Statin use and breast cancer: prospective results from the Women's Health Initiative.
Despite experimental observations suggesting that 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (statins) have antitumor activity, clinical studies have reached mixed conclusions about the relationship between statin use and breast cancer risk. To investigate associations between potency, duration of use, and type of statin used and risk of invasive breast cancer, we examined data for 156,351 postmenopausal women who were enrolled in the Women's Health Initiative. Information was collected on breast cancer risk factors and on the use of statins and other lipid-lowering drugs. Cox proportional hazards regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Statistical tests were two-sided. Over an average follow-up of 6.7 years, 4383 invasive breast cancers were confirmed by medical record and pathology report review. Statins were used by 11,710 (7.5%) of the cohort. Breast cancer incidence was 4.09 per 1000 person-years (PY) among statin users and 4.28 per 1000 PY among nonusers. In multivariable models, the hazard ratio of breast cancer among users of any statin, compared with nonusers, was 0.91 (95% CI = 0.80 to 1.05, P = .20). There was no trend in risk by duration of statin use, with HR = 0.80 (95% CI = 0.63 to 1.03) for < 1 year of use, HR = 0.99 (95% CI = 0.80 to 1.23) for 1- < 3 years of use, and HR = 0.94 (95% CI = 0.75 to 1.18) for > or = 3 years of use. Hydrophobic statins (i.e., simvastatin, lovastatin, and fluvastatin) were used by 8106 women, and their use was associated with an 18% lower breast cancer incidence (HR = 0.82, 95% CI = 0.70 to 0.97, P = .02). Use of other statins (i.e., pravastatin and atorvastatin) or nonstatin lipid-lowering agents was not associated with breast cancer incidence. Overall statin use was not associated with invasive breast cancer incidence. Our finding that use of hydrophobic statins may be associated with lower breast cancer incidence suggests possible within-class differences that warrant further evaluation.


[Clinical characteristics and prognostic significance of preherpetic neuralgia].
Herpes zoster is a world-wide disease of older age commonly presenting with preherpetic pain. The aim of the study was to determine clinical characteristics of preherpetic neuralgia and its influence on occurrence of postherpetic neuralgia. A prospective, controlled trial included 88 patients with preherpetic neuralgia. 44 herpes zoster patients without preherpetic neuralgia were included in the control group. All of them were clinically followed-up for three months after complete healing of skin lesions. Older age (> 60 years) was significantly predominant (59.1%) compared with other age groups (p < 0.01) as well as female sex (59.9%) compared with the male sex (p < 0.01). There was no significant predominance of any type of preherpetic neuralgia (stabbing, burning, itching, dull pain). More intense preherpetic pain (reported as "severe" and "moderate") was established more often than mild pain. The mean duration of preherpetic pain was 4.4 days (ranged between 1-20 days). Postherpetic neuralgia developed in 36/88 patients with preherpetic neuralgia (affecting predominantly older than 50 years of age--31/36), but there was no significant difference in proportion of postherpetic neuralgia (PHN) according to those without preherpetic neuralgia. People older than 60 years are the most common age group among herpes zoster patients suffering from preherpetic neuralgia. Sex distribution of patients with preherpetic pain reveals highly significant predominance of female sex. Opposite to some other authors' reports, preherpetic neuralgia and its severity have not been proven as risk factors for postherpetic neuralgia in patients involved in our trial.


Measuring suitability of soybean products for early-weaned pigs with immunological criteria.
Two trials were conducted to determine the suitability of soybean products for baby pigs. Weanling pigs (n = 40 and 48 in Trials 1 and 2, respectively) were infused orally (6 g/d) with dried skim milk, soybean meal (SBM, 48% CP); soy protein concentrate, moist extruded soy protein concentrate, or soy protein isolate from d 7 to 12 of age. Pigs were then fed a diet containing the same protein source for 1 (Trial 1) or 2 (Trial 2) wk after weaning (d 21 of age). To avoid exposure of pigs to soybean proteins, the dams of pigs were fed a corn-corn gluten meal-based diet supplemented with lysine and tryptophan from d 109 of gestation. All pigs in Trial 1 were killed at 28 d of age, and samples of ileal digesta and small intestine were obtained. In Trial 2, the soy protein isolate was not included, and all pigs were fed a diet containing 4% soybean oil and 1.25% lysine for the last 3 wk of the trial. Growth performance, skin-fold thickness, after intradermal injection of extracts of the corresponding proteins, and anti-soy immunoglobulin G (IgG) titers were measured. Results indicated that pigs fed diets containing SBM had lower (P less than .05) villus height and xylose absorption but higher (P less than .05) serum anti-soy IgG titers and increased skin-fold thickness compared with the mean of pigs given milk and all other soy treatments.(ABSTRACT TRUNCATED AT 250 WORDS)


The Prison Rape Elimination Act (PREA): Snitching, Sexuality, and Normalizing Deviance.
The normalization of deviance in the form of prison rape finds common themes in media, rape myths, and common discourse. However, these portrayals fail to include real world policies and the perspectives of incarcerated populations. As such, the normalization of deviance is assessed in the context of the implementation of the Prison Rape Elimination Act (PREA). A thematic analysis was conducted using qualitative survey responses from 407 males incarcerated in three medium-level security state prisons in the Southern United States. Surprisingly, respondents rejected stereotypical notions of sexuality (institutional deviancy) and snitching (cultural deviancy) surrounding prison rape. Rather, respondents favored standardized safety procedures and institutional responses designed to reduced risk, while also endorsing views that traditional snitching codes were not applicable to prison rape. This study provides implications for researchers and practitioners, particularly in the context of the implementation of PREA.


Determinants of health workers intention to use malaria rapid diagnostic test in Kintampo North Municipality, Ghana - a cross-sectional study.
Resistance to antimalarial drugs resulting from overuse of the medication remains a threat to malaria control and elimination in endemic settings including Ghana. Reliance on clinical signs alone results in patients being diagnosed with malaria falsely. The World Health Organization and local guidelines recommend test-based diagnosis with malaria rapid diagnostic test (mRDT) or microscopy before prescription of antimalarial drugs. Despite the scale-up of mRDT through the procurement of mRDT kits and training of health workers on mRDT-led diagnosis of malaria, its use remains low with about 85% health workers reporting satisfaction with the presumptive diagnosis. A quantitative cross-sectional study was conducted to investigate the determinants of intention to use mRDT among health workers in Kintampo North Municipality, Ghana. A total of 110 health workers were surveyed from February to April 2017. Intention to use mRDT was measured as the primary outcome with a 5-item scale questionnaire based on the Technology Acceptance Model (TAM). We then tested its association with hypothesized determinants: coherence, cognitive participation, collective action, and reflexive action informed by the Normalization Process Theory (NPT) as well as health workers' background characteristics using linear regression modeling. The mean intention to use mRDT score was 82% (SD: 12.6). The regression model showed health workers intention to use mRDT was positively associated with coherence (β = 0.40, 95% CI 0.16-0.65) and cognitive participation (β = 0.36, 95% CI 0.15-0.58). Intention to use mRDT score was 6.85 units higher among health workers with three or more years of experience compared to those with less than 3 years of experience (β = 6.85 95% CI 0.59-13.12). However, intention to use mRDT score was inversely related to reflexive monitoring and collective action but not significant. The study identified that intention to use mRDT was positively influenced by health workers having a proper understanding of the aims and expected benefits (coherence) of the intervention and the availability of experienced staff and intervention champions (cognitive participation) to promote mRDT use among health workers.


The Emergence of Network Activity Patterns in the Somatosensory Cortex - An Early Window to Autism Spectrum Disorders.
Across mammalian species, patterned activity in neural populations is a prominent feature of developing sensory cortices. Numerous studies have long appreciated the diversity of these patterns, characterizing their differences in spatial and temporal dynamics. In the murine somatosensory cortex, neuronal co-activation is thought to guide the formation of sensory maps and prepare the cortex for sensory processing after birth. While pioneering studies deftly utilized slice electrophysiology and unit recordings to characterize correlated activity, a detailed understanding of the underlying circuits remains poorly understood. More recently, advances in in vivo calcium imaging in awake mouse pups and increasing genetic tractability of neuronal types have allowed unprecedented manipulation of circuit components at select developmental timepoints. These novel approaches have proven fundamental in uncovering the identity of neurons engaged in correlated activity during development. In particular, recent studies have highlighted interneurons as key in refining the spatial extent and temporal progression of patterned activity. Here, we discuss how emergent synchronous activity across the first postnatal weeks is shaped by underlying gamma aminobutyric acid (GABA)ergic contributors in the somatosensory cortex. Further, the importance of participation in specific activity patterns per se for neuronal maturation and perdurance will be of particular highlight in this survey of recent literature. Finally, we underscore how aberrant neuronal synchrony and disrupted inhibitory interneuron activity underlie sensory perturbations in neurodevelopmental disorders, particularly Autism Spectrum Disorders (ASDs), emphasizing the importance of future investigative approaches that incorporate the spatiotemporal features of patterned activity alongside the cellular components to probe disordered circuit assembly.


Chronic immune thrombocytopenic purpura in hemophilia A.
Chronic immune thrombocytopenic purpura resistant to steroid therapy occurred in a 30-year-old patient with severe hemophilia A. This association has recently been reported in other patients, and a possible relation to the acquired immune deficiency syndrome (AIDS) has been suggested. Although this patient had been treated with factor VIII concentrate for 4 years, the proportions of helper and suppressor T cells were normal, and there was no evidence of AIDS. An uncomplicated splenectomy gave excellent results. All patients with hemophilia should have their platelet counts monitored closely and should report any unusual pattern of bleeding.


Agaricus blazei Murrill from Brazil: an ingredient for nutraceutical and cosmeceutical applications.
Operations for sorting mushrooms at the industrial level usually generate large amounts of bio-residues not conforming to strict morphological criteria for commercial purposes, even though their biological content is not compromised. In this context, the present work aimed at evaluating the potential for reutilizing industrially discarded Agaricus blazei Murill (ABM). Thus, the content of essential nutrients and the chemical composition were determined, and MTT and LDH assays were used to evaluate the viability and cell death of Caco-2 and HT29 cell lines of an ethanolic extract prepared from ABM (preliminary safety tests for nutraceutical applications). The extract was incorporated into a semi-solid base cosmetic cream and cell viability effects of the extract, and of the final cream formulation, on a keratinocyte cell line (HaCaT) were studied (preliminary safety tests for cosmeceutical applications). Essential nutrients, such as proteins and carbohydrates, and a low fat content were determined for ABM. Twenty-two fatty acids were detected, with polyunsaturated fatty acids (PUFA) (∼53%) being the most abundant fraction. The cell viabilities of Caco-2 and HT29 cells were maintained up to 100 μg mL-1. After incorporation into the base cream, a formulation with a pale yellow colour and favourable pH was obtained. The cell viability of HaCaT cells in the presence of the extract and the final cream formulation was maintained in a concentration dependent manner, which indicates the safety of this extract for cosmeceutical applications. The results suggest that ABM residues can be used as an inexpensive and sustainable source of nutraceutical and cosmeceutical ingredients.


Evolving strategies in the treatment of acute myocardial infarction-induced cardiogenic shock.
Despite advances in medical technology and re-vascularization interventions, the mortality rate for cardiogenic shock (CS) following acute myocardial infarction has remained at 50%. The majority of these mortalities are from left ventricular failure resulting in multi-system organ dysfunction. The field of mechanical circulatory support (MCS) has evolved within the past decade, with improved outcomes from extracorporeal membrane oxygenation as well as continuous-flow left ventricular assist devices (CF LVADs). In this paper, we discuss our institutional treatment strategies, the rationale for the protocol development, and our improved outcomes when using MCS in patients with refractory CS following acute myocardial infarction.


Carbachol activates protein kinase C in dispersed gastric chief cells.
We used an 'in situ' kinase assay to examine agonist-induced protein kinase C. (PKC) activation in dispersed chief cells from guinea-pig stomach. Phorbol 12-myristate 13-acetate (PMA), a phorbol ester, and carbamoylcholine, a cholinergic agent, caused a 4- and 3-fold increase in pepsinogen secretion from dispersed chief cells respectively. Whereas PMA caused a rapid 3-fold increase in peptide kinase activity, carbachol caused a 15% increase in activity that was inhibited by the PKC inhibitor, CGP 41,251. Concentrations of carbamoylcholine and a Ca2+ ionophore that were sub-maximal for stimulation of pepsinogen secretion did not cause PKC activation. These results indicate that, in the absence of PKC activation, other mechanisms, most likely involving changes in cellular Ca2+, are sufficient to stimulate pepsinogen secretion. Nevertheless, carbamoylcholine stimulated maximal secretion of pepsinogen only at concentrations that also resulted in activation of PKC. Moreover, these data indicate that relatively small increases in PKC activity (5-10%) can stimulate pepsinogen secretion from dispersed chief cells.


Effect of diacylglycerol interfacial crystallization on the physical stability of water-in-oil emulsions.
The influence of diacylglycerol (DAG) combined with polyglycerol polyricinoleate (PGPR) on the stability of water-in-oil (W/O) emulsions containing hydrogenated palm oil (HPO) was studied. Polarized light microscope revealed that DAG promoted HPO to crystallize at the water-oil interface, providing the combination of Pickering and network stabilization effects. It was proposed that the molecular compatibility of fatty acids in DAG with HPO accounted for the promotional effect. The interfacial crystallization of DAG together with the surface activity of PGPR led to the formation of emulsions with uniform small droplets and high freeze-thaw stability. Further exploration of physical properties indicated that the combination of DAG and PGPR dramatically improved the emulsion's viscoelasticity and obtained a larger deformation yield. Water droplets in DAG-based emulsions acted as active fillers to improve the network rigidity. Therefore, DAG is a promising material to be used as emulsifier to enhance the physical stability of W/O emulsions.


The coming of age of phosphoproteomics--from large data sets to inference of protein functions.
Protein phosphorylation is one of the most common post-translational modifications used in signal transduction to control cell growth, proliferation, and survival in response to both intracellular and extracellular stimuli. This modification is finely coordinated by a network of kinases and phosphatases that recognize unique sequence motifs and/or mediate their functions through scaffold and adaptor proteins. Detailed information on the nature of kinase substrates and site-specific phosphoregulation is required in order for one to better understand their pathophysiological roles. Recent advances in affinity chromatography and mass spectrometry (MS) sensitivity have enabled the large-scale identification and profiling of protein phosphorylation, but appropriate follow-up experiments are required in order to ascertain the functional significance of identified phosphorylation sites. In this review, we present meaningful technical details for MS-based phosphoproteomic analyses and describe important considerations for the selection of model systems and the functional characterization of identified phosphorylation sites.


HIV neutralization assay using polymerase chain reaction-derived molecular signals.
Characterization of the capacity of human polyclonal antibody to neutralize wild-type patient isolates has important implications for vaccine development. We report the development of a polymerase chain reaction-based neutralization assay that quantitatively measures each infection using HIV proviral formation. These molecular end points identified the absence or quantitative diminution of DNA provirus formation as well as a delay in the kinetics of HIV DNA provirus formation. Using both laboratory strain prototype isolates (HIV-1-MN, HIV-IIIb) and primary wild-type patients' isolates, neutralization end points were reproducibly determined. End points were reached within 72 h, thereby minimizing the impact of subsequent rounds of infection on interpretation of results. Although the neutralization titer of polyclonal sera was usually comparable using standard technology, this assay did find isolate-dependent variation in the relationship between p24 production and HIV proviral DNA formation. Finally, we noted the disparity between the ability of human sera to neutralize prototype and wild-type isolates in primary peripheral blood mononuclear cell targets. We believe this assay provides unique opportunities to characterize the initial events of virus-antibody interaction and will help to elucidate clinically relevant neutralization immunoregulatory mechanisms.


THE EFFECTS OF CURRENT FLOW ON BIOELECTRIC POTENTIAL : I. VALONIA.
The effect of direct current flow upon the potential difference across the protoplasm of impaled Valonia cells was studied. Current density and direction were controlled in a bridge which balanced the ohmic resistances, leaving the changes (increase, decrease, or reversal) of the small, normally negative, bioelectric potential to be recorded continuously, before, during, and after current flow, with a string galvanometer connected into a vacuum tube detector circuit. Two chief states of response were distinguished: State A.-Regular polarization, which begins to build up the instant current starts to flow, the counter E.M.F. increasing most rapidly at that moment, then more and more slowly, and finally reaching a constant value within 1 second or less. The magnitude of counter E.M.F. is proportional to the current density with small currents flowing in either direction across the protoplasm, but falls off at higher density, giving a cusp with recession to lower values; this recession occurs with slightly lower currents outward than inward. Otherwise the curves are much the same for inward and outward currents, for different densities, for charge and discharge, and for successive current flows. There is a slight tendency for the bioelectric potential to become temporarily positive following these current flows. Records in the regular state (State A) show very little effect of increased series resistance on the time constant of counter E.M.F. This seems to indicate that a polarization rather than a static capacity is involved. State B.-Delayed and non-proportional polarization, in which there is no counter E.M.F. developed with small currents in either direction across the protoplasm, nor with very large outward currents. But with inward currents a threshold density is reached at which a counter E.M.F. rather suddenly develops, with a sigmoid curve rising to high positive values (200 mv. or more). There is sometimes a cusp, after which the P.D. remains strongly positive as long as the current flows. It falls off again to negative values on cessation of current flow, more rapidly after short flows, more slowly after longer ones. The curves of charge are usually quite different in shape from those of discharge. Successive current flows of threshold density in rapid succession produce quicker and quicker polarizations, the inflection of the curve often becoming smoothed away. After long interruptions, however, the sigmoid curve reappears. Larger inward currents produce relatively little additional positive P.D.; smaller ones on the other hand, if following soon after, have a greatly increased effectiveness, the threshold for polarization falling considerably. The effect dies away, however, with very small inward currents, even as they continue to flow. Over a medium range of densities, small increments or decrements of continuing inward current produce almost as regular polarizations as in State A. Temporary polarization occurs with outward currents following soon after the threshold inward currents, but the very flow of outward current tends to destroy this, and to decondition the protoplasm, again raising the threshold, for succeeding inward flows. State A is characteristic of a few freshly gathered cells and of most of those which have recovered from injuries of collecting, cleaning, and separating. It persists a short time after such cells are impaled, but usually changes over to State B for a considerable period thereafter. Eventually there is a reappearance of regular polarization; in the transition there is a marked tendency for positive P.D. to be produced after current flow, and during this the polarizations to outward currents may become much larger than those to inward currents. In this it resembles the effects of acidified sea water, and of certain phenolic compounds, e.g. p-cresol, which produce State A in cells previously in State B. Ammonia on the other hand counteracts these effects, producing delayed polarization to an exaggerated extent. Large polarizations persist when the cells are exposed to potassium-rich solutions, showing it is not the motion of potassium ions (e.g. from the sap) which accounts for the loss or restoration of polarization. It is suggested that inward currents restore a protoplasmic surface responsible for polarization by increasing acidity, while outward currents alter it by increasing alkalinity. Possibly this is by esterification or saponification respectively of a fatty film. For comparison, records of delayed polarization in silver-silver chloride electrodes are included.


Loss of chromosome Y in primary tumors.
Certain cancer types afflict female and male patients disproportionately. The reasons include differences in male/female physiology, effect of sex hormones, risk behavior, environmental exposures, and genetics of the sex chromosomes X and Y. Loss of Y (LOY) is common in peripheral blood cells in aging men, and this phenomenon is associated with several diseases. However, the frequency and role of LOY in tumors is little understood. Here, we present a comprehensive catalog of LOY in >5,000 primary tumors from male patients in the TCGA. We show that LOY rates vary by tumor type and provide evidence for LOY being either a passenger or driver event depending on context. LOY in uveal melanoma specifically is associated with age and survival and is an independent predictor of poor outcome. LOY creates common dependencies on DDX3X and EIF1AX in male cell lines, suggesting that LOY generates unique vulnerabilities that could be therapeutically exploited.


Tai Chi Training Evokes Significant Changes in Brain White Matter Network in Older Women.
Background: Cognitive decline is age relevant and it can start as early as middle age. The decline becomes more obvious among older adults, which is highly associated with increased risk of developing dementia (e.g., Alzheimer's disease). White matter damage was found to be related to cognitive decline through aging. The purpose of the current study was to compare the effects of Tai Chi (TC) versus walking on the brain white matter network among Chinese elderly women. Methods: A cross-sectional study was conducted where 42 healthy elderly women were included. Tai Chi practitioners (20 females, average age: 62.9 ± 2.38 years, education level 9.05 ± 1.8 years) and the matched walking participants (22 females, average age: 63.27 ± 3.58 years, educational level: 8.86 ± 2.74 years) underwent resting-state functional magnetic resonance imaging (rsfMRI) scans. Diffusion tensor imaging (DTI) and graph theory were employed to study the data, construct the white matter matrix, and compare the brain network attributes between the two groups. Results: Results from graph-based analyses showed that the small-world attributes were higher for the TC group than for the walking group (p < 0.05, Cohen's d = 1.534). Some effects were significant (p < 0.001) with very large effect sizes. Meanwhile, the aggregation coefficient and local efficiency attributes were also higher for the TC group than for the walking group (p > 0.05). However, no significant difference was found between the two groups in node attributes and edge analysis. Conclusion: Regular TC training is more conducive to optimize the brain functioning and networking of the elderly. The results of the current study help to identify the mechanisms underlying the cognitive protective effects of TC.


Bioethics principles, informed consent, and ethical care for special populations: curricular needs expressed by men and women physicians-in-training.
Physicians-in-training today are learning in an ethical environment that is unprecedented in its complexity. There is a call for new approaches in preparing medical students and residents for the ethical and professional issues they will encounter. The perspectives of physicians-in-training at different levels regarding the level of curricular attention needed for emerging bioethics concepts, practical informed consent considerations, and the care of special populations are unknown. The authors performed a hypothesis-driven, confidential survey study to assess perceived needs and preferences among medical students and residents related to medical ethics education at the University of New Mexico School of Medicine. A total of 336 physicians-in-training volunteered (62% response rate). Overall, strong interest was expressed for increased curricular attention to the domains of bioethics principles, informed consent, and care of special populations. Women students expressed greater interest generally. For certain domains, clinical students expressed relatively less curricular need and psychiatry and primary care residents expressed relatively greater curricular need. Two of the four hypotheses were supported, a third received partial support, and a fourth was not supported by the findings. To be valuable and effective, new ethics curricular approaches must be responsive to the current complex ethical environment and attentive to the preferences of medical students and residents of both genders, at different stages of training, with different patient care responsibilities. This hypothesis-driven study provides guidance for the inclusion of novel and important ethics domains in training curricula across medical school and diverse residency programs.


First Report of Chaetomella raphigera Causing Leaf Spot on Rosa chinensis in China.
China rose, Rosa chinensis Jacq., is extensively cultivated as an ornamental plant in China (1). During the course of a disease survey of China rose in Henan Province, a leaf spot was observed on about 20 China roses, cultivated in a garden in Zhengzhou, Henan Province, in early October 2012. The early symptom appeared as small round, pale brown lesions on the leaves. Lesions expanded into 5 to 15-mm-diameter spots that were near round or irregular and brown. Both sporodochial and pycnidial conidiomata developed in necrotic areas of diseased leaves when placed in moist chambers. Pycnidia were elongated, reniform, with a single raphe over the top, pale to dark brown, and 260 to 350 × 150 to 210 μm. Sporodochia were pale luteous and 100 to 280 × 80 to 180 μm. Setae, conidiophores, conidiogenous cells, and conidia were the same between two types of conidioma. Setae were pale to dark brown, 0 to 2 septate, straight with rounded end, clavate to curved at apex, and 22 to 60 × 2 to 5 μm. Conidiophores were up to 120 × 1 to 2 μm, filiform, cylindric, and branched. Conidiogenous cells were enteroblastic, collar and channel minute. Conidia were nonseptate, hyaline, ellipsoid or cymbiform, smooth, guttulate, and 4 to 6.5 × 1.5 to 2.5 μm. Two pure cultures (zm12276-1 and zm12276-2) were obtained by picking spores from independent conidiomata on one leaf and then subsequently grown on potato dextrose agar (PDA), producing the same two kinds of conidiomata. The characteristics of conidial size and distinctly different conidiomata with setae are diagnostic of Chaetomella raphigera M.E. Swift (3,4). The identity of our fungus (zm12276-1) was confirmed to be C. raphigera by DNA sequencing of the ITS1-5.8S-ITS2 region. The DNA sequence was 99% identical to those of the other C. raphigera isolates (AY487076 and AY487085) (2). The ITS sequence from zm12276-1 was deposited in GenBank (KF483474). Pathogenicity was tested by inoculating 10 leaves of R. chinensis with mycelia plug from colony of zm12276-1 (0.5 cm in diameter). An equal number of fresh leaves inoculated with the plugs of non-colonized PDA medium served as the control. All leaves were incubated in clear plastic box with a dish of sterile distilled water at 25°C under ambient light. After 7 days, 90% of the inoculated leaves showed symptoms identical to those observed on R. chinensis leaves affected in the field. From each of the symptomatic leaves, C. raphigera was recovered, whereas controls remained symptom-free and no fungus was isolated from the control leaves. Koch's postulates were repeated three times with the same results using the pure culture of zm12276-1. C. raphigera has been previously reported on Rosa sp. in the United States (4). To our knowledge, this is the first report of C. raphigera infecting R. chinensis in China. The disease cycle and the control strategies in the regions are being further studied. References: (1) C. Z. Gu and K. R. Robertson. Pages 339-381 in: Flora of China, vol. 9. Science Press, Beijing and Missouri Botanical Garden, 2003. (2) A. Y. Rossman et al. Mycol. Progr. 3:275, 2004. (3) B. C. Sutton. The Coelomycetes. CAB International Publishing, New York, 1980. (4) M. E. Swift. Mycologia 22:165, 1930.


Myasthenia gravis. Residues of the alpha and gamma subunits of muscle acetylcholine receptor involved in formation of immunodominant CD4+ epitopes.
We propagated from myasthenia gravis (MG) patients by stimulation in vitro with synthetic sequences (alpha 48-67, alpha 304-322, gamma 75-94 and gamma 321-340) of the human muscle acetylcholine receptor (AChR), CD4+ lines against four 20-residue sequence regions of the AChR alpha and gamma subunits that are recognized by Th cells of most MG patients. Most lines secreted IL-2 and not IL-4, suggesting that they comprise Th1 cells. For three lines we verified that, as reported previously, AChR epitopes are presented by DR molecules: their response to the relevant peptide was abolished by anti-DR Abs. The DR molecules presenting AChR epitopes were identified by testing the response of the lines to the relevant peptide, using APC from donors homozygous for the different DR alleles of the line. We tested the lines with single residue-substituted analogues of the epitope sequence. The results of these experiments indicated that the lines were polyclonal and recognized overlapping epitopes. Their response was abolished by some substitutions, identifying residues common to all epitopes within a given region, whereas other substitutions reduced but did not obliterate the response, indicating residues included in some but not all epitopes recognized by the line. Comparison of the residues involved in epitope formation for different lines supported the conclusion that within the 20-residue immunodominant regions investigated here, the same sequence segment is involved in formation of epitopes, even in DR-discordant patients.


Heptadentate chelates for 89Zr-radiolabelling of monoclonal antibodies.
Herein, we report the synthesis of three new bifunctional heptadentate metal ion binding chelates derived from desferrioxamine B (DFO) linked to a tripeptide unit that comprises of a glutamic acid and two glycine residues. The three DFO derivatives were also functionalised with a photoactivatable aryl azide unit for light-triggered labelling of proteins. The chelates were obtained in 3 synthetic steps in good overall yields by using solid phase peptide synthesis (SPPS). Density Functional Theory (DFT) calculations were used to estimate thermodynamic formation constants (log β) of the corresponding Zr4+ complexes. Quantitative zirconium-89 radiolabelling (>95%) was obtained in <5 min at room temperature, and the stability of the radioconjugates toward different competitors (human serum, EDTA and Fe3+) was assessed in vitro. One-pot 89Zr-photoradiosynthesis produced [89Zr]Zr-2-onartuzumab directly from the formulated, clinical-grade sample MetMAb™, without pre-purifying the monoclonal antibody (mAb) component, with an isolated decay-corrected radiochemical yield of 36.4 ± 2.4%. PET imaging and biodistribution studies were performed in female athymic nude mice bearing subcutaneous xenografts derived from the MKN-45 human gastric cancer cell line to assess the pharmacokinetic profile and tumour binding of [89Zr]Zr-2-onartuzumab. Specific tumour uptake of [89Zr]Zr-2-onartuzumab was confirmed by using competitive inhibition (blocking) studies and bone uptake was significantly reduced compared to the parent DFO analogue.


Operational point of neural cardiovascular regulation in humans up to 6 months in space.
Entering weightlessness affects central circulation in humans by enhancing venous return and cardiac output. We tested whether the operational point of neural cardiovascular regulation in space sets accordingly to adopt a level close to that found in the ground-based horizontal position. Heart rate (HR), finger blood and brachial blood pressure (BP), and respiratory frequency were collected in 11 astronauts from nine space missions. Recordings were made in supine and standing positions at least 10 days before launch and during spaceflight (days 5-19, 45-67, 77-116, 146-180). Cross-correlation analyses of HR and systolic BP were used to measure three complementary aspects of cardiac baroreflex modulation: 1) baroreflex sensitivity, 2) number of effective baroreflex estimates, and 3) baroreflex time delay. A fixed breathing protocol was performed to measure respiratory sinus arrhythmia and low-frequency power of systolic BP variability. We found that HR and mean arterial pressure did not differ from preflight supine values for up to 6 mo in space. Respiration frequency tended to decrease during prolonged spaceflight. Concerning neural markers of cardiovascular regulation, we observed in-flight adaptations toward homeostatic conditions similar to those found in the ground-based supine position. Surprisingly, this was not the case for baroreflex time delay distribution, which had somewhat longer latencies in space. Except for this finding, our results confirm that the operational point of neural cardiovascular regulation in space sets to a level close to that of an Earth-based supine position. This adaptation level suggests that circulation is chronically relaxed for at least 6 mo in space.


Ferulic acid inhibits bovine endometrial epithelial cells against LPS-induced inflammation via suppressing NK-κB and MAPK pathway.
Endometritis is one of the most common reproductive diseases caused by bacterial infection in the cow. Ferulic acid is a major effective component extracted from Ligusticum wallichii. Ferulic acid displays pharmacological effects such as anti-inflammation and antioxidation. The aim of the present study was to investigate the protective effects of ferulic acid on inflammation induced by lipopolysaccharide (LPS) in bovine endometrial epithelial cells (BEECs). BEECs were pretreated with ferulic acid followed by LPS treatment. QRT-PCR analysis showed the mRNA expression of LPS-induced proinflammatory cytokines (IL1B, IL6, TNFA, and IL8) was decreased with ferulic acid pretreatment. Western blot analysis showed that ferulic acid inhibited the degradation of IκB and phosphorylation of NF-κB p65. Ferulic acid suppressed the phosphorylation of MAPKs, including p38 and JNK. All of these results indicated that ferulic acid may be considered as a potential anti-inflammatory drug for curing endometritis.


Activation of the alpha-7 nicotinic acetylcholine receptor (α7 nAchR) reverses referred mechanical hyperalgesia induced by colonic inflammation in mice.
In the current study, we investigated the effect of the activation of the alpha-7 nicotinic acetylcholine receptor (α7 nAchR) on dextran sulphate sodium (DSS)-induced colitis and referred mechanical hyperalgesia in mice. Colitis was induced in CD1 male mice through the intake of 4% DSS in tap water for 7 days. Control mice received unadulterated water. Referred mechanical hyperalgesia was evaluated for 7 days after the beginning of 4% DSS intake. Referred mechanical hyperalgesia started within 1 day after beginning DSS drinking, peaked at 3 days and persisted for 7 days. This time course profile perfectly matched with the appearance of signs of colitis. Both acute and chronic oral treatments with nicotine (0.1-1.0 mg/kg, p.o.) were effective in inhibiting the established referred mechanical hyperalgesia. The antinociceptive effect of nicotine was completely abrogated by cotreatment with the selective α7 nAchR antagonist methyllycaconitine (MLA) (1.0 mg/kg). Consistent with these results, i.p. treatment with the selective α7 nAchR agonist PNU 282987 (0.1-1.0 mg/kg) reduced referred mechanical hyperalgesia at all periods of evaluation. Despite their antinociceptive effects, nicotinic agonists did not affect DSS-induced colonic damage or inflammation. Taken together, the data generated in the present study show the potential relevance of using α7 nAchR agonists to treat referred pain and discomfort associated with inflammatory bowel diseases.


Dual antithrombotic treatment in chronic coronary syndrome: European Society of Cardiology criteria vs. CHADS-P2A2RC score.
According to the 2019 European Society of Cardiology (ESC) guidelines on chronic coronary syndromes (CCS), adding a P2Y12 inhibitor or rivaroxaban to aspirin should be considered in high-risk patients. We estimated the proportion of patients eligible for treatment with the ESC criteria and examined if a recently validated risk score (CHADS-P2A2RC) could improve risk prediction. We included 61 338 CCS patients undergoing first-time coronary angiography in Western Denmark (2003-16) and classified them according to the ESC criteria and the CHADS-P2A2RC score. The ESC criteria identified 33.9% as high risk, 53.3% as moderate risk, and 12.8% as low risk. The CHADS-P2A2RC score identified 24.9% as high risk (≥4 points), 48.1% as moderate risk (2-3 points), and 27.0% as low risk (≤1 points). Major adverse cardiovascular events per 100 person-years were 4.8 [95% confidence interval (CI) 4.6-5.0] in patients considered high risk with both schemes, 2.1 (95% CI 2.0-2.2) in patients considered high risk with the ESC but low-to-moderate risk with the CHADS-P2A2RC criteria, 3.8 (95% CI 3.6-4.1) in patients considered low-to-moderate risk with the ESC but high risk with the CHADS-P2A2RC criteria, and 1.5 (95% CI 1.5-1.6) in patients considered low-to-moderate risk with both schemes. The CHADS-P2A2RC score enabled correct downward risk reclassification of 5161 patients (8%) without events, yielding an improved specificity of 9.7%, a loss of sensitivity of 4.4%, and an overall net reclassification index of 0.053. Based on the 2019 ESC guidelines, dual antithrombotic treatment should be considered in one-third of CCS patients. The CHADS-P2A2RC score improved risk classification and may particularly identify low-risk patients with limited benefit from treatment.


Recurrence rates after abdominal surgery for complete rectal prolapse: a multicenter pooled analysis of 643 individual patient data.
This study was designed to determine what impact surgical technique, means of access, and method of rectopexy have on recurrence rates following abdominal surgery for full-thickness rectal prolapse. Consecutive individual patient data on age, gender, surgical technique (mobilization-only, mobilization-resection-pexy, or mobilization-pexy), means of access (open or laparoscopic), rectopexy method (suture or mesh), follow-up length, and recurrences were collected from 15 centers performing abdominal surgery for full-thickness rectal prolapse between 1979 and 2001. Recurrence was defined as the presence of full-thickness rectal prolapse after abdominal surgery. Chi-squared test and Cox proportional hazards regression analysis were used to assess statistical heterogeneity. Recurrence-free curves were generated and compared using the Kaplan-Meier method and log-rank test, respectively. Abdominal surgery consisted of mobilization-only (n = 46), mobilization-resection-pexy (n = 130), or mobilization-pexy (n = 467). There were 643 patients. After excluding center 8, there was homogeneity on recurrence rates among the centers with recurrences (n = 8) for age (hazards ratio, 0.6; 95 percent confidence interval, 0.2-1.7; P = 0.405), gender (hazards ratio, 0.6; 95 percent confidence interval, 0.1-2.3; P = 0.519), and center (hazards ratio, 0.3; 95 percent confidence interval, 0.1-1.5; P = 0.142). However, there was heterogeneity between centers with (n = 8) and without recurrences (n = 6) for gender (P = 0.0003), surgical technique (P < 0.0001), means of access (P = 0.01), and rectopexy method (P < 0.0001). The median length of follow-up of individual centers varied from 4 to 127 months (P < 0.0001). There were 38 recurrences at a median follow-up of 43 (range, 1-235) months. The pooled one-, five-, and ten-year recurrence rates were 1.06, 6.61, and 28.9 percent, respectively. Age, gender, surgical technique, means of access, and rectopexy method had no impact on recurrence rates. Although this study is likely underpowered, the impact of mobilization-only on recurrence rates was similar to that of other surgical techniques.


A tool for simulating and communicating uncertainty when modelling species distributions under future climates.
Tools for exploring and communicating the impact of uncertainty on spatial prediction are urgently needed, particularly when projecting species distributions to future conditions.We provide a tool for simulating uncertainty, focusing on uncertainty due to data quality. We illustrate the use of the tool using a Tasmanian endemic species as a case study. Our simulations provide probabilistic, spatially explicit illustrations of the impact of uncertainty on model projections. We also illustrate differences in model projections using six different global climate models and two contrasting emissions scenarios.Our case study results illustrate how different sources of uncertainty have different impacts on model output and how the geographic distribution of uncertainty can vary.Synthesis and applications: We provide a conceptual framework for understanding sources of uncertainty based on a review of potential sources of uncertainty in species distribution modelling; a tool for simulating uncertainty in species distribution models; and protocols for dealing with uncertainty due to climate models and emissions scenarios. Our tool provides a step forward in understanding and communicating the impacts of uncertainty on species distribution models under future climates which will be particularly helpful for informing discussions between researchers, policy makers, and conservation practitioners.


Enabling Energy Efficiency and Polarity Control in Germanium Nanowire Transistors by Individually Gated Nanojunctions.
Germanium is a promising material for future very large scale integration transistors, due to its superior hole mobility. However, germanium-based devices typically suffer from high reverse junction leakage due to the low band-gap energy of 0.66 eV and therefore are characterized by high static power dissipation. In this paper, we experimentally demonstrate a solution to suppress the off-state leakage in germanium nanowire Schottky barrier transistors. Thereto, a device layout with two independent gates is used to induce an additional energy barrier to the channel that blocks the undesired carrier type. In addition, the polarity of the same doping-free device can be dynamically switched between p- and n-type. The shown germanium nanowire approach is able to outperform previous polarity-controllable device concepts on other material systems in terms of threshold voltages and normalized on-currents. The dielectric and Schottky barrier interface properties of the device are analyzed in detail. Finite-element drift-diffusion simulations reveal that both leakage current suppression and polarity control can also be achieved at highly scaled geometries, providing solutions for future energy-efficient systems.


The outlook for population growth.
Projections of population size, growth rates, and age distribution, although extending to distant horizons, shape policies today for the economy, environment, and government programs such as public pensions and health care. The projections can lead to costly policy adjustments, which in turn can cause political and economic turmoil. The United Nations projects global population to grow from about 7 billion today to 9.3 billion in 2050 and 10.1 billion in 2100, while the Old Age Dependency Ratio doubles by 2050 and triples by 2100. How are such population projections made, and how certain can we be about the trends they foresee?


A method to estimate urinary electrolyte excretion in patients at risk for developing cerebral salt wasting.
Two major criteria are necessary to diagnose cerebral salt wasting (CSW): a cerebral lesion and a large urinary excretion of Na+ and Cl- at a time when the extracellular fluid (ECF) volume is contracted. Nevertheless, it is difficult for the physician to confirm from bedside observation that a patient has a contracted ECF volume. Hyponatremia, although frequently present, should not be a criterion for a diagnosis of salt wasting. A contracted ECF volume is unlikely if there are positive balances of Na+ and Cl-. The goal of this study was to assess the accuracy of calculating balances for Na+ plus K+ and of Cl- over 1 to 10 days in an intensive care unit (ICU) setting. A prospective comparison of measured and estimated quantities of Na+ plus K+ and of Cl- excreted over 1 to 10 days in 10 children and 12 adults who had recently received a traumatic brain injury or undergone recent neurosurgery. Plasma concentrations of electrolytes were recorded at the beginning and end of the study period. The total volumes infused and excreted and the concentrations of Na+, K+, and Cl- in the infusate were obtained from each patient's ICU chart. The electrolytes in the patients' urine were measured and calculated. Correlations between measured and calculated values for excretions of Cl- and of Na+ plus K+ were excellent. Mass balances for Na+ plus K+ and for Cl- can be accurately estimated. These data provide information to support or refute a clinical diagnosis of CSW. The danger of relying on balances for these electrolytes measured within a single day to diagnose CSW is illustrated.


Pathogenesis of glomerular sclerosis in subtotally nephrectomized analbuminemic rats.
The Nagase analbuminemic rat (NAR), a mutant of the Sprague-Dawley (SD) strain, exhibits persistent hypercholesterolemia, thrombocytosis, and enhanced platelet aggregation, abnormalities possibly involved in the genesis of glomerular sclerosis (GS). Previous observations suggest that these rats never develop aging GS. We studied the development of GS in NAR after 5/6 nephrectomy (Nx). Fifteen days after Nx, marked glomerular hypertension was observed in NAR, compared with only mild elevations in SD rats. Glomerular hypertrophy was more marked in SD rats than in NAR. Enalapril normalized glomerular volume and partially reversed glomerular hypertension in NAR without altering platelet function or cholesterol levels. Glomerular endothelial injury and intraluminal fibrin deposition were seen only in NAR. Two months after Nx, severe GS and massive glomerular lipid deposition were seen in NAR, whereas only mild glomerular injury occurred in SD rats. Enalapril attenuated GS and prevented lipid deposition in NAR. Glomerular hypertension may be a key factor in the genesis of GS in this model in association with endothelial injury, intracapillary coagulation, and lipid accumulation.


The fetal inflammatory response syndrome.
The fetal inflammatory response syndrome (FIRS) is a condition characterized by systemic inflammation and an elevation of fetal plasma interleukin-6. This syndrome has been observed in fetuses with preterm labor with intact membranes, preterm prelabor rupture of the membranes, and also fetal viral infections such as cytomegalovirus. FIRS is a risk factor for short-term perinatal morbidity and mortality after adjustment for gestational age at delivery and also for the development of long-term sequelae such as bronchopulmonary dysplasia and brain injury. Multiorgan involvement in FIRS has been demonstrated in the hematopoietic system, thymus, adrenal glands, skin, kidneys, heart, lung, and brain. This article reviews the fetal systemic inflammatory response as a mechanism of disease. Potential interventions to control an exaggerated inflammatory response in utero are also described.


Influence of high-density lipoprotein cholesterol on coronary collateral formation in a population with significant coronary artery disease.
Coronary collateral circulation plays an important role in protecting myocardium from ischemia and reducing cardiovascular events. Low High-density lipoprotein cholesterol (HDL-C) level is a strong risk factor for coronary artery disease (CAD) and is associated with poor cardiovascular outcome. It was recently reported to be associated with poor coronary collateral development in Turkish population. Hence, we investigated the influence of HDL-C on coronary collateral formation in Chinese population. We evaluated 970 consecutive patients undergoing coronary angiography, and 501 patients with significant coronary artery disease (SCAD) were finally analyzed. The collateral scoring system developed by Rentrop was used to classify patient groups as those with poor or good collaterals. The patients with poor collaterals had fewer diseased vessels (1.97 ± 0.84 vs 2.47 ± 0.68, p < 0.001) and lower diffuse score (2.65 ± 1.63 vs 3.76 ± 1.78, p < 0.001). There was no significant difference in HDL-C and other variables between good and poor collaterals. Multivariate analysis showed only number of diseased vessels (odd ratio 0.411, p < 0.001) was a significant predictor of poor collateral development. The extent of CAD severity but not HDL-C level was the most powerful predictor of coronary collateral formation in our Chinese population with SCAD.


Using local culture and gender roles to improve male involvement in maternal health in southern Nigeria.
Group health talks were conducted in Ekiadolor, Southern Nigeria, to improve male attitudes and practices regarding their involvement in prenatal care and family planning. Intervention planners highlight the importance of embedding local cultural norms along with co-opting gendered beliefs for purposes of planning and implementing the group talks. The authors facilitated 9 groups of adult males mostly from the traditional hierarchy of the community. Using gender theory as an analytical lens along with the application of local cultural beliefs and norms, a useful communication intervention was developed that increased the possibility of positive male engagement in maternal health in 1 Nigerian community.


Effect of feed rate and drill speed on temperatures in equine cortical bone.
To examine the amount of heat generated in equine cortical bone by a 6.2-mm drill, using low- and high-speed and controlled feed rate drilling. 10 metacarpal bones harvested from five 2-year-old draft-type horses. Drilling on metacarpal bones was done using a machine shop mill with which the feed rate and drill speed could be precisely controlled. Bones were drilled, using 6 combinations of feed rate (1, 2, and 3 mm advance/s) and drill speed (317 and 1,242 revolutions/min [rpm], with maximal temperatures recorded by thermocouples placed 1, 1.5, and 2 mm from the drill. Maximal temperatures were evaluated for the effect of feed rate, drill speed, cortical thickness, and distance from the drill, using linear regression analysis. Increasing feed rate from 1 to 2 and from 2 to 3 mm/s significantly decreased mean maximal temperature. Increasing drill speed from 317 to 1242 rpm significantly increased mean maximal temperature. Increasing cortical thickness significantly increased mean maximal temperature, and increasing the distance from the drill hole significantly decreased mean maximal temperatures. On the basis of our results, we recommend using low drill speeds while applying sufficient axial force to advance the drill as rapidly as possible through the bone. Results of using this in vitro model suggest that temperatures at the drill-bone interface may be sufficiently high to result in significant thermal necrosis when drilling equine cortical bone.


In vitro activation of a transcription factor by gamma interferon requires a membrane-associated tyrosine kinase and is mimicked by vanadate.
Gamma interferon (IFN-gamma) activates the formation of a DNA-binding protein complex (FcRF gamma) that recognizes the gamma response region (GRR) of the promoter for the human high-affinity Fc gamma receptor. In a membrane-enriched fraction prepared from human peripheral blood monocytes, IFN-gamma activation of FcRF gamma occurred within 1 min and was ATP dependent. Activation of FcRF gamma required a tyrosine kinase activity, and recognition of the GRR sequence by FcRF gamma could be abrogated by treatment with a tyrosine-specific protein phosphatase. Treatment of cells with vanadate alone resulted in the formation of FcRF gamma without the need for IFN-gamma. UV cross-linking and antibody competition experiments demonstrated that the FcRF gamma complex was composed of at least two components: the 91-kDa protein of the IFN-alpha-induced transcription complex ISGF3 and a 43-kDa component that bound directly to the GRR. Therefore, specificity for IFN-induced transcriptional activation of early response genes requires at least two events: (i) ligand-induced activation of membrane-associated protein by tyrosine phosphorylation and (ii) formation of a complex composed of an activated membrane protein(s) and a sequence-specific DNA-binding component.


Global isolation by distance despite strong regional phylogeography in a small metazoan.
Small vagile eukaryotic organisms, which comprise a large proportion of the Earth's biodiversity, have traditionally been thought to lack the extent of population structuring and geographic speciation observed in larger taxa. Here we investigate the patterns of genetic diversity, amongst populations of the salt lake microscopic metazoan Brachionus plicatilis s. s. (sensu stricto) (Rotifera: Monogononta) on a global scale. We examine the phylogenetic relationships of geographic isolates from four continents using a 603 bp fragment of the mitochondrial COI gene to investigate patterns of phylogeographic subdivision in this species. In addition we investigate the relationship between genetic and geographic distances on a global scale to try and reconcile the paradox between the high vagility of this species and the previously reported patterns of restricted gene flow, even over local spatial scales. Analysis of global sequence diversity of B. plicatilis s. s. reveals the presence of four allopatric genetic lineages: North American-Far East Asian, Western Mediterranean, Australian, and an Eastern Mediterranean lineage represented by a single isolate. Geographically orientated substructure is also apparent within the three best sampled lineages. Surprisingly, given this strong phylogeographic structure, B. plicatilis s. s. shows a significant correlation between geographic and genetic distance on a global scale ('isolation by distance' - IBD). Despite its cosmopolitan distribution and potential for high gene flow, B. plicatilis s. s. is strongly structured at a global scale. IBD patterns have traditionally been interpreted to indicate migration-drift equilibrium, although in this system equilibrium conditions are incompatible with the observed genetic structure. Instead, we suggest the pattern may have arisen through persistent founder effects, acting in a similar fashion to geographic barriers for larger organisms. Our data indicates that geographic speciation, contrary to historical views, is likely to be very important in microorganisms. By presenting compelling evidence for geographic speciation in a small eukaryote we add to the growing body of evidence that is forcing us to rethink our views of global biodiversity.


Antimicrobial Susceptibility Testing of Antimicrobial Peptides to Better Predict Efficacy.
During the development of antimicrobial peptides (AMP) as potential therapeutics, antimicrobial susceptibility testing (AST) stands as an essential part of the process in identification and optimisation of candidate AMP. Standard methods for AST, developed almost 60 years ago for testing conventional antibiotics, are not necessarily fit for purpose when it comes to determining the susceptibility of microorganisms to AMP. Without careful consideration of the parameters comprising AST there is a risk of failing to identify novel antimicrobials at a time when antimicrobial resistance (AMR) is leading the planet toward a post-antibiotic era. More physiologically/clinically relevant AST will allow better determination of the preclinical activity of drug candidates and allow the identification of lead compounds. An important consideration is the efficacy of AMP in biological matrices replicating sites of infection, e.g., blood/plasma/serum, lung bronchiolar lavage fluid/sputum, urine, biofilms, etc., as this will likely be more predictive of clinical efficacy. Additionally, specific AST for different target microorganisms may help to better predict efficacy of AMP in specific infections. In this manuscript, we describe what we believe are the key considerations for AST of AMP and hope that this information can better guide the preclinical development of AMP toward becoming a new generation of urgently needed antimicrobials.


WDR82-Mediated H3K4me3 Is Associated with Tumor Proliferation and Therapeutic Efficacy in Pediatric High-Grade Gliomas.
Pediatric high-grade gliomas (pHGGs) are common malignant brain tumors without effective treatment and poor patient survival. Abnormal posttranslational modification at the histone H3 tail plays critical roles in tumor cell malignancy. We have previously shown that the trimethylation of lysine 4 at histone H3 (H3K4me3) plays a significant role in pediatric ependymoma malignancy and is associated with tumor therapeutic sensitivity. Here, we show that H3K4me3 and its methyltransferase WDR82 are elevated in pHGGs. A reduction in H3K4me3 by downregulating WDR82 decreases H3K4me3 promoter occupancy and the expression of genes associated with stem cell features, cell proliferation, the cell cycle, and DNA damage repair. A reduction in WDR82-mediated H3K4me3 increases the response of pediatric glioma cells to chemotherapy. These findings suggest that WDR82-mediated H3K4me3 is an important determinant of pediatric glioma malignancy and therapeutic response. This highlights the need for a more thorough understanding of the potential of WDR82 as an epigenetic target to increase therapeutic efficacy and improve the prognosis for children with malignant gliomas.


Cytotoxicity of fumonisin B(1) in spheroid and monolayer cultures of rat hepatocytes.
Fumonisin B(1) (FB(1)), the most prevalent member of toxins produced by several species of Fusarium molds, which occur mainly in maize, causes several fatal hepatopathies and nephropathies of animals. The current study was scrutinized to ascertain different cytotoxic and morphological transformations in rat hepatocytes induced by the treatments of diverse concentrations (300, 500, or 1000 microM) of fumonisin B(1) in vitro, using both monolayer and spheroid cultures. In each hepatocyte culture, the cytotoxicity of FB(1) was augmented in dose- and time-response manners. Morphological transformations among FB(1)-treated groups integrated accumulation of lipid droplets, cytoplasmic vacuolation in hepatocyte monolayers, and bleb formation in the hepatocyte spheroids. Additionally, electron microscopy revealed the loss of microvilli, mitochondrial swelling, and formation of lamellar membranous whorl in the vacuoles and bile canaliculi-like structures. Appearance of electron dense bodies in the monolayers, and loss of cell-to-cell contact in spheroids were depicted in 1000 microM FB(1)-treated hepatocytes. These outcomes insinuate different vital events in explaining morphological transformations in the cell membrane and organelles, induced by fumonisins in rat hepatocytes.


Application of the Goes double-skin peri-areolar mastopexy with and without implants: A 14-year experience.
Peri-areolar mastopexy is commonly used for mild ptosis requiring no more than 3cm of nipple elevation. The nature of areolar scar and gland remodelling inherent to a circular skin reduction prompts circumspection when correcting more moderate-to-severe cases. The purpose herein is to convey the reproducibility and applicability of the Goes double-skin peri-areolar mastopexy without mesh, for breast ptosis requiring nipple elevation of 4-9cm, in a series outside the work of the principal innovator. A series of 217 consecutive patients underwent circumareolar eccentric skin excision based on four cardinal landmarks, deepithelialised dermal sleeve and glandular reshaping with and without implants (174 augmentation-mastopexies and 43 mastopexies). Implantation and implant change involved the use of saline implants placed in the subpectoral space. Average nipple elevation was 5.1cm in the augmentation-mastopexy group and 6.5cm in the mastopexy group. There were major complications in 4.4% of breasts and occurred only in the mastopexy-augmentation group. There was no nipple loss, serious infection or haematoma. There were minor complications in 13.1% of breasts (11.8% in the mastopexy-augmentation group, and 18.6% in the mastopexy group). A minimal (10%) areolar necrosis occurred on a breast in one patient undergoing augmentation-mastopexy for tubular breasts with micromastia. Revision rate was 4% for the entire series. Based on the principles of circular skin design with fixed skin landmarks, internal breast shaping and special attention when augmentation is done simultaneously, the peri-areolar double-skin mastopexy can be safe, effective and reproducible when applied to cases of increasing complexity.


Two consecutive hydrolethalus syndrome-affected pregnancies in a nonconsanguinous black couple: discussion of problems in prenatal differential diagnosis of midline malformation syndromes.
Hydrolethalus syndrome is a rare autosomal recessive (AR) disorder characterized by polyhydramnios, CNS abnormalities, cleft lip/palate, micrognathia, and polydactyly. Its molecular basis is unknown and prenatal diagnosis is challenging due to phenotypic overlap with several other midline malformation syndromes. A 34-year-old G3P2, nonconsanguinous, married, African-American woman was referred at 19 weeks of gestation after ultrasound findings of "multiple congenital anomalies." A previous pregnancy had been terminated following ultrasound findings of polyhydramnios, cleft lip/palate, polydactyly, severe hydrocephalus, and a Dandy-Walker malformation (DWM). Level II ultrasound evaluation of the current pregnancy demonstrated all of the anomalies which had been present in her previous pregnancy. Karyotype of amniocytes was 46,XX. Autopsy following pregnancy termination confirmed ultrasound findings. The pedigree, sonographic, and autopsy findings in this case were most consistent with hydrolethalus syndrome, although other AR multiple midline malformation syndromes were considered. Our case was detected by 19 weeks. Confident differential diagnosis is difficult for the geneticist and even more so for the sonologist given the technical limitations of ultrasound. It is uncertain whether these mendelian midline malformation syndromes represent slightly different phenotypic expressions of a common genetic defect or are manifestations of allelic and or locus heterogeneity. We suggest that for prenatal diagnostic purposes, in the absence of knowledge of the molecular basis of these disorders, the fine distinctions are not crucial as long as their mendelian inheritance is recognized and presence or absence of manifestations which make them severe are ascertained.


The African-centric P47S Variant of TP53 Confers Immune Dysregulation and Impaired Response to Immune Checkpoint Inhibition.
The tumor suppressor TP53 is the most frequently mutated gene in cancer and is mutationally inactivated in 50% of sporadic tumors. Inactivating mutations in TP53 also occur in Li Fraumeni syndrome (LFS). In addition to germline mutations in TP53 in LFS that completely inactivate this protein, there are many more germline mutant forms of TP53 in human populations that partially inactivate this protein: we call these partially inactivating mutations "hypomorphs." One of these hypomorphs is a SNP that exists in 6%-10% of Africans and 1%-2% of African Americans, which changes proline at amino acid 47 to serine (Pro47Ser; P47S). We previously showed that the P47S variant of p53 is intrinsically impaired for tumor suppressor function, and that this SNP is associated with increased cancer risk in mice and humans. Here we show that this SNP also influences the tumor microenvironment, and the immune microenvironment profile in P47S mice is more protumorigenic. At basal levels, P47S mice show impaired memory T-cell formation and function, along with increased anti-inflammatory (so-called "M2") macrophages. We show that in tumor-bearing P47S mice, there is an increase in immunosuppressive myeloid-derived suppressor cells and decreased numbers of activated dendritic cells, macrophages, and B cells, along with evidence for increased T-cell exhaustion in the tumor microenvironment. Finally, we show that P47S mice demonstrate an incomplete response to anti-PD-L1 therapy. Our combined data suggest that the African-centric P47S variant leads to both intrinsic and extrinsic defects in tumor suppression. Findings presented here show that the P47S variant of TP53 influences the immune microenvironment, and the immune response to cancer. This is the first time that a naturally occurring genetic variant of TP53 has been shown to negatively impact the immune microenvironment and the response to immunotherapy.


[Diprivan as a component of the anesthesia in emergency surgical interventions in children].
Sixty-seven children aged 5-15 years were induced to narcosis and narcotized with diprivan. The patients were operated on for appendicitis, peritonitis, osteomyelitis, phlegmons of different localization, and craniocerebral injuries. For induction, diprivan was intravenously injected in a dose of 3-4 mg/kg. During the main narcosis (central analgesia with fentanyl in a total dose of 0.008 mg/kg/h) diprivan was infused by microjets in a dose of 6-9 mg/kg/h in combination with nitrogen oxide and oxygen in 1:1 ratio. Control group consisted of similar age-matched patients, to whom central analgesia without diprivan was administered. Respiration rate, heart rate, systolic and diastolic arterial pressure, mean arterial pressure (MAP), SaO2, and clinical course of anesthesia were examined at different stages of analgesia and surgery. During induction anesthesia the respiratory rate decreased by 27% and SaO2 decreased to 92.75 +/- 1.2% due to the specific effect of diprivan. MAP decreased by 4.8%. During the traumatic moment of surgery, respiratory rate increased by 20.1%, SaO2 was 98.25 +/- 0.24%, and heart rate increased by 22.6%. In the controls this period of surgery was associated with a more expressed reaction of the cardiovascular system, presenting as tachycardia (114.5 +/- 3.6) and increase of MAP by 10.1%. After anesthesia pain sensitivity returned earlier, due to which tachycardia and negligible hypertension were observed.


Differential urinary specific gravity as a molecular phenotype of the bladder cancer genetic association in the urea transporter gene, SLC14A1.
Genome-wide association studies (GWAS) identified associations between markers within the solute carrier family 14 (urea transporter), member 1 (SLC14A1) gene and risk of bladder cancer. SLC14A1 defines the Kidd blood groups in erythrocytes and is also involved in concentration of the urine in the kidney. We evaluated the association between a representative genetic variant (rs10775480) of SLC14A1 and urine concentration, as measured by urinary specific gravity (USG), in a subset of 275 population-based controls enrolled in the New England Bladder Cancer Study. Overnight urine samples were collected, and USG was measured using refractometry. Analysis of covariance was used to estimate adjusted least square means for USG in relation to rs10775480. We also examined the mRNA expression of both urea transporters, SLC14A1 and SLC14A2, in a panel of human tissues. USG was decreased with each copy of the rs10775480 risk T allele (p-trend = 0.011) with a significant difference observed for CC vs. TT genotypes (p-value(tukey) = 0.024). RNA-sequencing in the bladder tissue showed high expression of SLC14A1 and the absence of SLC14A2, while both transporters were expressed in the kidney. We suggest that the molecular phenotype of this GWAS finding is the genotype-specific biological activity of SLC14A1 in the bladder tissue. Our data suggest that SLC14A1 could be a unique urea transporter in the bladder that has the ability to influence urine concentration and that this mechanism might explain the increased bladder cancer susceptibility associated with rs10775480.


Myo-inositol does not modulate PI turnover in MDCK cells under hyperosmolar conditions.
The relationship between free cellular myo-inositol concentration and phosphatidylinositol turnover was evaluated in Madin-Darby canine kidney (MDCK) cells under isosmolar and hyperosmolar conditions. MDCK cells exposed to high extracellular sodium chloride were documented to increase their free myo-inositol content as measured by gas-liquid chromatography in both a time- and concentration-dependent manner. Measurement of phosphatidylinositol, phosphatidylinositol 4-monophosphate, and phosphatidylinositol 4,5-bisphosphate mass failed to reveal changes under conditions where the myo-inositol concentration was more than threefold higher compared with control conditions. CDP diacylglycerol:myo-inositol 3-phosphatidyltransferase activity, measured in plasma membranes from MDCK cells grown under control and hyperosmolar conditions, was kinetically similar with comparable observed Michaelis constant (Km) and maximal rate of enzyme reaction. Moreover, the apparent Km was significantly below the estimated intracellular myo-inositol concentration consistent with exposure of the transferase to saturating concentrations of myo-inositol under both conditions. Finally, bradykinin-stimulated myo-inositol trisphosphate mass was measured by use of a competitive binding assay. Both basal and hormone-stimulated myo-inositol 1,4,5-trisphosphate levels were not significantly different under control and hyperosmolar conditions. These data indicate that bulk free myo-inositol content is unlikely to regulate phosphatidylinositol turnover and myo-inositol trisphosphate formation under hyperosmolar conditions.


Effects of Dimensional Analysis on Infusible Medication Calculation Skills Among Nursing Students in an Intensive Care Unit.
Medication errors are among the most common life-threatening mistakes made in health care. The ability to accurately calculate drug doses, especially in intensive care units (ICUs), where the majority of medications are infused, reduces medication errors. Researchers have proposed dimensional analysis to improve mathematical calculations of drugs. This study was conducted to determine the effects of dimensional analysis on the infusible medication calculation skills among nursing students in ICUs. In this quasi-experimental study, the research samples consisted of sixth-semester nursing students who were assigned to an intervention group (n = 34) and a control group (n = 32). For the intervention group, the calculations of common infusible drugs in the ICU were taught using the dimensional analysis method, whereas the control group received training without the dimensional analysis method. Data collection instruments included a demographic characteristics questionnaire and a 10-item questionnaire of drug calculations that were measured before and after the intervention in both groups. Data analysis was performed using SPSS 22. The mean pretest scores for infusible drug calculations of nursing students in the ICU were 5.15 ± 2.35 for the intervention group and 5.25 ± 2.56 for the control group (P = .86). The mean posttest scores of the intervention group and control group were 9.22 ± 0.79 and 6.27 ± 1.87, respectively (P = .0001). Dimensional analysis training significantly improved the infusible medication calculation skills of nursing students in the ICU. It is recommended to include this method in undergraduate, graduate, and continuing education nursing courses to increase skills in calculating infusible drugs and to reduce medication errors.


[Moderate cognitive impairment syndrome in cerebral vascular insufficiency].
Frequency of clinical and psychological peculiarities of moderate (mild) cognitive impairment (MCI) in cerebral vascular insufficiency (CVI) was studied in 42 patients, mean age 67.7 +/- 7.7 years. Along with neurological examination, a battery of psychiatric and neuropsychological scales and tests was used. MCI was diagnosed in 28 (66.7%) patients. In 20 patients (47.6%), cognitive hypoactivity was most prominent related to impaired neurodynamics and regulation of voluntary activity which may reflect subcortical and frontal lobes functions. In 8 patients (20.1%), there was a prominent memory impairment characteristic of hippocampus lesion. The authors suggest the presence of concomitant neurodegeneration in patients with amnesic MCI.


[Steroidal alkaloid batrachotoxin--instrument for studying voltage-regulated sodium channels].
Results of recent studies on the batrachotoxin (BTX) effect on the properties of voltage-operated sodium channels in excitable membranes are summarized in the review. The following problems are considered: allosteric interaction of the BTX receptor with structural entities of the sodium channel responsible for its activation, inactivation, ion selectivity, binding of polypeptide (scorpion and anemone) toxins, local anesthetics and many blocking drugs; relationship between BTX-induced changes in the sodium conductance and intramembrane charge movement; relationship between ion selectivity and effective pK of the selectivity filter acid group of sodium channels modified by BTX or aconitine; effects of BTX on the behaviour and conductance (gamma) of single sodium channels. The problem of the BTX receptor location and possible mechanism of the sodium channel modification by BTX are discussed.


Social housing of large primates: methodology for refinement of husbandry and management.
Improvement of primate facilities is potentially costly, and is constrained by health and safety considerations and by limited experience in smaller units. During the last decade, most units have progressed from two-tier, single housing on grid floors, but there are still opportunities for refinements to reduce contingent suffering. The methodology of housing rhesus monkeys loose in rooms without cages has been documented in a video presentation. The animals have defined health status, but routine room maintenance and animal handling encourage close staff contact, generating health and safety concerns. The management changes have resulted in less aggressive, more-cooperative animals that are less stressed by capture. There are more natural behaviours, together with decreased animal and staff stress, resulting in better experimental models. The cages remain cleaner, releasing staff to spend more time on positive reinforcement training. There is better use of available space, and experimental immunology studies have been included within the breeding colony. The project has demonstrated a way of providing a management system that results in major benefits to animal welfare, staff morale and to the quality of the scientific studies undertaken. The methodology is now being used in an experimental unit housing animals for neuroscience. Continuing challenges include some social unrest within groups, managing animal health and maintaining high levels of personnel safety.


A randomized, open-label study to investigate the effect of belimumab on pneumococcal vaccination in patients with active, autoantibody-positive systemic lupus erythematosus.
Objective Intravenous belimumab 10 mg/kg is approved as an add-on therapy in patients with active, autoantibody-positive systemic lupus erythematosus. This study aimed to assess the impact of belimumab on immune response to pneumococcal vaccination in patients with systemic lupus erythematosus. Methods This was a Phase 4, open-label study (GSK BEL115470; NCT01597492) conducted in the United States. Patients were randomized (7:9) to receive a 23-valent pneumococcal vaccination four weeks prior to (pre-belimumab cohort) or 24 weeks after (belimumab-concurrent cohort) commencing four-weekly belimumab 10 mg/kg intravenous treatment plus standard systemic lupus erythematosus therapy. Analyses of vaccine titers were performed on the as-treated population (received ≥1 dose of belimumab). The primary endpoint was the proportion of patients with positive antibody responses (≥2-fold increase from pre-vaccination levels, or post-vaccination level ≥ 0.6 µg/mL if pre-vaccination levels were unquantifiable) to ≥1 of 23 pneumococcal vaccine serotypes, four weeks post vaccination. Other endpoints included the proportion of patients with positive antibody responses to ≥2 to ≥10, and ≥11-23 (post hoc analysis) of serotypes. Safety was assessed by monitoring adverse events. Results Seventy-nine patients received pneumococcal vaccination (pre-belimumab cohort, n = 34; belimumab-concurrent cohort, n = 45). The majority (87.3% [69/79]) completed the study; 10 (12.7%) withdrew (patient request, n = 3; adverse event, n = 3; lost to follow-up, n = 2; other, n = 2). At Week 4 post-vaccination, 97.0% (32/33) and 97.6% (40/41) of patients (pre-belimumab and concurrent belimumab cohorts, respectively) had a positive response to ≥1 of 23 pneumococcal serotypes. Over 85% of patients in both cohorts responded to ≥10 of serotypes, approximately 80% responded to ≥12 serotypes, and approximately two-thirds responded to ≥16 serotypes. Little difference was observed between cohorts across a broad response, up to 23 serotypes. Eight (23.5%) patients experienced an adverse event considered by the investigator to be treatment-related in the pre-belimumab cohort and four (8.9%) in the belimumab-concurrent cohort; seven patients experienced non-fatal serious adverse events (pre-belimumab cohort, 11.8% [ n = 4]; concurrent-belimumab cohort, 6.7% [ n = 3]), and no deaths were reported. Conclusion The proportion of patients generating a response to ≥1 pneumococcal serotype did not differ between the pre-belimumab and belimumab-concurrent cohorts; the proportions were also comparable across a broader response (from ≥2 serotypes to 23 serotypes).


Autophagy and regulation of aquaporins in the kidneys.
Aquaporins (AQPs) are water channel proteins that facilitate the transport of water molecules across cell membranes. To date, seven AQPs have been found to be expressed in mammal kidneys. The cellular localization and regulation of the transport properties of AQPs in the kidney have been widely investigated. Autophagy is known as a highly conserved lysosomal pathway, which degrades cytoplasmic components. Through basal autophagy, kidney cells maintain their functions and structure. As a part of the adaptive responses of the kidney, autophagy may be altered in response to stress conditions. Recent studies revealed that autophagic degradation of AQP2 in the kidney collecting ducts leads to impaired urine concentration in animal models with polyuria. Therefore, the modulation of autophagy could be a therapeutic approach to treat water balance disorders. However, as autophagy is either protective or deleterious, it is crucial to establish an optimal condition and therapeutic window where autophagy induction or inhibition could yield beneficial effects. Further studies are needed to understand both the regulation of autophagy and the interaction between AQPs and autophagy in the kidneys in renal diseases, including nephrogenic diabetes insipidus.


Gamma interferon levels during Chlamydia trachomatis pneumonia in mice.
Host defense against murine Chlamydia trachomatis (mouse pneumonitis agent [MoPn]) in a murine model was investigated. Gamma interferon (IFN-gamma) was produced in the lungs by both MoPn-susceptible nude athymic (nu/nu) and MoPn-resistant heterozygous (nu/+) mice. In vivo depletion of IFN-gamma in nu/nu mice led to exacerbation of infection. Fluorescence-activated cell sorter analysis disclosed induction of GL3 antibody-positive cells (putatively gamma/delta+ T cells) in nu/nu mouse lung during infection with MoPn. Treatment of nu/nu mice in vivo with antibody to NK cells (anti-asialo GM1 antibody) or to gamma/delta cells (UC7-13D5) did not significantly decrease IFN-gamma production in the lung. However, treatment of severe combined immunodeficiency mice (which lack gamma/delta cells) with antibody to NK cells significantly reduced lung IFN-gamma levels.


Hemithyroidectomy is the preferred initial operative approach for an indeterminate fine needle aspiration biopsy diagnosis.
Fine needle aspiration biopsy represents the critical initial diagnostic test used for evaluation of thyroid nodules. Our objectives were to determine the cytological distribution, the utility of clinicopathologic characteristics for predicting malignancy and the true proportion of cancer among individuals who presented with indeterminate cytology and had undergone thyroid surgery for suspicion of cancer. We retrospectively reviewed 1040 consecutive primary thyroid operations carried out over an 8-year period at a tertiary care endocrine referral centre. Follicular neoplasm (FN), Hürthle cell neoplasm (HN), neoplasms suspicious for but not diagnostic of papillary carcinoma (IP) and neoplasms with cellular atypia (IA) were reviewed. In all, 380 individuals presented with cytologically indeterminate thyroid nodules. Of these, 252 (66%) patients had FN, 47 (12%) HN, 44 (12%) IP, 26 (7%) IA and 11 (4%) had mixed diagnoses. Biopsied lesions were found to be malignant on pathological evaluation in 102 (27%) patients: 49 (19%) with FN, 11 (23%) HN, 28 (64%) IP and 9 (35%) with IA. Hemithyroidectomy was adequate definitive treatment in 196 of 225 (87%) patients with FN and 39 of 42 (93%) with HN. Significant associations with a cancer diagnosis were identified for smaller tumour size in patients with FN (p = 0.004) and right thyroid lobe location in patients with IP (p = 0.012), although these factors were nonsignificant in the corrected analyses for multiple comparisons. In a review of the experience at a Canadian centre, 4 operations were carried out to identify each cancer, and hemithyroidectomy was the optimal initial and definitive surgical approach for most patients.


Developing a national dissemination plan for collaborative care for depression: QUERI Series.
Little is known about effective strategies for disseminating and implementing complex clinical innovations across large healthcare systems. This paper describes processes undertaken and tools developed by the U.S. Department of Veterans Affairs (VA) Mental Health Quality Enhancement Research Initiative (MH-QUERI) to guide its efforts to partner with clinical leaders to prepare for national dissemination and implementation of collaborative care for depression. An evidence-based quality improvement (EBQI) process was used to develop an initial set of goals to prepare the VA for national dissemination and implementation of collaborative care. The resulting product of the EBQI process is referred to herein as a "National Dissemination Plan" (NDP). EBQI participants included: a) researchers with expertise on the collaborative care model for depression, clinical quality improvement, and implementation science, and b) VA clinical and administrative leaders with experience and expertise on how to adapt research evidence to organizational needs, resources and capacity. Based on EBQI participant feedback, drafts of the NDP were revised and refined over multiple iterations before a final version was approved by MH-QUERI leadership. 'Action Teams' were created to address each goal. A formative evaluation framework and related tools were developed to document processes, monitor progress, and identify and act upon barriers and facilitators in addressing NDP goals. The National Dissemination Plan suggests that effectively disseminating collaborative care for depression in the VA will likely require attention to: Guidelines and Quality Indicators (4 goals), Training in Clinical Processes and Evidence-based Quality Improvement (6 goals), Marketing (7 goals), and Informatics Support (1 goal). Action Teams are using the NDP as a blueprint for developing infrastructure to support system-wide adoption and sustained implementation of collaborative care for depression. To date, accomplishments include but are not limited to: conduct of a systematic review of the literature to update VA depression treatment guidelines to include the latest evidence on collaborative care for depression; training for clinical staff on TIDES (Translating Initiatives for Depression into Effective Solutions project) care; spread of TIDES care to new VA facilities; and integration of TIDES depression assessment tools into a planned update of software used in delivery of VA mental health services. Thus far, common barriers encountered by Action Teams in addressing NDP goals include: a) limited time to address goals due to competing tasks/priorities, b) frequent turnover of key organizational leaders/stakeholders, c) limited skills and training among team members for addressing NDP goals, and d) difficulty coordinating activities across Action Teams on related goals. MH-QUERI has partnered with VA organizational leaders to develop a focused yet flexible plan to address key factors to prepare for national dissemination and implementation of collaborative care for depression. Early indications suggest that the plan is laying an important foundation that will enhance the likelihood of successful implementation and spread across the VA healthcare system.


In situ monitoring Alzheimer's disease β-amyloid aggregation and screening of Aβ inhibitors using a perylene probe.
A cationic perylene tetracarboxylic acid diimide derivative (1) is employed as a probe for in situ monitoring of Aβ aggregation and screening Aβ inhibitors. The assay is based on the fluorescence change through the aggregation of compound 1 following Aβ assembly. Importantly, this probe, compared with the well known amyloid-staining compound thioflavin T (ThT), is more sensitive to Aβ oligomer, which is highly toxic and plays a crucial role in the early stages of Alzheimer's disease.


[FREQUENCY OF OCCURRENCE OF POLYMORPHIC VARIANTS OF IL28B GENE AND GENOTYPES OF HEPATITIS C VIRUS IN POPULATION OF YAKUTIA: CLINICAL OUTCOMES].
Study clinical outcomes in patients with chronic hepatitis C depending on genotype of hepatitis C virus (HCV) and IL28B gene polymorphism. 592 indi- viduals Were examined, 75 ofthosehad HCVRNAgenotypes determined by PCR. Genotyping of single nucleotide polymorphisms (SNP) - rs12979860 (C/T) and rs8099917 (T/G) in IL28B gene was carried out by real-time PCR. HCV RNA was detected in 72 examined residents of Yakutia. HCV lb genotype was determined in 74.2% of cases, 3a - in 11.4%, la and 2 - 5.7% each. Frequency of polymorph variant rs12979860 CC was 72.2%, CT - 27.8%, rs8099917 TT - 61.1%, TG - 23.2%. Combination of HCV lb with polymorphic variants of IL28B'gene rs12979860 CC and rs8099917 CT showed a less aggressive course of the disease. On the other hand, HCV infection of individuals with geno- type 3a and polymorphism rs12979860 CC or rs809917 TT of IL28B gene showed a more severe clinical presentation. The presence ofpolyorirphvariants rs8099917 T/G and rs12979860 C/T showed more severe clinical outcomes of HCV infection (viral load up to 19035212 copies, cirrhosis with ascite, hepatocarcinoma).


The impacts of multiple healthcare reforms on catastrophic health spending for poor households in China.
Many developing nations witness systemic healthcare reforms where the expansion of health financing mechanisms and reforms of the service delivery system are being rolled out simultaneously. Yet, poorly coordinated reforms and negative interactions between multiple policies may offset synergies and undermine intended reform outcomes. This study examines how multiple healthcare reforms affect catastrophic health spending of low-income households in China. We characterize two broad types of health policy reforms: expansion- and constraint-oriented policies in the domains of financing, services delivery, and pharmaceuticals introduced since 2009. We adopt an innovative methodology by matching macro-level policy text data collected using big data techniques with micro-level health expenditure data drawn from a nationally representative survey. Employing a linear probability analysis and controlling for household and year fixed effects, we find that more expansion-oriented policies, especially in the domain of financing, increased the incidence of catastrophic health spending of poor households. In contrast, constraint-oriented policies, particularly in the domain of health services delivery, lead to a lower incidence of catastrophic health spending. This type of policy is thus better able to mitigate the positive relationship between expansion-oriented policies and the incidence of catastrophic health spending. This study suggests that while the expansion of benefit package in the domain of financing is indeed a decisive move towards universal health coverage, the essential financial protection of the poor cannot be achieved without strong and coordinated supply-side reforms towards cost containment. Health policy makers must take a strategic view of the complex interactions of multiple policy interventions in both financing and service delivery domains.


Modulation of orbitofrontal-striatal reward activity by dopaminergic functional polymorphisms contributes to a predisposition to alcohol misuse in early adolescence.
Abnormalities in reward circuit function are considered a core feature of addiction. Yet, it is still largely unknown whether these abnormalities stem from chronic drug use, a genetic predisposition, or both. In the present study, we investigated this issue using a large sample of adolescent children by applying structural equation modeling to examine the effects of several dopaminergic polymorphisms of the D1 and D2 receptor type on the reward function of the ventral striatum (VS) and orbital frontal cortex (OFC), and whether this relationship predicted the propensity to engage in early alcohol misuse behaviors at 14 years of age and again at 16 years of age. The results demonstrated a regional specificity with which the functional polymorphism rs686 of the D1 dopamine receptor (DRD1) gene and Taq1A of the ANKK1 gene influenced medial and lateral OFC activation during reward anticipation, respectively. Importantly, our path model revealed a significant indirect relationship between the rs686 of the DRD1 gene and early onset of alcohol misuse through a medial OFC × VS interaction. These findings highlight the role of D1 and D2 in adjusting reward-related activations within the mesocorticolimbic circuitry, as well as in the susceptibility to early onset of alcohol misuse.


[The sites of high affinity binding of L-[3H]glutamic acid in human platelets. A new type of platelet receptor?].
The total membrane fraction of human platelets was found to contain high affinity sites of L-[3H]glutamic acid binding (Kd = 100 nM, Bmax = 1.06 pmol/mg protein). The pH optimum for binding is at pH approximately 6.9 Na+ (1-150 mM) inhibit glutamate binding by platelet membranes (IC50 = 12 mM). Ca2+ (50-100 microM) stimulate the binding by 10-20% and inhibit it by 20-30% at concentrations of 1-5 mM. Monoclonal antibodies to the glutamate receptor strongly suppress the L-[3H]glutamate binding by platelet membranes (IC50 = 300 nm). The presence in human platelets of a glutamate-sensitive receptor complex similar to the central nervous system glutamate receptor is postulated.


Subcutaneous rhabdomyosarcoma in an old rabbit.
An 11-year-old castrated male rabbit presented with a subcutaneous mass in the right hind limb. The mass comprised solid and myxoid areas. Solid areas were characterized by a storiform or interlacing pattern of spindle cells, strap cells, multinucleated giant cells and round cells with eccentrically located nuclei, whereas the myxoid areas were composed predominantly of elongated fusiform cells with hyperchromatic nuclei embedded in Alcian Blue-positive myxoid stroma. Immunohistochemically, tumor cells in both areas were positive for desmin and vimentin. Ultrastructurally, the tumor cells in the solid areas had abundant myofilaments with electron dense Z-band structures. Based on these pathological findings, this case was diagnosed as rhabdomyosarcoma in a rabbit.


[Standardized assessment of personality disorders in older adults: State-of-the-art.]
The double ageing evolution in Europe is a tremendous challenge for health care. Older adults with a personality disorder place an additional burden: they have more somatic and psychiatric co-morbidity than those without a personality disorder. Moreover, they experience less quality of life than individuals without personality disorders. This is in sharp contrast to the dearth of empirical research concerning the construct of personality disorders in later life, the very limited amount of available diagnostic tools, criteria of classification systems like DSM not being attuned to the elderly context and the lack of age-neutrality of popular instruments to measure personality disorders. Therefore, in the Netherlands and Belgium a start was made to develop and validate age-specific instruments and to examine the applicability of the alternative dimensional-hybrid DSM-5 classification of personality disorders in older adults. These recent developments and how to apply them for a personalized assessment in older adults will be discussed. Finally, we advise a phased test-based diagnostic approach in which the above-mentioned instruments, combined with measures of adaptive features or more specific tests, can contribute to an assessment optimizing the balance between restricting the load for the older patient and still being sufficiently comprehensive to result in a personalized approach of the diagnostic process.