets. Function and pathway analysis showed that miR-142-3p was most relevent with metabolism. As predicted, the overexpression of miR-142-3p inhibited aerobic glycolysis and thus proliferation of HCC cells. Mechanistically, we identified lactate dehydrogenase A (LDHA), one of the important catalyticase for aerobic glycolysis, as the target of miR-142-3p. Exogenous expression of miR-142-3p reduced the protein levels of LDHA in both SK-Hep-1 and Huh7 cells. Dual luciferase report assays showed the expression of LDHA was directly modulated by miR-142-3p. miR-142-3p-induced deduction of aerobic glycolysis and proliferation were reversed by LDHA overexpression. Taken together, these results indicate that miR-142-3p could act as a tumor suppressor in HCC by targeting LDHA, suggesting new therapeutic targets for HCC treatment.

Exposure to pro-inflammatory cytokines upregulates MMP-9 synthesis by mesenchymal stem cells-derived osteoprogenitors. An intimate interplay exists between the bone and the immune system, which has been recently termed osteoimmunology. The activity of immune cells affects the intrinsic balance of bone mineralization and resorption carried out by the opposing actions of osteoblasts and osteoclasts. The aim of this study was to determine the possible interaction between inflammatory-induced conditions and matrix metalloproteinases-2,-9 (MMP-2,-9) synthesis and secretion by bone marrow-derived osteoprogenitor cells during advanced stages of osteogenesis. Rat bone marrow-derived mesenchymal stem cells (MSCs) were cultured in the presence of osteogenic supplements in order to direct the cells towards the osteogenic differentiation lineage. At the late stages of osteogenesis, assessed by histochemistry, immunohistochemistry and RT-PCR, cultures were exposed to pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 alpha (IL-1 alpha). Biochemical, histochemical and molecular biology techniques were used to discern the influence of pro-inflammatory cytokines on MMP-2,-9 synthesis and secretion. Results indicated that MMP-9 synthesis and secretion were significantly induced after exposure to the cytokines (TNF-alpha, IL-1 alpha) treatment, while MMP-2 levels remained unchanged. These results indicate that in response to inflammatory processes, osteoblasts, in addition to osteoclasts, can also be involved and contribute to the process of active bone resorption by secretion and activation of MMPs.

The association between rural-urban continuum, maternal education and adverse birth outcomes in Québec, Canada. Rural relative to urban area and low socioeconomic status (SES) are associated with adverse birth outcomes. Whether a graded association of increasing magnitude is present across the urban-rural continuum, accounting for SES, is unclear. We examined the association between rural-urban continuum, SES and adverse birth outcomes. Singleton births from 1999 to 2003 (n = 356,147) were linked to Québec municipalities ranked on a continuum of 3 urban and 4 rural areas based on population and economic base. Maternal education was used to represent SES. Odds ratios (OR) were calculated for preterm birth (PTB), low birth weight (LBW), and small-for-gestational-age (SGA) birth, accounting for municipality and individual-level covariates. We used stratified analyses to examine interaction between SES and rural-urban continuum. Relative to metropolitan area residence, living in small urban or rural areas was associated with adverse birth outcomes. Living in rural areas was associated with SGA birth (OR 1.11, 95% CI 1.05-1.17) and LBW (OR 1.15, 95% CI 1.05-1.26), and living in small urban areas was associated with PTB (OR 1.14, 95% CI 1.08-1.20). Upon stratification by education, living in remote rural relative to metropolitan areas was associated with adverse birth outcomes among university educated mothers only, and living in small urban areas was associated with adverse birth outcomes among mothers with lesser but not higher education. An SES gradient was present in all rural-urban areas, particularly for SGA birth. Differences in perinatal health exist across the rural-urban continuum, and maternal education has a modifying influence.

Biocompatible reduced graphene oxide prepared by using dextran as a multifunctional reducing agent. A large-scale, cost-effective, and environmentally friendly synthetic strategy for biocompatible reduced graphene oxide (RGO) by using dextran as a reducing and stabilization agent has been developed. Dextran-coated RGO (D-RGO) was readily soluble in water with high biocompatibility.

Guided gingival fibroblast attachment to titanium surfaces: an in vitro study. To assess the potential of gingival fibroblasts to attach in a predetermined linear orientation to a nano-topography of aligned fibres on titanium surfaces and determine the ability of such cells to deposit aligned collagen fibre matrix. smooth glass and rough titanium substrates were coated with polytetrafluoroethylene (PTFE) nano-fibres. Ammonia plasma treatment was used to modify the surface chemistry. Human gingival fibroblasts were cultured on substrates and orientation and collagen deposition was assessed. Straight, unidirectional, parallel PTFE nano-fibres were deposited over the titanium features. By 7 days, the majority of cells were observed to orient to untreated fibres despite the presence of competing titanium surface features. On plasma-treated fibre-coated titanium substrates, cell orientation was mixed. On uncoated substrates, the majority of cells oriented to the titanium surface features. On fibre-coated glass substrates, cells oriented themselves with untreated and plasma-treated fibres and secreted collagen in the same direction after 1 week. On uncoated glass substrates, there was no preferred direction of collagen orientation. Polytetrafluoroethylene nano-fibres induced cell and collagen orientation. Surface chemistry appeared only to affect cell behaviour at early time points. An implant surface that controls cell orientation may also influence the orientation of collagen, providing improved gingival support.

The polymorphous light eruption-severity assessment score does not reliably predict the results of phototesting. Polymorphous light eruption (PLE) is a very common photodermatosis in which patient history is highly specific. Phototesting is used to confirm the diagnosis and to determine the action spectrum and the severity of this disease. In daily practice and in research studies, it would be convenient to assess disease severity by patient history only. This study aims to assess PLE disease severity via patient history and compares this with severity assessment via phototesting. Sixty-one patients with PLE were asked 10 standard questions and all were phototested. The answers to the standard questions were coded with linear scores ranging from 0 to 10. The score of each question was plotted as independent variable in a multiple linear regression model against the score of the phototest (minimal number of irradiations necessary to elicit a positive skin lesion, with a maximum of 6 irradiations) as dependent variable using an enter approach. Furthermore, the scores of the separate questions were added to form a total score, the PLE-severity assessment score (PLE-SAS). The medians of these PLE-SASs were compared with the result scores obtained by phototesting. Phototesting was done with ultraviolet A and ultraviolet B irradiation. Fifty-seven of the 61 patients had a positive test result (93%). Using the multiple linear regression model, the severity assessment by patient history (PLE-SAS) compared with the result of phototesting showed two significant contributing questions (adjusted PLE-SAS) (P < 0.05) but with a regression coefficient of 0.2. A significant difference in median scores with the severity assessment (PLE-SAS and adjusted PLE-SAS) between patients testing positive after 1-3 irradiations compared with those testing positive after 4-6 irradiations was present (P < 0.05). However, the overlap quartile range between both groups was such that the PLE-SAS and the adjusted PLE-SAS have little predictive value in individual patients. We showed that in PLE, disease severity as determined using the PLE-SAS or adjusted PLE-SAS did not reliably predict severity as assessed by phototesting. Two significant contributing questions were not discriminating enough to be used as predicting questions to assess severity. Accurate patient history proved to be a reliable method to diagnose PLE. Phototesting is useful to determine the responsible ultraviolet action spectrum and to exclude differential diagnoses like photosensitive eczema, lupus erythematosus or chronic actinic dermatitis. PLE-SAS cannot replace phototesting for determining the severity of PLE.

Cytologic findings and potential pitfalls in proliferative myositis and myositis ossificans diagnosed by fine needle aspiration cytology: report of four cases and review of the literature. Proliferative myositis (PM) and myositis ossificans (MO) are two uncommon, benign pseudosarcomatous lesions of soft tissue. Despite their benign nature, they are often misdiagnosed for malignant soft tissue tumors because of their alarming clinical presentation. Fine needle aspiration cytology (FNAC) is a quick and simple method that can accurately diagnose such lesions, provided that the cytopathologist is adequately familiar with the cytomorphological features of these lesions as opposed to the features of sarcomas. In this report, we present three cases of PM and one case of MO diagnosed by FNAC. Their cytomorphological features are described, and related literature is reviewed.

Target specificity of selective estrogen receptor modulators within human endometrial cancer cells. Selective estrogen receptor modulators (SERMs) are estrogen receptor (ER) ligands that function as antagonists in some tissues, but have either partial or full agonist activity in others. SERMs often display variable partial agonist activity in uterine tissues and this activity can be displayed in uterine cell lines such as the human Ishikawa endometrial adenocarcinoma cell line. In this study, we compared the effects of several ER ligands including some SERMs on alkaline phosphatase (AP) activity and the expression of an ER target gene, the progesterone receptor (PR), in Ishikawa cells. As expected, estradiol (E2) was a potent and efficacious activator of both AP activity and PR mRNA expression. 4-Hydroxytamoxifen (4OHT) stimulated AP activity to a level 47% of that of E2 (100nM), while CP 336156 (lasofoxifene) increased AP activity 18%. A benzothiophene, such as LY 117018, a raloxifene analog, stimulated AP even less with values approximately 11% of E2-stimulated levels. A pure antiestrogen, ICI 182,780 did not stimulate AP activity. Interestingly, when we examined the ability of these compounds to increase the expression of the ER target gene, PR, a different rank order of efficacy was detected. After E2, CP 336156 was the most efficacious in increasing PR mRNA with a maximal stimulation of 20% of E2 levels, while 4OHT stimulated only 17%. LY 117018 increased PR mRNA expression 8% while ICI 182,780 did not increase PR mRNA expression at all. These data illustrate the target specificity that a SERM is able to display within a single cell type independent of "tissue specificity" and differential levels of expression of various cofactors. While 4OHT is 160% more active than CP 336156 in terms of inducing AP activity in the Ishikawa cells, CP 336156 has equivalent activity as 4OHT when one examines the ability of these SERMs to induce PR mRNA expression. Since the stimulation of Ishikawa cells by ER ligands is often used to assess the potential in vivo uterotrophic activity, these data indicate that examination of several endpoints in these cells may be necessary in order to fully characterize the activity of SERMs.

Selenocysteine, a highly specific component of certain enzymes, is incorporated by a UGA-directed co-translational mechanism. The opal termination codon UGA is used in both prokaryotic and eukaryotic species to direct the specific insertion of selenocysteine into certain selenium-dependent enzymes. So far a formate dehydrogenase (hydrogenase-linked) of Escherichia coli and glutathione peroxidases of murine, human and rat origin have been identified as enzymes containing selenocysteine residues encoded by UGA. A novel seryl-tRNA, anticodon UCA, that specifically recognizes the UGA codon is required for selenocysteine incorporation into formate dehydrogenase. A eukaryotic UGA suppressor tRNA with UCA anticodon that accepts serine and is phosphorylated to O-phosphoseryl-tRNA may have a corresponding function in glutathione peroxidase synthesis. Other factors required for the unusual usage of the in-frame UGA codons to specify selenocysteine incorporation and the biochemical mechanism involved in distinguishing these from normal UGA termination codons are discussed.

Winning medical groups. What does it take to win? Quite simply, excellence. Twenty suggestions for promoting excellence are provided to help you turn your medical group practice into a winning organization--an organization with quality management as well as quality medical care.

Is the adrenal cortex a target for gonadotropins? The human adrenal cortex expresses low levels of luteinizing hormone/chorionic gonadotropin receptors (LHCGR), a characteristic gonad-specific G-protein coupled receptor (GPCR). LHCGR levels increase in the adrenal cortex after exposure to chronically elevated gonadotropins (e.g. after gonadectomy). In fact, heightened ectopic LHCGR levels are observed in a subclass of human adrenocortical tumors, and gonadotropin-responsive adrenocortical hyperplasia and tumors occur in several animal species. These findings suggest that adrenocortical responsiveness to LH/CG might be a physiological phenomenon that is amplified in the presence of elevated gonadotropin levels. Such increased gonadotropin action can induce pathologies ranging from adrenocorticotropic hormone (ACTH)-independent Cushing syndrome to malignant adrenal tumors. The authors review the current information on adrenocortical responses to gonadotropins in experimental animals and humans.

Non-markovian decoherence of localized nanotube excitons by acoustic phonons. We demonstrate that electron-phonon interaction in quantum dots embedded in one-dimensional systems leads to pronounced, non-Markovian decoherence of optical transitions. The experiments that we present focus on the line shape of photoluminescence from low-temperature axially localized carbon nanotube excitons. The independent boson model that we use to model the phonon interactions reproduces with very high accuracy the broad and asymmetric emission lines and the weak red-detuned radial breathing mode replicas observed in the experiments. The intrinsic phonon-induced pure dephasing of the zero-phonon line is 2 orders of magnitude larger than the lifetime broadening and is a hallmark of the reduced dimensionality of the phonon bath. The non-Markovian nature of this decoherence mechanism may have adverse consequences for applications of one-dimensional systems in quantum information processing.

Association between neutrophil functions and periparturient disorders in cows. Neutrophil functions were examined in healthy periparturient dairy cows (n = 46) and in cows with retained placenta and metritis complex (n = 20); metritis (n = 18); or mastitis (n = 13). Blood samples (50 ml) were collected from each cow via jugular vein twice weekly from 1.5 weeks before to 4 weeks after parturition. Neutrophil function was evaluated, using 6 tests: random migration, chemotaxis, ingestion, myeloperoxidase activity (iodination), superoxide production (cytochrome C reduction), and antibody-dependent cell-mediated cytotoxicity. Ability to ingest bacteria and random migration activity of neutrophils from clinically normal cows were high around parturition and increased immediately after parturition, whereas myeloperoxidase activity and antibody-dependent cell-mediated cytotoxicity ability of neutrophils from these cows decreased after parturition. Measurement of neutrophil function in 4 ovariectomized cows revealed significant (P < 0.0005) seasonal changes in results of all 6 functional assays. We observed various defects of neutrophil function in all cows with abnormal conditions after parturition. Before parturition, superoxide production activity by neutrophils from cows with metritis and chemotaxis by neutrophils from cows with mastitis were significantly (P < 0.001 and P < 0.05, respectively) lower, indicating that a defect of neutrophil function may be a predisposing factor in the development of these disorders. In conclusion, the host defense role of neutrophils in periparturient cows was impaired, principally because of a defect in killing capacity, which may increase susceptibility to infections. We also investigated the in vitro effects of arachidonic acid metabolites and recombinant human colony-stimulating factors (rhCSF) on functions of neutrophils from clinically normal and postparturient cows with abnormalities, including retained placenta, metritis, or mastitis (n = 5/group). Each abnormal cow was matched for postpartum period with a clinically normal cow. Neutrophils from individual cows were preincubated with arachidonic acid metabolites (prostaglandin F2 alpha, 10(-7) M; prostaglandin E2, 10(-6) M; leukotriene B4, 10(-8) M; and lipoxin B, 10(-8) M) and rhCSF (rh-granulocyte-CSF, 1,000 or 6,000 U/ml; rh-granulocyte-macrophage-CSF, 5 or 15 ng/ml) in a 37 C water bath for 30 minutes before submitting them to function assays. There was no response by neutrophils from either clinically normal or abnormal postparturient cows to treatment with either arachidonic acid metabolites or rhCSF in any of the 6 functional assays. However, preincubation of neutrophils alone in a 37 C water bath for 30 minutes resulted in some alteration of neutrophil function.(ABSTRACT TRUNCATED AT 400 WORDS)

Abundance and Impact of Doubly Charged Polyatomic Argon Interferences in ICPMS Spectra. Doubly charged molecular ions of alkaline earth metals and argon could be identified as spectral interferences in an inductively coupled plasma mass spectrometer. These molecular ions were found to occur at abundances reaching about 10(-4) relative to the alkaline earth atomic ion abundances. They can thus substantially affect ultratrace analyses and, when present at similar concentration as the analyte elements, also isotope ratio measurements. For the case of Cu and Zn isotope ratio analyses, the same mass concentration of Sr was found to alter the measured (63)Cu/(65)Cu and (64)Zn/(66)Zn isotope ratios by -0.036‰ to -0.95‰ due to SrAr(2+), appearing at m/Q 63 and 64. BaAr(2+) can affect Sr isotope analyses, MgAr(2+) may impair S isotope ratio measurements, while CaAr(2+) may cause interference to Ca(+) isotopes. The abundances of the doubly charged molecular ions were higher than those of the corresponding singly charged species, which is in accordance with their generally higher bond dissociation energies. The relative abundances were found to depend significantly on the inductively coupled plasma (ICP) operating conditions and generally increase with increasing carrier gas flow rates or lower gas temperature of the ICP. They also increase by about an order of magnitude when a desolvated aerosol is introduced to the ICP.

[The female brain and the male brain]. Sex differences in the nervous system are prevalent throughout the animal kingdom. In humans, the corpus callosum and anterior commissure are larger in females, whereas some hypothalamic nuclei and associated structures are larger in males. Numerous studies in rodents have demonstrated that when these nuclei are exposed to circulating androgens during the critical period around birth, they develop into male-typical structures. In addition to this organizational effect, androgens exert an activational effect during adulthood. For example, sexually dimorphic gene expression in the hypothalamus and amygdala depends on circulating androgen levels. Cckar encodes a G protein-coupled receptor and its expression is sexually dimorphic. The major of Cckar-expressing neurons in the ventrolateral division of ventromedial hypothalamus (VMHvl) also express progesterone receptor (PR), with a female-biased expansion of arborizations in the anteroventral periventricular hypothalamic nucleus. Selective ablation of these PR-positive neurons in the VMHvl results in a marked reduction in female sexual receptivity and male aggression, demonstrating that these sexually dimorphic neurons contribute to gendered behavior in mammals. Remarkable sex differences in single neurons have been documented in the fruitfly (Drosophila melanogaster). The fruitless (fru) gene in the fruitfly is considered as a major regulator of male courtship circuitry; a male specific fru-expressing neuron cluster, P1, can initiate male courtship when artificially activated even in the absence of courtship target (e.g., a female). The fru gene encodes a set of putative transcription factors that appear to orchestrate the transcription of ~100 genes by recruiting chromatin regulators, histone deacetylase 1 or heterochromatin protein 1a, to the target sites. These studies have unraveled the causal link among genes, brain sexual dimorphisms and gendered behaviors.

Partial repair of massive rotator cuff tears: the evolution of a concept. Partial repair of massive rotator cuff tears has eliminated the need for tendon transfers to close large defects. Side-to-side repair is usually done as a first step, with the margins of the tear then repaired to bone. Side-to-side repair causes a "margin convenience" toward the greater tuberosity, enhancing the mechanics of the construct by decreasing the strain at the free margin of the rotator cuff tear. By combining tendon-to-tendon repair with the tendon-to-bone repair, the surgeon can create a functional rotator cuff in most patients with massive tears.

DAMGO, a mu-opioid receptor selective ligand, distinguishes between mu-and kappa-opioid receptors at a different region from that for the distinction between mu- and delta-opioid receptors. The structural basis of opioid receptors (OPRs) for the subtype-selective binding of DAMGO, a mu-opioid receptor selective ligand, was investigated using chimeric mu/kappa-OPRs. Replacement of the region from the middle of the fifth transmembrane domain to the C-terminal of mu-OPR with the corresponding region of mu-OPR remarkably decreased the binding affinity to DAMGO, while the reciprocal chimera revealed the high affinity to DAMGO. These results indicate that DAMGO distinguishes between mu- and mu-OPRs at the region around the third extracellular loop, different from the case of the distinction between mu-and delta-OPRs in which the region around the first extracellular loop is important. Furthermore, displacement studies revealed that the region around the third extracellular loop is involved in the discrimination between mu- and kappa-OPRs not only by peptidic mu- selective ligands but also by non-peptidic ligands, such as morphine and naloxone.

Evaluation of blood oxygen saturation in vivo from diffuse reflectance spectra. A simple method to evaluate the hemoglobin oxygen saturation and relative hemoglobin concentration in a tissue from diffuse reflectance spectra in the visible wavelength range is put forward in this paper. It was assumed that while oxygenated and deoxygenated hemoglobin contributions to light attenuation are strongly variable functions of wavelength, all other contributions to the attenuation including scattering are smooth wavelength functions and can be approximated by Taylor series expansion. Based on this assumption, a simple, robust algorithm suitable for real time monitoring of the hemoglobin oxygen saturation in the tissue has been derived. This algorithm can be used with different fiber probe configurations for delivering and collecting light passed through the tissue. An experimental technique using this algorithm has been developed for in vivo monitoring during artery occlusion and in vitro monitoring of blood samples. The experimental results obtained are presented in the paper.

Preparing the patient for prostate surgery. 1. Explaining the what, why, and where of the prostate and the perioperative phases of surgery in easy-to-understand terms will provide a better understanding of the outcome for the patient. 2. The obligation of the nursing staff is to teach patients what the procedure involves so that they can be prepared to lead as normal a life as possible postoperatively. 3. As health care providers, we must ensure that quality care is given to all patients. By teaching and providing the necessary tools, patients will not be afraid to address their health problems.

Platelet glycoprotein IIIa (platelet antigen 1/platelet antigen 2) polymorphism and 1-year outcome in patients with stable coronary artery disease. Platelet glycoprotein IIb/IIIa is a membrane receptor which plays a key role in coronary artery disease and thrombotic events. However, there is a considerable controversy regarding the clinical impact of glycoprotein IIIa platelet antigen 1 (PlA1)/platelet antigen 2 (PlA2) polymorphism as a risk factor for myocardial infarction. To evaluate the association between glycoprotein IIIa PlA1/PlA2 polymorphism and 1-year cardiovascular events occurrence in aspirin-treated patients with stable coronary artery disease. We prospectively included 188 postacute coronary syndrome patients (183 men) aged 59 ± 10 years and receiving aspirin (250 mg/day). The clinical outcome at 1 year was the composite end point of nonfatal myocardial infarction, stroke, recurrent unstable angina or cardiac death. Genotyping for PlA1/PlA2 polymorphism was conducted using PCR and restriction fragment length polymorphism analysis. The genotype distribution of glycoprotein IIIa PlA1/PlA2 polymorphism was PlA1/PlA1, 55.3%; PlA1/PlA2, 39.3% and PlA2/PlA2, 4%. Incidence of composite end point in homozygous PlA1/PlA1 carriers was significantly higher than in PlA2/PlA2 and PlA1/PlA2 patients [14.4 vs. 3.6% odds ratio 4.5 (1.2-16.6, 95% confidence interval); P = 0.012]. Multivariate analysis identified three strong predictive factors of cardiac death: age more than 65 years [odds ratio = 6.8, (1.4-34, 95% confidence interval); P = 0.018], ventricular ejection fraction less than 50% [odds ratio = 8.6, (1.7-42.6, 95% confidence interval); P = 0.008] and homozygous PlA1/PlA1 genotype [odds ratio = 8.8, (1.0-78.6, 95% confidence interval); P = 0.014]. Our results demonstrated that glycoprotein IIIa PlA1/PlA1 genotype carriers have a significantly increased risks of acute vascular ischemic events associated with a poor prognosis at 1 year. These postacute coronary syndrome patients might require an optimized secondary antithrombotic prophylaxis strategy.

Improved Li-storage performance with PEDOT-decorated MnO2 nanoboxes. In this paper, MnO2 nanoboxes coated with poly(3,4-ethylenedioxythiophene) film (denoted as MnO2@PEDOT) are investigated as an anode material in lithium-ion batteries. The MnO2 nanoboxes are developed through the surface chemical oxidation decomposition of MnCO3 cubes and the subsequent removal of their remaining cores. PEDOT is coated on the surface of MnO2 nanoboxes via in situ polymerization of 3,4-ethylenedioxythiophene. The charge-discharge tests demonstrate that this special configuration endows the resulting MnO2@PEDOT with remarkable electrochemical performances, that is a reversible capacity of 628 mA h g-1 after 850 cycles at a current density of 1000 mA g-1 and a rate capacity of 367 mA h g-1 at 3000 mA g-1. The results indicate that the nanoboxes provide the paths for Li-ion diffusion, the reaction sites for Li-ion intercalation/deintercalation and the space to buffer the volume change during the charge-discharge process, while the conductive polymer ensures the structural stability and improves the electronic conductive property of MnO2.

Identification of a genetic variant associated with rotator cuff repair healing. A familial and genetic predisposition for the development of rotator cuff tearing has been identified. The purpose of this study was to determine if a familial predisposition exists for healing after rotator cuff repair and if the reported significant association with a single-nucleotide polymorphism (SNP) in the ESRRB gene is present in patients who fail to heal. The study recruited 72 patients undergoing arthroscopic rotator cuff repair for a full-thickness posterosuperior tear. Magnetic resonance imaging studies were performed at a minimum of 1 year postoperatively (average, 2.6 years). Healing failures were classified as lateral or medial. Self-reported family history of rotator cuff tearing data and genome-wide genotypes were available. Characteristics of cases with and without a family history of rotator cuff tearing were compared, and a comparison of the frequency of SNP 1758384 (in ESRRB) was performed between patients who healed and those who failed to heal. Of the rotator cuff repairs, 42% failed to heal; 42% of patients reported a family history of rotator cuff tear. Multivariate regression analysis showed a significant association between familiality and overall healing failure (medial and lateral failures) (P = .036) and lateral failures independently (P = .006). An increased risk for the presence of a rare allele for SNP rs17583842 was present in lateral failures compared with those that healed (P = .005). Individuals with a family history of rotator cuff tearing were more likely to have repair failures. Significant association of a SNP variant in the ESRRB gene was also observed with lateral failure.

Patterns of patient attendance and dental service utilization in northern Labrador 1985-1989. The purpose of the present study was to identify patterns of dental patient attendance and service utilization using both epidemiological and service record data from six satellite clinics in Northern Labrador, Canada, between 1985-1989. Baseline attendances were derived for the region from the analysis of 1985-1988 data, the period prior to the introduction of a non-insured health benefit scheme. The results demonstrated that females and persons under the age of 21 years frequented the dentist the most. The effects of this non-insured health benefit scheme introduced in January 1989, was then compared to the baseline pattern of attendance. This dental coverage removed all financial barriers for dental treatment for a population of Inuit origin in this northern area (or 91% of the population). An increase in the uptake of all dental treatments by 10-40%, and a doubling of fillings and denture treatments was observed. About 7% more patients frequented the dentist in 1989. Attendances of the middle-aged and elderly patients increased by 4%. Mean number of appointments per person per year increased from the baseline level of 1.8 to 2.5. The largest increase in population attendances was observed in Hopedale, while Nain remained the community with the best attendance record. No better monthly patterns of attendance were identified for 1989 compared to the baseline. Future studies should continue to evaluate changes in treatment needs, demands and service utilization in the area on a longitudinal basis. There is also a need for more literature on patterns of dental attendances in northern areas.

Correction of a genetic defect by nuclear transplantation and combined cell and gene therapy. Immune-deficient Rag2(-/-) mice were used as nuclear donors for transfer into enucleated oocytes, and the resulting blastocysts were cultured to isolate an isogenic embryonic stem cell line. One of the mutated alleles in the Rag2(-/-) ES cells was repaired by homologous recombination, thereby restoring normal Rag2 gene structure. Mutant mice were treated with the repaired ES cells in two ways. (1) Immune-competent mice were generated from the repaired ES cells by tetraploid embryo complementation and were used as bone marrow donors for transplantation. (2) Hematopoietic precursors were derived by in vitro differentiation from the repaired ES cells and engrafted into mutant mice. Mature myeloid and lymphoid cells as well as immunoglobulins became detectable 3-4 weeks after transplantation. Our results establish a paradigm for the treatment of a genetic disorder by combining therapeutic cloning with gene therapy.

Development and validation of a rapid ultra high pressure liquid chromatographic method for the determination of methylxanthines in herbal infusions. An ultra high pressure liquid chromatographic method coupled with diode array detector (UHPLC-DAD) has been developed and validated for the fast separation and determination of three major methylxanthines, i.e., caffeine, theophylline and theobromine, in various herbal beverages. Isocratic elution using 0.1vol% formic acid/CH3OH (92.5:7.5, v/v) enabled the completion of the separation cycle in less than 3min using a flow rate of 0.7mL/min and a column temperature of 50°C. Validation of the method included linearity (0.5-50mg/L), limits of detection (12-35μg/L) and quantification (40-120μg/L), precision, matrix effect and accuracy. The percent recoveries ranged between 90 and 108%.

The epidemiology of seizure disorders in infancy and childhood: definitions and classifications. Seizures are one of the most common neurological symptoms that occur in infancy and childhood. They represent many different disorders with many different causes. Neonatal seizures occur in ~1.5% of neonates, febrile seizures in 2-4% of young children, and epilepsy in up to 1% of children and adolescents. Seizures provoked by other acute insults such as head trauma also occur although their precise frequency in children is hard to estimate. Ultimately, seizures are symptoms of various neurological insults and conditions. Although neonatal seizures, febrile seizures, and epilepsy overlap to a degree in that children with neonatal or febrile seizures are at increased risk of epilepsy, these different disorders have somewhat different risk factors and their own epidemiology. Furthermore, to the extent that environmental (e.g., infections, malnutrition) and medical system factors (vaccinations, prenatal care) and population genetics play roles, very different risks and patterns are seen in different areas of the world. Within each of these sets of disorders, designated as neonatal or febrile seizures and epilepsy, there are many highly specific conditions that, especially in the case of epilepsy, may have considerable implications for treatment and prognosis and consequently may require care from a specialist.