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A cost utility analysis of treatment options for gallstone disease: methodological issues and results. The techniques of cost utility analysis (CUA) were used to evaluate the treatment of gallstone disease by open and laparoscopic cholecystectomy and by extracorporeal shockwave lithotripsy (ESWL). The application of the techniques in this context raised three methodological questions which are not satisfactorily resolved in the literature. The first is whether an ex ante or ex post perspective is best adopted for the measurement of quality of life (QoL). The second is the method for converting a short term deterioration in QoL followed by full health into QALYs and the reliability of the methods available. The third is the issue of indirect costs which, in the context of a temporary disease state, cannot be easily avoided. The economic evaluation found laparoscopic cholecystectomy to be generally superior than the competitor technologies (entailing lower costs and better outcomes). However, the results were sensitive to assumptions about the perspective for measuring benefits and the inclusion of indirect costs.

[Weizsäcker's concept of time from the current viewpoint]. Carl Friedrich von Weizsäcker's concept of time is deeply based on the asymmetry between past and future, which he considers as a fundamental aspect of Nature. I review these ideas and their philosophical back ground and confront them with a presentation of the concept of time in modern physics. I argue that the observed irreversibility of our world can be understood from fundamental laws which are invariant under time reversal. I conclude with an outlook on the expected theory of quantum gravity.

Rabbit meat as a source of bacterial foodborne pathogens. Even though worldwide production of rabbit meat is >1,000,000 tons, little information is available for rabbit meat microbiology. This study provides data on the prevalence of Salmonella, Escherichia coli O157:H7, Yersinia enterocolitica, Listeria spp., motile Aeromonas spp., and Staphylococcus aureus on rabbit meat. A total of 24 rabbit carcasses from two abattoirs and 27 rabbit meat packages from supermarket displays were examined. In addition to culturing methods, associated virulence genes were investigated by PCR in suspect isolates and samples. Neither Salmonella nor E. coli O157:H7 was detected. All samples were negative for virulence-associated invA, stx1, and stx2 genes. At one abattoir, two carcasses (3.9%) carried Y. enterocolitica yst-, and two were positive for the yst gene, although viable Y. enterocolitica cells were not recovered from these samples. Seven samples (13.7%) were contaminated with Listeria. Of them, three were positive for hly and iap genes (Listeria monocytogenes hly+ / iap+), two carried Listeria seeligeri, one carried Listeria ivanovii, and one carried Listeria innocua. For detectable motile Aeromonas spp. (average count, 1.77 +/- 0.62 log CFU/g), the contamination rate was 35.3%, although ca. 90% of the samples were positive for the aerA and/or hlyA genes. The majority of aeromonad isolates were Aeromonas hydrophila aerA+ / hlyA+. Aeromonas caviae, Aeromonas popoffii, Aeromonas schubertii, and the two biovars of Aeromonas veronii were also isolated. The prevalence of S. aureus contamination (average count, 1.37 +/- 0.79 log CFU/g) was 52.9%. Among 27 S. aureus isolates, two harbored genes for staphylococcal enterotoxin B (seb), and two harbored genes for staphylococcal enterotoxin C (sec). The remaining isolates were negative for sea, seb, sec, sed, and see.

Intrahepatic cholestasis induced by amoxicillin/clavulanic acid (Augmentin): a report on two cases. Two patients who developed a severe but reversible cholestatic jaundice during and after treatment with an amoxicillin/clavulanic acid preparation (Augmentin) are described. The diagnosis of drug-induced intrahepatic cholestasis was based on the clinical course, biochemical pattern and on histological findings. Since amoxicillin alone does not induce liver injury, the combination of amoxicillin and clavulanic acid or clavulanic acid alone could be responsible for this adverse reaction, probably through a metabolic idiosyncrasy or a hypersensitivity mechanism. Although more than 100 cases of hepatotoxic reactions have been reported to the pharmaceutical company (Beecham Laboratories) and several reports have been published, the incidence of hepatotoxicity of this antibiotic is relatively rare, since this antibiotic has been widely used. However, recognition of this benign and reversible cholestatic syndrome is important to avoid unnecessary, expensive and invasive diagnostic procedures.

Epidemiology of childhood burns in Maiduguri north-eastern Nigeria. Burns is a global problem and has its toll especially in a developing region like ours where poverty and ignorance are still rife. Previous studies in the sub-region have lumped children and adults together. We retrospectively studied the factors that lead to burns in children and the peculiarities in managing them. All case notes of burns injury in children managed at the University of Maiduguri Teaching Hospital between 1991-2000 were retrospectively studied. A total of 219 children were studied. Children of age below 5 years were affected more than children above 5 years (168 vs. 51) with toddlers 1-2 years constituting a significant proportion of those below 5 years (71 vs. 168). The male to female ratio was 1.6:1 with a preponderance of male children below 10 years and the females between 11-15 years of age. The commonest cause of burns was scald (64.4%) in the household, which is usually accidental, but 3 were suicide attempts by teenage pregnant females 11-15 years protesting forced marriages, a cultural problem in our environment. Flame burns ranked second (27.4%) and results mainly from careless storage, adulteration and hawking of petroleum products. More than 50% of the patients sustained major burns resulting in high morbidity and mortality rate of 16%. Burn is a major public health problem and will require public/school health education campaign on childhood household safety. Appropriate legislation and enforcement on the sale of petroleum products would help to reduce the scourge.

Effect of recombinant human insulin-like growth factor-1 on the inflammatory response to acute renal injury. Renal ischemic injury evokes an inflammatory response with increased cytokine and major histocompatibility complex (MHC) expression and a mild interstitial infiltrate. This "injury response" could contribute to the tendency of ischemically injured renal transplants to reject. The studies presented here evaluated the ability of recombinant human insulin-like growth factor-1 (rhlGF-1) given after renal injury to prevent renal inflammation. The left renal pedicle of CBA and BALB/c mice was clamped for 60 min, and rhlGF-1 (25, 50, 100 micrograms) was administered sc at 2, 24, 48, 72, and 96 h after reflow. Cytokine and MHC expression was monitored in the injured kidney, compared with the contralateral kidney. In untreated mice, a single episode of injury induced the expression of MHC mRNA and products and tumor necrosis factor-alpha (TNF-alpha) mRNA, and depressed preproepidermal growth factor (ppEGF) mRNA, for up to 5 wk. With immunohistology, epithelial Class I and II MHC expression was shown to be increased for 2 wk, and Class II positive interstitial cells were shown to be increased for up to 5 wk. The ischemically injured kidneys from mice treated with rhlGF-1 and examined at 5 days showed a dose-dependent normalization of all of the changes of the injury response. This included prevention of the increased expression of MHC and cytokines and the Class II positive interstitial cells, and restoration of ppEGF mRNA. Thus the complex and long-lasting increase in proinflammatory cytokines and MHC expression that follow renal ischemia can be interrupted by treatment with rhlGF-1 beginning 2 h after the injury. This therapy may have applications to the injury response in renal transplants.

Both JNK and apoptosis pathways regulate growth and terminalia rotation during Drosophila genital disc development. Apoptosis is necessary for the regulation of growth during development, but the precise details of this regulation have not been completely characterized. In this study, we used the Drosophila genital disc as a model to analyze the contribution of apoptosis to growth regulation. We studied the expression or activity of several elements of the apoptotic death pathway such as Drosophila inhibitor of apoptosis1, caspases, the apoptotic genes reaper (rpr) and head involution defective, as well as elements of the Jun-NH2-terminal kinase (JNK) pathway. We found that the JNK pathway is active in a dynamic, asymmetric and genitalia-specific manner. Apoptosis, as measured in terms of the expression of a variety of apoptotic molecules, occurs in a JNK-dependent and -independent manner and was detected among engrailed (en) expressing cells. JNK regulation of apoptotic genes is necessary to control growth in both sexes and rotation in males; this regulatory role is necessary to execute en(+) cell death and to activate expression of rpr in these cells. rpr is up-regulated at antero-posterior borders, and this expression appears to be of particular importance in the control of growth, since the balance between cell proliferation and death in those regions appears to depend on the equilibrium between pro- and anti-apoptotic factors at a cellular level.

Morphogenetic Alterations in Melipona quadrifasciata anthidioides (Hymenoptera: Apidae) Associated with Pesticides. Bees are major pollinators of both native flora and cultured crops. Nonetheless, despite their key functional role in ecosystems and agriculture, bee populations have been affected worldwide by deforestation and contamination by insecticides. Conversely, little is known about the effects of pesticides on morphogenetic development of neotropical stingless bees. We compared the fluctuating asymmetry (FA) in newly emerged bees and foragers of Melipona quadrifasciata anthidioides exposed to pesticides (experimental greenhouse and cultivated field). In addition, visitation behavior of foragers was inferred from pollen analyses and direct observation. A significant increase of FA (P < 0.001) was detected in bees from the greenhouse. Even though pesticides might affect their development, foragers seem to avoid contaminated plants whenever possible, as confirmed by pollen and visitation analyses. Consequently, the conservation of natural forests in agricultural landscapes is essential to ensure the health of colonies in stingless bees.

Organization, alternative splicing, polymorphism, and phylogenetic position of lamprey CD45 gene. CD45 of jawed vertebrates is a receptor-type protein tyrosine phosphatase regulating lymphocyte development and activation. To shed light on the evolution of the CD45 gene, the organization of its orthologue in the lamprey, a jawless vertebrate, was determined. Compared to its mammalian and fugu counterparts, the lamprey gene was found to be lacking several exons in the segment encoding the extracellular part of the protein. In consequence, this part contains only one instead of the two or three fibronectin type III domains typical of the mammalian molecules. The lamprey transcripts of the CD45 gene occur in several variants originating by alternative splicing, including some not observed previously in other vertebrates. Most remarkable of these are splice variants generated by the use of intra-exonic splicing signals and thus lacking one half, one third, or two thirds of an exon and yet apparently translated in the correct reading frame. The lamprey gene contains polymorphic sites not only in the segment encoding the extracellular portion but also in the segment specifying the cytoplasmic part of the molecule. Polymorphism is generated by both mutations and recombination. Some of the alleles may have persisted long enough to represent transspecies polymorphism presumably maintained by positive selection. Phylogenetic analysis suggests that ancestors of the CD45 gene may have existed before the divergence of coelomate from pseudocoelomate metazoans.

Negative cone biopsies. A reappraisal. To analyze the incidence of negative cone biopsies and evaluate the significance of the findings. The study population consisted of women who underwent cervical conization at a university teaching hospital from February 1996 to December 2001. Three modalities were used for conization: CO2 laser, large loop excision of the transformation zone and needle excision of the transformation zone. Negative cones were defined as those not showing evidence of human papillomavirus infection, intraepithelial neoplasia of squamous or glandular origin, or invasive disease. During the study period, 817 conizations were performed. Of these, 206 (25%) were negative. Less than half the patients (41.7%) had a punch biopsy that matched the subsequent cone biopsy specimen. The negative cone rate in women with a punch biopsy showing cervical intraepithelial neoplasia (CIN) 1 was 60% in contrast with those who had a biopsy indicating CIN 2-3; the latter percentage was 16.5%, and the difference was statistically significant. Close adherence to international guidelines during workup of an abnormal smear, meticulous colposcopy performed by a certified colposcopist and careful evaluation of punch biopsies by pathologists might help to decrease the negative cone rate.

Graphene-nickel interfaces: a review. Graphene on nickel is a prototypical example of an interface between graphene and a strongly interacting metal, as well as a special case of a lattice matched system. The chemical interaction between graphene and nickel is due to hybridization of the metal d-electrons with the π-orbitals of graphene. This interaction causes a smaller separation between the nickel surface and graphene (0.21 nm) than the typical van der Waals gap-distance between graphitic layers (0.33 nm). Furthermore, the physical properties of graphene are significantly altered. Main differences are the opening of a band gap in the electronic structure and a shifting of the π-band by ∼2 eV below the Fermi-level. Experimental evidence suggests that the ferromagnetic nickel induces a magnetic moment in the carbon. Substrate induced geometric and electronic changes alter the phonon dispersion. As a consequence, monolayer graphene on nickel does not exhibit a Raman spectrum. In addition to reviewing these fundamental physical properties of graphene on Ni(111), we also discuss the formation and thermal stability of graphene and a surface-confined nickel-carbide. The fundamental growth mechanisms of graphene by chemical vapor deposition are also described. Different growth modes depending on the sample temperature have been identified in ultra high vacuum surface science studies. Finally, we give a brief summary for the synthesis of more complex graphene and graphitic structures using nickel as catalyst and point out some potential applications for graphene-nickel interfaces.

Photochemical internalisation, a minimally invasive strategy for light-controlled endosomal escape of cancer stem cell-targeting therapeutics. Despite progress in radio-, chemo- and photodynamic-therapy (PDT) of cancer, treatment resistance still remains a major problem for patients with aggressive tumours. Cancer stem cells (CSCs) or tumour-initiating cells are intrinsically and notoriously resistant to conventional cancer therapies and are proposed to be responsible for the recurrence of tumours after therapy. According to the CSC hypothesis, it is imperative to develop novel anticancer agents or therapeutic strategies that take into account the biology and role of CSCs. The present review outlines our recent study on photochemical internalisation (PCI) using the clinically relevant photosensitiser TPCS2a/Amphinex® as a rational, non-invasive strategy for the light-controlled endosomal escape of CSC-targeting drugs. PCI is an intracellular drug delivery method based on light-induced ROS-generation and a subsequent membrane-disruption of endocytic vesicles, leading to cytosolic release of the entrapped drugs of interest. In different proof-of-concept studies we have demonstrated that PCI of CSC-directed immunotoxins targeting CD133, CD44, CSPG4 and EpCAM is a highly specific and effective strategy for killing cancer cells and CSCs. CSCs overexpressing CD133 are PDT-resistant; however, this is circumvented by PCI of CD133-targeting immunotoxins. In view of the fact that TPCS2a is not a substrate of the efflux pumps ABCG2 and P-glycoprotein (ABCB1), the PCI-method is a promising anti-CSC therapeutic strategy. Due to a laser-controlled exposure, PCI of CSC-targeting drugs will be confined exclusively to the tumour tissue, suggesting that this drug delivery method has the potential to spare distant normal stem cells.

Nurse teacher models in clinical education from the perspective of student nurses--A mixed method study. The aim was to describe and compare the clinical teacher's role in different models of clinical practice from the perspective of student nurses. The study took place in collaboration with two Swedish universities that applied different educational models in clinical practice. A mixed method approach was used. The quantitative part had a comparative design and the qualitative part had a descriptive design. The study group consisted of 114 student nurses (response rate 87%). Fifty-three of them had met clinical teachers employed at the university and not participating in the daily clinical work (University Nurse Teachers, UNTs), whilst 61 had met clinical teachers dividing their time between teaching and nursing (Clinical Nurse Teachers, CNTs). Eight students participated in the qualitative part of the study. A questionnaire including the CLES+T scale was used to ascertain the students' perception of the clinical teacher's role, complemented by interviews directed towards an enrichment of this perception. Students meeting CNTs agreed more strongly than those meeting UNTs that the teacher had the ability to help them integrate theory and practice. Whilst spontaneous meetings between students and CNTs occurred, students mostly met UNTs in seminars. Students meeting UNTs felt alone but did appreciate having someone outside the clinical environment to provide support if they did not get along with their preceptor. In the case of UNTs, it is important that they keep their knowledge of clinical issues updated and visit the clinical placement not only for seminars but also to give students emotional support. In the case of CNTs, it is important that they are members of the faculty at the university, take part in the planning of the clinical courses and are able to explain the learning goals to the students.

Primary bladder angiosarcoma with no apparent previous exposure to carcinogens: a case report. Angiosarcomas are rare vascular neoplasms, and visceral involvement is quite uncommon. Predisposing factors that are thought to contribute to the development of angiosarcomas include ionizing radiation and chemical agents. Particularly, the association of angiosarcomas with therapeutic radiation has been previously emphasized. Nonurothelial bladder tumors are quite rare, too. Sarcomas represent the most common mesenchymal tumors of the bladder and generally share an extremely aggressive biologic behavior. A 67-year-old, white woman presented with primary angiosarcoma of the bladder and with no apparent risk factors or previous exposure to the carcinogens typically related to such neoplasms. A biopsy performed due to gross hematuria by endoscopic resection revealed an infiltrative, poorly differentiated neoplasm that was interpreted as high grade papillary urothelial carcinoma. A radical cystectomy, with regional lymphadenectomy and bilateral hysterosalpingo-oophorectomy, was performed. The pathological examination revealed a voluminous and extensively necrotic mass, histologically compatible with an angiosarcoma of the bladder. Despite a multimodal therapeutic approach, the patient died within a short time. This report summarizes the clinical course and highlights the histological features of this tumor. This case falls within the limited group of primary angiosarcoma of the bladder with very aggressive clinical features in a patient without recognized risk factors.

Revised planetary protection policy for solar system exploration. In order to control contamination of planets by terrestrial microorganisms and organic constituents, U.S. planetary missions have been governed by a planetary protection (or planetary quarantine) policy which has changed little since 1972. This policy has recently been reviewed in light of new information obtained from planetary exploration during the past decade and because of changes to, or uncertainties in, some parameters used in the existing quantitative approach. On the basis of this analysis, a revised planetary protection policy with the following key features is proposed: deemphasizing the use of mathematical models and quantitative analyses; establishing requirements for target planet/mission type (i.e., orbiter, lander, etc.) combinations; considering sample return missions a separate category; simplifying documentation; and imposing implementing procedures (i.e., trajectory biasing, cleanroom assembly, spacecraft sterilization, etc.) by exception, i.e., only if the planet/mission combination warrants such controls.

[Papillary and cystic tumor of the pancreas. Histological, immunohistochemical and flow cytometric study]. The authors are reporting a case of papillary and cystic neoplasm of the pancreas. This rare malignant epithelial neoplasm occurs mostly in young women and has a more favorable prognosis than the adenocarcinoma. Radiologic investigations showed a well demarcated, heterogeneous, hypovascular mass. The histological study showed the proliferation of epithelial cells in a papillary pattern. The immunochemistry was negative for markers of adenocarcinoma but positive for vimentin, alpha-1-antitrypsin, alpha-1-antichymotrypsin and neuron specific enolase. Receptors of progesterone were also detected. By flow cytometric analysis, the tumours was hypoploid. The histogenesis of these tumours remained controversed. Ultrastructural details of the neoplastic cells suggest that these tumours originate from small duct cells; detection in several cases of markers for endocrine neoplasm suggests that they originate from primitive multipotential cells, that may show exocrine or endocrine differentiation.

High-permeability membrane hemodialysis and hemofiltration in acute hepatic coma: experimental and clinical results. A high-permeability polyacrylonitrile membrane was used for hemodialysis in experimental animals with induced liver ischemia and for acute treatment of 39 patients with fulminant hepatic failure. Measurements were made of amino acids and other relevant compounds; nine patients survived. In long-term studies, the polyacrylonitrile membrane was used for hemofiltration in ten clinical cases of fulminant hepatic failure and coma. Five patients, including two pregnant women, survived.

Pressure-derived fractional flow reserve to assess serial epicardial stenoses: theoretical basis and animal validation. Background-Fractional flow reserve (FFR) is an index of stenosis severity validated for isolated stenoses. This study develops the theoretical basis and experimentally validates equations for predicting FFR of sequential stenoses separately. Methods and Results-For 2 stenoses in series, equations were derived to predict FFR (FFR(pred)) of each stenosis separately (ie, as if the other one were removed) from arterial pressure (P(a)), pressure between the 2 stenoses (P(m)), distal coronary pressure (P(d)), and coronary occlusive pressure (P(w)). In 5 dogs with 2 stenoses of varying severity in the left circumflex coronary artery, FFR(pred) was compared with FFR(app) (ratio of the pressure just distal to that just proximal to each stenoses) and to FFR(true) (ratio of the pressures distal to proximal to each stenosis but after removal of the other one) in case of fixed distal and varying proximal stenoses (n=15) and in case of fixed proximal and varying distal stenoses (n=20). The overestimation of FFR(true) by FFR(app) was larger than that of FFR(true) by FFR(pred) (0.070+/-0.007 versus 0.029+/-0.004, P<0.01 for fixed distal stenoses, and 0.114+/-0.01 versus 0.036+/-0. 004, P<0.01 for fixed proximal stenoses). This overestimation of FFR(true) by FFR(app) was larger for fixed proximal than for fixed distal stenoses. Conclusions-The interaction between 2 stenoses is such that FFR of each lesion separately cannot be calculated by the equation for isolated stenoses (P(d)/P(a) during hyperemia) applied to each separately but can be predicted by more complete equations taking into account P(a), P(m), P(d), and P(w).

Approaches to methadone treatment: harm reduction in theory and practice. The paper analyses methadone treatment in Copenhagen -- as it is described by methadone users and staff at different outpatient centres. The starting point is a theoretical model distinguishing between two different approaches to methadone treatment: 'palliative' and 'curative'. Included in the model are three dimensions (1) treatment goals at the methadone centres (abstinence vs. stabilisation) (2) treatment focus (focus on addiction vs. focus on the consequences of addiction) and (3) conceptualisation of methadone (methadone as similar to or different from heroin). The paper shows that there is a discrepancy between the attitudes of the staff and those of the users. While the staff favour an almost clear-cut palliative approach to methadone treatment, defining curative goals as both unrealistic and as belonging to the past, the users prefer an approach that does not exclude the goal of abstinence and does not focus on the consequences of drug use alone but also on their problematic relationship to drugs (legal as well as illegal). Furthermore, the users' attitudes towards methadone are far more ambivalent than the staff's. For the users, methadone is not just medicine; it is also a dependence-producing and 'dangerous' drug.

Bilateral testicular germ cell tumours: a single hospital experience. The incidence of testicular germ cell tumours (TGCT) is increasing and the improvement in survival may lead to an increased incidence of bilateral tumours. We examined the incidence, prognosis, clinical and histological characteristics, treatment and outcome of patients with bilateral TGCTs based on 15 years of experience from a single institution. We reviewed the charts from all patients treated for a testicular tumour germ cell at Hospital Vall d'Hebron in Barcelona, Spain. The information was retrospectively obtained from the patients' hospital. All the patients were evaluated with clinical history, physical exam, serum markers (alphaFP, LDH and betahCG), ultrasonographic evaluation of the testicles, computed tomography (CT) scans of the chest, abdomen and pelvis, surgery, location and histology of first and second tumour, treatment after the surgery and follow-up. Of 151 patients with TGCT, 8 (5.3%) developed bilateral tumours, seven (4.6%) were metachronous and one (0.7%) synchronous tumours. Two patients underwent testis-sparing surgery for the second tumour. All the patients are alive without evidence of disease based on physical exam, tumour markers and CT scan. Survival in patients with bilateral testicular germ cell tumours (BTGCT) is similar to that of patients with unilateral TGCT. There is no standard therapy to treat BTGCT and each patient requires a tailored therapeutic treatment.

Multidisciplinary perspective on the management of appendiceal adenocarcinoma: case review of 10 patients from a university hospital and current considerations. Adenocarcinoma of the vermiform appendix is rare. It constitutes less than 0.5% of all gastrointestinal malignancies. Pathologically, appendiceal neoplasms are categorized into various subtypes depending on cell lineage. We considered a case series of appendiceal invasive adenocarcinomas from 2004 to 2013 managed in a teaching hospital. We discuss our management dilemmas, given the lack of randomized controlled trial data that exist. A detailed look at the histopathology, case series, and literature is presented. Ideal standards ought to be constructed for the management of this rare pathology, with a particular focus on exploring the indications and potential benefits, as well as difficulties, of ileocolic lymphadenectomy. Appendiceal adenocarcinoma ought to be managed in the same way as a cecal adenocarcinoma.

Esophageal submucosa: the watershed for esophageal cancer. Submucosal esophageal cancers (pT1b) are considered superficial, implying good survival. However, some are advanced, metastasizing to regional lymph nodes. Interplay of cancer characteristics and lymphatic anatomy may create a watershed, demarcating low-risk from high-risk cancers. Therefore, we characterized submucosal cancers according to depth of invasion and identified those with high likelihood of lymph node metastases and poor survival. From 1983 to 2010, 120 patients underwent esophagectomy for submucosal cancers at Cleveland Clinic. Correlations were sought among cancer characteristics (location, dimensions, histopathologic cell type, histologic grade, and lymphovascular invasion [LVI]), and their associations with lymph node metastasis were identified by logistic regression. Associations with mortality were identified by Cox regression. As submucosal invasion increased, cancer length (P < .001), width (P < .001), area (P < .001), LVI (P = .007), and grade (P = .05) increased. Invasion of the deep submucosa (P < .001) and LVI (P = .06) predicted lymph node metastases: 45% (23/51) of deep versus 10% (3/29) of middle-third and 7.5% (3/40) of inner-third cancers had lymph node metastases, as did 46% (12/26) with LVI versus 18% (17/94) without. Older age and lymph node metastases predicted worse 5-year survival: 94% for younger pN0 patients, 62% for older pN0 patients, and 36% for pN1-2 patients regardless of age. Submucosal cancer characteristics and lymphatic anatomy create a watershed for regional lymph node metastases in the deep submucosa. This previously unrecognized divide distinguishes superficial submucosal cancers with good survival from deep submucosal cancers with poor survival. Aggressive therapy of more superficial cancers is critical before submucosal invasion occurs.

Access points to the different levels of health care and demographic predictors in a country without a gatekeeping system. Results of a cross-sectional study from Austria. The challenges for health care systems are evident both in terms of costs and of healthy life expectancy. It was the aim of this study to assess the access points towards the different levels of care and predictors for consulting a specialist without having consulted a general practitioner (GP), a common way of access to the Austrian health care system, a system without gatekeeping function. The database used for this analysis was the Austrian Health Interview Survey 2006-07, with data from 15 474 people. Statistical analyses included descriptive statistics as well as multivariate logistic regression models. In the 12 months before the survey, 78.8% consulted a GP, 67.4% consulted a specialist, 18.6% visited an outpatient department and 22.8% had a hospital stay at least once. Overall, 15.1% visited a specialist, 8.5% an outpatient department and 8.1% a hospital without consulting a GP concomitantly. One of the main reasons for direct specialist use was a preventive check-up visit. Tertiary education and migration background increased significantly the chance of having been to a specialist without GP contact for both sexes. The overall access rates for specialists as well as the access rates for specialist without GP consultations were high. The findings point into the direction of a benefit through a structurally supported advocacy role for primary health care professionals. The knowledge gained could contribute to the health policy debate on the importance of coordination and continuity with special respect to demographic factors showing the importance of target-group-specific interventions.

Computational simulation of therapeutic parent artery occlusion to treat giant vertebrobasilar aneurysm. We applied computational fluid dynamics (CFD) analysis to assess 3D digital subtraction angiography findings in a patient with a giant vertebrobasilar aneurysm to simulate and compare the consequences of left and right vertebral artery occlusion. The balloon occlusion test suggested that occlusion of the right vertebral artery is the better way to treat this patient's aneurysm from the point of view of aneurysmal thrombosis and isolation from the circulation. The computer simulation supported this conclusion, at the same time indicating that from the point of view of pressure distribution on the wall of the aneurysm, the right vertebral occlusion may be also accompanied by an undesirable effect. A high-pressure area on the aneurysm wall in systole was revealed. This high pressure potentially could lead to subsequent aneurysmal growth, which indeed occurred, as was revealed by a follow-up examination 6 months later. This study is a good example of possible future applications of CFD in patients with cerebrovascular disease before therapeutic intervention.

Porencephaly and schizencephaly in adopted infants. Frequency ascertainment in a risk group. A formal inquiry on the health state of 1206 legally adopted children from Indonesia revealed cerebral palsy in 9 (0.9% of 1029 responses obtained), including two who had died. CT examination performed in 7 cases was abnormal in all. Four types of lesions were seen: 1. Bilateral full thickness porencephalies (BFTP lesion) in 4 cases, amounting to 0.4% of the total population on which response was obtained. 2. Full thickness porencephaly of the area of one internal carotid artery in 1 case. 3. Schizencephaly-like lesion in 1 case, confirmed by magnetic resonance imaging. 4. Supratentorial midline cyst resulting in hydrocephalus. The frequency of the BFTP lesion found in 4 out of 7 cerebral palsied investigated by CT is remarkable in view of its rarity in radiological studies on cerebral palsy and because of its relationship to prenatal rather than perinatal damage according to previous pathological studies. This is the first systematic study on the neurodevelopmental outcome of a group of adopted babies which indicates an increased risk to specific prenatal brain damage.

Heart failure patients' awareness and perceptions of the risk of using NSAIDs: a pilot study. The use of an NSAID by individuals with heart failure increases the likelihood of exacerbating the problem. Patients with heart failure were interviewed using a standardized questionnaire to determine their perceptions of the risks involved with the use of an NSAID. Of the 28 patients interviewed, 2 had been advised to avoid a particular medicine, but could not remember which medicine. The use of an analgesic that could exacerbate their heart failure was regarded as high risk (score >5 on a scale of 1-10) by 22 (79%) of the patients. In this small sample, most patients with heart failure were not aware of the risks of using NSAIDs. However, based on their responses, most patients would avoid the use of NSAIDs once educated about the adverse effects that these drugs might have on their heart failure.

Preparation of flexible models of hollow gastrointestinal organs. Flexible models of hollow gastrointestinal organs can be easily prepared by coating air-dried organs with a commercially available clear plastic compound. The plastic infiltrates the full thickness of organ walls to support and protect internal as well as external structures. Models are flexible, resistant to fluids, and lightweight. This plasticizing technique is particularly useful for the preservation and study of large animal gastrointestinal tracts.

Single capripoxvirus recombinant vaccine for the protection of cattle against rinderpest and lumpy skin disease. A recombinant capripoxvirus has been constructed containing a full-length cDNA of the fusion protein gene of rinderpest virus. The gene was inserted in the thymidine kinase gene of the capripox genome under the control of the vaccinia virus major late promoter p11 together with the Escherichia coli gpt gene in the opposite orientation under the control of the vaccinia early/late promoter p7.5. A vaccine prepared from this recombinant virus protected cattle against clinical rinderpest after a lethal challenge with a virulent virus isolate. In addition, the vaccine protected the cattle against lumpy skin disease.

Primary (autoimmune) hypophysitis: a single centre experience. Autoimmune hypophysitis (AH) is a rare autoimmune inflammatory disorder of pituitary gland. To analyse clinical, hormonal, radiological features and management outcomes of AH. Retrospective analysis of patients with primary hypophysitis (where secondary causes of hypophysitis were ruled out) was carried out from 2006 to 2012. AH emerged as the most plausible aetiology and the diagnosis of exclusion. Twenty-four patients with AH (21 females and 3 males) were evaluated. They presented with symptoms of expanding sellar mass (83.3%), symptoms of anterior pituitary hormone deficiencies (58.3%), and diabetes insipidus (16.7%). The anterior pituitary hormonal axes affected were cortisol (75%), thyroid (58.33%) and gonadotropin (50%). All had sellar mass on magnetic resonance imaging, which was symmetrical (91.7%) and homogenously enhancing (91.7%). Stalk thickening, suprasellar extension, loss of posterior pituitary hyperintensity and parasellar T2 dark sign were seen in 87.5, 87.5, 71.5, and 50% respectively. In addition to hormone replacement, five (20.83%) patients underwent trans-sphenoidal surgery, fifteen (62.5%) were watchfully monitored, while four cases (16.67%) received steroid pulse therapy. On follow up imaging, the sellar mass regressed in all, while, stalk thickening was persistent in 13/19 (68.4%) non-operated patients at median follow up of 1 year. Pituitary hormone axis recovery was seen in 10 (41.67%) and was seen in cortisol 10/18 (55.5%) followed by gonadotropin 5/12 (41.67%) axis. Characteristic radiology helps in diagnosis of AH even without tissue diagnosis. Non-operative treatment is the preferred treatment modality. Steroid pulse therapy potentially improves pituitary axis recovery.

HBV genotypic resistance to lamivudine in kidney recipients and hemodialyzed patients. Lamivudine is a potent inhibitor of human immunodeficiency virus reverse transcriptase and hepatitis B virus (HBV) DNA polymerase. Its overall efficiency is clearly hampered by relapse at discontinuation and by risk of genotypic resistance. We describe herein the first cases of HBV resistance to lamivudine in kidney recipients and hemodialyzed patients. We analyzed 26 HBV-infected kidney recipients and five hemodialyzed patients treated with lamivudine who became serum HBV DNA-negative (by Digene test). The biological and virological follow-up identified breakthrough as defined by the reappearance of serum HBV DNA. In two cases of breakthrough, HBV DNA was amplified and sequenced through the polymerase domain, including the YMDD motif, before the beginning of treatment and at time of breakthrough to determine genotypic mutations. Ten breakthroughs (reappearance of serum HBV DNA) were observed after a median follow-up of 11 months in eight kidney recipients and two hemodialyzed patients after a median duration of treatment of 16.5 (from 4 to 31) months of treatment. Previous HBe/anti-HBe seroconversion was not observed in the patients who escaped. In two kidney recipients, the comparison of HBV-DNA sequences before the treatment and after the breakthrough identified in one case a mutation of the highly conserved YMDD motif (YVDD), whereas in the second case, no genotypic mutation was observed in the sequenced region. We report the first cases of HBV genotypic resistance to lamivudine in kidney recipients and hemodialysis patients. Genotypic resistance is observed after 4-31 months of therapy. The YMDD mutation does not account for all cases of virological escape.

Serum levels of testosterone and luteinizing hormone in patients with chronic renal disease. Androgen metabolism has been studied in 33 patients (17 males, 16 females) with chronic renal disease not undergoing dialysis treatment. The mean value of serum testosterone was reduced in both sexes, whereas that of serum leteinizing hormone (LH) was elevated in the males. The parameters became increasingly pathological with decreasing renal function. There was no correlation between serum testosterone and serum LH, indicating an inadequate hypothalamic-pituitary response to the testicular dysfunction. The clinical significance of this relative hypoandrogenaemia is obscure. A possible relation to the anaemia and bone disease of chronic renal failure is discussed.

Hyperdontia in children--case reports. Dental anomalies are craniofacial abnormalities of form, function or position of the teeth, bones and tissues of the jaw and mouth. Dental anomalies can range from missing or stained teeth to cleft palates. The National Institute of Dental and Craniofacial Research (NIDCR) estimates that in the United States a baby is born every hour with a craniofacial defect. Dental anomalies are caused by hereditary, systemic, traumatic or local factors. The abnormalities of the teeth can be divided into those that are influenced by environmental forces and those that are idiopathic or appear hereditary in nature. In many cases the cause and effect are obvious. In others the primary nature of the problem is less distinct.

Theoretical study of the temperature dependence of dynamic effects in thymidylate synthase. A theoretical study of the temperature dependence of dynamic effects in the rate limiting step of the reaction catalyzed by thymidylate synthase is presented in this paper. From hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) optimizations of transition state structures within a fully flexible molecular model, free downhill molecular dynamics trajectories have been performed at four different temperatures. The analysis of the reactive and non-reactive trajectories in the enzyme environment has allowed us to study the geometric and electronic coupling between the substrate, the cofactor and the protein. The results show how the contribution of dynamic effects to the rate enhancement measured by the transmission coefficients is, at the four studied temperatures, negligible. Nevertheless, the rare event trajectories performed have shown how the hydride transfer and the scission of the conserved active site cysteine residue (Cys146 in E. coli) take place in a concerted but asynchronous way; the latter takes place once the transfer has occurred. The analysis of the dynamics of the protein reveals also how the relative movements of some amino acids, especially Arg166, and a water molecule, promotes the departure of the Cys146 from the dUMP. Finally, it seems that the protein environment creates an almost invariant electric field in the active site of the protein that stabilizes the transition state of the reaction, thus reducing the free energy barrier.

Changing patterns of mortality in 25 European countries and their economic and political correlates, 1955-1989. We investigated trends in mortality in European countries by cause of death in the period 1955-1989, and studied the role of economic and political conditions. We extracted data on age-standardised mortality by country (n = 25), sex, cause of death (n = 17) and calendar year from an internationally harmonised dataset. We analysed changes in dispersion of mortality as well as changes in the association of mortality with average income and levels of democracy. After 1960, dispersion in all-cause mortality in Europe as a whole increased due to diverging trends for many specific causes of death, particularly for cerebrovascular disease. This coincided with widening disparities in average income, and strengthening of the association between levels of democracy and mortality. Divergence in Central and Eastern Europe could largely be explained from stagnating trends in average income and an increasing mortality disadvantage related to its democratic deficit. Although this was a politically stable period, mortality patterns were highly dynamic, and prefigured the more dramatic mortality trends after 1990. Economic and political stagnation probably explains the diverging trends in Central and Eastern Europe.

Enhanced generation of perfluoroalkyl carboxylic acids (PFCAs) from fluorotelomer alcohols (FTOHs) via ammonia-oxidation process. With the phase-out of persistent, bioaccumalative, and toxic perfluoroalkyl carboxylic acids (PFCAs), it is needed to explore the potential release of PFCAs from precursors being emitted into the environment. Biotransformation of fluorotelomer alcohols (FTOHs) via biological processes in wastewater treatment plants (WWTPs) leads to discharge of PFCAs into receiving waters. However, the commonly existed microbial activity that can impact on FTOHs biodegradation in WWTPs remains unclear. The objective of present research was to explore the relationship between ammonia-oxidation process and the enhanced PFCAs generation from FTOHs biodegradation under aerobic activated sludge. The obtained results indicate that the cometabolism process performed by nitrifying microorganisms (NMs) was responsible for enhanced PFCAs generation. Among NMs, the ammonia-oxidation bacteria that can express non-specific enzyme of ammonia monooxygenases resulted in the enhanced PFCAs generation from FTOHs. Meanwhile, the different addition amount of ammonia contributed to different defluorination efficiency of FTOHs. The present study further correlated the enhanced PFCAs generation from FTOHs biodegradation with ammonia-oxidation process, which can provide practical information on effective management of PFCAs generation in WWTPs.

Wheel running and environmental enrichment differentially modify exon-specific BDNF expression in the hippocampus of wild-type and pre-motor symptomatic male and female Huntington's disease mice. Brain-derived neurotrophic factor (BDNF) is an essential neurotrophin and regulation of its expression is complex due to multiple 5' untranslated exons which are separately spliced to a common coding exon to form unique mRNA transcripts. Disruption of BDNF gene expression is a key to the development of symptoms in Huntington's disease (HD), a fatal neurodegenerative condition. Abnormal epigenetic modifications are associated with reduced gene expression in late-stage HD but such regulation of BDNF gene expression has yet to be investigated. We hypothesized that BDNF gene expression is altered in the HD hippocampus of pre-motor symptomatic R6/1 transgenic HD mice, correlating with a change in the DNA methylation profile. The effects of wheel-running and environmental enrichment on wild-type mice, in association with a proposed environment-mediated correction of BDNF gene expression deficits in HD mice, were also investigated. Using real-time PCR, levels of total BDNF mRNA were found to be reduced in the hippocampus of both male and female HD mice. Wheel-running significantly increased total BDNF gene expression in all groups of mice except male HD mice. In contrast, environmental enrichment significantly increased expression only in male wild-type animals. Further quantification of BDNF exon-specific transcripts revealed sex-specific changes in relation to the effect of the HD mutation and differential effects on gene expression by wheel-running and environmental enrichment. The HD-associated reduction of BDNF gene expression was not due to increased methylation of the gene sequence. Furthermore, environment-induced changes in BDNF gene expression in the wild-type hippocampus were independent of the extent of DNA methylation. Overall, the results of this study provide new insight into the role of BDNF in HD pathogenesis in addition to the mechanisms regulating normal BDNF gene expression.

Hyperpolarization of the liver cell membrane by palmitate as affected by glucose and lactate: implications for control of feeding. Since the membrane potential of liver cells being in contact with vagal afferents has been proposed to represent a major signal in metabolic control of food intake, we investigated the effect of palmitate, glucose and lactate on the membrane potential of hepatocytes with microelectrodes using superfused mouse liver slices. The mice used for the experiments were fed a fat-enriched diet (18% fat). Palmitate (0.5 mM) hyperpolarized the membrane of hepatocytes by 3-4 mV, and this hyperpolarization was not affected by 5-10 mM glucose and 0.5-1 mM lactate. Glucose alone did not influence the potential, even when mice fed a high carbohydrate diet were employed. At lactate concentrations > or = 2 mM the palmitate induced hyperpolarization was eliminated and 5 mM lactate or pyruvate alone hyperpolarized the liver cell membrane. Similar to the palmitate induced hyperpolarization, the lactate induced hyperpolarization was prevented by the K-channel blocker TEA, suggesting that activation of K channels is involved in the hyperpolarization. The results show that physiological concentrations of glucose and lactate do not affect the hyperpolarization of the liver cell membrane due to fatty acid oxidation. The implications of these findings with regard to control of food intake by fatty acid oxidation and lactate metabolism are discussed. The observations are consistent with a signal function of the hepatic membrane potential in physiological control of food intake by fatty acid oxidation. Hepatic lactate metabolism at supraphysiological lactate concentrations may also produce a satiety signal coded by the hepatic membrane potential.

[New methods for the evaluation of bone quality. Assessment of bone quality by HR-pQCT.] Bone microstructure is one of the important factors for defining bone quality. High Resolution peripheral Quantitative CT(HR-pQCT)enables us to evaluate bone microstructure in patients with osteoporosis noninvasively. It is applied to fracture risk assessment, analysis for pathogenesis of osteoporosis, and study of effects of osteoporosis drugs.

Successful importation of cytarabine into the United States during a critical national drug shortage. The importation of cytarabine into the United States during a critical national drug shortage is described. In March 2011, the hospital pharmacy team at an acute care hospital was struggling to supply cytarabine for four specific patients, all of whom needed critical maintenance therapy after induction. Cytarabine was not available from any source in the United States, and the team had no realistic projected release dates for back orders. Idis UK, a pharmaceutical distributor, was asked to identify available drug and eventually found an unrestricted source of cytarabine in Switzerland. Once available drug was identified, a price quote for the supply amount was written for our consideration. This was inspected carefully to ensure that the drug, strength, dosage form, and any other ingredients listed were indeed what were expected. The pharmacy department worked with the hospital's department of finance and accounting to submit the necessary financial paperwork. Payment was electronically sent to the distributor before the drug was shipped. Before the order for cytarabine was placed, the associated risks and benefits were assessed. The patients provided consent to treatment with the unapproved product. Acceptance of the price quote and instructions to order the drug were e-mailed to the distributor. The necessary documentation was completed and included with the shipment. The importation process, from initial inquiries to delivery, took 21 days. The importation of cytarabine amid a drug shortage required a complex process that involved the efforts of an overseas distributor, the cooperation of multiple health professionals, and meticulous attention to detail.

Synthetic access to poly-substituted 6-alkoxyindoles from 1,3-cyclohexanediones and nitroolefins through facile aromatization reaction. 6-Alkoxy-3-arylindoles were efficiently prepared from 1,3-cyclohexanedione enol ethers and beta-nitrostyrenes. Michael addition using the kinetically generated enolate, followed by Zn reduction of a nitro group of the resulting adducts produced the nitrones which were then treated with acetic anhydride to induce aromatization by dehydration and N-acetylation, which furnished the desired indoles by the DDQ oxidation. This methodology provides an easy entry toward various poly-substituted 6-alkoxyindoles.

Androgen action in female reproductive physiology. In the last decade, it has been proven that androgens acting via the androgen receptor (AR) play an important role in the regulation of female reproductive function. However, the specific site of action and the precise pathways involved remain to be fully elucidated. This review aims to combine findings from emerging basic research to provide new insights into the roles of AR-mediated actions, and the mechanisms involved, in normal ovarian, uterine, and mammary gland function. Our understanding of the specific roles of androgens in females has been hindered as females with complete androgen insensitivity cannot be generated by natural breeding, and interpretation of results from pharmacological studies has led to confusion as some androgens can be converted into estrogens, which can mediate actions via estrogen receptors. However, with the creation of global and cell-specific female AR knockout mouse models by Cre-LoxP technology, and the use of aromatizable and nonaromatizable androgens, novel roles for androgens in the regulation of female reproductive physiology have been revealed. AR-mediated mechanisms play important roles in mediating normal ovarian, uterine, and mammary gland function and there is hope that further elucidation of the role of androgens in female reproductive physiology may translate into the development of novel, evidence-based, and targeted treatment for androgen-associated conditions.

Fecal source tracking, the indicator paradigm, and managing water quality. Fecal source tracking is used because standard methods of measuring fecal contamination in water by enumerating fecal indicator bacteria (FIB) do not identify the sources of the contamination. This paper presents a critical review of source tracking with emphasis on the extent to which methods have been tested (especially in comparison with other methods and/or with blind samples), when methods are applicable, their shortcomings, and their usefulness in predicting public health risk or pathogen occurrence. In addition, the paper discusses the broader question of whether fecal source tracking and fecal indicator monitoring is the best approach to regulate water quality and protect human health. Many fecal source-tracking methods have only been tested against sewage or fecal samples or isolates in laboratory studies (proof of concept testing) and/or applied in field studies where the "real" answer is not known, so their comparative performance and accuracy cannot be assessed. For source tracking to be quantitative, stability of ratios between host-specific markers in the environment must be established. In addition, research is needed on the correlation between host-specific markers and pathogens, and survival of markers after waste treatments. As a result of the exclusive emphasis on FIB in legislation, monitoring has concentrated on FIB and lost sight of pathogens. A more rational approach to regulating water quality would start with available epidemiological data to identify pathogens of concern in a particular water body, and then use targeted pathogen monitoring coupled with targeted fecal source tracking to control them. Baseline monitoring of indicators would become just one tool among many.

Atrial fibrillation pathophysiology: implications for management. Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is an important contributor to population morbidity and mortality. An arrhythmia that is particularly common in the elderly, AF is growing in prevalence with the aging of the population. Our understanding of the basic mechanisms that govern AF occurrence and persistence has been increasing rapidly. This article reviews the basic pathophysiology of AF over a broad range of levels, touching on the tissue mechanisms that maintain the arrhythmia, the relationship between clinical presentation and basic mechanisms, ion channel and transporter abnormalities that lead to ectopic impulse formation, basic models and tissue determinants of reentry, ion channel determinants of reentry, the nature and roles of electric and structural remodeling, autonomic neural components, anatomic factors, interactions between atrial and ventricular functional consequences of AF, and the basic determinants of atrial thromboembolism. We then review the potential implications of the basic pathophysiology of the arrhythmia for its management. We first discuss consequences for improved rhythm control pharmacotherapy: targeting underlying conditions, new atrium-selective drug targets, new targets for focal ectopic source suppression, and upstream therapy aiming to prevent remodeling. We then review the implications of basic mechanistic considerations for rate control therapy, AF ablation, and the prevention of thromboembolic events. We conclude with some thoughts about the future of translational research related to AF mechanisms.

Micronuclei and nuclear anomalies in Mexico's indigenous population. To determine the number of micronuclei and nuclear anomalies in Mexico's indigenous population. One hundred twenty indigenous individuals were evaluated, including thirty from the ethnicities Cora, Huichol, Tarahumara and Tepehuano. The number of micronuclei (MN) and any nuclear abnormality (NA) in oral mucosa cells, including cells with nuclear buds, binucleated cells, cells with karyolysis, karyorrhetic, condensed chromatin and pyknotic cells were determined for each participant. Tepehuano and Tarahumaras showed the greatest damage to DNA. The Tepehuano group presented the highest number of MN and NA, this being a significant difference (p < 0.05) compared with the rest of the studied groups. This group also presented the highest herbicide exposure (46.7%). In relation to the smoking and drinking habits, these were more frequent in the Tarahumara group (33.3 and 50% respectively). The ethnic diversity, habits and customs may influence the DNA nuclear integrity in the Amerindian groups.

[Study on transmission rate and quantitative structure-property relationships of alkaloids and iridoid compounds on UF membranes with MWCOS of 1000]. Taking alkaloids and iridoid as the study, relationships of quantitative molecular structure and transmission rate on UF membrane were developed initially at exploring the mechanism of UF in Chinese herb decoction and to lay a foundation for the optimal design of membrane technology in the production of Chinese drugs preparation. The transmission rate of eight alkaloids and iridoid compounds in three UF membranes was determined, and quantitative structure-property relationships between quantitative molecular structure and transmission rate were developed by the data mining method of PLS or SVM. Quantitative structure-property relationship models of three membranes were developed by the data mining method of PLS or SVM, correlation coefficients were all greater than 0.9. The parameters in the models included LUMO, AlogP, CMR, K&H2, K&H3. The relationship of UF transmission rate of these eight compounds and their molecular weight are not simply linearly dependent, the main factors which affect the UF transmission rate are capacity of gain or loss electron, hydrophilicity or hydrophobic and compound spatial structure.

In vitro, greenhouse and field assessments of cassava lines for resistance to anthracnose disease caused by Colletotrichum gloeosporioides f.sp. manihotis. Fifty-three cassava lines were selected from breeding populations at the International Institute of Tropical Agriculture (IITA), Ibadan, Nigeria and screened in vitro for resistance to cassava anthracnose disease (CAD). The in vitro inoculation of stem cuttings with the fungus Colletotrichum gloeosporioides f.sp. manihotis showed significant differences (p +/- 0.05) in acervuli production and in the sensitivity of the cassava lines to the fungal infection after 7 days of incubation at 25 degrees C. Cassava lines 88/01084, 91/00595, 91/00475, 91/00344, 91/00684, 91/00313, 91/00422, and 91/00344 were highly resistant, with necrotic lesion sizes less than 7 mm. In contrast pedigree lines 88/02549, 89/0008, 91/00390 and 91/00402 were highly susceptible with the largest necrotic lesion size being greater than 20 mm. Ten cassava lines from the in vitro screening that showed varying levels of resistance to CAD were selected, based on their flowering abilities for diallel hydridization trials, and were further screened in greenhouse and field trials for CAD resistance. The greenhouse and field screening showed significant varietal differences (p +/- 0.05) in sensitivity to the fungus. In all cases, the progeny lines showed correlated levels of resistance irrespective of the type of screening or assessments. Correlation analysis of the in vitro, greenhouse and field assessments showed that there was a good correspondence among all three methods of evaluating for CAD.

Perioperative management of the patient with diabetes mellitus undergoing outpatient or elective surgery. Perioperative management for elective or outpatient surgical procedures should be tailored to the individual patient with diabetes mellitus. The approach will vary depending on whether the patient is insulin requiring or not and whether recent diabetes control has been good or poor. Elevated blood glucose prior to surgery will often improve with correction of the condition requiring surgery.

Effects of intravenous or endotracheal lidocaine on circulatory changes during recovery from general anesthesia. Intravenous lidocaine (1.5 mg.kg(-1)) was not effective in attenuating the circulatory changes and the cough reflex induced by airway stimulation during recovery from general anesthesia, whereas endotracheal 4% lidocaine (3 ml) was effective. The arterial concentration of the intravenously administered-lidocaine peaked at a level of 9.52 +/- 0.81 microg.ml(-1) 0.5 min later. The arterial concentration of the endotracheally administered-lidocaine peaked at 1.44 +/- 0.13 microg.ml(-1) 15 min later. These findings indicate that the endotracheal administration of lidocaine may be superior to the intravenous administration for attenuating the circulatory changes and the cough reflex during recovery from general anesthesia, and that the arterial concentration of lidocaine did not correlate with the clinical efficacy for this purpose.

Membrane ERalpha-dependent activation of PKCalpha in endometrial cancer cells by estradiol. The purpose of this study was to investigate the role of the oestrogen receptor subtypes ERalpha and ERbeta in mediating the non-genomic effects of 17-beta-estradiol (E(2)) in two human endometrial cancer cell lines (RL95-2 and HEC-1A) expressing different levels of these receptor subtypes. Western blotting analysis using phosphorylation site-specific antibodies showed that physiological concentrations of E(2) rapidly (<20 min) activated PKCalpha, but not PKCdelta in the RL95-2 cell line. E(2) had no effect on PKCalpha or PKCdelta activity in the HEC-1A cell line and suppressed basal levels of PKA activity in both cell lines. PKCalpha activation coincided with its membrane translocation. ERalpha was detected in the RL95-2 cell line by Western blotting and RT-PCR but not in the HEC-1A cells, which did express ERbeta. A selective ERalpha agonist PPT had the same effect as E(2) on PKCalpha activation in the RL95-2 cells, but the selective ERbeta agonist DPN had no such effect. A 46kDa variant of ERalpha increased in abundance in the cell membrane within 20 min of E(2) treatment suggesting that ERalpha mediated the E(2) non-genomic effects on PKCalpha through the formation of a membrane associated signalling complex.

[Sport injuries in full contact and semi-contact karate]. Karate enjoys great popularity both in professional and recreational sports and can be classified into full, half and low contact styles. The aim of this study was the analysis of sports injuries in Kyokushinkai (full contact) and traditional Karate (semi-contact). In a retrospective study design, 215 active amateur karateka (114 full contact, 101 semi-contact) were interviewed by means of a standardised questionnaire regarding typical sport injuries during the last 36 months. Injuries were categorised into severity grade I (not requiring medical treatment), grade II (single medical treatment), grade III (several outpatient medical treatments) and grade IV (requiring hospitalisation). In total, 217 injuries were reported in detail. 125 injuries (58%) occurred in full contact and 92 (42%) in semi-contact karate. The time related injury rate of full contact karateka was 1.9/1000 h compared to 1.3/1000 h of semi-contact karateka (p < 0.05). The most common types of injuries were musculoskeletal contusions (33% full contact, 20% semi-contact), followed by articular sprains with 19% and 16%. The lower extremity was affected twice as often in full contact (40%) as in semi-contact (20%) karate. Training injuries were reported by 80% of the full contact and 77% of the semi-contact karateka. Most injuries, both in training and competition, occurred in kumite. 75% of the reported injuries of full contact and 70% of semi-contact karateka were classified as low grade (I or II). The high rate of injuries during training and kumite (sparring) points to specific prevention goals. The emphasis should be put on proprioceptive training and consistent warm-up. In the actual competition the referees play a vital role regarding prevention.

[Validity of "Gravistat" device for the improvement of statics and locomotion: interrelation with neuro-auto-immune reactions]. The purpose was to study the interrelation between effectiveness of the dynamic proprioceptive correction (DPC) of static and locomotor disorders at the late residual phase of children's cerebral paralysis (CCP) with the help of "Gravistat" and the auto-immune reactions (AIR) to neurospecific proteins (NSP). Data of an original method of AIR evaluation by the ratio of IgC to proteins S-100 and alpha-2-glycoprotein in blood serum make it evident that the method can pinpoint events in the perinatal period (3.5-18 yrs.) both in healthy individuals and patients with residual CCP. In addition, the method can predict efficiency of the DPC therapy of CCP and, probably, cerebral circulation disturbances, craniocerebral injury, and other conditions with a neuro-autoimmune component.

The latest advancements in proteomic two-dimensional gel electrophoresis analysis applied to biological samples. Two-dimensional gel electrophoresis (2DE) is one of the fundamental approaches in proteomics for the separation and visualization of complex protein mixtures. Proteins can be analyzed by 2DE using isoelectric focusing (IEF) in the first dimension, combined to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) in the second dimension, gel staining (silver and Coomassie), image analysis, and 2DE gel database. High-resolution 2DE can resolve up to 5,000 different proteins simultaneously (∼2,000 proteins routinely), and detect and quantify <1 ng of protein per spot. Here, we describe the latest developments for a more complete analysis of biological fluids.

CT venous phase venography with 64-detector CT angiography in the diagnosis of acute pulmonary embolism. The value of computed tomographic (CT) venography in combination with CT pulmonary angiography has been questioned because of the potential dangers of radiation. Accordingly, we retrospectively evaluated the diagnostic yield of 64-detector CT angiography with CT venography. Among patients who routinely underwent CT venography with CT angiography, the CT angiogram showed acute pulmonary embolism (PE) in 206 of 1903 patients (10.8%). A positive CT venogram in a patient with a negative CT angiogram was shown in 25 of 1903 patients (1.3%). Either the CT angiogram or the CT venogram showed venous thromboembolism in 231 of 1903 patients (12.1%). The proportion of patients with venous thromboembolism diagnosed only by a CT venogram was 25 of 231 (10.8%). In conclusion, the proportion of patients with venous thromboembolism diagnosed only by a CT venogram is sufficiently high to merit consideration of its use especially in those at high risk for DVT.

Predictive Value of Preoperative Magnetic Resonance Imaging Findings for Survival and Local Recurrence in Patients Undergoing En Bloc Resection of Sacral Chordomas. Few studies have assessed the prognostic importance of preoperative magnetic resonance imaging (MRI) scan findings in patients undergoing en bloc resection of sacral chordomas. To (1) report in-depth imaging characteristics of sacral chordomas, (2) describe the patterns of local and distant recurrence, and (3) determine imaging predictors of overall survival (OS) and local recurrence (LR). This retrospective case series was obtained from a prospectively maintained spine database from 1995 to 2016. All patients underwent en bloc resection of sacral chordomas. Detailed demographic, outcome, and MRI data were collected. A survival analysis was completed with multivariable cox regression to assess the impact of MRI findings on OS and LR. A total of 41 patients underwent en bloc resection of sacral chordoma with preoperative MRI scans. Tumor characteristics included lobulated: (93%) and soft tissue tail (54%). The following areas had tumor invasion lobulated: sacroiliac (SI) joint (15%), ilium (5%), piriformis (61%), gluteus (46%), subcutaneous fat (32%), and lumbosacral venous plexus (22%). After multivariable analysis, only subcutaneous fat extension was an independent predictor of decreased OS (hazard ratio 5.30, 95% confidence interval 1.47-19.19, P = .011). Though not significant after multivariable analysis, the following factors were significant predictors of LR after univariate logrank testing: above the L5/S1 disc space (P = .004), SI joint invasion (P = .036), and piriformis extension (P = .022). The presence of subcutaneous fat extension was an independent predictor of decreased OS. Other MRI findings with potential for future evaluation include size, presence of soft tissue tail, extension above L5/S1, and SI joint and piriformis invasion.

The influence of targeted temperature management on the pharmacokinetics of drugs administered during and after cardiac arrest: a systematic review. Pharmacokinetic parameters of drugs are widely investigated under normothermic conditions and normal hemodynamic parameters. The European Resuscitation Council recommends the use of targeted temperature management (TTM) with a target temperature of 34 °C in cardiac arrest (CA) patients. The aim of this literature review is to investigate the influence of CA combined with TTM on the pharmacokinetics of drugs. Results of preclinical and clinical studies are compared with each other. Only the most important drugs, administered during CA in emergency setting, were studied. A literature search was conducted within PubMed and Google Scholar. The search terms included 'therapeutic hypothermia', 'TTM', 'drug metabolism', 'pharmacokinetics during hypothermia', 'cardiac arrest/etiology'. In Pubmed, MeSH-terms were also included: 'myocardial infarction/therapy', 'heart arrest/complications' and 'hypothermia'. To search for preclinical studies: the search terms 'pigs' and 'swine' were used. After the primary shift of relevant findings, further articles were found through references of these (snowballing method), as well as through related articles as suggested by the databases. Due to the reduced cardiac output during TTM, most of the distribution volume ([Formula: see text]) of drugs included in this literature study is decreased. Only the [Formula: see text] of chlorzoxazone in CA rats and midazolam in non-CA patients are significantly increased during respectively deep and mild hypothermia. The renal, hepatic and biliary clearance of drugs administered during CA/TTM/hypothermia are decreased. The combination of a decreased [Formula: see text] and a decrease in the metabolization/excretion of drugs during CA/TTM result in higher plasma concentrations compared to the plasma concentrations during CA without TTM.

Prenatal diagnosis of beta-thalassemia by reverse dot-blot hybridization in southern China. Beta-thalassemia (thal) is the most common genetic disease and is widely distributed in southern China. Prenatal diagnosis is needed to prevent the birth of thalassemic offspring in couples at-risk. This can be performed in the first or second trimester of pregnancy by DNA analysis using polymerase chain reaction (PCR). As there are more than 30 mutations causing beta-thal in Chinese, the point mutation detection by reverse dot-blot for common mutations together with direct DNA sequencing was developed for prenatal diagnosis. Using reverse dot-blot, we were able to offer complete diagnosis in 315 (99.4%) of 317 pregnancies. Only two fetuses needed the DNA sequencing technique for diagnosis. Of the 319 at-risk fetuses, 82 (25.7%) were found to be normal, 143 (44.8%) to be heterozygous for beta-thal and 94 (29.5%) to be affected with beta-thal. Therefore, the combination of reverse dot-blot with direct DNA sequencing can perform prenatal diagnosis by DNA analysis in almost all cases at- risk of beta-thal in southern China.

On ultrasound-induced microbubble oscillation in a capillary blood vessel and its implications for the blood-brain barrier. The complex interaction between an ultrasound-driven microbubble and an enclosing capillary microvessel is investigated by means of a coupled, multidomain numerical model using the finite volume formulation. This system is of interest in the study of transient blood-brain barrier disruption (BBBD) for drug delivery applications. The compliant vessel structure is incorporated explicitly as a distinct domain described by a dedicated physical model. Red blood cells (RBCs) are taken into account as elastic solids in the blood plasma. We report the temporal and spatial development of transmural pressure (P(tm)) and wall shear stress (WSS) at the luminal endothelial interface, both of which are candidates for the yet unknown mediator of BBBD. The explicit introduction of RBCs shapes the P(tm) and WSS distributions and their derivatives markedly. While the peak values of these mechanical wall parameters are not affected considerably by the presence of RBCs, a pronounced increase in their spatial gradients is observed compared to a configuration with blood plasma alone. The novelty of our work lies in the explicit treatment of the vessel wall, and in the modelling of blood as a composite fluid, which we show to be relevant for the mechanical processes at the endothelium.

[The validity of screening for hypertension in school-age children. A cross-sectional study of a sample of 861 pupils of the towns of Local Health Unit No. 22 of Vittoria (Sicily)]. In order to define the validity of a screening program for hypertension in schools, aiming to prevent an hypertensive status in adult age, we screened 861 children from schools on the area of our Medical District (U.S.L. 22--Vittoria--Sicily). The object of our study is to search for risk factors of hypertension, detectable at school age and, if existing, which age is more suitable for a screening program. We randomly sampled 861 children from different schools, aging 6, 10 and 13 years. The first step was to define the prevalence of hypertension and obesity in the sample, and the correlation between the two factors (transversal study). We found an overall prevalence of obesity at 6, 10, and 13 years of 6.69%, 18.22% and 17.7% respectively. The prevalence of hypertension was 4.01%, 11.4%, and 6.98% at 6, 10 and 13 years respectively. The second step is to create a personal record of each child, which will be followed up to the age of 18 years, containing familial and nutritional informations, periodic evaluations of height, weight, blood pressure and biologic sampling (longitudinal study). Our preliminary results confirmed the correlation between obesity and hypertension, although they do not help to clarify why the prevalence of hypertension decreases from 10 to 13 years whereas obesity maintains the same prevalence at the mentioned ages.

Expressing TERF1 in tobacco enhances drought tolerance and abscisic acid sensitivity during seedling development. Previously, we reported on a tomato ERF transcription activator, TERF1, which was concluded to act as a linker between ethylene and osmotic signal pathways. We now report on the regulatory role of TERF1 in ABA sensitivity and drought response during seedling development. Northern blotting analysis indicated that the transcripts of TERF1 were significantly accumulated in response to drought, cold and ABA. TERF1 activated GCC box- or DRE-driven reporter gene expression in transient expression assay, subsequently increasing the tolerance to drought and the osmoticum, PEG6000, in tobacco expressing TERF1. Further tests showed that TERF1 did not affect the seed germination, but greatly enhanced the sensitivity during tobacco seedling development under ABA treatment. This ABA hypersensitivity in transgenic TERF1 tobacco is both indirect ethylene action and expressions of ABA responsive genes, demonstrating that TERF1 is a multifunctional ERF protein that can integrate different stress signal pathways.

Retinoid receptors in human esophageal squamous cell carcinoma: retinoid X receptor as a potent prognostic factor. Retinoids regulate cell proliferation and differentiation in normal and neoplastic tissue. These effects are mainly mediated by two types of nuclear retinoid receptors, retinoic acid receptors (RAR) and retinoid X receptors (RXR). RXR have been demonstrated to play important roles in esophageal carcinoma, but the expression of RXRβ and RXRγ has not been examined in esophagus. Therefore, we examined the immunoreactivity of all subtypes of RAR and RXR in 53 non-neoplastic esophageal epithelium and 74 esophageal squamous cell carcinoma tissues. In non-neoplastic epithelium RARβ immunoreactivity was marked in the basal layer and weak in the suprabasal layer, but immunoreactivity of other retinoid receptors was detected in both of layers. In addition, the status of RARβ and RXRβ immunoreactivity inversely correlated with that of lymph node metastasis (P= 0.0477 and P= 0.0034, respectively); decreased RXRβ immunoreactivity of carcinoma cells was positively associated with adverse clinical outcome of the patients (P= 0.0187). These findings all indicate the important roles of retinoid receptors, especially, RXR in the esophageal squamous cell carcinoma.

Micropuncture and microanalytic studies of the rat testis and epididymis. Micropuncture techniques developed for the study of renal physiology have been adapted for investigation of the male reproductive tract. Ultramicro specimens were obtained in vivo from the tubules of the rat testis and epididymis. These samples were analyzed for sperm morphology and concentration. The new methods developed to conduct these studies are discussed in detail. The mean in vivo spermatocrits were 0.411 plus and minus 0.029, 0.355 plus and minus 0.019, and 0;731 plus and minus 0.028 in the seminiferous tubule, caput epididymidis, and caudal spermatocrit was significantly higher than the spermatocrit in the caput or seminiferous tubule. The percentages of abnormal spermatozoa in the caput and cauda were 5.5% plus and minus .7% and 4.3% plus and minus .6%, respectively.

Chalkstring of the mind. A little knowledge is o dangerous thing' goes the saying and the relevance of this remark will not, I hope, be confirmed by the future actions of certain misguided nurses. I say misguided because it is a foolish and unreasonable nurse who will accept nursing responsibilities outside of her competency.

Effect of inoculum-substrate ratio on acclimatization of pharmaceutical effluent in an anaerobic batch reactor. Anaerobic treatment has gained tremendous success over the past two decades for treatment of industrial effluents. Over the past 30 years, the popularity of anaerobic wastewater treatment has increased as public utilities and industries have utilized its considerable benefits. Low biomass production, row nutrient requirements and the energy production in terms of methane yield are the significant advantages over aerobic treatment process. Due to the disadvantages reported in the earlier investigations, during the past decade, anaerobic biotechnology now seems to become a stable process technology in respect of generating a high quality effluent. The objective of the present experimental study was to compare the biodegradability of recalcitrant effluent (pharmaceutical effluent) for various inoculum-substrate ratios. The batch experiments were conducted over 6 months to get effect of ratio of inoculum-substrate on the acclimatization of pharmaceutical effluent. The tests were carried out in batch reactors, serum bottles, of volume 2000 mL and plastic canes of 10000 mL. Each inoculum was filled with a cow dung, sewage and phosphate buffer. The batch was made-up of diluted cow dung at various proportions of water and cow dung, i.e., 1:1 and 1:2 (one part of cow dung and one part of water by weight for 1:1). The bottles were incubated at ambient temperature (32 degrees C-35 degrees C). The bottles were closed tightly so that the anaerobic condition is maintained. The samples were collected and biodegradability was measured once in four days. The bottles were carefully stirred before gas measurement. The substrate was added to a mixture of inoculum and phosphate nutrients. The variations in pH, conductivity, alkalinity, COD, TS, TVS, VSS, and VFA were measured for batch process. The biogas productivity was calculated for various batches of inoculum-substrate addition and conclusions were drawn for expressing the biodegradability of pharmaceutical effluent on acclimatization period and influent COD concentration.

Poisoning hospitalisations among reproductive-aged women in the USA, 1998-2006. To describe poisoning hospitalisations among reproductive-aged women from 1998 to 2006. 1998-2006 data from the Nationwide Inpatient Sample of the Healthcare Cost and Utilisation Project were used to identify hospitalisations for poisonings among US women aged 15-44 years. Differences in hospitalisation characteristics were compared by intent using χ(2) statistics. Trends in poisoning hospitalisation rates were calculated overall and by subgroup. There were approximately 636,000 poisoning hospitalisations in women aged 15-44 years during 1998-2006. Hospitalisations for intentionally self-inflicted poisonings had a higher proportion of women aged 15-24 years and privately insured women than did unintentional poisonings (p<0.001). Poisoning hospitalisations in rural areas and those that resulted in death were more likely to be of undetermined intent than those for which intent was specified (p<0.001). Co-diagnoses of substance abuse (34.5%) or mental disorders (66.5%) were high. The rate of poisoning hospitalisations overall and unintentional poisoning hospitalisations increased 6% and 22%, respectively, during this period (p<0.001). The most frequently diagnosed poisoning agent was acetaminophen. Poisonings attributable to acetaminophen, opioids, central nervous system stimulants and benzodiazepines increased, while poisonings attributable to antidepressants decreased (p<0.05). The increase in unintentional poisoning hospitalisations among women aged 15-44 years and the changing profile of poisoning agents should inform the healthcare community's poisoning prevention strategies. Poisoning prevention strategies should include a component to address substance abuse and mental health disorders among reproductive-age women.

Mild traumatic brain injury, meaning made of trauma, and posttraumatic stress: a preliminary test of a novel hypothesis. Research has demonstrated that a substantial number of veterans returning from Iraq and Afghanistan with mild traumatic brain injury (mTBI) also contend with symptoms of posttraumatic stress disorder (PTSD). One possible contributing factor for the development and/or exacerbation of PTSD symptoms among individuals with mTBI could involve challenges processing trauma and integrating their memories into existing global meaning systems. The goal of this study was to provide a preliminary examination of whether meaning made of trauma could account for the association between mTBI and PTSD (i.e., reexperiencing, avoidance, and hyperarousal symptoms). The sample was comprised of 162 Iraq and/or Afghanistan veterans who presented for health care services at a Department of Veterans Affairs hospital. These veterans completed a two-level evaluation for mTBI as well as a self-report questionnaire assessing demographic and military background factors, meaning made of trauma, and PTSD symptomatology. Drawing on structural equation modeling, results indicated that probable mTBI was indirectly associated with the three domains of PTSD symptomatology via veterans' meaning made of trauma. Although the cross-sectional nature of this study limits the conclusions that can be drawn, these results offer support for difficulties with meaning-making as a contributing factor for risk of PTSD among veterans with mTBI. (PsycINFO Database Record (c) 2013 APA, all rights reserved).

Flavones and isoflavones from the west African Fabaceae Erythrina vogelii. The CH(2)Cl(2)/MeOH extract of the stem bark of Erythrina vogelii (Fabaceae) from Nigeria has yielded two novel isoflavones, 7,4'-dihydroxy-8-(gamma,gamma-dimethylallyl)-2''zeta-(4''-hydroxyisopropyl)dihydrofurano[1'',3'':5,6]isoflavone (vogelin H) (1) and 7,4'-dihydroxy-8-[(2'''zeta,3'''-dihydroxy-3'''-methyl)butyl]-2'',2''-dimethyl-3'',4''-dehydropyrano[1'',4'':5,6]isoflavone (vogelin I) (2), a novel flavone, 7,4'-dihydroxy-2'',2''-dimethyl-3'',4''-dehydropyrano[1'',4'':5,6]flavone (vogelin J) (3), and eight known flavonoids.

Effect of pH during heat processing of partially hydrolyzed whey protein. Whey protein isolate was modified by proteolysis using a broad-spectrum protease in combination with heat treatment of the hydrolysate. Half of the beta-lactoglobulin content was hydrolyzed when the degree of hydrolysis reached 5.1%. alpha-Lactalbumin and BSA were not attacked by the enzyme. Heating of the hydrolysate resulted in the formation of small and large aggregates, the proportion of which depended on the degree of hydrolysis and the pH during heating. The decrease in total sulfhydryl groups, as the degree of hydrolysis and heating pH increased, was associated with the formation of disulfide bonds. Whey protein hydrolysis at a degree of hydrolysis of 1.7%, followed by heating at pH 8.0, resulted in the highest amount of accessible sulfhydryl groups, reflecting the unfolded structure of the aggregates. Hydrolysate solubility at neutral pH averaged 98% when pH during heating was 4.0 or 8.0. Heating of whey protein at pH 6.0 resulted in a much lower solubility, which was attributed to the high proportion of large aggregates. Solubility of the hydrolysate at pH 4.5 was higher when pH during heating was adjusted to 4.0. Solubility of the hydrolysate heated at pH 6.0 and 8.0 improved with degree of hydrolysis > 1.7%. Results are discussed in relation to interactions of proteins and peptides during heat processing.

Health-Related Quality of Life and Cancer-Related Symptoms During Interdisciplinary Outpatient Rehabilitation for Malignant Brain Tumor. The aim of the study was to determine the relationships between functional outcomes, clinical symptoms, and health-related quality of life among patients with malignant brain tumors receiving interdisciplinary outpatient rehabilitation. A prospective study of 49 adults with malignant brain tumors participating in outpatient therapies was performed. Outcome measures included the Functional Assessment of Cancer Therapy-Brain (FACT-Br) for health-related quality of life and the Patient-Reported Outcome Measures Instrument Survey (PROMIS) Depression and Pain Behavior scales measured at admission, discharge, 1 and 3 mos after discharge. Day Rehabilitation Outcome Scale (DayROS), a functional measure, was measured at admission and discharge. The FACT-Br scores, PROMIS pain, and PROMIS depression scores did not significantly change. There were many negative associations seen between FACT-Br and PROMIS depression (all P < .0001) and less associations with PROMIS pain. There was a positive correlation between Day Rehabilitation Outcome Scale and FACT-Br (P = .0058) and a negative association with PROMIS pain (P = .028), but not with PROMIS depression. There were no correlations between Day Rehabilitation Outcome Scale gains and change in PROMIS depression, FACT-Br total, or PROMIS pain. Health-related quality of life, pain, and depression did not worsen. Patients who reported less depression and pain had better reported health-related quality of life. Level of function was also associated with HRQOL and pain, but not depression.

Improving performance of an accountable care organization on a quality measure assessing β-blocker use in systolic heart failure. The implementation and outcomes are described for a clinical pharmacist-generated initiative to improve the performance of a Medicare Pioneer accountable care organization (ACO) quality measure evaluating the percentage of patients at least 18 years of age with heart failure and a left ventricular ejection fraction (LVEF) of less than 40% who are prescribed with an evidence-based β-blocker (carvedilol, metoprolol succinate, or bisoprolol). Atrius Health clinical pharmacists developed several educational documents to facilitate appropriate prescribing of evidence-based therapies in patients with heart failure. After educating clinicians, clinical pharmacists reviewed patient charts to determine eligibility for initiating or switching to evidence-based β-blocker therapy. Medicare Pioneer ACO patients 18-85 years of age with heart failure and a current or prior LVEF of less than 40% were reviewed. Patients had a current prescription for metoprolol tartrate, atenolol, or no β-blocker. Patients were considered ineligible if they had a documented contraindication or intolerance to β-blocker therapy or were clinically unstable. Recommendations to initiate or switch to an appropriate β-blocker were sent electronically by a clinical pharmacist to an eligible patient's treating physician before a scheduled office visit. In approximately three months, 48 patients underwent chart review by a clinical pharmacist. Performance improved by 8% after the implementation, with 82% of eligible patients achieving the quality measure in 2014-an increase from 74% in 2013. The performance on a Medicare Pioneer ACO quality measure evaluating β-blocker use in systolic heart failure improved in a one-year period after a clinical pharmacist-generated initiative was implemented at Atrius Health practice sites.

Large-volume leukapheresis for peripheral blood progenitor cell collection in low body weight pediatric patients: a single center experience. Peripheral blood progenitor cells (PBPC) have became the preferred source of stem cells for autologous transplantation because of easier accessibility, rapid engraftment, and lower tumor cell contamination. In pediatric patients is very important to optimize peripheral blood stem cells (PBSC) harvesting to obtain a sufficient number of cells with a reduced number of leukapheresis. In this study we prospectively analyzed data on 43 large volume leukapheresis (LVL) from 20 consecutive low body weight pediatric patients with various malignancies. Patients' mean body weight was 16.6 kg (range, 8.9-32.0 kg), and the median age was 4 years (range, 1-10 y ears). Instead of saline, it was used irradiated and leukoreduced red blood cell (RBC) units to prime the machine in 15 patients weighting 25 kg or less. The median number of LVL was 2 (range, 1-4) and a mean of 5.2 patient's blood volume was processed per session lasting 165 min (range, 118-239). The mean number of CD34+ cells, one day before leukapheresis was 49 mm(-3) (range, 9-219). The PBPC collection yielded 24.7 x 10(8) total nucleated cells/kg (range, 6.2-74.0), 10.7 x 10(6) kg(-1) CD34+ cells (range, 3.6-53.7); 49.8 x 10(4) CFU-GM/kg (range, 6.4-198.1), and 65.6 x 10(4) BFU-E/kg (range, 7.6-198.1). The platelet count decreased significantly after each procedure 39.8 +/- 9.1 x 10(9) mm(-3) (range, 18.000-76.000) (p < 0.001). In conclusion, our data show that LVL for collection of PBPC in low weight pediatric patients is a safe and efficient procedure, but it may expose the patient to the risk of thrombocytopenia.

[Study of a sub-population of T-lymphocytes with the HLA-DR molecule in rheumatoid polyarthritis]. The sub-population of T-lymphocytes which express the DR antigen was studied in 48 patients with rheumatoid arthritis and in 42 controls. The sub-population of T-lymphocytes which express DR was found to be larger in the patients with rheumatoid arthritis. This increase is even more marked in cases of rheumatoid arthritis with high erythrocyte sedimentation rates and with a high level of immune complexes.

Unfolding spectrometer slit broadening effects from broad spectra. A method is described in which approximate correction for spectral slit broadening is performed at the same time that reflectance or transmittance data are being fitted with analytic dispersion curves. The method is valid for spectra whose structure is not too sharp on a scale comparable with the spectrometer resolution. It is not to be used for sharp line spectra. The key problem that is solved is to find the fastest way to compute the slit broadening effect on the spectra obtained from the trial dispersion curves. The method is applied, as an example, to analyze some reststrahlen data taken with a grating spectrometer in the far ir from a sample of PrCl(3). The same approximate method could also be used with data from other types of spectrometers having different slit broadening functions, such as from two-crystal x-ray spectrometers, in regions where very sharp spikes do not appear in the spectra.

Insecticidal action of mammalian galectin-1 against diamondback moth (Plutella xylostella). Previous studies showed that mammalian galectin-1 (GAL1) could interact with chitosan or chitin, one component of the peritrophic membrane (PM). This finding suggests that the PM could be a target of GAL1, which prompted the authors to explore the effect of GAL1 on larval growth and its potential mechanism. The development of Plutella xylostella (L.) larvae was significantly disturbed after they were fed recombinant GAL1. The histochemical structure and immunostaining pattern suggested that GAL1 treatment resulted in dose- and time-dependent disruption of the microvilli and abnormalities in these epithelial cells. Ultrastructural studies showed that the PM was not present in the midgut of GAL1-treated insects; instead, numerous bacteria were found in the lumen area. These results indicate that the protective function of the PM was disrupted by GAL1 treatment. Moreover, in vitro data showed that GAL1 interacts with chitosan/chitin in a dose-dependent manner, and also specifically binds to the PM in vitro. In view of the fact that the carbohydrate recognition domain of GAL1 recognises the structural motif N-acetyl lactosamine (Gal beta 1-4 GlcNAc), which is similar to that of chitin (beta-1,4 N-acetyl-D-glucosamine), it is proposed that the insecticidal mechanism of GAL1 involves direct binding with chitin to interfere with the structure of the PM.

Sex ratio of triplet births in Japan. The effects of paternal and maternal ages, gestational age and the socioeconomic factor of occupation on the sex ratio of triplet individuals were analysed using data on 4,290 triplet individuals which occurred in Japan during the period from 1955 to 1967 and in 1974. The sex ratios among live births and fetal deaths slightly decreased with time. The decline of the sex ratio was related to the decline of age-specific fertility in older mothers. The mean sex ratio was 0.479 during the period. The sex ratio is not high but similar to those of Europe and the USA. The sex ratio was lower in triplets than in twins or the general population. It seems that predominant male triplets may be selectively aborted in early gestational age compared with that of twins or the general population.

Low temperature growth of gallium oxide thin films via plasma enhanced atomic layer deposition. Herein we describe an efficient low temperature (60-160 °C) plasma enhanced atomic layer deposition (PEALD) process for gallium oxide (Ga2O3) thin films using hexakis(dimethylamido)digallium [Ga(NMe2)3]2 with oxygen (O2) plasma on Si(100). The use of O2 plasma was found to have a significant improvement on the growth rate and deposition temperature when compared to former Ga2O3 processes. The process yielded the second highest growth rates (1.5 Å per cycle) in terms of Ga2O3 ALD and the lowest temperature to date for the ALD growth of Ga2O3 and typical ALD characteristics were determined. From in situ quartz crystal microbalance (QCM) studies and ex situ ellipsometry measurements, it was deduced that the process is initially substrate-inhibited. Complementary analytical techniques were employed to investigate the crystallinity (grazing-incidence X-ray diffraction), composition (Rutherford backscattering analysis/nuclear reaction analysis/X-ray photoelectron spectroscopy), morphology (X-ray reflectivity/atomic force microscopy) which revealed the formation of amorphous, homogeneous and nearly stoichiometric Ga2O3 thin films of high purity (carbon and nitrogen <2 at.%) under optimised process conditions. Tauc plots obtained via UV-Vis spectroscopy yielded a band gap of 4.9 eV and the transmittance values were more than 80%. Upon annealing at 1000 °C, the transformation to oxygen rich polycrystalline β-gallium oxide took place, which also resulted in the densification and roughening of the layer, accompanied by a slight reduction in the band gap. This work outlines a fast and efficient method for the low temperature ALD growth of Ga2O3 thin films and provides the means to deposit Ga2O3 upon thermally sensitive polymers like polyethylene terephthalate.

Discovery of selective and orally available spiro-3-piperidyl ATP-competitive MK2 inhibitors. The identification of a potent, selective, and orally available MK2 inhibitor series is described. The initial absence of oral bioavailability was successfully tackled by moving the basic nitrogen of the spiro-4-piperidyl moiety towards the electron-deficient pyrrolepyridinedione core, thereby reducing the pK(a) and improving Caco-2 permeability. The resulting racemic spiro-3-piperidyl analogues were separated by chiral preparative HPLC, and the activity towards MK2 inhibition was shown to reside mostly in the first eluting stereoisomer. This led to the identification of new MK2 inhibitors, such as (S)-23, with low nanomolar biochemical inhibition (EC(50) 7.4 nM) and submicromolar cellular target engagement activity (EC(50) 0.5 μM).

Organizational change and employee mental health: A prospective multilevel study of the associations between organizational changes and clinically relevant mental distress. Objective The aim of the present paper was to elucidate the relationship between exposure to separate, multiple or repeated organizational change at both individual- and work-unit level and subsequent clinically relevant mental distress amongst employees two years after change had taken place. Methods A full panel, prospective design was utilized. Data were collected at two time-points two years apart, by self-administered, online questionnaires. Organizational change was measured by six items pertaining to separate types of change. Mental distress was measured using HSCL-10, with cut-off set to ≥1.85 to identify clinically relevant distress. Baseline sample consisted of 7985 respondents, of whom 5297 participated at follow-up. A multilevel analytic strategy was chosen as data were nested within work-units. Effects associated with exposure to organizational change at both individual- and work-unit level were estimated. Results Separate change: At the individual level, company reorganization [odds ratio (OR) 1.29, 95% confidence interval (CI) 1.01‒1.65], downsizing (1.51, 95% CI 1.12‒2.03) and layoffs (OR 1.46, 95% CI 1.01‒2.12) were prospectively associated with mental distress. At work-unit level, company reorganization (OR 1.46, 95% CI 1.04-2.04) was associated with mental distress, but the statistically significant association diminished when adjusting for the work factors job control, job demands and support. Multiple changes: At the individual level, exposure to multiple organizational changes at baseline were associated with mental distress at follow-up (OR 1.75, 95% CI 1.28‒2.38). Repeated change: At the individual level, exposure to repeated organizational change was associated with mental distress at follow-up (OR 1.84, 95% CI 1.29‒2.63). Conclusions Exposure to organizational changes at the individual level indicated an elevated risk of subsequent clinically relevant mental distress following both separate, multiple and repeated organizational changes. These associations were also present at work-unit level, but diminished when adjusting for certain work factors, indicating a possible mediating effect.

Higher energy intake at dinner decreases parasympathetic activity during nighttime sleep in menstruating women: A randomized controlled trial. Previous studies have found more frequent increases in dietary intake and nonrestorative nocturnal sleep during the luteal phase than in the follicular phase, but few studies have investigated how increased energy intake at dinner influences sleep by considering the correlation between female hormone and cardiac autonomic nervous system (ANS) activity. This study examined the effects of energy intake at dinner on ANS activity during nighttime sleep in order to evaluate restorative sleep in healthy women. We also examined whether ANS activity is associated with female hormone dynamics. Twenty-four healthy collegiate women participated in this randomized crossover trial. Each was assigned to receive a High Energy Dinner (HED) or Low Energy Dinner (LED) treatment. Energy ratios of each test meal (breakfast, lunch, and dinner) to total energy intake were 1:1:2 and 1:2:1 for HED and LED treatments, respectively. Each participant wore an ECG recorder before dinner and removed it upon waking the next morning. Power spectral analysis of heart rate variability was used to calculate low frequency (LF), high frequency (HF), and total spectral power (TP). Cardiac sympathetic (SNS) and parasympathetic (PNS) nervous system activity were evaluated as LF/HF and HF/TP, respectively. Mean HF/TP for the entire sleeping period was lower with HED treatment compared to LED treatment (41.7 ± 11.4 vs. 45.0 ± 12.13, P = .034). Intergroup comparisons of the initial 3-h sleeping period revealed that LF/HF (0.87 ± 0.82 vs. 0.66 ± 0.82, P = .013) and HF/TP (45.6 ± 13.9 vs. 51.5 ± 11.8, P = .002) were higher and lower, respectively, with HED treatment compared to LED treatment. Progesterone levels were positively correlated with LF/HF with LED treatment, and negatively correlated with HF/TP with both HED and LED treatments. Higher energy intake at dinner increases and decreases SNS and PNS activities, respectively, resulting in nonrestorative nocturnal sleep. In addition, a negative correlation was observed between progesterone and PNS activity, highlighting the difficulty of increasing PNS activity during sleep in the luteal phase compared to the follicular phase.

Bioscience and analytical thinking machines. Is science being limited by the restricted vision of the analytical scientist? Adrian Stevenson from the Institute of Biotechnology at University of Cambridge argues that human 3D visualisation abilities to find patterns are inadequate and that artificial intelligence may hold the vital key to understanding information dense biological systems.

Idiopathic granulomatous orbital inflammation. Idiopathic granulomatous inflammation is regarded as a histopathologic variant of an orbital pseudotumor and has a similar clinical presentation and treatment. However, the differential diagnosis including sarcoidosis, Wegener's granulomatosis, trauma, and infection must be ruled out. We present a 77-year-old man with a biopsy-proven lacrimal gland granulomatous inflammation of an unknown origin. Management by surgical debulking via an anterior orbitotomy achieved a good result with minimal complications.

Comparative auto-controlled study between swim-up and Percoll preparation of fresh semen samples for in-vitro fertilization. This study compared swim-up and Percoll preparation of fresh semen samples for in-vitro fertilization. Sixty trials of in-vitro fertilization (IVF), 38 with normal semen and 22 with abnormal semen, comprising 734 oocytes were included in the study. Each semen sample was prepared by both a swim-up technique and a simplified discontinuous (50%, 70%, 90%) Percoll gradient. The oocytes for each trial were distributed at random between the two sperm preparations and incubated with the same number of motile spermatozoa. Percoll gradient preparation produced a significantly higher final concentration of spermatozoa than swim-up preparation (mean +/- SEM: 6.6 +/- 1.5 x 10(6)/ml versus 1.9 +/- 0.2 x 10(6)/ml; P less than 0.01) but a significantly lower sperm motility (69 +/- 2% versus 94 +/- 1%; P less than 0.001) and a lower number of normal forms (55 +/- 2% versus 64 +/- 2%; P less than 0.01). The ability of the Percoll gradient method to extract motile spermatozoa was higher than that of the swim-up technique (20 +/- 15.6% versus 0.8 +/- 13.6%). Nevertheless, the rates of fertilization (61%), fertilization failure (18%) and polyspermia (9%), embryo quality evaluated by mean embryo scores (3.8 +/- 0.3) and the mean number of spare embryos frozen per trial (1.4 +/- 0.3) were strictly identical in both groups. The 24 pregnancies (including three from frozen--thawed embryos) obtained in these 60 trials (40% per oocyte retrieval) could not be separated according to the sperm preparation method, as embryos from both groups were replaced together.(ABSTRACT TRUNCATED AT 250 WORDS)

Recursive Mahalanobis separability measure for gene subset selection. Mahalanobis class separability measure provides an effective evaluation of the discriminative power of a feature subset, and is widely used in feature selection. However, this measure is computationally intensive or even prohibitive when it is applied to gene expression data. In this study, a recursive approach to Mahalanobis measure evaluation is proposed, with the goal of reducing computational overhead. Instead of evaluating Mahalanobis measure directly in high-dimensional space, the recursive approach evaluates the measure through successive evaluations in 2D space. Because of its recursive nature, this approach is extremely efficient when it is combined with a forward search procedure. In addition, it is noted that gene subsets selected by Mahalanobis measure tend to overfit training data and generalize unsatisfactorily on unseen test data, due to small sample size in gene expression problems. To alleviate the overfitting problem, a regularized recursive Mahalanobis measure is proposed in this study, and guidelines on determination of regularization parameters are provided. Experimental studies on five gene expression problems show that the regularized recursive Mahalanobis measure substantially outperforms the nonregularized Mahalanobis measures and the benchmark recursive feature elimination (RFE) algorithm in all five problems.

Clinical spectrum of enterovirus 71 infection in children in southern Taiwan, with an emphasis on neurological complications. An outbreak of enterovirus 71 (EV71) infection occurred in Taiwan in 1998. The clinical spectrums and laboratory findings for 97 patients with virus culture-proven EV71 infections were analyzed. Eighty-seven percent of the patients were younger than age 5 years. Hand-foot-and-mouth syndrome occurred in 79% of the children and central nervous system (CNS) involvement in 35%, including nine fatal cases. The predominant neurological presentations were myoclonus (68%), vomiting (53%), and ataxia (35%). Brain stem encephalitis was the cardinal feature of EV71 CNS involvement during this outbreak. Magnetic resonance imaging and pathological findings illustrated that the midbrain, pons, and medulla were the target areas. EV71 brain stem encephalitis can present either with cerebellar signs and an initially mild, reversible course or with overwhelming neurogenic shock and neurogenic pulmonary edema (NPE) resulting in a fatal outcome. Brain stem encephalitis that progressed abruptly to neurogenic shock and NPE was indicative of poor prognosis in this epidemic. Early aggressive treatment and close monitoring of the neurological signs are mandatory to improve the chance of survival.

Chemical screening platforms for autophagy drug discovery to identify therapeutic candidates for Huntington's disease and other neurodegenerative disorders. Autophagy is a cellular degradation process involved in the clearance of aggregate-prone proteins associated with neurodegenerative diseases. While the mTOR pathway has been known to be the major regulator of autophagy, recent advancements into the regulation of autophagy have identified mTOR-independent autophagy pathways that are amenable to chemical perturbations. Several chemical and genetic screens have been undertaken to identify small molecule and genetic regulators of autophagy, respectively. The small molecule autophagy enhancers offer great potential as therapeutic candidates not only for neurodegenerative diseases, but also for diverse human diseases where autophagy acts as a protective pathway. This review highlights the various chemical screening platforms for autophagy drug discovery pertinent for the treatment of neurodegenerative diseases.

Telithromycin: the first of the ketolides. To review the chemistry, spectrum of activity, pharmacology, clinical efficacy, and safety of telithromycin. A MEDLINE search from 1966 to December 2000 was performed via OVID and PubMed using the following search terms: HMR 3647, HMR3647, Ketek, RU 66647, and telithromycin. An extensive review of retrieved literature, abstracts from international scientific conferences, and minutes from regulatory authority meetings was also performed. Medicinal chemistry, in vitro, animal, and human trials were reviewed for information on the antimicrobial activity, clinical efficacy, pharmacology, and safety of telithromycin. Several chemical modifications to the macrolide structure have led to the development of telithromycin, the first ketolide antimicrobial that demonstrates improved activity against penicillin- and macrolide/azalide-resistant Streptococcus pneumoniae due to its unique binding to the ribosomal target site. Although telithromycin may be useful in the treatment of community-acquired respiratory tract infections due to its activity against common typical and atypical pathogens, questions concerning its reliable activity against Haemophilus influenzae need to be addressed. Telithromycin's pharmacokinetics permit once-daily dosing for abbreviated periods and good distribution into lung tissue and phagocytic cells. Clinical and bacteriologic cure rates have been similar to those of comparator agents in human efficacy trials; however, the incidence of adverse gastrointestinal events were generally higher with telithromycin patients. Like other macrolides and many newer fluoroquinolones, telithromycin's ability to prolong the QTc interval is a potential safety issue, especially in elderly patients with predisposing conditions or those who are concurrently receiving drugs that are substrates for CYP2D6 and 3A4. Liver function test elevations demonstrated during clinical trials, although not overtly severe, may warrant monitoring in some patients taking multiple hepatically metabolized/cleared agents. Telithromycin offers potential advantages over traditional macrolides/azalides for community-acquired respiratory tract infections caused by macrolide-resistant pathogens. Further studies are needed to elucidate its clinical efficacy against H. influenzae, potential drug interactions, and safety in various subpopulations.

An investigation of rugby scrimmaging posture and individual maximum pushing force. Although rugby is a popular contact sport and the isokinetic muscle torque assessment has recently found widespread application in the field of sports medicine, little research has examined the factors associated with the performance of game-specific skills directly by using the isokinetic-type rugby scrimmaging machine. This study is designed to (a) measure and observe the differences in the maximum individual pushing forward force produced by scrimmaging in different body postures (3 body heights x 2 foot positions) with a self-developed rugby scrimmaging machine and (b) observe the variations in hip, knee, and ankle angles at different body postures and explore the relationship between these angle values and the individual maximum pushing force. Ten national rugby players were invited to participate in the examination. The experimental equipment included a self-developed rugby scrimmaging machine and a 3-dimensional motion analysis system. Our results showed that the foot positions (parallel and nonparallel foot positions) do not affect the maximum pushing force; however, the maximum pushing force was significantly lower in posture I (36% body height) than in posture II (38%) and posture III (40%). The maximum forward force in posture III (40% body height) was also slightly greater than for the scrum in posture II (38% body height). In addition, it was determined that hip, knee, and ankle angles under parallel feet positioning are factors that are closely negatively related in terms of affecting maximum pushing force in scrimmaging. In cross-feet postures, there was a positive correlation between individual forward force and hip angle of the rear leg. From our results, we can conclude that if the player stands in an appropriate starting position at the early stage of scrimmaging, it will benefit the forward force production.

Response of human aldosteronoma cells in culture to the N-terminal glycopeptide of pro-opiomelanocortin and gamma 3-MSH. Cells were isolated from one of two adenomas from the adrenal cortex of a hypertensive patient with primary hyperaldosteronism. A primary culture of these cells responded with increased aldosterone secretion to gamma 3-MSH and human (residues 1-76) and porcine (residues 1-80) N-terminal peptides of pro-opiomelanocortin (POMC). EC50 was lowest for gamma 3-MSH, while maximal response was greater for both N-terminal peptides of POMC. We conclude that gamma 3-MSH derived from the N-terminal segment of POMC contains the active core of the aldosterone-stimulating activity of the N-terminal on these adrenal cells.

Formation of multinucleated cells that respond to osteotropic hormones in long term human bone marrow cultures. Studies of osteoclasts and their precursors in normal and pathological states have been severely hampered by the lack of an in vitro system for forming osteoclasts. We developed a human marrow culture system in which multinucleated cells with several characteristics of osteoclasts form. Multinucleated cells began to form during the first week of culture, with maximum numbers formed after 3 weeks. PTH (25-50 ng/ml) and 1,25-dihydroxyvitamin D3 (10(-10)-10(-8) M) increased formation of these cells, and these effects were inhibited by calcitonin. These multinucleated cells contained nonspecific esterase and tartrate-resistant acid phosphatase, a marker enzyme of osteoclasts, and had several ultrastructural features of osteoclasts. We used this marrow cell culture technique to study a patient with hyperparathyroidism and markedly increased osteoclasts on bone marrow biopsy. The marrow from this patient formed increased numbers of multinucleated cells in vitro. After parathyroidectomy both multinucleated cell formation in vitro and osteoclast numbers on bone biopsy decreased significantly. This long term marrow culture system represents the first demonstration of human osteoclast-like cell formation in vitro. This system should permit studies to evaluate factors controlling formation of cells with certain osteoclast characteristics in vitro and their precursors as well as to evaluate abnormalities in osteoclast formation in patients with metabolic bone disease.

Nutritional problems of the elderly. Malnutrition is common in elderly persons living in institutions and in the community. In many cases, the problem arises from a highly individual constellation of interacting physiologic, economic, and psychosocial causes that have the common effect of reducing nutrient intake. Protein-calorie and micronutrient undernutrition added to the normal effects of aging can undermine functional independence and diminish the quality of life of the elderly. The spectrum of the elderly is extremely broad, and, consequently, nutritional assessment and support must be highly individualized to be effective. A multidisciplinary approach focusing on prompt identification and treatment of correctable causes of undernutrition is most effective. There is a wide range of support modalities, from simple supplemental foods to total parenteral nutrition, any of which may be used successfully in an elderly patient, provided that the necessary care is taken to define the goals of therapy and to provide patient assessment and monitoring.

Effects of centrally acting beta adrenergic agonists on discrete trial conditioned avoidance behavior in rats. The acute effects of centrally acting beta adrenergic agonists on discrete trial conditioned avoidance responding in rats were examined. Clenbuterol (0.01-3.0 mg/kg), salbutamol (0.01-30 mg/kg), and prenalterol (30-300 mg/kg) suppressed avoidance responding in a dose-dependent manner at doses that did not produce escape failures. For comparative purposes, the effects of the tricyclic antidepressant desipramine (1.0-30 mg/kg) and the antipsychotic haloperidol (0.03-0.3 mg/kg) were similarly assessed. Both compounds suppressed avoidance responding in a dose-dependent manner. Only haloperidol (0.3 mg/kg) produced escape failures. Administered alone, the beta adrenergic antagonist propranolol (1.0 and 10 mg/kg) did not affect avoidance behavior. When administered prior to clenbuterol (0.1 mg/kg), salbutamol (1.0 mg/kg), or prenalterol (100 mg/kg), propranolol antagonized the beta adrenergic agonist-induced suppression of avoidance responding. The suppressive effect of desipramine (3.0 mg/kg) on avoidance performance only tended to be attenuated by propranolol. Propranolol had no effect on the ability of haloperidol (0.1 mg/kg) to reduce avoidance responding. These results suggest that the effects of the beta adrenergic agonists clenbuterol, salbutamol, and prenalterol on discrete trial avoidance behavior are mediated, in part, through agonist interactions with beta adrenergic receptors.

Recognition and treatment of oncologic emergencies. An oncologic emergency is a clinical condition resulting from a structural or metabolic change caused by cancer or its treatment that requires immediate medical intervention to prevent loss of life or quality of life. Five oncologic emergencies (septic shock, syndrome of inappropriate antidiuretic hormone, tumor lysis syndrome, disseminated intravascular coagulopathy, and spinal cord compression) are defined and described physiologically and clinically. Also, appropriate treatment of each oncologic emergency is discussed.

Survey on tuberculosis teaching in Brazilian nursing schools, 2004. To characterise tuberculosis (TB) teaching in Brazilian nursing schools by state and region and its theoretical and practical contents. In an educational research survey in 2004, 347 nursing schools were identified. Questionnaires were posted to faculties providing training in TB. Data were compiled in a database with a view to descriptive result analysis. Replies to the questionnaire were received by 32% of the nursing schools contacted. Undergraduate TB teaching is heterogeneous. For training in theory, the principle teaching method is through classes in 102 (91.9%) nursing schools. Practical TB teaching is carried out at the primary care level (89.2%). Teachers update their knowledge through events and internet; little reference is made to manuals. The time devoted to practical TB teaching ranges from 10 to 20 hours, although this is not always included in student training. Teaching in TB should go beyond the traditional model that focuses only on biological aspects. It should introduce tools that lead to permanent behavioural change, such as a more human approach and social and psychological aspects, such as living conditions, habits and customs. It should involve new partners, such as families, communities and other health professionals, and identify obstacles within the university.

New cladiellane diterpenes from the soft coral Cladiella australis of the Andaman and Nicobar Islands. Five new cladiellane diterpenes, (1R*,2R*,3R*,6S*,7S*,9R*,10R*,14R*)-3- acetoxy-6-(3-methylbutanoyloxy)cladiell-11(17)-en-7-ol [2], (1R*,2R*,3R*,6S*,7S*,9R*, 10R*,14R*)-3-butanoyloxycladiell-11(17)-en-6,7-diol [3], (1R*,2R*,3R*,6S*,9R*,10R*,14R*)-3-acetoxycladiell-7(16),11(1 7)-dien-6-ol [4], 3-acetoxycladiell-11(17)-en-6-one [5], and its stereoisomer [6], have been isolated from the soft coral Cladiella australis collected on the coasts of the Andaman and Nicobar Islands of the Indian Ocean. In addition, sclerophytins C [7] and E [8], reported earlier from Sclerophytum capitalis, were also isolated. The structures of these metabolites were elucidated by interpretation of spectral data.

Stage II papillary clear cell adenocarcinoma of the vagina during observation in a diethylstilbestrol-exposed daughter. Although many cases of Diethylstilbestrol (DES)-associated clear cell adenocarcinoma (CCA) of the cervix and vagina have occurred, few have arisen in patients whose initial gynecologic evaluation has revealed only nonmalignant DES-related changes. We report a case of a 32-year-old lady who developed a stage II CCA after 8 years of thorough gynecologic examinations. This case substantiates the need for long-term gynecologic assessment in DES daughters.

Site-directed mutagenesis on the m2 muscarinic acetylcholine receptor: the significance of Tyr403 in the binding of agonists and functional coupling. The first step in the transmembrane signal mediated by G protein-coupled receptors is binding of agonist to receptors at the cell surface. The mechanism of the resulting receptor activation is not clear, but models based on the ternary complex model are capable of explaining most of the observations that have been reported in G protein-coupled receptors. This model suggests that a single agonist/receptor/G protein complex capable of activating G protein is formed as the result of agonist binding. Extensions of this basic model differ primarily in whether an equilibrium between active and inactive conformations is required to explain experimental results. We report results on ligand binding and coupling to physiological effector systems of the m2 muscarinic acetylcholine receptor site-directed mutant Y403F (residue 403 mutated from tyrosine to phenylalanine) expressed in Chinese hamster ovary cells and compare our results with results reported for the homologous Y506F mutation in the m3 muscarinic receptor [J. Biol. Chem. 267:19313-19319 (1992)]. The mutation in the m2 muscarinic receptor reduced absolute agonist affinities more dramatically than in the m3 muscarinic receptor. Unlike the results reported for the m3 subtype mutant, in which coupling to physiological effector systems was reduced, coupling to effector systems for the mutant in the m2 subtype was robust. In the Y403F m2 muscarinic receptor, the difference between the two agonist binding affinities was greater than in the wild-type receptor, whereas in the m3 subtype, the effect of the mutation was to decrease this difference. A prediction of the ternary complex model is that relative binding affinities will affect the steady state concentration of the agonist/receptor/G protein complex and, as the result, the extent of G protein coupling. These results can best be rationalized by this model, which suggests that the activation of G protein-coupled receptors is achieved by the relative affinity of agonist for two receptor states and does not require the existence of multiple states in conformational equilibrium.

Ras signalling on the endoplasmic reticulum and the Golgi. Current models evoke the plasma membrane (PM) as the exclusive platform from which Ras regulates signalling. We developed a fluorescent probe that reports where and when Ras is activated in living cells. We show that oncogenic H-Ras and N-Ras engage Raf-1 on the Golgi and that endogenous Ras and unpalmitoylated H-Ras are activated in response to mitogens on the Golgi and endoplasmic reticulum (ER), respectively. We also demonstrate that H-Ras that is restricted to the ER can activate the Erk pathway and transform fibroblasts, and that Ras localized on different membrane compartments differentially engages various signalling pathways. Thus, Ras signalling is not limited to the PM, but also proceeds on the endomembrane.

Lymphocyte-Specific Chromatin Accessibility Pre-determines Glucocorticoid Resistance in Acute Lymphoblastic Leukemia. Glucocorticoids play a critical role in the treatment of lymphoid malignancies. While glucocorticoid efficacy can be largely attributed to lymphocyte-specific apoptosis, its molecular basis remains elusive. Here, we studied genome-wide lymphocyte-specific open chromatin domains (LSOs), and integrated LSOs with glucocorticoid-induced RNA transcription and chromatin modulation using an in vivo patient-derived xenograft model of acute lymphoblastic leukemia (ALL). This led to the identification of LSOs critical for glucocorticoid-induced apoptosis. Glucocorticoid receptor cooperated with CTCF at these LSOs to mediate DNA looping, which was inhibited by increased DNA methylation in glucocorticoid-resistant ALL and non-lymphoid cell types. Our study demonstrates that lymphocyte-specific epigenetic modifications pre-determine glucocorticoid resistance in ALL and may account for the lack of glucocorticoid sensitivity in other cell types.

A Comparative Study of the Susceptibility of Listeria Species to Sanitizer Treatments When Grown under Planktonic and Biofilm Conditions. Listeria species are ubiquitous in nature and can adapt to survive in a variety of niches, including food processing environments. Listeria species that colonize these environments may also have the potential to persist. Food safety strategies designed to manage these niches include regular cleaning and disinfection with proven sanitizers containing biocide-active compounds. Typically, these sanitizers are effective against bacteria growing under planktonic conditions, but their efficacy may be compromised when bacteria are contained in biofilms. The susceptibility of persistent Listeria isolates, i.e., those capable of forming biofilms, to a selection of sanitizers was investigated. A quaternary ammonium compound-based sanitizer was the biocide most effective against planktonic bacteria, with a MIC of 0.0015 to 0.006%. In contrast, ethanol-based sanitizers were the least effective. Although, no triclosan tolerance was observed for planktonic Listeria isolates, triclosan was the only biocide that resulted in a significant biomass reduction. Differences between Listeria species were observed; L. monocytogenes and L. welshimeri biofilms were more tolerant to quaternary ammonium compound-based sanitizers than were L. innocua biofilms. These findings extend our understanding of the application of commonly used sanitizers in the food industry and the efficacy of these sanitizers against Listeria species and their associated biofilms.

Autoantigens in insulin-dependent diabetes mellitus: molecular cloning and characterization of human IA-2 beta. In this study, we describe the isolation, expression, and characterization of a new member of the transmembrane protein tyrosine phosphatase family from human brain, designated IA-2 beta. The 3853-bp cDNA encodes 986 amino acids with a molecular mass of 108,044 daltons (a predicted pI value of 5.8). The intracellular domain of human IA-2 beta is 74% identical to human IA-2. Northern blot analysis showed that IA-2 beta cDNA recognized two transcripts (approximately 5.0 kb and 4.0 kb) in four of five human insulinomas, one glucagonoma, and in normal human brain, pituitary, and pancreas, but not in a variety of other normal tissues. Rabbit antiserum, raised against the intracellular domain of IA-2 beta, reacted with pancreatic islets. Treatment of in vitro-translated full-length IA-2 beta protein with trypsin converted it into a 37-kD fragment. Using recombinant human IA-2 beta, we developed a radioimmunoprecipitation assay to measure autoantibodies in the sera of patients with insulin-dependent diabetes mellitus (IDDM). Seventy-six new-onset IDDM patients were tested. Thirty-seven percent (28 of 76) of the IDDM sera-but less than 1% of the control sera (1 of 174)-reacted with IA-2 beta. The same IDDM sera tested for autoantibodies to IA-2 and glutamic acid decarboxylase (GAD65) showed that 64% (49 of 76) and 57% (43 of 76), respectively, were positive. All but two of the IA-2 beta autoantibody-positive sera also reacted with IA-2, supporting the close sequence similarity between the two molecules. Combination of any two markers, such as IA-2 beta and IA-2, or IA-2 beta and GAD65, or IA-2 and GAD65, revealed that 67%, 74%, and 87% of IDDM sera were positive for autoantibodies, respectively. Blocking of IDDM sera with recombinant IA-2, IA-2 beta, or GAD65 resulted in marked inhibition of reactivity of IDDM sera with pancreatic islet sections as measured by islet cell autoantibody immunofluorescence. This result suggests that these three autoantigens are the major targets of islet-cell autoantibody reactivity.

Analysis of the list of patients awaiting transfer from a geriatric department to local-authority welfare residential accommodation and evaluation of priorities. An analysis of the waiting list of patients in the geriatric department waiting for transfer to welfare residential accommodation revealed that those who lived alone had no close relatives, had to pay rent for their accommodation and would need assistance with fees had to wait the longest for welfare accommodation while those who lived with relatives or who had close relatives, who owned their houses and appeared to be able to manage full fees gained access to welfare accommodation homes more quickly. It also was apparent that hose who were mentally confused were disadvantaged in that they took longest to transfer to a residential home. There should be a reappraisal of priorities for transfer of patients from hospital to a welfare home.