Reimbursement of care for severe trauma under SwissDRG.
Treatment of patients with severe injuries is costly, with best results achieved in specialised care centres. However, diagnosis-related group (DRG)-based prospective payment systems have difficulties in depicting treatment costs for specialised care. We analysed reimbursement of care for severe trauma in the first 3 years after the introduction of the Swiss DRG reimbursement system (2012-2014). The study included all patients with solely basic insurance, hospital admission after 01.01.2011 and discharge in 2011 or 2012, who were admitted to the resuscitation room of the University Hospital of Zurich, aged ≥16 years and with an injury severity score (ISS) ≥16 (n = 364). Clinical, financial and administrative data were extracted from the electronic medical records. All cases were grouped into DRGs according to different SwissDRG versions. We considered results to be significant if p ≤0.002. The mean deficit decreased from 12 065 CHF under SwissDRG 1.0 (2012) to 2 902 CHF under SwissDRG 3.0 (2014). The main reason for the reduction of average deficits was a refinement of the DRG algorithm with a regrouping of 23 cases with an ISS ≥16 from MDC 01 to DRGs within MDC21A. Predictors of an increased total loss per case could be identified: for example, high total number of surgical interventions, surgeries on multiple anatomical regions or operations on the pelvis (p ≤0.002). Psychiatric diagnoses in general were also significant predictors of deficit per case (p<0.001). The reimbursement for care of severely injured patients needs further improvement. Cost neutral treatment was not possible under the first three versions of SwissDRG.


Circulating glucose levels modulate neural control of desire for high-calorie foods in humans.
Obesity is a worldwide epidemic resulting in part from the ubiquity of high-calorie foods and food images. Whether obese and nonobese individuals regulate their desire to consume high-calorie foods differently is not clear. We set out to investigate the hypothesis that circulating levels of glucose, the primary fuel source for the brain, influence brain regions that regulate the motivation to consume high-calorie foods. Using functional MRI (fMRI) combined with a stepped hyperinsulinemic euglycemic-hypoglycemic clamp and behavioral measures of interest in food, we have shown here that mild hypoglycemia preferentially activates limbic-striatal brain regions in response to food cues to produce a greater desire for high-calorie foods. In contrast, euglycemia preferentially activated the medial prefrontal cortex and resulted in less interest in food stimuli. Indeed, higher circulating glucose levels predicted greater medial prefrontal cortex activation, and this response was absent in obese subjects. These findings demonstrate that circulating glucose modulates neural stimulatory and inhibitory control over food motivation and suggest that this glucose-linked restraining influence is lost in obesity. Strategies that temper postprandial reductions in glucose levels might reduce the risk of overeating, particularly in environments inundated with visual cues of high-calorie foods.


Invasive multidrug-resistant non-typhoidal Salmonella infections in Africa: zoonotic or anthroponotic transmission?
In Africa, multidrug-resistant non-typhoidal salmonellae (NTS) are one of the leading causes of morbidity and high mortality in children under 5 years of age, second in importance only to pneumococcal disease. The authors studied NTS isolates from paediatric admissions at two hospitals in Nairobi, Kenya, and followed the index cases to their homes, where rectal swabs and stools from parents and siblings, and from animals in close contact, were obtained. The majority of NTS obtained from cases were Salmonella enterica serotype Typhimurium (106 out of 193; 54.9%) and Salmonella enterica serotype Enteritidis (64; 33.2%), a significant proportion (34.2%) of which were multiply resistant to three or more antibiotics, including ampicillin, tetracycline, cotrimoxazole and chloramphenicol. Only 23.4% of NTS were fully susceptible to all 10 antibiotics tested. Of the 32 NTS obtained from contacts (nine adults and 23 children) at the homes of index cases, 21 (65.6%) isolates were similar by antibiotic-susceptibility profiles and plasmid content, and their XbaI- and SpeI-digested chromosomal DNA patterns were indistinguishable from those of the corresponding index cases. Only three out of 180 (1.7%) samples from environmental sources, including animals, soil, sewers and food, contained NTS matching those from corresponding index cases. The carriage of NTS in an asymptomatic population was represented by 6.9% of human contacts from 27 out of 127 homes sampled. This population of carriers may represent an important reservoir of NTS that would play a significant role in the epidemiology of community-acquired NTS bacteraemia in children.


Plastic pollution solutions: emerging technologies to prevent and collectmarineplastic pollution.
As plastic waste accumulates in the ocean at alarming rates, the need for efficient and sustainable remediation solutions is urgent. One solution is the development and mobilization of technologies that either 1)prevent plastics from entering waterways or2) collect marine and riverineplastic pollution. To date, however, few reports have focused on these technologies, and information on various technological developments is scattered. This leaves policymakers, innovators, and researchers without a central, comprehensive, and reliable source of information on the status of available technology to target this global problem. The goal of this study was to address this gap by creating a comprehensive inventory of technologies currently used or in development to prevent the leakage of plastic pollution or collect existing plastic pollution. Our Plastic Pollution Prevention and Collection Technology Inventory (https://nicholasinstitute.duke.edu/plastics-technology-inventory) can be used as a roadmap for researchers and governments to 1) facilitate comparisons between the scope of solutions and the breadth and severity of the plastic pollution problem and 2) assist in identifying strengths and weaknesses of current technological approaches. We created this inventory from a systematic search and review of resources that identified technologies. Technologies were organized by the type of technology and target plastics (i.e., macroplastics, microplastic, or both). We identified 52 technologies that fall into the two categories of prevention or collection of plastic pollution. Of these, 59% focus specifically on collecting macroplastic waste already in waterways. While these efforts to collect plastic pollution are laudable, their current capacity and widespread implementation are limited in comparison to their potential and the vast extent of the plastic pollution problem. Similarly, few technologies attempt to prevent plastic pollution leakage, and those that do are limited in scope. A comprehensive approach is needed that combines technology, policymaking, and advocacy to prevent further plastic pollution and the subsequent damage to aquatic ecosystems and human health.


Epidemiology and diagnosis of feline panleukopenia virus in Egypt: Clinical and molecular diagnosis in cats.
This work aimed to study epidemiology and diagnosis of feline panleukopenia virus (FPV) using clinical examination, direct ELISA, RNA viral isolation and identification, and knowing phylogenetic tree of our isolate. One hundred and sixty-five cats of different ages and sex were examined. Each cat was examined clinically to detect the clinical manifestations of the disease showing symptoms suggestive of feline panleukopenia (FP) as well as ELISA, and polymerase chain reaction (PCR) amplification analyses were conducted. Our finding includes (a) clinical signs detected in 165 of 165 cats were in the form of lethargy, fever, anorexia, thirst, vomiting, diarrhea, dehydration, and leukopenia. (b) ELISA results revealed that 66 of all examined cats were positive for FPV. (c) The amplification products from all positive samples were confirmed as FPV (VP1) gene by nucleotide sequences analysis, in which 75 samples were positive using PCR amplification for the FPV. (d) Statistical evaluation of ELISA results in comparison to PCR findings. ELISA showed 88%, 100%, and 94.5% for sensitivity, specificity, and accuracy, respectively, while the prevalence of FP among the examined population was 45%. No effect of sex, breed, and age on ELISA results as recorded using Chi-square analysis. The results of the sequence analysis indicated that PCR products of the FPV cDNA exhibited very low variation in their nucleotide sequence of all isolates compared with the published FPV genome, which could be suggested that FPV appears to be genomically stasis compared with other Parvoviruses. The genome sequence of FPLV strain in this study has been deposited in GenBank under the accession number KY466003. Our isolate closely related 100% to isolates from Portugal, which might be the origin of infection to Egypt through importation of cats.


Catalytic activity of halohydrin dehalogenases towards spiroepoxides.
A novel activity of halohydrin dehalogenases towards spiroepoxides has been found. The enzyme from Arthrobacter sp. (HheA) catalysed highly regioselective azidolysis of spiroepoxides containing 5, 6 and 7-membered cycloalkane rings, while the enzyme from Agrobacterium radiobacter (HheC), besides high regioselectivity, also displayed moderate to high enantioselectivity (E up to >200) that can be applied for the kinetic resolution of chiral spiroepoxides. The orientations of spiroepoxides in the active site of halohydrin dehalogenases were studied by quantum-chemical calculations and docking simulations. Analyses of the complexes obtained revealed the origins of diastereoselectivity and enantioselectivity of the investigated biotransformations.


Biogenesis of the apical endosome-lysosome complex during differentiation of absorptive epithelial cells in rat ileum.
Absorptive cells of the neonatal rat ileum have an elaborate apical endocytic complex consisting of tubular and vesicular endosomes, multivesicular bodies (MVB), and a giant lysosomal vacuole. This system develops rapidly over the last 3 days (20-22) of gestation. We followed the assembly of this complex by ultrastructural analysis and immunocytochemistry using antigenic markers for microvilli, endosomal tubules and lysosomal membranes. At 19 days gestation, low levels of lactase appeared on microvilli but specialized apical endosomal tubules and lysosomes were absent. At 20 days, expression of microvillar lactase increased and the endosomal marker entubin appeared, in parallel with the appearance of specialized apical endosomal tubules. The compartments of the apical endosome-lysosome system were assembled sequentially after differentiation of the apical plasma membrane domains; first endosomal tubules and vesicles, followed by MVB, and ending with the assembly of the giant lysosome shortly after birth. During early stages of the assembly process, membrane components of the tubular endosomes and lysosomes appeared in the apical plasma membrane before being restricted to their respective intracellular compartments.


Structural determination and gas-phase synthesis of monomeric, unsolvated IZnCH3 (X̃(1)A(1)): a model organozinc halide.
The first experimental structure of a monomeric organozinc halide, IZnCH3, has been measured using millimeter-wave direct absorption spectroscopy in the frequency range 256-293 GHz. IZnCH3 is a model compound for organozinc halides, widely used in cross-coupling reactions. The species was produced in the gas phase by reaction of zinc vapor with iodomethane in the presence of a dc discharge. IZnCH3 was identified on the basis of its pure rotational spectrum as well as those of the isotopically substituted species I(66)ZnCH3, I(64)Zn(13)CH3, and I(64)ZnCD3. IZnCH3 is unmistakably a symmetric top molecule (X̃(1)A1) belonging to the C3v point group, in agreement with DFT calculations, with the following experimentally determined structural parameters: rIZn = 2.4076(2) Å, rZnC = 1.9201(2) Å, rCH = 1.105(9) Å, and ∠H-C-H = 108.7(5)°. The basic methyl group geometry is not significantly altered in this molecule. Experimental observations suggest that IZnCH3 is synthesized in the gas phase by direct insertion of activated atomic zinc into the carbon-iodine bond of iodomethane.


Measuring perinatal complications: methodologic issues related to gestational age.
Perinatal outcomes differ by week of gestational age. However, it appears that how measures to examine these outcomes vary among various studies. The current paper explores how perinatal complications are reported and how they might differ when different denominators, numerators, and comparison groups are utilized. One issue that can clearly affect absolute rates and trends is how groups of women are categorized by their gestational age. Since most perinatal outcomes can only occur in women and neonates who have delivered, using the number of pregnancies delivered (PD) as the denominator of outcomes is appropriate. However, for an outcome such as antepartum stillbirth, all women who are pregnant at a particular gestational age are at risk. Thus, the denominator should include all ongoing pregnancies (OP). When gestational age is used by week this means using both deliveries during a particular week plus those women who deliver beyond the particular week of gestation in the denominator. Researchers should be careful to make sure they are utilizing the appropriate measure of perinatal complications so they do not report findings that would be misleading to clinicians, patients, and policy makers.


Investigation of 2 models to set and evaluate quality targets for hb a1c: biological variation and sigma-metrics.
A major objective of the IFCC Task Force on Implementation of HbA1c Standardization is to develop a model to define quality targets for glycated hemoglobin (Hb A1c). Two generic models, biological variation and sigma-metrics, are investigated. We selected variables in the models for Hb A1c and used data of external quality assurance/proficiency testing programs to evaluate the suitability of the models to set and evaluate quality targets within and between laboratories. In the biological variation model, 48% of individual laboratories and none of the 26 instrument groups met the minimum performance criterion. In the sigma-metrics model, with a total allowable error (TAE) set at 5 mmol/mol (0.46% NGSP), 77% of the individual laboratories and 12 of 26 instrument groups met the 2σ criterion. The biological variation and sigma-metrics models were demonstrated to be suitable for setting and evaluating quality targets within and between laboratories. The sigma-metrics model is more flexible, as both the TAE and the risk of failure can be adjusted to the situation-for example, requirements related to diagnosis/monitoring or international authorities. With the aim of reaching (inter)national consensus on advice regarding quality targets for Hb A1c, the Task Force suggests the sigma-metrics model as the model of choice, with default values of 5 mmol/mol (0.46%) for TAE and risk levels of 2σ and 4σ for routine laboratories and laboratories performing clinical trials, respectively. These goals should serve as a starting point for discussion with international stakeholders in the field of diabetes.


Analysis of molecular marker expression reveals neuronal homology in distantly related arthropods.
Morphological studies suggest that insects and crustaceans of the Class Malacostraca (such as crayfish) share a set of homologous neurons. However, expression of molecular markers in these neurons has not been investigated, and the homology of insect and malacostracan neuroblasts, the neural stem cells that produce these neurons, has been questioned. Furthermore, it is not known whether crustaceans of the Class Branchiopoda (such as brine shrimp) or arthropods of the Order Collembola (springtails) possess neurons that are homologous to those of other arthropods. Assaying expression of molecular markers in the developing nervous systems of various arthropods could resolve some of these issues. Here, we examine expression of Even-skipped and Engrailed, two transcription factors that serve as insect embryonic CNS markers, across a number of arthropod species. This molecular analysis allows us to verify the homology of previously identified malacostracan neurons and to identify additional homologous neurons in malacostracans, collembolans and branchiopods. Engrailed expression in the neural stem cells of a number of crustaceans was also found to be conserved. We conclude that despite their distant phylogenetic relationships and divergent mechanisms of neurogenesis, insects, malacostracans, branchiopods and collembolans share many common CNS components.


Magnetic resonance imaging susceptibility artifacts due to metallic foreign bodies.
Susceptibility artifacts due to metallic foreign bodies may interfere with interpretation of magnetic resonance (MR) imaging studies. Additionally, migration of metallic objects may pose a risk to patients undergoing MR imaging. Our purpose was to investigate prevalence, underlying cause, and diagnostic implications of susceptibility artifacts in small animal MR imaging and report associated adverse effects. MR imaging studies performed in dogs and cats between April 2008 and March 2010 were evaluated retrospectively for the presence of susceptibility artifacts associated with metallic foreign bodies. Studies were performed using a 1.0 T scanner. Severity of artifacts was graded as 0 (no interference with area of interest), 1 (extension of artifact to area of interest without impairment of diagnostic quality), 2 (impairment of diagnostic quality but diagnosis still possible), or 3 (severe involvement of area of interest resulting in nondiagnostic study). Medical records were evaluated retrospectively to identify adverse effects. Susceptibility artifacts were present in 99/754 (13.1%) of MR imaging studies and were most common in examinations of the brachial plexus, thorax, and cervical spine. Artifacts were caused by identification microchips, ballistic fragments, skin staples/suture material, hemoclips, an ameroid constrictor, and surgical hardware. Three studies were nondiagnostic due to the susceptibility artifact. Adverse effects were not documented.


A qualitative investigation of patients' understanding of carbohydrate in the clinical management of type 2 diabetes.
A healthy diet is the cornerstone of type 2 diabetes (T2DM) self-management. Carbohydrate is of particular interest as the nutrient with the greatest direct effect on blood glucose (BG) levels. The present study aimed to explore T2DM patients' understanding of carbohydrate and beliefs around the role of carbohydrate in T2DM management. Fifteen semi-structured interviews were conducted with T2DM patients. Interviews were audio-recorded and transcribed, and a deductive thematic approach to analysis was employed using the Framework method. Four significant themes emerged: (i) a naïve conceptual understanding of carbohydrate and sugar-centric specificity to dietary behaviours; (ii) a narrow focus on BG management to the neglect of overall dietary balance; (iii) positive reception of moderate dietary advice focused on portion control from healthcare professionals (HCPs); and (iv) the impact of external moderators of dietary choices, including the influence of significant others, emotional and opportunistic eating and budgetary constraints. Participants' beliefs and understanding of carbohydrate led to an overemphasis on sugar restriction for blood glucose control to the neglect of their overall dietary balance. Diabetes educators need to place greater emphasis on the role of various types of carbohydrate foods for glycaemic control, as well as on concepts of wider metabolic health, during T2DM dietary education. Participants placed a high level of trust and value on practical, moderate portion control advice from HCPs regarding carbohydrate foods. However, HCPs need to be cognisant of external moderators of behaviour, such as the influence of family and friends, budgetary constraints and environmental eating triggers.


The molecular biogeochemistry of manganese(II) oxidation.
Micro-organisms capable of oxidizing the redox-active transition metal manganese play an important role in the biogeochemical cycle of manganese. In the present mini-review, we focus specifically on Mn(II)-oxidizing bacteria. The mechanisms by which bacteria oxidize Mn(II) include a two-electron oxidation reaction catalysed by a novel multicopper oxidase that produces Mn(IV) oxides as the primary product. Bacteria also produce organic ligands, such as siderophores, that bind to and stabilize Mn(III). The realization that this stabilized Mn(III) is present in many environments and can affect the redox cycles of other elements such as sulfur has made it clear that manganese and the bacteria that oxidize it profoundly affect the Earth's biogeochemistry.


Immune response and stromal changes in ductal carcinoma in situ of the breast are subtype dependent.
Ductal carcinoma in situ (DCIS) associated stromal changes and influx of immune cells might be mediators of progression to invasive breast cancer. We studied the interaction between DCIS-associated stromal changes, and immune cell distribution and composition in a well-characterized patient cohort. We included 472 patients with DCIS. The presence of stromal changes, signs of regression, and DCIS-associated immune cell position were determined on hematoxylin and eosin-stained slides. Immune cell composition was characterized by immunohistochemistry (CD4, CD8, CD20, CD68, and FOXP3). The number of intraductal immune cells was quantified per mm2. The interaction between stromal changes, signs of DCIS regression, immune cell composition and location was explored. Stromal changes and signs of DCIS regression were identified in 30 and 7% of the patients, respectively. Intraductal immune cells mainly comprised CD68+ macrophages and CD8+ T cells. Patients with stromal changes had significantly less influx of immune cells within the duct. DCIS regression was associated with an increased number of intraductal FOXP3+ T cells. The highest number of intraductal CD8+ T cells was seen in the ER+ HER2+ subtype. We suggest that DCIS-associated stromal changes prevent the interaction between immune cells and DCIS cells. However, in case of DCIS regression, we surmise a direct interaction between DCIS cells and immune cells, in particular FOXP3+ cells. Furthermore, the increased number of intraductal CD8+ T cells in the ER+ HER2+ DCIS subtype suggests a subtype-specific immune response, which is likely to play a role in the distinct biological behavior of different DCIS subtypes.


Jurisdictional, socioeconomic and gender inequalities in child health and development: analysis of a national census of 5-year-olds in Australia.
Early child development may have important consequences for inequalities in health and well-being. This paper explores population level patterns of child development across Australian jurisdictions, considering socioeconomic and demographic characteristics. Census of child development across Australia. Teachers complete a developmental checklist, the Australian Early Development Index (AEDI), for all children in their first year of full-time schooling. Between May and July 2009, the AEDI was collected by 14 628 teachers in primary schools (government and non-government) across Australia, providing information on 261 147 children (approximately 97.5% of the estimated 5-year-old population). Level of developmental vulnerability in Australian children for five developmental domains: physical well-being, social competence, emotional maturity, language and cognitive skills and communication skills and general knowledge. The results show demographic and socioeconomic inequalities in child development as well as within and between jurisdiction inequalities. The magnitude of the overall level of inequality in child development and the impact of covariates varies considerably both between and within jurisdiction by sex. For example, the difference in overall developmental vulnerability between the best-performing and worst-performing jurisdiction is 12.5% for males and 7.1% for females. Levels of absolute social inequality within jurisdictions range from 8.2% for females to 12.7% for males. The different mix of universal and targeted services provided within jurisdictions from pregnancy to age 5 may contribute to inequality across the country. These results illustrate the potential utility of a developmental census to shed light on the impact of differences in universal and targeted services to support child development by school entry.


A novel uracil-DNA glycosylase with broad substrate specificity and an unusual active site.
Uracil-DNA glycosylases (UDGs) catalyse the removal of uracil by flipping it out of the double helix into their binding pockets, where the glycosidic bond is hydrolysed by a water molecule activated by a polar amino acid. Interestingly, the four known UDG families differ in their active site make-up. The activating residues in UNG and SMUG enzymes are aspartates, thermostable UDGs resemble UNG-type enzymes, but carry glutamate rather than aspartate residues in their active sites, and the less active MUG/TDG enzymes contain an active site asparagine. We now describe the first member of a fifth UDG family, Pa-UDGb from the hyperthermophilic crenarchaeon Pyrobaculum aerophilum, the active site of which lacks the polar residue that was hitherto thought to be essential for catalysis. Moreover, Pa-UDGb is the first member of the UDG family that efficiently catalyses the removal of an aberrant purine, hypoxanthine, from DNA. We postulate that this enzyme has evolved to counteract the mutagenic threat of cytosine and adenine deamination, which becomes particularly acute in organisms living at elevated temperatures.


Polymorphisms in OCTN1 and OCTN2 transporters genes are associated with prolonged time to progression in unresectable gastrointestinal stromal tumours treated with imatinib therapy.
The two basic mainstays of gastrointestinal stromal tumours (GIST) treatment are surgery and imatinib, a selective tyrosine kinase inhibitor that allows achieving a stable or responding disease in about 80% of patients with unresectable/metastatic GIST. Response to imatinib mainly depends from KIT and PDGFRα mutational status. Nevertheless, some patients with a potentially responsive genotype do not respond, and others develop a pattern of resistance to imatinib which is not associated with secondary mutations. This emphasizes the presence of mechanisms of resistance other than the receptor-related genotype, and the need of biological predictors to select the optimal therapeutic strategy, particularly now that other potent inhibitors are available. We investigated a panel of 31 polymorphisms in 11 genes, potentially associated with the pharmacogenetics of imatinib, in a group of 54 unresectable/metastatic GISTs treated with imatinib 400mg daily as first line therapy. Included in this analysis were polymorphisms in the transporters' family SLC22, SLCO, ABC, and in the metabolizing genes CYP-3A4 and -3A5. Time to progression was significantly improved in presence of the C allele in SLC22A4 (OCTN1 rs1050152), and the two minor alleles (G) in SLC22A5 (OCTN2 rs2631367 and rs2631372). Importantly, multivariate analysis, adjusting for age, gender, KIT/PDGFRα mutational status, and tumour size, revealed that all the three genotypes maintained independent predictive significance. In conclusion, in this study we showed that SLC22A4 and SLC22A5 genotypes may be an important predictor of time to progression in GIST patients receiving imatinib therapy. Further investigations are required in an attempt to further personalize GIST therapy.


SU-E-T-567: Improve Dose Conformity with IMRT Using Shorter Source to Tumor Distance.
To reduce the potential of late toxicity (tissue necrosis and cognitive function loss) from brain radiotherapy, we studied a novel planning technique for MLC-equipped linear accelerators (LINACS) that reduces the high doses delivered outside the PTV, enhancing radiation dose conformity. The feasibility of improving dose conformity by using variable source-to-tumor distances was tested on brain CT datasets with tumor contours representing solitary lesions and an example with two lesions. For the single tumor cases, different tumor volumes from 2 to 83 cc were explored, while an example double lesion had a total volume of 13 cc. Three different source-to-axis distances (SADs), 100, 80 and 65 cm, were used to create separate 5-field IMRT plans with the same beam angles for all SADs. For each example, the PTV dose coverage and critical organ doses were constrained to be the same, except for the normal brain doses that were determined by the dose conformity. High dose spillage outside the PTV was quantified by R50 (the ratio between the 50% isodose volume and the PTV), and the V12 (volume of normal brain receiving 12Gy or higher). R50 decreased monotonically with shorter SAD for all examples. Compared with 100 cm SAD, average R50 reductions of 13% and 19% were observed with 80 and 65 cm SAD respectively. Improved conformity was more notable on smaller lesions and the multiple lesion case. V12 also decreases significantly with shorter SAD. Improvement in dose conformity can be achieved on existing LINACS by reducing the treatment distance for each IMRT field. Sharper beam penumbra and smaller projected MLC leaf width contribute to the improvement. Precise delivery of non- isocentric beams can be challenging on traditional LINACS, but the problem is much more manageable on machines with precise robotic gantry and couch capabilities.


E-cadherin bridges cell polarity and spindle orientation to ensure prostate epithelial integrity and prevent carcinogenesis in vivo.
Cell polarity and correct mitotic spindle positioning are essential for the maintenance of a proper prostate epithelial architecture, and disruption of the two biological features occurs at early stages in prostate tumorigenesis. However, whether and how these two epithelial attributes are connected in vivo is largely unknown. We herein report that conditional genetic deletion of E-cadherin, a key component of adherens junctions, in a mouse model results in loss of prostate luminal cell polarity and randomization of spindle orientations. Critically, E-cadherin ablation causes prostatic hyperplasia which progresses to invasive adenocarcinoma. Mechanistically, E-cadherin and the spindle positioning determinant LGN interacts with the PDZ domain of cell polarity protein SCRIB and form a ternary protein complex to bridge cell polarity and cell division orientation. These findings provide a novel mechanism by which E-cadherin acts an anchor to maintain prostate epithelial integrity and to prevent carcinogenesis in vivo.


High-dose zinc to terminate angina pectoris: a review and hypothesis for action by ICAM inhibition.
We reviewed the literature related to the effects of high-dose zinc in arteriosclerosis-induced angina pectoris. Lipid peroxidation and LDL oxidation are believed to be critical for arteriosclerosis, and consequently angina pectoris. Administration of biologically available zinc was a beneficial treatment in a significant percentage of patients with severely symptomatic, inoperable atherosclerotic disease. In these patients, there was no difference in zinc concentration between patients with and without atherosclerosis in whole blood, erythocytes or hair, but there was a major difference between normal aorta and diseased aortas (40.6 ppm zinc in normal aorta vs. 23.2 ppm zinc in atherosclerotic aorta, 40.6 ppm zinc in normal aorta vs. 19.4 ppm zinc in atherosclerotic aneurysm aorta, and no difference between normal and aneurysm aorta), although copper was low in aneurysm aorta. Medication with high-dose zinc sulfate to raise zinc serum concentrations from 95 to 177 microg/dl resulted in objective improvement in 12 of 16 of these patients, including a patient that also had Raynaud's disease. Long term environmental exposure to zinc resulted in a 40% reduction in the incidence of angina of effort compared to people not exposed to environmental zinc (P<0.01) and a 40% reduction in the incidence of probable ischemia in exercise (P<0.001). Lead had no effect while cadmium exposure resulted in more than tripling the incidence of angina of effort (P<0.001). The antioxidative action of zinc prevents oxidation of LDL cholesterol and consequently stops the main mechanism of atherogenesis. Zinc blocks calcium and its several actions on atherogenesis. Increased amounts of cytotoxic cytokines such as TNF-alpha, IL-beta and IL-8, often produced in the elderly, are blocked by high-dose zinc. We hypothesize that higher serum concentrations of LDL cholesterol resulting from administration of 300 mg of zinc per day is caused by a release of low density cholesterol from cardiovascular tissues, beneficially flushing it into the serum where it is readily observed, thus decreasing arteriosclerosis, increasing circulation, terminating angina pectoris and restoring more youthful cardiac function. Although prevention of cholesterol-induced arteriosclerosis by zinc is predicted from findings related to oxidative stress and lipid peroxidation, removal of LDL might be attributable to action of ionic zinc on ICAM inhibition. In stark contrast to current practice, high-dose zinc should be considered as basic in the strategy of prophylaxis and therapy of the atherosclerosis process to terminate angina pectoris and restore youthful cardiac function.


[Are children from resort spa healthy? The overweight and obesity in children from Kudowa-Zdrój].
Overweight and obesity are becoming a more and more common problem among children and teenagers. . The aim of this study is to evaluate the development of children and teenagers from Kudowa-Zdroj and to assess the prevalence of overweight and obesity in this population. . The study included 545 children, aged 5-16 years from Kudowa-Zdroj. The following anthropometric parameters were assessed: body weight and height, BMI, Quetelet index, Rohrer's index, waist circumference, hip circumference and waist to height ratio (WHtR). . Overweight or obesity diagnosed by BMI SDS were observed in 26.7% of children from grades 0-3, 22.02% of children from grades 4-6 and 22.52% of Junior High School students. Students in grades 0-3 (mean 0.95 ± 2.17) achieved higher BMI SDS compared to students in grades 4-6 (mean 0.37 ± 1.71) and secondary school (mean 0.65 ± 1.61) (p= 0.023).Overweight or obesity diagnosed by Rohrer index SDS and Quetelet index SDS were observed in 22,84% and 17,13% children. Elevated value of the hip circumference SDS was found in 19.48% of children and waist circumference SDS was increased in 17.5% of children. In the group of children with overweight and obesity 59.4% had elevated waist circumference SDS and 53.4% waist circumference SDS. WHtR was elevated in 8.3% of children, more often in boys (p <0.001), 3.1% of girls and 13.07% of boys. . The BMI is the best index for diagnosis of overweight and obesity. Overweight and obesity are common disorders among children from Kudowa-Zdroj. It is recommended to educate children, adolescence and their family about healthy lifestyle in order to reduce the prevalence of overweight and obesity.


Psoriasin overexpression confers drug resistance to cisplatin by activating ERK in gastric cancer.
Psoriasin, a member of the S100 multigenic family, which is aberrantly expressed in a variety of human tumors, is considered as an attractive molecular target for cancer treatment. The present study aimed to characterize the role of psoriasin in gastric cancer (GC), the associated pathways through which it contributes to cancer development and progression, and the effect of psoriasin on cellular response to pre-operative chemotherapy in patients with GC. Expression of psoriasin mRNA and protein were analyzed using quantitative polymerase chain reaction and immunohistochemistry of gastric cancer cohorts, respectively. Gastric cancer cell models with differential expression of psoriasin were generated using stable cell lines that overexpressed psoriasin. The in vitro biological functions of the cells in response to psoriasin overexpression and to chemotherapeutic agents were assessed using various cell-based assays. Psoriasin was overexpressed in patients with advanced GC, and high psoriasin levels led to poor clinical outcomes. Increasing psoriasin expression in GC cell lines promoted cell proliferation, migration and invasion in vitro. Furthermore, psoriasin overexpression caused alterations in the levels of epithelial-mesenchymal transition-associated proteins, and activated the extracellular signal-regulated kinase signaling pathway. Additionally, higher levels of psoriasin expression were significantly associated a lack of response to neoadjuvant chemotherapy in patients with GC. Psoriasin overexpression tended to decrease the sensitivity of GC cells to cisplatin, potentially by inhibiting apoptosis or increasing the S-phase population. Taken together, these results indicate that psoriasin may be a promising therapeutic target for GC treatment, and a potential molecular marker to predict patient response to pre-operative chemotherapy.


Combined transcriptomic and proteomic analysis reveals a diversity of venom-related and toxin-like peptides expressed in the mat anemone Zoanthus natalensis (Cnidaria, Hexacorallia).
Venoms from marine animals have been recognized as a new emerging source of peptide-based therapeutics. Several peptide toxins from sea anemone have been investigated as therapeutic leads or pharmacological tools. Venom complexity should be further highlighted using combined strategies of large-scale sequencing and data analysis which integrated transcriptomics and proteomics to elucidate new proteins or peptides to be compared among species. In this work, transcriptomic and proteomic analyses were combined to identify six groups of expressed peptide toxins in Zoanthus natalensis. These include neurotoxin, hemostatic and hemorrhagic toxin, protease inhibitor, mixed function enzymes, venom auxiliary proteins, allergen peptides, and peptides related to the innate immunity. Molecular docking analysis indicated that one expressed Zoanthus Kunitz-like peptide, ZoaKuz1, could be a voltage-gated potassium channels blocker and, hence, it was selected for functional studies. Functional bioassays revealed that ZoaKuz1 has an intrinsic neuroprotective activity in zebrafish model of Parkinson's disease. Since pharmacological blockade of KV channels is known to induce neuroprotective effects, ZoaKuz1 holds the potential to be developed in a therapeutic tool to control neural dysfunction by slowing or even halting neurodegeneration mediated by ion-channel hyperactivity.


Effects of walking exercise on nocturia in the elderly.
We investigated whether nocturia in the elderly was improved by walking exercise, which involved walking rapidly for 30 min or more in the evening or night for 8 weeks. A questionnaire related to micturition and exercise, blood pressure, body composition analysis, blood biochemistry tests, and urinalysis were performed before and after 8 weeks of exercise to investigate the effects of walking. Thirty men (71 years old on average) continued the walking exercise for long enough to undergo evaluation. The number of episodes of nocturia decreased significantly (p < 0.001) from 3.3 +/- 0.7 to 1.9 +/- 0.8 after 8 weeks of walking exercise. The daytime urinary frequency, blood pressure, body weight, body fat ratio, edema ratio, serum catecholamines, triglycerides, and total cholesterol were also decreased. After 8 weeks of exercise, 20 of the subjects (67%) stated that sleep was deeper than before exercise. Assessment of the overall improvement showed that excellent or good results were obtained in 18 patients (60%). The main factor related to the influence of walking exercise on nocturia was that sleep became deeper, which increased the arousal threshold bladder volume. Walking exercise may also have a preventive effect on lifestyle-related diseases.


Inhibition of Nav1.7 and Nav1.4 sodium channels by trifluoperazine involves the local anesthetic receptor.
The calmodulin (CaM) inhibitor trifluoperazine (TFP) can produce analgesia when given intrathecally to rats; however, the mechanism is not known. We asked whether TFP could modulate the Na(v)1.7 sodium channel, which is highly expressed in the peripheral nervous system and plays an important role in nociception. We show that 500 nM and 2 muM TFP induce major decreases in Na(v)1.7 and Na(v)1.4 current amplitudes and that 2 muM TFP causes hyperpolarizing shifts in the steady-state inactivation of Na(v)1.7 and Na(v)1.4. CaM can bind to the C-termini of voltage-gated sodium channels and modulate their functional properties; therefore we investigated if TFP modulation of sodium channels was due to CaM inhibition. However, the TFP inhibition was not replicated by whole cell dialysis of a calmodulin inhibitory peptide, indicating that major effects of TFP do not involve a disruption of CaM-channel interactions. Rather, our data show that TFP inhibition is state dependent and that the majority of the TFP inhibition depends on specific amino-acid residues in the local anesthetic receptor site in sodium channels. TFP was also effective in vivo in causing motor and sensory blockade after subfascial injection to the rat sciatic nerve. The state-dependent block of Na(v)1.7 channels with nanomolar concentrations of TFP raises the possibility that TFP, or TFP analogues, might be useful for regional anesthesia and pain management and could be more potent than traditional local anesthetics.


Prospective, randomized, multi-center trial of antibody induction therapy in simultaneous pancreas-kidney transplantation.
A randomized, multicenter, prospective study was conducted at 18 pancreas transplant centers in the United States to determine the role of induction therapy in simultaneous pancreas-kidney (SPK) transplantation. One hundred and 74 recipients were enrolled: 87 recipients each in the induction and noninduction treatment arms. Maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil, and corticosteroids. There were no statistically significant differences between treatment groups for patient, kidney, and pancreas graft survival at 1-year. The 1-year cumulative incidence of any treated biopsy-confirmed or presumptive rejection episodes (kidney or pancreas) in the induction and noninduction treatment arms was 24.6% and 31.2% (p = 0.28), respectively. The 1-year cumulative incidence of biopsy-confirmed, treated, acute kidney allograft rejection in the induction and noninduction treatment arms was 13.1% and 23.0% (p = 0.08), respectively. Biopsy-confirmed kidney allograft rejection occurred later post-transplant and appeared to be less severe among recipients that received induction therapy. The highest rate of Cytomegalovirus (CMV) viremia/syndrome was observed in the subgroup of recipients who received T-cell depleting antibody induction and received organs from CMV serologically positive donors. Decisions regarding the routine use of induction therapy in SPK transplantation must take into consideration its differential effects on risk of rejection and infection.


How Did Institut Pasteur's NGS Core Facility, Biomics, Manage the Coronavirus Disease 2019 Crisis?
In 2020, research entities at the Institut Pasteur (IP) in Paris, as elsewhere around the world, were closed because of the coronavirus disease 2019 (COVID-19) pandemic. However, IP core facilities, laboratories, services, and departments working on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and priority projects were authorized to continue working both on site and remotely. Given the importance of its role in SARS-CoV-2 genome-sequencing initiatives, the IP Biomics core facility was fully functional during the first (i.e., March-June 2020) and second (i.e., November-December 2020) national lockdowns. We describe here how Biomics successfully implemented an emergency management plan to deal with this health crisis. We highlight the internal deployment of the institutional business continuity plan (BCP) through a series of actions. We also address the impact of the COVID-19 crisis on Biomics staff and collaborators. The added value of quality management and the limitations of risk management systems are discussed. Finally, we suggest that the Biomics infrastructure and the BCP described here could be used for benchmarking purposes, for other next-generation sequencing core facilities wishing to implement/improve their processes, and for future major crisis management.


Integrated Flow Chamber System for Live Cell Microscopy.
In vitro quantification of the effect of mechanical loads on cells by live microscopy requires precise control of load and culture environment. Corresponding systems are often bulky, their setup and maintenance are time consuming, or the cell yield is low. Here, we show the design and initial testing of a new cell culture system that fits on standard light microscope stages. Based on the parallel plate principle, the system allows for live microscopy of cells exposed to flow-induced shear stress, features short setup time and requires little user interaction. An integrated feedback-controlled heater and a bubble trap enable long observation times. The key design feature is the possibility for quick exchange of the cultured cells. We present first test results that focus on verifying the robustness, biocompatibility, and ease of use of the device.


The sitting height/height ratio for age in healthy and short individuals and its potential role in selecting short children for SHOX analysis.
To determine the presence of abnormal body proportion, assessed by sitting height/height ratio for age and sex (SH/H SDS) in healthy and short individuals, and to estimate its role in selecting short children for SHOX analysis. Height, sitting height and weight were evaluated in 1,771 healthy children, 128 children with idiopathic short stature (ISS), 58 individuals with SHOX defects (SHOX-D) and 193 females with Turner syndrome (TS). The frequency of abnormal body proportion, defined as SH/H SDS >2, in ISS children was 16.4% (95% CI 10-22%), which was higher than in controls (1.4%, 95% CI 0.8-1.9%, p < 0.001). The SHOX gene was evaluated in all disproportionate ISS children and defects in this gene were observed in 19%. Among patients with SHOX-D, 88% of children (95% CI 75-100%) and 96% of adults had body disproportion. In contrast, SH/H SDS >2 were less common in children (48%, 95% CI 37-59%) and in adults (28%, 95% CI 20-36%) with TS. Abnormal body proportions were observed in almost all individuals with SHOX-D, 50% of females with TS and 16% of children considered ISS. Defects in SHOX gene were identified in 19% of ISS children with SH/H SDS >2, suggesting that SH/H SDS is a useful tool to select children for undergoing SHOX molecular studies.


DNA barcoding for the identification of sand fly species (Diptera, Psychodidae, Phlebotominae) in Colombia.
Sand flies include a group of insects that are of medical importance and that vary in geographic distribution, ecology, and pathogen transmission. Approximately 163 species of sand flies have been reported in Colombia. Surveillance of the presence of sand fly species and the actualization of species distribution are important for predicting risks for and monitoring the expansion of diseases which sand flies can transmit. Currently, the identification of phlebotomine sand flies is based on morphological characters. However, morphological identification requires considerable skills and taxonomic expertise. In addition, significant morphological similarity between some species, especially among females, may cause difficulties during the identification process. DNA-based approaches have become increasingly useful and promising tools for estimating sand fly diversity and for ensuring the rapid and accurate identification of species. A partial sequence of the mitochondrial cytochrome oxidase gene subunit I (COI) is currently being used to differentiate species in different animal taxa, including insects, and it is referred as a barcoding sequence. The present study explored the utility of the DNA barcode approach for the identification of phlebotomine sand flies in Colombia. We sequenced 700 bp of the COI gene from 36 species collected from different geographic localities. The COI barcode sequence divergence within a single species was <2% in most cases, whereas this divergence ranged from 9% to 26.6% among different species. These results indicated that the barcoding gene correctly discriminated among the previously morphologically identified species with an efficacy of nearly 100%. Analyses of the generated sequences indicated that the observed species groupings were consistent with the morphological identifications. In conclusion, the barcoding gene was useful for species discrimination in sand flies from Colombia.


Globular and asymmetric acetylcholinesterase in the synaptic basal lamina of skeletal muscle.
The aim of this study was to characterize the molecular forms of acetylcholinesterase (AChE) associated with the synaptic basal lamina at the neuromuscular junction. The observations were made on the neuromuscular junctions of cutaneous pectoris muscles of frog, Rana pipiens, which are similar to junctions of most other vertebrates including mammals, but are especially convenient for experimentation. By measuring relative AChE activity in junctional and extrajunctional regions of muscles after selective inactivation of extracellular AChE with echothiophate, or of intracellular AChE with DFP and 2-PAM, we found that > 66% of the total AChE activity in the muscle was junction-specific, and that > 50% of the junction-specific AChE was on the cell surface. More than 80% of the cell surface AChE was solubilized in high ionic strength detergent-free buffer, indicating that most, if not all, was a component of the synaptic basal lamina. Sedimentation analysis of that fraction indicated that while asymmetric forms (A12, A8) were abundant, globular forms sedimenting at 4-6 S (G1 and G2), composed > 50% of the AChE. It was also found that when muscles were damaged in various ways that caused degeneration of axons and muscle fibers but left intact the basal lamina sheaths, the small globular forms persisted at the synaptic site for weeks after phagocytosis of cellular components; under certain damage conditions, the proportion of globular to asymmetric forms in the vacated basal lamina sheaths was as in normal junctions. While the asymmetric forms required high ionic strength for solubilization, the extracellular globular AChE could be extracted from the junctional regions of normal and damaged muscles by isotonic buffer. Some of the globular AChE appeared to be amphiphilic when examined in detergents, suggesting that it may form hydrophobic interactions, but most was non-amphiphilic consistent with the possibility that it forms weak electrostatic interactions. We conclude that the major form of AChE in frog synaptic basal lamina is globular and that its mode of association with the basal lamina differs from that of the asymmetric forms.


Growth hormone, gender and face shape in Prader-Willi syndrome.
Prader-Willi syndrome is a neurodevelopmental disorder resulting from the absence of expression of paternally expressed gene(s) in a highly imprinted region of chromosome 15q11-13. The physical phenotype includes evidence of growth retardation due to relative growth hormone deficiency, small hands and feet, a failure of normal secondary sexual development, and a facial appearance including narrow bifrontal diameter, almond-shaped palpebral fissures, narrow nasal root, and thin upper vermilion with downturned corners of the mouth. Anecdotally, the face of individuals with PWS receiving hGH treatment is said to "normalize." We used dense surface modelling and shape signature techniques to analyze 3D photogrammetric images of the faces of 72 affected and 388 unaffected individuals. We confirmed that adults with Prader-Willi syndrome who had never received human growth supplementation displayed known characteristic facial features. Facial growth was significantly reduced in these adults, especially in males. We demonstrated that following human growth hormone (hGH) supplementation, vertical facial growth of affected individuals falls within the normal range. However, lateral and periorbital face shape and nose shape differences in affected children who have received hGH therapy remain sufficiently strong to be significantly discriminating in comparisons with age-sex matched, unaffected individuals. Finally, we produced evidence that age at initiation and length of treatment with hGH do not appear to play a role in normalization or in consistent alteration of the face shape of affected individuals. This is the first study to provide objective shape analysis of craniofacial effects of hGH therapy in Prader-Willi syndrome.


Widespread amphibian extinctions from epidemic disease driven by global warming.
As the Earth warms, many species are likely to disappear, often because of changing disease dynamics. Here we show that a recent mass extinction associated with pathogen outbreaks is tied to global warming. Seventeen years ago, in the mountains of Costa Rica, the Monteverde harlequin frog (Atelopus sp.) vanished along with the golden toad (Bufo periglenes). An estimated 67% of the 110 or so species of Atelopus, which are endemic to the American tropics, have met the same fate, and a pathogenic chytrid fungus (Batrachochytrium dendrobatidis) is implicated. Analysing the timing of losses in relation to changes in sea surface and air temperatures, we conclude with 'very high confidence' (> 99%, following the Intergovernmental Panel on Climate Change, IPCC) that large-scale warming is a key factor in the disappearances. We propose that temperatures at many highland localities are shifting towards the growth optimum of Batrachochytrium, thus encouraging outbreaks. With climate change promoting infectious disease and eroding biodiversity, the urgency of reducing greenhouse-gas concentrations is now undeniable.


Stable small bubble clusters in two-dimensional foams.
Key features of the mechanical response of amorphous particulate materials, such as foams, emulsions, and granular media, to applied stress are determined by the frequency and size of particle rearrangements that occur as the system transitions from one mechanically stable state to another. This work describes coordinated experimental and computational studies of bubble rafts, which are quasi-two dimensional systems of bubbles confined to the air-water interface. We focus on small mechanically stable clusters of four, five, six, and seven bubbles with two different sizes with diameter ratio σL/σS ≃ 1.4. Focusing on small bubble clusters, which can be viewed as subsystems of a larger system, allows us to investigate the full ensemble of clusters that form, measure the respective frequencies with which the clusters occur, and determine the form of the bubble-bubble interactions. We emphasize several important results. First, for clusters with N > 5 bubbles, we find using discrete element simulations that short-range attractive interactions between bubbles give rise to a larger ensemble of distinct mechanically stable clusters compared to that generated by long-range attractive interactions. The additional clusters in systems with short-range attractions possess larger gaps between pairs of neighboring bubbles on the periphery of the clusters. The ensemble of bubble clusters observed in experiments is similar to the ensemble of clusters with long-range attractive interactions. We also compare the frequency with which each cluster occurs in simulations and experiments. We find that the cluster frequencies are extremely sensitive to the protocol used to generate them and only weakly correlated to the energy of the clusters.


The efficacy of nudge theory strategies in influencing adult dietary behaviour: a systematic review and meta-analysis.
Obesity has become a world-wide epidemic and is spreading to countries with emerging economies. Previously tested interventions are often too costly to maintain in the long term. This leaves a need for improved strategies for management of the epidemic. Nudge Theory presents a new collection of methods, deemed "nudges", which have the potential for low-cost and broad application to guide healthier lifestyle choices without the need for restrictive regulation. There has not yet been a large-scale examination of the effectiveness of nudges, despite several policy making bodies now considering their use. To address this gap in knowledge, an adapted systematic review methodology was used to collect and consolidate results from current Nudge papers and to determine whether Nudge strategies are successful in changing adults' dietary choices for healthier ones. It was found that nudges resulted in an average 15.3 % increase in healthier dietary or nutritional choices, as measured by a change in frequency of healthy choices or a change in overall caloric consumption. All of the included studies were from wealthy nations, with a particular emphasis on the United States with 31 of 42 included experiments. This analysis demonstrates Nudge holds promise as a public health strategy to combat obesity. More research is needed in varied settings, however, and future studies should aim to replicate previous results in more geographically and socioeconomically diverse countries.


Decatenation of DNA by the S. cerevisiae Sgs1-Top3-Rmi1 and RPA complex: a mechanism for disentangling chromosomes.
Genetic evidence indicates that Saccharomyces cerevisiae Sgs1, Top3, and Rmi1 resolve topologically linked intermediates arising from DNA replication and recombination. Using purified proteins, we show that Sgs1, Top3, Rmi1, and replication protein A (RPA) coordinate catenation and decatenation of dsDNA through sequential passage of single strands of DNA, establishing a unique pathway for dsDNA decatenation in eukaryotic cells. Sgs1 is required for dsDNA unwinding and, unexpectedly, also has a structural role in DNA strand passage. RPA promotes DNA unwinding by Sgs1 by trapping ssDNA, and it stimulates DNA strand passage by Top3. Paradoxically, Rmi1 has a unique regulatory capacity that slows DNA relaxation by Top3 but stimulates DNA decatenation. We establish that Rmi1 stabilizes the "open" Top3-DNA covalent complex formed as a transient intermediate of strand passage. This concerted activity of the Sgs1-Top3-Rmi1-RPA represents an important mechanism for disentangling structures resulting from the topological features of duplex DNA.


Metastatic patterns in soft-tissue sarcomas.
In 242 patients with recurrent soft-tissue sarcomas, the most common sites of initial recurrence were the primary site in 47.5% of patients and the lungs in 38% of patients. Further recurrences in the course of the disease concerned the lungs, bones, liver, and brain. Total survival and survival after recurrence were influenced by the histologic type, which also affected the site of recurrence. In the management of local recurrence, a five-year disease-free survival rate of 38% was achieved with surgical treatment, while radiation or chemotherapy alone was ineffective. Local recurrences resulted in significantly higher survival rates than those involving other organs. The disease-free interval was a significant prognostic indicator of subsequent survival in the whole group of patients and among those with local recurrence.


Surgical applications of methyl methacrylate: a review of toxicity.
Methyl methacrylate (MMA) is a monomer of acrylic resin widely used in a variety of medical, dental, and industrial applications. Its extensive use in surgery, particularly for arthroplasties, has often raised concerns regarding potential human toxicity for orthopaedic surgeons, surgical nurses, and other operating-room staff who are occupationally exposed to the compound. The main toxic effects of MMA exposure appear to involve the cardiovascular system. When exposed to MMA in the work environment, surgical staff have been reported to suffer from hypersensitivity, asthmatic reactions, local neurological symptoms, irritations and local dermatological reactions. The integrity of latex gloves may also be compromised following exposure to MMA during surgical procedures. At present, MMA is not thought to be carcinogenic to humans under normal conditions of use. Nevertheless, sound occupational hygiene practices should still be used to help reduce workplace exposure to MMA during orthopaedic and other medical procedures. Surgical staff should avoid direct contact with MMA mixtures wherever possible, and room ventilation and adequate airflow should also be optimized. In the present article, the authors review studies relating to MMA toxicity in surgical practice, updating in part a previous literature review and expanding on the toxicity of MMA within the surgical setting.


Ultrastructure of internal limiting membrane removed during plasmin-assisted vitrectomy from eyes with diabetic macular edema.
To study the effect of autologous plasmin enzyme (APE) on the adhesion of the vitreous cortex to the internal limiting membrane (ILM) in eyes with diabetic macular edema. Nonrandomized, comparative, interventional case series. Ten eyes of 10 patients with diabetic macular edema without a posterior vitreous detachment (PVD), which were treated with APE as an adjunct to conventional pars plana vitrectomy, and 10 eyes of 9 patients without a PVD, which underwent pars plana vitrectomy without APE, were studied. In the APE group, 0.4 IU of APE was injected into the midvitreous cavity in 9 eyes, and 0.8 IU of APE in 1 eye. Thirty minutes after plasmin injection, the eyes underwent pars plana vitrectomy with ILM peeling. All eyes in the control group had conventional vitreous surgery with ILM peeling. The removed ILMs were investigated for the presence of vitreous and for ultrastructural differences by transmission and scanning electron microscopy. The status of the vitreous and induction of a PVD during surgery, and the presence of vitreous and ultrastructural differences of the removed ILM by transmission and scanning electron microscopy. In APE-treated eyes, the degree of liquefaction of the vitreous was graded as high in 4 eyes. Spontaneous PVD occurred in 2 eyes, whereas core vitrectomy with a maximum vacuum of 100 mmHg induced a PVD in 2 additional eyes. In the control group, 8 eyes required suction with a maximum of 200 mmHg to induce the PVD. Scanning electron micrography of the removed ILM in the APE-treated eyes showed a smooth surface on the vitreous side in 8 eyes and only sparse collagen fibers in 2 eyes. Conversely, in the control group, dense vitreous fibers were found in 4 eyes, sparse collagen fibrils in 3 eyes, and a smooth retinal surface in 3 eyes. These findings indicate that APE helps separate the vitreous hyaloid from the ILM surface and may be a useful adjunct to conventional vitreous surgery for diabetic macular edema.


Rescuing human embryonic stem cell research: the Blastocyst Transfer Method.
Despite the therapeutic potential of human embryonic stem (HES) cells, many people believe that HES cell research should be banned. The reason is that the present method of extracting HES cells involves the destruction of the embryo, which for many is the beginning of a person. This paper examines a number of compromise solutions such as parthenogenesis, the use of defective embryos, genetically creating a "pseudo embryo" that can never form a placenta, and determining embryo death, and argues that none of these proposals are likely to satisfy embryoists, that is, those who regard the embryo as a person. This paper then proposes a method of extracting HES cells, what might be called the Blastocyst Transfer Method, that meets the ethical requirements of embryoists, and it considers some possible concerns regarding this method. It concludes by encouraging future HES cell research to investigate this method.


[Doctor-nurse delegation of the insertion of central venous lines].
The Léon Bérard Cancer Centre treats the disease in all its complexity with numerous disciplines such as surgery, medicine, radiotherapy, palliative care, home care, etc. The insertion of a central venous line is an essential part of cancer care and the nursing profession. It enables patients to have their treatment administered in the best possible conditions and without risk.


Carbohydrate quality is not associated with liver enzyme activity and plasma TAG and HDL concentrations over 5 years in an older population.
Non-alcoholic fatty liver disease (NAFLD) is closely associated with insulin resistance and obesity. Hence, carbohydrate quality could be of relevance to the risk of NAFLD, but prospective data are lacking. The aim of the present study was to investigate longitudinal associations between carbohydrate quality (including dietary glycaemic index (GI) and intakes of sugar, starch and fibre) and markers of liver function in an older Australian population. The analysis was based on 866 participants ( ≥ 49 years) of the Blue Mountains Eye Study with fasting blood specimens and dietary intake data at baseline and 5-year follow-up. Multi-level mixed regression analysis was used to relate dietary GI and sugar, starch and fibre intake to the liver enzymes alanine aminotransferase (ALT) and γ-glutamyltransferase (GGT), as well as fasting TAG and HDL-cholesterol (HDL-C). After adjustment for potential confounding factors, a lower fibre intake was cross-sectionally related to higher GGT (P= 0.02) and fasting TAG (P= 0.002) levels, with fruit fibre being the most relevant fibre source (P= 0.095 for GGT; P= 0.003 for TAG). A higher dietary GI was associated with lower HDL-C (P= 0.046). Changes in carbohydrate quality during 5 years were not related to changes in ALT, GGT, TAG or HDL-C (P≥ 0.08). In conclusion, the absence of longitudinal associations between carbohydrate quality and liver enzymes and serum lipids in this older population does not support a major role of carbohydrate nutrition in liver function among the elderly.


The home team advantage: reproduction in women indigenous to high altitude.
Although there is substantial evidence that environmental conditions disrupt reproductive function among newcomers to hypoxic settings, it is not certain that low oxygen pressure reduces fertility among those indigenous to high altitude. Even when fertility does appear to be relatively lower, numerous behavioral and sociocultural factors may be responsible. These are best examined within demographic frameworks that delineate a finite list of the proximate determinants of fertility. The findings presented here are based on several studies of indigenous Andean populations (Peruvian Quechua at 4000 m, Bolivian Quechua at 3100 m, Bolivian Aymara at 4000 m). Data on ovarian function suggest that neither progesterone levels nor menstrual cycle length or regularity are significantly different from those of women at lower altitudes. Data on two behavioral factors that determine fertility levels, coital frequency and infant feeding practices, suggest that the former is not likely to be of significance in co-habitating couples, but that variation in breastfeeding patterns has probably made a substantial contribution to differences in fertility among at least some populations at high altitude.


[Preventive health examinations of pregnant women in Denmark. Structure and organization].
In Denmark, pregnant women are offered antenatal care in a nationwide programme. This programme is organized around health examinations in general practice, midwives centres and hospital outpatient departments. During the winter 1986/87 a nationwide investigation of antenatal care was carried out in Denmark. A random sample of approximately 1/3 of the general practitioners, all of the midwives who had antenatal consultations and the medical staffs of 26 departments of obstetrics and gynaecology with more than 100 deliveries in 1985 received a questionnaire about the content of a definite antenatal examination and certain conditions of organization. The obstetricians could describe three different types of antenatal examinations depending upon the place and arrangement of work. The percentage replies received were 62 for general practice, 86 for the midwives and 62, 69 and 55 from the doctors in the place of delivery. 50% of the pregnant women had been attached to the same practice for at least five years. 70% of the general practitioners performed approximately one antenatal examination weekly. Only few hospital districts had attempted to have the first examination by the midwife at the 12th week of pregnancy. 25% of the places for examination by midwives were outside hospitals, which, according to the guidelines for antenatal care, do not entirely fulfill the intentions concerning situation in the patient's immediate surroundings. All of the obstetric departments offered routine examinations in the 16th-18th weeks and a number of these also routine examinations in the third trimester.(ABSTRACT TRUNCATED AT 250 WORDS)


Clinical and functional outcome after restorative proctocolectomy.
Restorative proctocolectomy and ileal pouch-anal anastomosis (IPAA) has been carried out on 88 patients since 1982. Three different pouch designs (J, S and W) were used. Ten pouches had to be removed. Detailed analysis was performed on 61 patients (J = 23, S = 15, W = 23) whose pouches had been functioning for at least 6 months. There was no significant difference in surgical complications before or after ileostomy closure between pouch designs but the hospital stay was greater after construction of an S pouch (P less than 0.05). There were no significant differences in stool frequency, degree of continence or urgency between the three types. Twelve patients with J pouches required antidiarrhoeal medication compared with only one with S and five with W pouches. Only seven patients with S pouches could defaecate spontaneously compared with 22 with W pouches and all patients with J pouches (P less than 0.001). Twenty-five of 29 patients who had preservation of the anal transition zone had perfect continence compared with 23 of 32 with a mucosal proctectomy (P = n.s.). Pouchitis occurred in 13 patients, all of whom had ulcerative colitis. In a subgroup of 23 patients, pouch evacuation was assessed scintigraphically. There was no difference in pouch capacity or total volume evacuated, but spontaneous evacuation was better in J and W pouches compared with S pouches.


Alcohol use and the Traveller community in the west of Ireland.
The Traveller community as ethnic minority is vulnerable to problematic alcohol use, because of social exclusion, discrimination, lack of awareness and difficulties in engaging with addiction treatment protocols. This research yielded an exploratory account of Travellers and alcohol use according to the perspectives of the Travellers and key service providers in the west of Ireland, within the context of a large-scale study on Travellers and substance use. The research consisted of 12 peer-accompanied focus groups of Traveller men and women (n = 57) and 45 semistructured interviews with a self-selecting sample of key service agencies. The research themes related to Traveller culture and alcohol use, sex differences, reasons for consuming alcohol, attitude to alcohol use, problematic alcohol use, levels of alcohol harm-related knowledge, perceptions of alcohol-related risk and experiences of addiction services. A thematic analysis of the information garnered guided this comparative analysis. The Traveller community, and in particular Traveller men, are presenting with increasingly problematic alcohol use, because of dissipation of their culture and their experiences of marginalisation, discrimination, depression, illiteracy and poverty. Difficulties engaging with law enforcement, community health and addiction services compromise their efforts to deal with this problem and home detoxification attempts are common. Services must aim to take into consideration the cultural needs of Travellers and provide appropriate educational materials, peer education programs and flexible treatment approaches for those Travellers experiencing problematic alcohol use.


Two modes for concentrating urine in rat inner medulla.
We used a mathematical model of the urine concentrating mechanism of rat inner medulla (IM) to investigate the implications of experimental studies in which immunohistochemical methods were combined with three-dimensional computerized reconstruction of renal tubules. The mathematical model represents a distribution of loops of Henle with loop bends at all levels of the IM, and the vasculature is represented by means of the central core assumption. Based on immunohistochemical evidence, descending limb portions that reach into the papilla are assumed to be only moderately water permeable or to be water impermeable, and only prebend segments and ascending thin limbs are assumed to be NaCl permeable. Model studies indicate that this configuration favors the targeted delivery of NaCl to loop bends, where a favorable gradient, sustained by urea absorption from collecting ducts, promotes NaCl absorption. We identified two model modes that produce a significant axial osmolality gradient. One mode, suggested by preliminary immunohistochemical findings, assumes that aquaporin-1-null portions of loops of Henle that reach into the papilla have very low urea permeability. The other mode, suggested by perfused tubule experiments from the literature, assumes that these same portions of loops of Henle have very high urea permeabilities. Model studies were conducted to determine the sensitivity of these modes to parameter choices. Model results are compared with extant tissue-slice and micropuncture studies.


Comparing radiopaque markers and 13C-labelled breath test in diabetic gastroparesis diagnostics.
Purpose: Determining gastric emptying is mandatory in the diagnosis of diabetic gastroparesis. Several methods of investigation exist, but none has proven reliable, inexpensive and accessible. In this study, we aimed to compare gastric emptying of radiopaque markers (ROM) and 13carbon-labelled gastric emptying breath tests for solids (GEBT). We also aimed to determine any association between gastric emptying and patient-reported symptoms, glycemic control and the patients' age, diabetes duration and occurrence of other late complications. Patients and methods: Forty-five patients (30 women, 15 men) with diabetes mellitus types 1 or 2 (40, 5) and symptoms of gastroparesis were examined with ROM and GEBT. All were interviewed, filled out symptom questionnaires and had HbA1c levels measured. Results: Forty percent of patients had delayed gastric emptying of ROM, while 55% had delayed gastric emptying of GEBT. Correlation between ROM and GEBT was not significant. Compared to GEBT, sensitivity for a positive ROM test was 0.52, while specificity was 0.74. In women, we found a higher specificity of 0.92, sensitivity 0.47. Difference in HbA1c between patients with positive and negative results was of borderline significance for both tests. GEBT (r=0.41, P=0.008) correlated with HbA1c. Patients with any late complications of diabetes had higher gastric retention of ROM (P=0.028), while patients with polyneuropathy (P=0.014) and diabetic wounds (P=0.004) had slower emptying with GEBT. None of the methods identified significant associations between gastric emptying and symptom scores, age or diabetes duration. Conclusions: As a measure of gastric emptying, the ROM test has benefits of being affordable and available. Compared to GEBT, the method has low diagnostic reliability. Before continued use, we recommend additional studies validating the test in diabetes patients.


The burden of migraine. A review of cost to society.
Migraine is a common episodic disorder with considerable impact on individuals and society. Migraine occurs with the highest prevalence between the ages of 25 and 55 years, potentially the most productive period of life. Severe migraine can lead to disruption of work, family and social life, the long term consequences of which may affect quality of life. The direct costs of migraine (due to medical care) are small compared with the indirect costs caused by absence from work and reduced productivity. Population-based studies are required to assess incidence, prevalence and distribution of the disease. These studies also reveal that migraine is currently underdiagnosed and undertreated. The cumulative impact of migraine on individuals produces the burden of illness on society. Measuring the severity of migraine is important in understanding the extent of the burden of migraine on the individual and on society. Measures of severity may be useful as predictors of disability and healthcare use. These measures may also be useful in assessing the need for patient care and treatment and help target those more disabled by migraine. Identifying and treating appropriate patients should reduce the impact of migraine on the individual and the burden of migraine on society.


The virulence regulatory protein ToxR mediates enhanced bile resistance in Vibrio cholerae and other pathogenic Vibrio species.
The transmembrane regulatory protein ToxR is required for expression of virulence factors in the human diarrheal pathogen Vibrio cholerae, including cholera toxin (CT) and the toxin coregulated pilus (TCP). ToxR is necessary for transcription of the gene encoding a second regulatory protein, ToxT, which is the direct transcriptional activator of CT and TCP genes. However, ToxR, independent of ToxT, directly activates and represses transcription of the outer membrane porins OmpU and OmpT, respectively. The genes encoding TCP and CT (and including ToxT) lie on horizontally acquired genetic elements, while the toxR, ompU, and ompT genes are apparently in the ancestral Vibrio chromosome. The contribution of ToxR-dependent modulation of outer membrane porins to cholera pathogenesis has remained unknown. We demonstrate that ToxR mediates enhanced bile resistance in a ToxT-independent manner. In both classical and El Tor biotypes of V. cholerae, a toxR mutant strain has a reduced minimum bactericidal concentration (MBC) of bile, the bile component deoxycholate (DC), and the anionic detergent sodium dodecyl sulfate (SDS) compared to both wild-type and toxT mutant strains. Classical and El Tor toxR mutant strains also exhibit reduced growth rates at subinhibitory concentrations of DC and SDS. Growth of either V. cholerae biotype in subinhibitory concentrations of bile or DC induces increased ToxR-dependent production of a major 38-kDa outer membrane protein, which was confirmed to be OmpU by Western blot. Measurement of transcription of a ompUp-lacZ fusion in both biotypes reveals stimulation (about two- to threefold) of ToxR-dependent ompU transcription by the presence of bile or DC, suggesting that ToxR may respond to the presence of bile. The toxR mutant strains of three additional human intestinal pathogenic Vibrio species, V. mimicus, V. fluvialis, and V. parahaemolyticus, display lower MBCs of bile, DC, and SDS and have altered outer membrane protein profiles compared to the parental wild-type strains. Our results demonstrate a conserved role for ToxR in the modulation of outer membrane proteins and bile resistance of pathogenic Vibrio species and suggest that these ToxR-dependent outer membrane proteins may mediate enhanced resistance to bile. We speculate that ToxR-mediated bile resistance was an early step in the evolution of V. cholerae as an intestinal pathogen.


Effects of dorsal hippocampal damage on conditioning and conditioned-response timing: A pooled analysis.
Behavioral findings suggest that the dorsal hippocampus (DHPC) plays a role in timing of appetitive conditioned responding. The present article explored the relationship between the extent of DHPC damage and timing ability, in a pooled analysis of three published studies from our laboratory. Initial analyses of variance confirmed our previous reports that DHPC damage reduced peak time (a measure of timing accuracy). However, the spread (a measure of timing precision) was unchanged, such that the coefficient of variation (spread/peak time) was significantly larger in DHPC-lesioned animals. This implies that, in addition to the well-established effect of DHPC lesions on timing accuracy, DHPC damage produced a deficit in precision of timing. To complement this analysis, different generalized linear mixed-effects models (GLMMs) were performed on the combined dataset, to examine which combinations of the different behavioral measures of timing were the best predictors of the degree of hippocampal damage. The results from the GLMM analysis suggested that the greater the DHPC damage, the greater the absolute difference between the observed peak time and reinforced duration. Nevertheless, this systematic relationship between damage and performance was not specific to the temporal domain: paradoxically the greater the damage the greater the magnitude of peak responding. We discuss these lesion effects in terms of scalar timing theory.


[Young men who have sex with men: a group at high risk for HIV infection?].
To compare variables associated with the risk of HIV among men ≤ 25 years old who have sex with men (YMSM) and those >25 years old, and to determine the variables associated with unprotected anal intercourse (UAI) in YMSM with casual sexual partners. For 1 month, 485 participants ≤ 25 years old and 1,470 aged >25 years old completed a pen-and-paper survey carried out in gay venues (GV) or via the Internet in Madrid, Barcelona, Bilbao and San Sebastián (Spain). The survey investigated sexual behaviors in the past 3 months according to whether the men met sexual partners in GV (SPGV) or on the Internet (SPI). No significant differences were found between YMSM and those >25 years old with respect to UAI with SPGV (23% vs. 30%, p>0.05) and SPI (29% vs. 30%, p>0.05), condom use in the last anal intercourse and having had a sexually-transmitted infection (STI) in the last year (19% vs. 23%, p>0.05). However, respondents>25 years old had a higher average number of SPGV (9.2 vs. 7, p<0.05) and SPI (8.9 vs. 6.4, p<0.05), were more likely to have used drugs while having UAI (68% vs. 55%, p<0.05, with SPI, and 73% vs. 55%, p<0.05, with SPGV) and had a higher prevalence of HIV (11% vs. 4%, p<0.05). When exploring other variables, we found that YMSM more frequently had receptive UAI with SPI (73% vs. 57%, p<0.05), had less time to be in a stable relationship, and their sexual partner more frequently convinced them to have UAI (8% vs. 0%, p<0.05). In multivariate analysis, UAI in YMSM with casual sexual partners was not associated with any of the variables. YMSM do not constitute a group at increased risk of HIV/STI infection compared with respondents >25 years old. However, there are some variables could contribute to vulnerability in this group.


Combined staged endoscopic and microsurgical approach of a third ventricular choroid plexus papilloma in an infant.
Choroid plexus papillomas of the third ventricle in newborn infants are quite rare and present a significant surgical challenge. This case report illustrates the utility of endoscopy in facilitating tumor resection. A 6-week-old boy, born prematurely at a gestational age of 35 weeks, presented with hydrocephalus secondary to a choroid plexus papilloma in the third ventricle, extending to the aqueduct of Sylvius and into the fourth ventricle. On admission, he was found to have clinical signs of raised intracranial pressure. MRI revealed a homogeneously enhancing mass primarily in the third ventricle. The initial surgical procedure was insertion of a ventriculo-peritoneal shunt, followed by an endoscopic biopsy, which allowed the surgeons to mobilize the tumor into the right lateral ventricle. This facilitated a subsequent transcortical approach to completely remove the tumour. The authors present a case of choroid plexus papilloma in an uncommon location with a unique surgical approach and a successful outcome with no neurological deficits. We detail our surgical approach and the complexity of approaching a tumor located in the third ventricle of an infant.


Leptin as a mediator of tumor-stromal interactions promotes breast cancer stem cell activity.
Breast cancer stem cells (BCSCs) play crucial roles in tumor initiation, metastasis and therapeutic resistance. A strict dependency between BCSCs and stromal cell components of tumor microenvironment exists. Thus, novel therapeutic strategies aimed to target the crosstalk between activated microenvironment and BCSCs have the potential to improve clinical outcome. Here, we investigated how leptin, as a mediator of tumor-stromal interactions, may affect BCSC activity using patient-derived samples (n = 16) and breast cancer cell lines, and determined the potential benefit of targeting leptin signaling in these model systems. Conditioned media (CM) from cancer-associated fibroblasts and breast adipocytes significantly increased mammosphere formation in breast cancer cells and depletion of leptin from CM completely abrogated this effect. Mammosphere cultures exhibited increased leptin receptor (OBR) expression and leptin exposure enhanced mammosphere formation. Microarray analyses revealed a similar expression profile of genes involved in stem cell biology among mammospheres treated with CM and leptin. Interestingly, leptin increased mammosphere formation in metastatic breast cancers and expression of OBR as well as HSP90, a target of leptin signaling, were directly correlated with mammosphere formation in metastatic samples (r = 0.68/p = 0.05; r = 0.71/p = 0.036, respectively). Kaplan-Meier survival curves indicated that OBR and HSP90 expression were associated with reduced overall survival in breast cancer patients (HR = 1.9/p = 0.022; HR = 2.2/p = 0.00017, respectively). Furthermore, blocking leptin signaling by using a full leptin receptor antagonist significantly reduced mammosphere formation in breast cancer cell lines and patient-derived samples. Our results suggest that leptin/leptin receptor signaling may represent a potential therapeutic target that can block the stromal-tumor interactions driving BCSC-mediated disease progression.


Vitamin D receptor gene haplotype is associated with late-onset Alzheimer's disease.
Vitamin D(3) is a neurosteroid that mediates its effects via the vitamin D receptor (VDR). The VDR gene is located on chromosome 12q13 and consists of 9 exons. VDR contains the DNA-binding site encoded by exons 2 and 3 and the ligand-binding site encoded by exons 4 - 9. Our earlier study showed that the ApaI polymorphic site of the VDR gene is associated with late-onset Alzheimer's disease (AD). Here, we investigated the association between additional polymorphisms of the VDR gene and AD using the same samples. Two single nucleotide polymorphisms (SNPs) in intron 8 (BsmI and Tru9I polymorphisms) and one in exon 2 (FokI polymorphism) of the VDR gene were examined in up to 108 AD patients and 115 age-matched controls. Genotypes were determined with polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. Haplotype analysis also included the previously studied polymorphic sites that were recognized by TaqI (in exon 9) and ApaI (in intron 8) restriction enzymes. There was no significant difference between AD patients and controls when their genotypes for BsmI, Tru9I and FokI polymorphic sites were compared. However, the frequency of "TaubF" haplotype (alleles of TaqI, ApaI, Tru9I, BsmI and FokI, respectively), which was determined by analyzing 5 polymorphisms together, was significantly higher in the AD patient group, suggesting that this haplotype is a risk factor in AD. Our results point out a possible link between AD and certain VDR polymorphisms and indicate that individuals with these polymorphisms might be vulnerable to AD.


Tumor necrosis factor induces tumor promoting and anti-tumoral effects on pancreatic cancer via TNFR1.
Multiple activities are ascribed to the cytokine tumor necrosis factor (TNF) in health and disease. In particular, TNF was shown to affect carcinogenesis in multiple ways. This cytokine acts via the activation of two cell surface receptors, TNFR1, which is associated with inflammation, and TNFR2, which was shown to cause anti-inflammatory signaling. We assessed the effects of TNF and its two receptors on the progression of pancreatic cancer by in vivo bioluminescence imaging in a syngeneic orthotopic tumor mouse model with Panc02 cells. Mice deficient for TNFR1 were unable to spontaneously reject Panc02 tumors and furthermore displayed enhanced tumor progression. In contrast, a fraction of wild type (37.5%), TNF deficient (12.5%), and TNFR2 deficient mice (22.2%) were able to fully reject the tumor within two weeks. Pancreatic tumors in TNFR1 deficient mice displayed increased vascular density, enhanced infiltration of CD4(+) T cells and CD4(+) forkhead box P3 (FoxP3)(+) regulatory T cells (Treg) but reduced numbers of CD8(+) T cells. These alterations were further accompanied by transcriptional upregulation of IL4. Thus, TNF and TNFR1 are required in pancreatic ductal carcinoma to ensure optimal CD8(+) T cell-mediated immunosurveillance and tumor rejection. Exogenous systemic administration of human TNF, however, which only interacts with murine TNFR1, accelerated tumor progression. This suggests that TNFR1 has basically the capability in the Panc02 model to trigger pro-and anti-tumoral effects but the spatiotemporal availability of TNF seems to determine finally the overall outcome.


Chemogenomic Profiling of Antileishmanial Efficacy and Resistance in the Related Kinetoplastid Parasite Trypanosoma brucei.
The arsenal of drugs used to treat leishmaniasis, caused by Leishmania spp., is limited and beset by toxicity and emergent resistance. Furthermore, our understanding of drug mode of action and potential routes to resistance is limited. Forward genetic approaches have revolutionized our understanding of drug mode of action in the related kinetoplastid parasite Trypanosoma brucei Therefore, we screened our genome-scale T. brucei RNA interference (RNAi) library against the current antileishmanial drugs sodium stibogluconate (antimonial), paromomycin, miltefosine, and amphotericin B. Identification of T. brucei orthologues of the known Leishmania antimonial and miltefosine plasma membrane transporters effectively validated our approach, while a cohort of 42 novel drug efficacy determinants provides new insights and serves as a resource. Follow-up analyses revealed the antimonial selectivity of the aquaglyceroporin TbAQP3. A lysosomal major facilitator superfamily transporter contributes to paromomycin-aminoglycoside efficacy. The vesicle-associated membrane protein TbVAMP7B and a flippase contribute to amphotericin B and miltefosine action and are potential cross-resistance determinants. Finally, multiple phospholipid-transporting flippases, including the T. brucei orthologue of the Leishmania miltefosine transporter, a putative β-subunit/CDC50 cofactor, and additional membrane-associated hits, affect amphotericin B efficacy, providing new insights into mechanisms of drug uptake and action. The findings from this orthology-based chemogenomic profiling approach substantially advance our understanding of antileishmanial drug action and potential resistance mechanisms and should facilitate the development of improved therapies as well as surveillance for drug-resistant parasites.


Response features determining spike times.
Interpreting messages encoded in single neuronal responses requires knowing which features of the responses carry information. That the number of spikes is an important part of the code has long been obvious. In recent years, it has been shown that modulation of the firing rate with about 25 ms precision carries information that is not available from the total number of spikes across the whole response. It has been proposed that patterns of exactly timed (1 ms precision) spikes, such as repeating triplets or quadruplets, might carry information that is not available from knowing about spike count and rate modulation. A model using the spike count distribution, the low-pass filtered PSTH (bandwidth below 30 Hz), and, to a small degree, the interspike interval distribution predicts the numbers and types of exactly-timed triplets and quadruplets that are indistinguishable from those found in the data. From this it can be concluded that the coarse (< 30 Hz) sequential correlation structure over time gives rise to the exactly timed patterns present in the recorded spike trains. Because the coarse temporal structure predicts the fine temporal structure, the information carried by the fine temporal structure must be completely redundant with that carried by the coarse structure. Thus, the existence of precisely timed spike patterns carrying stimulus-related information does not imply control of spike timing at precise time scales.


Alternative methods of anticoagulation for dialysis-dependent patients with heparin-induced thrombocytopenia.
Dialysis patients who are continually exposed to heparin are at risk for heparin-induced thrombocytopenia (HIT). Heparin-induced antibodies have been reported to occur in 0-12% of hemodialysis (HD) patients. The diagnosis or suspicion of HIT in this patient population requires careful confirmation of the diagnosis and substitution of heparin with an alternate anticoagulant for dialysis. Alternate agents such as the direct thrombin inhibitors (hirudin and argatroban) are available, but careful dosing and monitoring of the anticoagulant effect are required. Despite careful dosing, hemorrhagic complications have occurred with these agents. Unfortunately there are limited options for treatment of hemorrhagic complications and no specific antidotes are available for the direct thrombin inhibitors. In this report the currently available alternatives to heparin for dialysis, including dosing and monitoring recommendations, are reviewed.


Cytokine-mediated inflammation is independently associated with insulin sensitivity measured by the euglycemic insulin clamp in a community-based cohort of elderly men.
Both clinical and experimental studies suggest a close relation between an inflammatory state and insulin resistance. We investigated the association between cytokine-mediated inflammation (high sensitivity C reactive protein [hsCRP] and interleukin [IL] 6) and insulin sensitivity (insulin-mediated glucose disposal rate, assessed by the euglycemic insulin clamp) in a community-based cohort, with subgroup analyses of normal weight individuals without diabetes mellitus and metabolic syndrome (NCEP). hsCRP and IL-6 were inversely associated with insulin sensitivity (multivariable-adjusted regression coefficient for 1-SD increase of hsCRP -0.12 (-0.21-(-0.03), p=0.01) and of IL-6 -0.11 (-0.21-(-0.02), p=0.01) in models adjusting for age and components of the metabolic syndrome (systolic and diastolic blood pressure, antihypertensive drugs, HDL-cholesterol, triglycerides, fasting plasma glucose, waist circumference). The multivariable-adjusted association between hsCRP, IL-6 and insulin sensitivity were of a similar magnitude in normal weight individuals without diabetes and without the metabolic syndrome. Our data show that cytokine -mediated subclinical inflammation is independently associated with decreased insulin sensitivity also in apparently metabolically healthy normal weight individuals, indicating that the interplay between inflammatory processes and insulin resistance is present already in the early stages of the development of glucometabolic disease.


Medical Neighborhood Model for the Care of Chronic Kidney Disease Patients.
The patient-centered medical home is a popular model of care, but the patient-centered medical neighborhood (PCMN) is rarely described. We developed a PCMN in an academic practice to improve care for patients with chronic kidney disease (CKD). The purpose of this study is to identify the prevalence of CKD in this practice and describe baseline characteristics, develop an interdisciplinary team-based approach to care and determine cost associated with CKD patients. Patients with CKD stage 3a with comorbidities through stage 5 were identified. Data collected include demographics, comorbidities and whether patients had a nephrologist. Using a screening tool based on the 2012 Kidney Disease Improving Global Outcomes guidelines, a nurse care manager (NCM) made recommendations about management including indications for referral. A pharmacist reviewed patients' charts and made medication-related recommendations. Blue Cross Blue Shield (BCBS) insurance provided cost data for a subset of patients. A total of 1,255 patients were identified. Half did not have a formal diagnosis of CKD and three-quarters had never seen a nephrologist. Based on the results of the screening tool, the NCM recommended nephrology E-consult or full consult for 85 patients. The subset of BCBS patients had a mean healthcare cost of $1,528.69 per member per month. We implemented a PCMN that allowed for easy identification of a high-risk, high-cost population of CKD patients and optimized their care to reflect guideline-based standards.