Identification of PLA(2) and alpha-neurotoxin proteins in the venom of Pseudonaja affinis (dugite).
The Western brown snake Pseudonaja affinis (dugite), common to the Perth area of Western Australia, possesses one of the most lethal venoms in the world. Little is known, however, about the toxic protein constituents of the venom, other than those causing coagulopathic and procoagulant effects. The current study was therefore undertaken in order to identify other protein constituents and activities present. Crude venom induced a contraction in rat tracheal preparations through phospholipase A(2) (PLA(2)) activity, as shown by the complete and partial inhibition of contraction by PLA(2) inhibitors 4-bromophenacyl bromide and quinacrine. Further, a reduced degree of smooth muscle contraction in the presence of the leukotriene receptor antagonist SKF104353 suggested that this effect was mediated by leukotriene metabolites. The venom-induced contraction did not reoccur upon a second administration of the venom, despite the muscle retaining its contractile function and appearing histologically undamaged. Chromatographic separation of the protein constituents of the venom showed that PLA(2) activity was associated with all protein fractions. A low-molecular-weight component of the venom was further investigated through N-terminal sequencing and found to possess high identity to the short-chain alpha-neurotoxin family of toxins. Venom activity on cultured rat cardiac myocytes and cultured cortical neurons was also examined. The crude venom was found to temporarily inhibit the beating of the cardiac myocytes, after which the beating resumed erratically. Cortical neurons, however, were irreversibly affected, showing concentration-dependent cell death.


Biochemical and cellular determinants of bleomycin cytotoxicity.
Bleomycin is a mixture of cytotoxic glycopeptides which function as mininucleases, binding to DNA and producing single and double strand breaks by the formation of an activated oxygen complex. Bleomycin is an effective agent against a few human cancers, notably lymphomas, testicular and ovarian germ cell cancers and certain squamous carcinomas. Most human cancers are resistant to bleomycin a priori, however, and those which are initially sensitive frequently develop resistance to the drug during therapy. Several potential modes of resistance to bleomycin have been identified in cell culture and animal tumour models, although their relative importance in determining the responsiveness of human cancers to the drug is not well understood. Bleomycin is selectively toxic to cells in the M and G2 phases of the cell cycle, and generally more effective against actively dividing rather than resting cells. Thus, the cytokinetic state of the tumour cell population is an important determinant of drug activity. Oxygen is an essential substrate for bleomycin's action, with the degree of cytotoxicity directly related to ambient oxygen. Both acutely and chronically hypoxic cells form a substantial fraction of the cell population of many tumours, and may serve as a reservoir of cells resistant to bleomycin on this epigenetic basis. Metabolic inactivation of bleomycin is a mechanism of resistance to the drug in some cells and may influence toxicity in normal tissues. Bleomycin hydrolase activity is low in lungs and skin, the two major sites of normal tissue toxicities, and levels of this enzyme have been elevated in some but not all tumour cell lines selected for resistance to bleomycin. The capacity to repair or withstand single and double strand DNA breaks may also be an important determinant of resistance to the drug. Most yeast and mammalian cell mutants, which are hypersensitive to ionizing radiation because of defects in DNA repair, are also more sensitive to bleomycin than wild-type cells. A number of agents which interact with membranes or inhibit DNA repair, such as ethanol, lidocaine, verapamil and caffeine, have been reported to sensitize cells to bleomycin in vitro.


Health workforce cultural competency interventions: a systematic scoping review.
Addressing health workforce cultural competence is a common approach to improving health service quality for culturally and ethnically diverse groups. Research evidence in this area is primarily focused on cultural competency training and its effects on practitioners' knowledge, attitudes, skills and behaviour. While improvements in measures of healthcare practitioner cultural competency and other healthcare outcomes have been reported, there are concerns around evidence strength and quality. This scoping review reports on the intervention strategies, outcomes, and measures of included studies with the purpose of informing the implementation and evaluation of future interventions to improve health workforce cultural competence. This systematic scoping review was completed as part of a larger systematic literature search conducted on cultural competence intervention evaluations in health care in Canada, the United States, Australia and New Zealand published from 2006 to 2015. Overall, 64 studies on cultural competency interventions were found, with 16 aimed directly at the health workforce. There was significant heterogeneity in workforce intervention strategies, measures and outcomes reported across studies making comparisons of intervention effects difficult. The two main workforce intervention strategies identified were cultural competency training and other professional development interventions including other training and mentoring. Positive outcomes were commonly reported for improved practitioner knowledge (9/16), skills (7/16), and attitudes/beliefs (5/16). Although health care (6/16) and health (2/16) outcomes were reported in some studies there was very limited evidence of positive intervention impacts. Only four studies utilised existing validated measurement tools to assess intervention outcomes. Training and development of the health workforce remain a principle strategy towards the goal of improved cultural competence in health services and systems. Diverse approaches are available to increase health workforce cultural competence. However, the effects of interventions beyond practitioner knowledge and attitudes remains unclear. Assessment of practitioner behavioural outcomes as well as measures of intervention impact on healthcare and health outcomes are needed to build a stronger evidence base.


Immunomodulatory effects of serotype B glucuronoxylomannan from Cryptococcus gattii correlate with polysaccharide diameter.
Glucuronoxylomannan (GXM), the major capsular component in the Cryptococcus complex, interacts with the immune system in multiple ways, which include the activation of Toll-like receptors (TLRs) and the modulation of nitric oxide (NO) production by phagocytes. In this study, we analyzed several structural parameters of GXM samples from Cryptococcus neoformans (serotypes A and D) and Cryptococcus gattii (serotypes B and C) and correlated them with the production of NO by phagocytes and the activation of TLRs. GXM fractions were differentially recognized by TLR2/TLR1 (TLR2/1) and TLR2/6 heterodimers expressed on TLR-transfected HEK293A cells. Higher NF-kappaB luciferase reporter activity induced by GXM was observed in cells expressing TLR2/1 than in cells transfected with TLR2/6 constructs. A serotype B GXM from C. gattii was the most effective polysaccharide fraction activating the TLR-mediated response. This serotype B polysaccharide, which was also highly efficient at eliciting the production of NO by macrophages, was similar to the other GXM samples in monosaccharide composition, zeta potential, and electrophoretic mobility. However, immunofluorescence with four different monoclonal antibodies and dynamic light-scattering analysis revealed that the serotype B GXM showed particularities in serological reactivity and had the smallest effective diameter among the GXM samples analyzed in this study. Fractionation of additional serotype B GXMs, followed by exposure of these fractions to macrophages, revealed a correlation between NO production and reduced effective diameters. Our results demonstrate a great functional diversity in GXM samples from different isolates and establish their abilities to differentially activate cellular responses. We propose that serological properties as well as physical chemical parameters, such as the diameter of polysaccharide molecules, may potentially influence the inflammatory response against Cryptococcus spp. and may contribute to the differences in granulomatous inflammation between cryptococcal species.


European institutional accreditation of general thoracic surgery.
To improve standardization of general thoracic surgery (GTS) practice across Europe, the European Society of Thoracic Surgeons (ESTS) has implemented a program of Institutional Accreditation. We reviewed the methods and rules of engagement of this program. A composite performance score (CPS) including outcome and process indicators is used to measure institutional performance and assess eligibility for accreditation. Eligible units are invited to participate and accept a local audit performed by an external auditors team composed by data inspectors and thoracic surgeons. In addition to data quality, a series of structural, procedural and qualification characteristics are inspected. Once the visit is complete, the team will produce an audit report to be sent to the members of the database committee for deliberation on the institutional accreditation of that unit. The Database committee will send an executive report to the ESTS Executive Committee for their final decision on the accreditation.


Physiological profile and predictors of cycling performance in ultra-endurance triathletes.
To report physiological profiles, and investigate the relationship between selected physiological variables and cycling performance in ultra-endurance triathletes. ten male (mean+/-SD, age; 32+/-5 years) ultra-endurance triathletes participated in the study. Physiological profiles were compared with 10 male age-matched control subjects. left ventricular structure (wall thickness [LVPWd], internal diameter [LVIDd], and mass [LVM]) and function (diastolic filling, fractional shortening, and stroke volume [SV]) were assessed using standard M-Mode, 2D, and Doppler echocardiography. Maximal and sub-maximal exercise gas exchange responses were measured on-line during a maximal ramping cycle-ergometer exercise test. Ultra-endurance triathletes demonstrated significantly larger LVPWd, LVIDd, LVM, SV, VO2max anaerobic threshold (AT), and power to body-mass ratio compared with controls. Cycling performance for both Ironman and half Ironman were significantly correlated with LVPWd, LVM, and SV. LVIDd was significantly correlated Ironman cycle time alone. Oxygen consumption (VO2) at AT, percentage of VO2max at AT, and peak power to bodymass ratio were significantly correlated to bike finish time in the half Ironman, but not Ironman. The correlation between cycling performance, LVM and SV suggests that the more conditioned athletes may be better able to maintain a high cardiac output during prolonged cycling. Sub-maximal gas exchange responses are predictors of cycling performance for the half-Ironman but not the Ironman. These results suggest that other factors including the longer duration swim prior to the cycling component, may impact upon cycle performance.


Moderate local and systemic respiratory syncytial virus-specific T-cell responses upon mild or subclinical RSV infection.
Respiratory syncytial virus (RSV) infections are a major cause of severe respiratory disease in infants. It has been shown that there is an increased frequency of childhood wheezing in ex-bronchiolitic preteen children. This was postulated to be mediated by a vigorous virus-specific Th2 response influencing the further development of the immune system. Little is known about the possible role of the immune response to clinically mild RSV infections in this respect. We have studied the RSV-specific cellular immune response in infants with a laboratory-confirmed RSV upper respiratory tract infection (URTI; n = 13, mean age 12 months, range 2-22 months) in comparison with infants with non-RSV mediated URTI (n = 9, mean age 9.3 months, range 4-18 months) or infants with severe RSV bronchiolitis (n = 11, mean age 2.3 months, range 1-6 months). RSV-specific cytokine-producing cells were enumerated using the ELISPOT method in peripheral blood mononuclear cells and nasal brush T-cells, collected during the acute and convalescent phase of the infection. Mixed Th1 (IFN-gamma) and Th2 (IL-4 and IL-13) responses were detected in all three groups. Frequencies of RSV-specific T-cells were lower in both URTI groups than in the RSV bronchiolitis group, and not significantly different between the RSV URTI and the non-RSV URTI group. The absence of vigorous virus-specific Th2 responses upon mild RSV infection does not support the hypothesis that these infections influence the development of the immune system and that they predispose for the development of atopic disease.


A contractual model for accountability and financial stability in a community-based family practice residency.
A contractual model is described that defines the relationship between the hospital and the Department of Family Practice. The model provides institutions supporting graduate training in family practice with a method that is accountable and cost effective. Application of this model at a community hospital over a five-year period is presented. The model resulted in expansion of the family practice residency, increased faculty numbers, increased income for the faculty, and control of the institution's cost of graduate medical education.


Reduction in Golgi apparatus dimension in the absence of a residential protein, N-acetylglucosaminyltransferase V.
Various proteins are involved in the generation and maintenance of the membrane complex known as the Golgi apparatus. We have used mutant Chinese hamster ovary (CHO) cell lines Lec4 and Lec4A lacking N-acetylglucosaminyltransferase V (GlcNAcT-V, MGAT5) activity and protein in the Golgi apparatus to study the effects of the absence of a single glycosyltransferase on the Golgi apparatus dimension. Quantification of immunofluorescence in serial confocal sections for Golgi α-mannosidase II and electron microscopic morphometry revealed a reduction in Golgi volume density up to 49 % in CHO Lec4 and CHO Lec4A cells compared to parental CHO cells. This reduction in Golgi volume density could be reversed by stable transfection of Lec4 cells with a cDNA encoding Mgat5. Inhibition of the synthesis of β1,6-branched N-glycans by swainsonine had no effect on Golgi volume density. In addition, no effect on Golgi volume density was observed in CHO Lec1 cells that contain enzymatically active GlcNAcT-V, but cannot synthesize β1,6-branched glycans due to an inactive GlcNAcT-I in their Golgi apparatus. These results indicate that it may be the absence of the GlcNAcT-V protein that is the determining factor in reducing Golgi volume density. No dimensional differences existed in cross-sectioned cisternal stacks between Lec4 and control CHO cells, but significantly reduced Golgi stack hits were observed in cross-sectioned Lec4 cells. Therefore, the Golgi apparatus dimensional change in Lec4 and Lec4A cells may be due to a compaction of the organelle.


The teleost cone cytoskeleton. Localization of actin, microtubules, and intermediate filaments.
This laboratory has been using the teleost retinal cone as a model for studying the mechanisms and regulation of retinal cell motility. In previous inhibitor studies, the authors have shown that dark-induced cone elongation requires microtubules, whereas light-induced contraction requires actin filaments. This study examines the distributions of actin filaments, microtubules, and intermediate filaments in the cone cytoskeleton. Actin filaments have been localized in isolated cones by labeling with fluorescent derivatives of phalloidin; microtubules were localized by immunofluorescent labeling with anti-tubulin. Actin, microtubule, and intermediate filament distributions have also been examined in detergent-lysed motile cell models of cones fixed with a new method that enhances preservation of the cytoskeleton. Longitudinal bundles of actin filaments extend from the cone's calycal processes through the ellipsoid and into the myoid. No actin filaments are detectable in the perinuclear region and axon, but filaments are present in both pre- and post-synaptic components of the synapse. Intermediate filaments are numerous in the perinuclear region and cone axon but relatively sparse in the myoid. In contrast, microtubule distribution is more uniform: numerous longitudinally oriented microtubules are present throughout the length of the cell. Thus the cone cytoskeleton reflects the highly polarized shape and function of the cell, with actin filaments localized to the distal movable part of the cell and intermediate filaments localized to the proximal part of the cell, which is anchored in the retina.


Osteogenic effect of bone marrow mesenchymal stem cell-derived exosomes on steroid-induced osteonecrosis of the femoral head.
Animal studies have demonstrated the therapeutic effect of mesenchymal stem cells (MSCs) on osteogenesis, but little is known about the functions of exosomes (Exos) released by bone MSCs (BMSCs). Here, we investigated the effect of BMSC Exos on steroid-induced femoral head necrosis (SFHN) and explored the vital genes involved in this process. BMSCs were isolated from healthy and SFHN rats. BMSC Exos were isolated using the Exosome Precipitation Kit and characterized by transmission electron microscopy and Western blotting. SFHN BMSCs were incubated with Exos from healthy BMSCs. Osteogenic ability was assessed by oil red O staining and alizarine red staining. Differentially expressed genes (DEGs) induced by Exos were screened using the Osteogenesis RT2 Profiler PCR Array. The effect of upregulated Sox9 was examined using lentivirus-mediated siRNA. The results revealed that BMSC Exos were 100-150 nm in size and expressed CD63. Moreover, BMSC Exo-treated SFHN cells exhibited suppressed adipogenesis compared to model cells. PCR array showed that eleven and nine genes were upregulated and downregulated, respectively, in the BMSC Exo-treated SFHN cells compared to the model group. Among the DEGs, osteogenesis-related genes, including Bmp2, Bmp6, Bmpr1b, Mmp9, and Sox9, may play important roles in SFHN. Furthermore, the DEGs were mainly involved in immune response, osteoblast differentiation, and in the transforming growth factor-β/bone morphogenetic protein signaling pathway. The level of the SOX9 protein was upregulated by Exos, and Sox9 silencing significantly decreased the osteogenic effect of BMSC Exos. Our data suggest that Exos derived from BMSCs mainly affect SFHN osteogenesis, and this finding can be further investigated to develop a novel therapeutic agent for SFHN.


Effect of potent γ-secretase modulator in human neurons derived from multiple presenilin 1-induced pluripotent stem cell mutant carriers.
Although considerable effort has been expended developing drug candidates for Alzheimer disease, none have yet succeeded owing to the lack of efficacy or to safety concerns. One potential shortcoming of current approaches to Alzheimer disease drug discovery and development is that they rely primarily on transformed cell lines and animal models that substantially overexpress wild-type or mutant proteins. It is possible that drug development failures thus far are caused in part by the limits of these approaches, which do not accurately reveal how drug candidates will behave in naive human neuronal cells. To analyze purified neurons derived from human induced pluripotent stem cells from patients carrying 3 different presenilin 1 (PS1) mutations and nondemented control individuals in the absence of any overexpression. We tested the efficacy of γ-secretase inhibitor and γ-secretase modulator (GSM) in neurons derived from both normal control and 3 PS1 mutations (A246E, H163R, and M146L). Adult human skin biopsies were obtained from volunteers at the Alzheimer Disease Research Center, University of California, San Diego. Cell cultures were treated with γ-secretase inhibitor or GSM. Comparisons of total β-amyloid (Aβ) and Aβ peptides 38, 40, and 42 in the media were made between vehicle- vs drug-treated cultures. Soluble Aβ levels in the media were measured by enzyme-linked immunosorbent assay. As predicted, mutant PS1 neurons exhibited an elevated Aβ42:Aβ40 ratio (P < .05) at the basal state as compared with the nondemented control neurons. Treatment with a potent non-nonsteroidal anti-inflammatory druglike GSM revealed a new biomarker signature that differs from all previous cell types and animals tested. This new signature was the same in both the mutant and control neurons and consisted of a reduction in Aβ42, Aβ40, and Aβ38 and in the Aβ42:Aβ40 ratio, with no change in the total Aβ levels. This biomarker discrepancy is likely due to overexpression of amyloid precursor protein in the transformed cellular models. Our results suggest that biomarker signatures obtained with such models are misleading and that human neurons derived from human induced pluripotent stem cells provide a unique signature that will more accurately reflect drug response in human patients and in cerebrospinal fluid biomarker changes observed during GSM treatment.


Paeonol: pharmacological effects and mechanisms of action.
Paeonia suffruticosa possesses various medicinal benefits and has been used extensively in traditional oriental medicine for thousands of years. Paeonol is the main component isolated from the root bark of Paeonia suffruticosa. The pharmacological effects of Paeonia suffruticosa are mostly attributed to paeonol. Paeonol injection has been successfully applied in China for nearly 50 years for inflammation/pain-related indications. Currently, the dosage forms of paeonol approved by China Food and Drug Administration include tablet, injection, and external preparations such as ointment and adhesive plaster. So far, the clinical applications of paeonol are mainly focusing on the anti-inflammatory activity. Studies of other pharmacological activities of paeonol are developing rapidly, and which may play an important role in the future. Besides, substantial mechanisms of pharmacological action of paeonol have been clarified in recent years. In this review, we summarize the pharmacological effects anti-inflammatory, neuroprotective, anti-tumor, anti-cardiovascular diseases and associated mechanisms of action of paeonol up to date.


Endoprosthetic reconstructions for bone metastases.
The purpose of the current study was to help define the role that endoprosthetic reconstructions have in the treatment of metastatic bone disease. Of the 522 endoprostheses implanted at the University of California at Los Angeles (UCLA) between December 1980 and January 2002, 37 (6.9%) were used in 37 patients with metastatic disease. Upper extremity locations outnumbered lower extremity locations 2:1. The 20 males and 17 females ranged in age from 10 to 82 years, with a median age of 54 years. Metastatic renal and breast carcinoma predominated and accounted for 60% of the lesions. The lesion was a primary metastasis in 27 patients (73%) and a revision of failed previous surgery in 10 patients (27%). Only five patients experienced local complications none of whom required reoperation or amputation. Thirty-three of the 37 patients died of disease progression at a median of 12 months (range, 4-49 months). Function after endoprosthetic reconstruction for metastatic disease is similar to that of function for endoprosthetic reconstructions used for primary malignant tumors, but clearly is dependent on the patient's general condition. Although infrequently used to treat bone metastases, endoprosthetic reconstruction can be a useful alternative reconstruction in selected situations.


A comparison of clinical and diagnostic interview schedule diagnoses. Physician reexamination of lay-interviewed cases in the general population.
We examined the level of agreement between diagnoses derived from data gathered by lay interviewers using the Diagnostic Interview Schedule (DIS) in a general population survey (the Epidemiologic Catchment Area project) and both DIS and clinical diagnoses made by psychiatrists. Overall percent agreement between the lay DIS and the psychiatrists clinical impression ranged from 79% to 96%. The chance-corrected concordance was .60 or better for eight of the 11 diagnoses. Specificities were all 90% or better. Sensitivities were lower, but lay results showed a bias for only two diagnoses: major depression was significantly underdiagnosed and obsessive illness was overdiagnosed. We compared the present results with those of previous studies from clinical settings. We explored possible reasons for disagreement and discussed the implications of the findings for psychiatric epidemiologic research.


A computational framework for post-TAVR cardiac conduction abnormality (CCA) risk assessment in patient-specific anatomy.
Cardiac conduction abnormality (CCA)- one of the major persistent complications associated with transcatheter aortic valve replacement (TAVR) may lead to permanent pacemaker implantation. Localized stresses exerted by the device frame on the membranous septum (MS) which lies between the aortic annulus and the bundle of His, may disturb the cardiac conduction and cause the resultant CCA. We hypothesize that the area-weighted average maximum principal logarithmic strain (AMPLS) in the MS region can predict the risk of CCA following TAVR. Rigorous finite element-based analysis was conducted in two patients (Balloon expandable TAVR recipients) to assess post-TAVR CCA risk. Following the procedure one of the patients required permanent pacemaker (PPM) implantation while the other did not (control case). Patient-specific aortic root was modeled, MS was identified from the CT image, and the TAVR deployment was simulated. Mechanical factors in the MS region such as logarithmic strain, contact force, contact pressure, contact pressure index (CPI) and their time history during the TAVR deployment; and anatomical factors such as MS length, implantation depth, were analyzed. Maximum AMPLS (0.47 and 0.37, respectively), contact force (0.92 N and 0.72 N, respectively), and CPI (3.99 and 2.86, respectively) in the MS region were significantly elevated in the PPM patient as compared to control patient. Elevated stresses generated by TAVR devices during deployment appear to correlate with CCA risk, with AMPLS in the MS region emerging as a strong predictor that could be used for preprocedural planning in order to minimize CCA risk.


Clinical application of whole-genome sequencing to inform treatment for multidrug-resistant tuberculosis cases.
The treatment of drug-resistant tuberculosis cases is challenging, as drug options are limited, and the existing diagnostics are inadequate. Whole-genome sequencing (WGS) has been used in a clinical setting to investigate six cases of suspected extensively drug-resistant Mycobacterium tuberculosis (XDR-TB) encountered at a London teaching hospital between 2008 and 2014. Sixteen isolates from six suspected XDR-TB cases were sequenced; five cases were analyzed in a clinically relevant time frame, with one case sequenced retrospectively. WGS identified mutations in the M. tuberculosis genes associated with antibiotic resistance that are likely to be responsible for the phenotypic resistance. Thus, an evidence base was developed to inform the clinical decisions made around antibiotic treatment over prolonged periods. All strains in this study belonged to the East Asian (Beijing) lineage, and the strain relatedness was consistent with the expectations from the case histories, confirming one contact transmission event. We demonstrate that WGS data can be produced in a clinically relevant time scale some weeks before drug sensitivity testing (DST) data are available, and they actively help clinical decision-making through the assessment of whether an isolate (i) has a particular resistance mutation where there are absent or contradictory DST results, (ii) has no further resistance markers and therefore is unlikely to be XDR, or (iii) is identical to an isolate of known resistance (i.e., a likely transmission event). A small number of discrepancies between the genotypic predictions and phenotypic DST results are discussed in the wider context of the interpretation and reporting of WGS results.


Quo vadis, data privacy?
Society can gain much value from Big Data. We can study census data to learn where to allocate public resources, medical records from hospitals to fight diseases, or data about students and teachers to evaluate the effectiveness of various approaches to learning and teaching. In all of these scenarios, we need to limit statistical disclosure: we want to release accurate statistics about the data while preserving the privacy of the individuals who contributed it. This paper gives an overview of recent advances and open challenges in the field, focusing on methods that probably limit how much an adversary can learn from a data release.


2-hydroxyestradiol is a prodrug of 2-methoxyestradiol.
Previous in vivo studies indicate that 2-hydroxyestradiol (2OHE) attenuates cardiovascular and renal diseases. In vitro studies suggest that the biological effects of 2OHE are mediated by 2-methoxyestradiol (2MEOE) after methylation of 2OHE by catechol-O-methyltransferase (COMT). This study tested the hypothesis that in vivo 2OHE is a prodrug of 2MEOE. We administered to male rats i.v. boluses of either 2OHE or 2MEOE and measured plasma levels of 2OHE and 2MEOE by gas chromatography-mass spectrometry at various time points after drug administration. After administration of 2OHE, plasma levels of 2OHE declined extremely rapidly [t(1/2(1)) = 0.94 min and t(1/2(2)) = 10.2 min] becoming undetectable after 45 min. Concomitant with the disappearance of 2OHE, 2MEOE occurred and then declined [t(1/2(1)) = 7.9 min and t(1/2(2)) = 24.9 min]. The peak concentration and total exposure (area under the curve) for 2OHE were much lower than for 2MEOE. 2OHE had a much higher plasma clearance (CL) and volume of distribution (V(d)) compared with 2MEOE (2OHE: CL = 1215 ml min(-1) kg(-1) and V(d) = 17,875 ml/kg; 2MEOE: CL = 50 ml min(-1) kg(-1) and V(d) = 1760 ml/kg). After administration of 2MEOE, plasma levels of 2MEOE declined [t(1/2(1)) = 2.5 min and t(1/2(2)) = 20.2 min] with a plasma CL of 50 ml min(-1) kg(-1) and a V(d) of 1500 ml/kg. We could not detect 2OHE in plasma from rats receiving 2MEOE. We conclude that the conversion of 2OHE to 2MEOE is so efficient that in terms of 2MEOE exposure, administration of 2OHE is bioequivalent to administration of 2MEOE itself.


Label-free optical detection of peptide synthesis on a porous silicon scaffold/sensor.
Mesoporous porous silicon (PSi) microcavity sensors are used to conduct conventional solid-phase peptide synthesis. The sensor optical response provides a convenient means to monitor the synthesis reaction in a nondestructive manner. Measurements indicate that peptide synthesis occurs only when the PSi sensor/scaffold is amine-terminated using, for example, the amino silane or deprotected acid-labile Rink linker. Equivalent coupling efficiencies of the first amino acid to both amine terminations are observed. Kinetic studies indicate that coupling reactions are 90% complete in 1 h. Quantitative analysis of the optical response following the synthesis of homo-oligopeptides (4-mers) suggests that coupling efficiencies and/or optical thickness changes depend on the peptide length. The synthesis of the cell adhesive oligopeptide (RGD) was monitored by the optical sensor response and validated by the cell culture of primary dermal fibroblasts. Secondary ion mass spectrometry (SIMS) analysis successfully detected peptide on the silicon wafer adjacent to the PSi. Our findings suggest the potential to exploit the high surface area, efficient coupling, and intrinsic optical detection properties of PSi for label-free high-throughput screening.


Predicting death by the loss of intestinal function.
The ability to predict when an individual will die can be extremely useful for many research problems in aging. A technique for predicting death in the model organism, Drosophila melanogaster, has been proposed which relies on an increase in the permeability of the fly intestinal system, allowing dyes from the diet to permeate the body of the fly shortly before death. In this study we sought to verify this claim in a large cohort study using different populations of D. melanogaster and different dyes. We found that only about 50% of the individuals showed a visible distribution of dye before death. This number did not vary substantially with the dye used. Most flies that did turn a blue color before death did so within 24 hours of death. There was also a measurable effect of the dye on the fly mean longevity. These results would tend to limit the utility of this method depending on the application the method was intended for.


Rigid endoscopic relay systems: a comparative study.
Relay systems in rigid endoscopes can compensate for aberrations in the objective and the eyepiece. Five classes of rigid relay systems are examined: conventional; glass Hopkins; plastic lens, glass-rod Hopkins; modified Hopkins; and gradient index. First-order theory, including achromatization, is developed for these systems. Design results are presented, and aberration, vignetting, and system length trade-offs are analyzed.


Current smoking and COVID-19 risk: results from a population symptom app in over 2.4 million people.
The association between current tobacco smoking, the risk of developing symptomatic COVID-19 and the severity of illness is an important information gap. UK users of the Zoe COVID-19 Symptom Study app provided baseline data including demographics, anthropometrics, smoking status and medical conditions, and were asked to log their condition daily. Participants who reported that they did not feel physically normal were then asked by the app to complete a series of questions, including 14 potential COVID-19 symptoms and about hospital attendance. The main study outcome was the development of 'classic' symptoms of COVID-19 during the pandemic defined as fever, new persistent cough and breathlessness and their association with current smoking. The number of concurrent COVID-19 symptoms was used as a proxy for severity and the pattern of association between symptoms was also compared between smokers and non-smokers. Between 24 March 2020 and 23 April 2020, data were available on 2 401 982 participants, mean (SD) age 43.6 (15.1) years, 63.3% female, overall smoking prevalence 11.0%. 834 437 (35%) participants reported being unwell and entered one or more symptoms. Current smokers were more likely to report symptoms suggesting a diagnosis of COVID-19; classic symptoms adjusted OR (95% CI) 1.14 (1.10 to 1.18); >5 symptoms 1.29 (1.26 to 1.31); >10 symptoms 1.50 (1.42 to 1.58). The pattern of association between reported symptoms did not vary between smokers and non-smokers. These data are consistent with people who smoke being at an increased risk of developing symptomatic COVID-19.


The Treatment Acceptability/Adherence Scale: Moving Beyond the Assessment of Treatment Effectiveness.
It is becoming more broadly recognized that beyond effectiveness, the acceptability of interventions for anxiety disorders is an important consideration for evidence-based practice. Although advances in treatments for anxious psychopathologies have demonstrated that cognitive-behavioural interventions are more desirable than other types of psychotherapy or pharmacotherapy, there continue to be problems with adherence and dropout. It has been suggested that low treatment acceptability may be partially responsible for high dropout rates. Although a number of preliminary investigations in this domain have been conducted, further progress is hampered by the absence of a single self-report measure that assesses both acceptability and anticipated adherence. Therefore, the current paper aimed to test the psychometric properties of the newly developed Treatment Acceptability/Adherence Scale (TAAS). In two studies of brief cognitive-behavioural interventions, the TAAS was administered immediately following the therapy session. In Study 1 (N = 120 non-clinical undergraduates), the therapy included two variants of an exposure-based intervention for contamination fear. In Study 2 (N = 27 individuals with obsessive-compulsive disorder), the therapy was a cognitively based intervention evaluating a novel treatment technique for checking compulsions. Measures of convergent and divergent validity were included. Results demonstrated that the TAAS exhibited sound psychometric properties across the two samples. It is hoped that this measure will help clinicians to predict and intervene when a treatment is not acceptable and/or when the client anticipates poor adherence to it. Furthermore, the TAAS may aid researchers in continuing to improve upon effective interventions for anxiety and related disorders.


Rare bilateral nasopalatine duct cysts: a case report.
The nasopalatine duct cyst (NPDC) is the most common of the non-odontogenic cyst of the jaws. This cysts are usually central or unilateral with no prevalence of side occurrence. The NPDC is the most frequent developmental, nonodontogenic cyst of the jaws. This cyst originates from epithelial remnants from the nasopalatine duct. The cells could be activated spontaneously during life, or are eventually stimulated by the irritating action of various agents (infection, etc.). Generally, patients present without clinical signs and symptoms. Therefore, the tentative diagnosis "nasopalatine duct cyst" is often based on a coincidental radiological finding on a routine panoramic view or occlusal radiograph. The definite diagnosis should be based on clinical, radiological and above all histopathologic findings. The therapy of nasopalatine duct cysts consists of an enucleation of the cystic tissue, only in rare cases a marsupialization needs to be performed. This report describes the appearance and treatment of a rare case of bilateral nasopalatine duct cyst.


Efficacy and Safety of 1:1 Fixed-Ratio Combination of Insulin Glargine and Lixisenatide Versus Lixisenatide in Japanese Patients With Type 2 Diabetes Inadequately Controlled on Oral Antidiabetic Drugs: The LixiLan JP-O1 Randomized Clinical Trial.
To assess the efficacy and safety of a 1:1 fixed-ratio combination of insulin glargine and lixisenatide (iGlarLixi) versus lixisenatide (Lixi) in insulin-naive Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on oral antidiabetic drugs (OADs). In this phase 3, open-label, multicenter trial, 321 patients with HbA1c≥7.5 to ≤10.0% (58-86 mmol/mol) and fasting plasma glucose (FPG) ≤13.8 mmol/L (250 mg/dL) were randomized 1:1 to iGlarLixi or Lixi for 52 weeks. The primary end point was change in HbA1c at week 26. Change in HbA1c from baseline to week 26 was significantly greater with iGlarLixi (-1.58% [-17.3 mmol/mol]) than with Lixi (-0.51% [-5.6 mmol/mol]), confirming the superiority of iGlarLixi (least squares [LS] mean difference -1.07% [-11.7 mmol/mol], P < 0.0001). At week 26, significantly greater proportions of patients treated with iGlarLixi reached HbA1c <7% (53 mmol/mol) (65.2% vs. 19.4%; P < 0.0001), and FPG reductions were greater with iGlarLixi than Lixi (LS mean difference -2.29 mmol/L [-41.23 mg/dL], P < 0.0001). Incidence of documented symptomatic hypoglycemia (≤3.9 mmol/L [70 mg/dL]) was higher with iGlarLixi (13.0% vs. 2.5%) through week 26, with no severe hypoglycemic events in either group. Incidence of gastrointestinal events through week 52 was lower with iGlarLixi (36.0% vs. 50.0%), and rates of treatment-emergent adverse events were similar. This phase 3 study demonstrated superior glycemic control and fewer gastrointestinal adverse events with iGlarLixi than with Lixi, which may support it as a new treatment option for Japanese patients with T2DM that is inadequately controlled with OADs.


8-Iso-prostaglandin F2α as a potential biomarker in patients with unipolar and bipolar depression.
Previous studies have shown that the disturbance of redox homeostasis plays a role in the pathogenesis of mood disorders. It is currently unclear whether oxidative stress parameters can be used as biomarkers (state vs. trait). The aim of the present study was to investigate oxidative stress markers in patients with major depressive disorder (MDD) and bipolar disorder (BP) in acute depressive episodes and remission, and healthy individuals. Thirty-two patients with a diagnosis of MDD, 32 patients with a diagnosis of BP and 32 matched healthy controls were included in the study. We measured the serum levels of markers of oxidative damage, including 8-hydroxy-2'-deoxyguanosine (8-OHdG), 8-Iso-prostaglandin F2α (8-iso-PGF2α; 8-isoprostane), and malondialdehyde (MDA), and also serum activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and glutathione reductase (GR) in both acute and remission phase, and in control group. After controlling for the effects of age, sex, body mass index, and smoking status, serum 8-iso-PGF2α levels were significantly higher in both patient groups compared to controls, regardless of disease phase. The activities of GPX and GR were significantly lower in the acute phase in MDD patients compared to controls. Serum GR activity was lower in both acute and remission phase in MDD compared to BP. Our results suggest that both MDD and BP are associated with a disturbed redox balance with a particularly pronounced increase in serum 8-iso-PGF2α levels in both groups and the presence of glutathione metabolism disorders in MDD patients. Further research is needed to confirm the importance of oxidative stress parameters as potential biomarkers of MDD and BP.


[Dynamic properties, electronic structure and functional activity of radioprotectors].
The methods of molecular dynamics and quantum chemistry were used to study the correlation between the functional activity of radioprotectors and their dynamic properties and atomic charges. It is shown that electrostatic interactions determine the correlation between the dynamics and functional activity of radioprotectors. The effects of conformation dynamics of aminothiols on the functions of radioprotectors is discussed.


COVID-19 and the US response: accelerating health inequities.
Health inequities have long defined health and the healthcare system in the USA. The clinical and research capacity across the USA is unparalleled, yet compared to other high and even some middle-income countries, the average health indicators of the population remain suboptimal in 2020, a finding at least in part explained by inequity in healthcare access. In this context, COVID-19 has rapidly emerged as a major threat to the public's health. While it was initially thought that severe acute respiratory syndrome coronavirus 2 would be the great equaliser as it would not discriminate, it is clear that COVID-19 incidence and mortality have rapidly reinforced health disparities drawn by historical and contemporary inequities. Here, we synthesise the data highlighting specific risks among particular marginalised and under-resourced communities including those in jails, prisons and detention centers, immigrants and the undocumented, people with disabilities and people experiencing homelessness across the USA. The drivers of these disparities are pervasive structural risks including limited access to preventive services, inability to comply with physical distancing recommendations, underlying health disparities and intersecting stigmas particularly affecting racial and ethnic minorities across the country, including African Americans, Latinx Americans and Native Americans. Advancing the COVID-19 response, saving lives and restarting the economy necessitate rapidly addressing these inequities rather than ignoring and even reinforcing them.


Thymol polymeric nanoparticle synthesis and its effects on the toxicity of high glucose on OEC cells: involvement of growth factors and integrin-linked kinase.
Nowadays, the drug delivery system is important in the treatment of diseases. A polymeric nanoparticle modified by oleic acid (NPMO) as a Thymol (Thy) drug release system was synthesized from Thymbra spicata and its neurotrophic and angiogenic effects on rat's olfactory ensheathing cells (OECs) in normal (NG) and high glucose (HG) conditions were studied. The NPMO was characterized by using different spectroscopy methods, such as infrared, HNMR, CNMR, gel permeation chromatography, dynamic light scattering, and atomic force microscopy. Load and releasing were investigated by HPLC. The toxicity against OECs diet-induced by MTT assay. ROS and generation of nitric oxide (NO) were evaluated using dichloro-dihydro-fluorescein and Griess method, respectively. The expression of protein integrin-linked kinase (ILK), vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) were evaluated by Western blotting. ThyNPMO is desirable for transferring drug as a carrier. The amount of Thy and extract (E) loaded on NPMO estimated at 43±2.5% and 41±1.8%, respectively. Then, 65% and 63% of the drug load were released, respectively. Thy, ThyNPMO, E, and ENPMO prevented HG-induced OECs cell death (EC50 33±1.5, 22±0.9, 35±1.8, and 25±1.1 μM, respectively). Incubation with Thy, ThyNPMO, E ,and ENPMO at high concentrations increased cell death with LC50 105±3.5, 82±2.8, 109±4.3, and 86±3.4 μM, respectively in HG states. OECs were protected by ThyNPMO and ENPMO in protective concentrations by reducing the amount of ROS and NO, maintaining ILK, reducing VEGF, and increasing BDNF and NGF. The mentioned mechanisms were totally reversed at high concentrations.


Anthropomorphic simulations of falls, shakes, and inflicted impacts in infants.
Rotational loading conditions have been shown to produce subdural hemorrhage and diffuse axonal injury. No experimental data are available with which to compare the rotational response of the head of an infant during accidental and inflicted head injuries. The authors sought to compare rotational deceleration sustained by the head among free falls, from different heights onto different surfaces, with those sustained during shaking and inflicted impact. An anthropomorphic surrogate of a 1.5-month-old human infant was constructed and used to simulate falls from 0.3 m (1 ft), 0.9 m (3 ft), and 1.5 m (5 ft), as well as vigorous shaking and inflicted head impact. During falls, the surrogate experienced occipital contact against a concrete surface, carpet pad, or foam mattress. For shakes, investigators repeatedly shook the surrogate in an anteroposterior plane; inflicted impact was defined as the terminal portion of a vigorous shake, in which the surrogate's occiput made contact with a rigid or padded surface. Rotational velocity was recorded directly and the maximum (peak-peak) change in angular velocity (delta theta(max)) and the peak angular acceleration (theta(max)) were calculated. Analysis of variance revealed significant increases in the delta theta(max) and theta(max) associated with falls onto harder surfaces and from higher heights. During inflicted impacts against rigid surfaces, the delta theta(max) and theta(max) were significantly greater than those measured under all other conditions. Vigorous shakes of this infant model produced rotational responses similar to those resulting from minor falls, but inflicted impacts produced responses that were significantly higher than even a 1.5-m fall onto concrete. Because larger accelerations are associated with an increasing likelihood of injury, the findings indicate that inflicted impacts against hard surfaces are more likely to be associated with inertial brain injuries than falls from a height less than 1.5 m or from shaking.


Closed fractures of the tibial shaft. A meta-analysis of three methods of treatment.
We reviewed the literature to determine the clinical outcomes of the treatment of closed fractures of the tibial shaft with immobilization in a cast, open reduction with internal fixation, or fixation with an intramedullary rod. We reviewed 2372 reports of comparative trials and uncontrolled studies of series of patients published between 1966 and 1993. Nineteen reports, involving six controlled trials and twenty-seven groups of patients, met our inclusion criteria. A structured questionnaire was used to assess the quality of the literature in terms of the experimental design and the method of assessment of outcome. Outcomes from controlled trials were summarized with odds ratios and risk differences, and outcomes from case series were summarized by the medians of the reported results. The studies that were reviewed generally had few subjects and were poorly designed. The comparative trials showed treatment with a cast to be associated with a lower rate of superficial infection than open reduction and internal fixation (mean difference, -5.81 per cent; p = 0.02) and open reduction and internal fixation to be associated with a higher rate of union by twenty weeks than treatment with a cast (mean difference, -18.07 per cent; p = 0.008). There were no other significant associations. There were insufficient data for us to evaluate any aspect of functional status, level of pain, or other patient-reported outcomes of any of the methods of treatment. The results of the present review suggest that the data from the published literature are inadequate for decision-making with regard to the treatment of closed fractures of the tibia.


Crystal structure and comparative functional analyses of a Mycobacterium aldo-keto reductase.
Aldo-keto reductases (AKRs) are a large superfamily of NADPH-dependent enzymes that catalyze the reduction of aldehydes, aldoses, dicarbonyls, steroids, and monosaccharides. While their precise physiological role is generally unknown, AKRs are nevertheless involved in the detoxification of a broad range of toxic metabolites. Mycobacteria contain a number of AKRs, the majority of which are uncharacterised. Here, we report the 1.9 and 1.6 A resolution structures of the apoenzyme and NADPH-bound forms, respectively, of an AKR (MSMEG_2407) from Mycobacterium smegmatis, a close homologue of the M. tuberculosis enzyme Rv2971, whose function is essential to this bacterium. MSMEG_2407 adopted the triosephosphate isomerase (alpha/beta)(8)-barrel fold exhibited by other AKRs. MSMEG_2407 (AKR5H1) bound NADPH via an induced-fit mechanism, in which the NADPH was ligated in an extended fashion. Polar-mediated interactions dominated the interactions with the cofactor, which is atypical of the mode of NADPH binding within the AKR family. Moreover, the nicotinamide ring of NADPH was disordered, and this was attributed to the lack of an "AKR-conserved" bulky residue within the nicotinamide-binding cavity of MSMEG_2407. Enzymatic characterisation of MSMEG_2407 and Rv2971 identified dicarbonyls as a preferred substrate family for hydrolysis, and the frontline antituberculosis drug isoniazid (INH) was shown to inhibit the enzyme activity of both recombinant MSMEG_2407 and Rv2971. However, differences between the affinities of MSMEG_2407 and Rv2971 for dicarbonyls and INH were observed, and this was attributable to amino acid substitutions within the cofactor- and substrate-binding sites. The structures of MSMEG_2407 and the accompanying biochemical characterisation of MSMEG_2407 and Rv2971 provide insight into the structure and function of AKRs from mycobacteria.


Analysis of the Variables Affecting the Incidence, Location, and Severity of Cage Subsidence Following Anterior Cervical Discectomy and Fusion Operation.
For surgical management of degenerative cervical spine disease with myeloradiculopathy, stand-alone cages are frequently used in 1- and 2-level anterior cervical discectomy and fusion (ACDF) operations with a paucity of literature on factors influencing cage subsidence. The aim of this study was to analyze the variables affecting the incidence, location, and severity of cage subsidence. Retrospective review of prospectively collected data of 77 patients (95 levels) undergoing ACDF surgery was conducted. Variables analyzed were age, gender, sagittal alignment, maximum disc height (superior, inferior, and procedure levels), cage size, shape, location, degree of subsidence (minor <2 mm, mild 2-4 mm, moderate 5-7.5 mm, severe >7.5 mm) and location of subsidence. The incidence of cage subsidence was 34% (32 levels), and 91% were minor or mild. Significantly lower mean maximum height of the inferior disc compared to the nonsubsidence group (5.17 versus 5.96; P = 0.0025) was recorded. Significantly greater incidence of subsidence (40%) was recorded in patients with abnormal cervical spine alignment (focal or diffuse kyphosis) versus 18% with normal alignment (P = 0.02). Greater incidence of subsidence was recorded with more anterior positioned cages (52%; p=0.01). No statistical significance was found for age, gender, superior disc height, or cage shape/size. Greater incidence of cage subsidence is significantly associated with a lower maximum disc height of the disc below the operated level (<5.5 mm), abnormal sagittal alignment, and more anteriorly positioned cages. We found that the vast majority of cage subsidence was focal, minor to mild, without having any immediate or late clinical implications in terms of need for revision surgery.


Interaction of beta-iodopenicillanate with the beta-lactamases of Streptomyces albus G and Actinomadura R39.
The beta-lactamases of Streptomyces albus G and Actinomadura R39 are inactivated by beta-iodopenicillanate. However, in contrast with the beta-lactamase I from Bacillus cereus, they also efficiently catalyse the hydrolysis of the inactivator; with the S. albus G enzyme, kcat. is larger than 25s-1 and the number of turnovers before inactivation is 515. With the A. R39 enzyme, kcat. is larger than 50s-1 and the number of turnovers before inactivation is 80. After hydrolysis of the beta-lactam amide bond, the product rearranges into 2.3-dihydro-2,2-dimethyl-1,4-thiazine-3,6-dicarboxylate, which exhibits an absorption maximum at 305 nm.


Parallel proteomic analysis in muscle-invasive bladder transitional cell carcinoma and cancer-related stroma.
To bring about improvements in cancer biology research and elucidate mechanism-based therapeutic targets, we studied the proteome expression profile of purified normal urothelial cells (cancer cells) and normal stromal cells (cancerous stromal cells). Based on the expression profile, biomarker discovery and the mechanisms of multi-step carcinogenesis were explored. We found that 1412/1403 unique proteins commonly appeared in 4 sets of paired cancer/normal tissue, and 1753 proteins were differentially expressed. Three hundred and forty-one proteins were repeatedly expressed in both cancer and cancer stromal cells; 358 proteins were repeatedly expressed in both normal urothelial and normal stromal cells. Among them, 186/203 proteins were specific repeat expressions in cancer/normal tissue and thought to play an important role in cancer-stroma interactions. Differential proteins were further analyzed using bioinformatic tools and compared with the published literature. GO enrichment/depletion analysis indicated that carcinogenesis involved all the biological processes and all the cellular components. Five hundred and sixty-eight differential proteins were located in the well-known biological Kyoto Encyclopedia of Genes and Genomes pathways, including metabolic pathways, ribosome spliceosome, and endocytosis. One hundred and thirty-nine of the 186 proteins that displayed specific repeat expressions in cancer tissue were located in the biological Kyoto Encyclopedia of Genes and Genomes pathways and are thought to be candidate biomarkers for targeted therapy.


Periosteal desmoid.
Periosteal desmoid is a benign tumor like reactive fibrous lesion developed by repeated micro trauma. We describe the case of a 14 year old boy with pain in his right knee who underwent plain radiography followed by radionuclide bone scan. The final diagnosis was that of periosteal desmoid.


Identification of quantitative trait loci for flowering time by a combination of restriction site-associated DNA sequencing and bulked segregant analysis in soybean.
Soybean (Glycine max) has a paleopolyploid genome, and many re-sequencing experiments to characterize soybean genotypes have been conducted using next-generation sequencing platforms. The accumulation of information about single nucleotide polymorphisms (SNPs) throughout the soybean genome has accelerated identification of genomic regions related to agronomically important traits through association studies. However, although many efficient mapping techniques that use next-generation sequencing are available, the number of practical approaches to identify genes/loci is still limited. In this study, we used a combination of restriction site-associated DNA sequencing (RAD-seq) and bulk segregant analysis (BSA) to identify quantitative trait locus (QTLs) for flowering time in a segregating population derived from a cross between Japanese soybean cultivars. Despite the homogeneous genetic background of the parents, over 7000 SNPs were identified and can be used to detect QTLs by RAD-seq BSA analysis. By comparing genotype frequency between early and late-flowering bulks from the F3 segregating population, we identified a QTL on Gm10, which corresponds to the previously identified E2 locus, and a QTL on Gm04, which is close to the E8 locus. Out of these SNPs, more than 2000 were easily converted to conventional DNA markers. Our approach would improve the efficiency of genetic mapping.


Migraine.
This issue provides a clinical overview of migraine, focusing on risk, prevention, diagnosis, treatment, follow-up, and practice improvement. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including MKSAP (Medical Knowledge and Self-Assessment Program). Annals of Internal Medicine editors develop In the Clinic in collaboration with the ACP's Medical Education and Publishing divisions and with the assistance of additional science writers and physician writers.


[Surgical treatment methods for the short saddle nose and high skin portion of the upper lip].
Remote results of treatment are analyzed in 10 patients with deformations of the nose combining a shortened nose and pulled in skin of the septum. The patients were operated on according to Burian. Good results were obtained in 4 cases, satisfactory in 5. A higher share of satisfactory results of Burian's operation is explained by the fact that it is very difficult to draw down the thick porous skin into a proper position, particularly at the tip of the nose. Additional operations are needed, deteriorating the cosmetic effect. The method proposed by the authors yields better results: 89% good and 16% satisfactory. The intervention is aimed directly at removal of the deformation and tissue defect. Mutual transposition of three flaps, one of which is a drawn columella and two other flaps from the upper lip fill the mucosal defect, repairs the pulled in skin part of the septum and elongates the tip of the nose. In addition, transposition of skin flaps from the upper third of the upper lip to the site of mucosal defect shortens the height of the upper lip, thus creating a correct proportion of the middle and lower thirds of the face.


Tackling COVID-19 in informal tented settlements (Lebanon): An assessment of preparedness and response plans and their impact on the health vulnerabilities of Syrian refugees.
This paper is exploring and critically accessing the nature and mechanisms of preparedness and response plans to COVID-19 in Syrian ITSs in Lebanon along with their immediate health impacts on refugees and their abilities to survive. Little is known to date about how such plans have been set up and how they have immediately impacted refugees, particularly those in countries affected by severe economic and political turbulences along with fragile health systems. This qualitative study has been conducted during the pandemic and hence is providing important and novel insights into a time-limited research window during which not only refugees' mobility was restricted but also research capabilities severely constrained. We are focusing on the relationships between refugees, health and the COVID-19 pandemic and unwrapping how very strict and control-led preventive mechanisms have emerged as a consequence of already stretched and problematic health and socio-economic systems. We are also demonstrating how the multi-level strategy and local responses have led to significant challenges to local municipalities, local NGOs and international aid agencies in order to reduce transmission risks in very unhealthy settings as they try to address wider needs. This paper concludes that the impact of the constraining preventive measures implemented to date means that refugee communities will suffer consequences for months and years to come, with their ability to survive being threatened and an expected long-term health impact for a population already at high risk of NCDs. We argue that more research will be needed into deconstructing further refugees' reactions to encampment mechanisms and mobility restrictions, particularly if survival becomes even more problematic; similarly relationships and tensions with local municipalities, as well as measures and support provided by local and international NGOs, will deserve attention. A key question remains about the likely scenario if cases start to spread widely in ITSs and, hence, what will happen to both refugees and host communities in a country with a health system on the edge of collapse.


Pharmacological blockage of transforming growth factor-β signalling by a Traf2- and Nck-interacting kinase inhibitor, NCB-0846.
Metastasis is the primary cause of death in cancer patients, and its management is still a major challenge. Epithelial to mesenchymal transition (EMT) has been implicated in the process of cancer metastasis, and its pharmacological interference holds therapeutic promise. Traf2- and Nck-interacting kinase (TNIK) functions as a transcriptional coregulator of Wnt target genes. Given the convergence of Wnt and transforming growth factor-β (TGFβ) signalling, we examined the effects of a small-molecule TNIK inhibitor (named NCB-0846) on the TGFβ1-induced EMT of lung cancer cells. NCB-0846 inhibited the TGFβ1-induced EMT of A549 cells. This inhibition was associated with inhibition of Sma- and Mad-Related Protein-2/3 (SMAD2/3) phosphorylation and nuclear translocation. NCB-0846 abolished the lung metastasis of TGFβ1-treated A549 cells injected into the tail veins of immunodeficient mice. The inhibition of EMT was mediated by suppression of the TGFβ receptor type-I (TGFBR1) gene, at least partly through the induction of microRNAs targeting the TGFBR1 transcript [miR-320 (a, b and d) and miR-186]. NCB-0846 pharmacologically blocks the TGFβ/SMAD signalling and EMT induction of lung cancer cells by transcriptionally downregulating TGFBRI expression, representing a potentially promising approach for prevention of metastasis in lung cancer patients.


Classification and Prediction of Post-Trauma Outcomes Related to PTSD Using Circadian Rhythm Changes Measured via Wrist-Worn Research Watch in a Large Longitudinal Cohort.
Post-Traumatic Stress Disorder (PTSD) is a psychiatric condition resulting from threatening or horrifying events. We hypothesized that circadian rhythm changes, measured by a wrist-worn research watch are predictive of post-trauma outcomes. 1618 post-trauma patients were enrolled after admission to emergency departments (ED). Three standardized questionnaires were administered at week eight to measure post-trauma outcomes related to PTSD, sleep disturbance, and pain interference with daily life. Pulse activity and movement data were captured from a research watch for eight weeks. Standard and novel movement and cardiovascular metrics that reflect circadian rhythms were derived using this data. These features were used to train different classifiers to predict the three outcomes derived from week-eight surveys. Clinical surveys administered at ED were also used as features in the baseline models. The highest cross-validated performance of research watch-based features was achieved for classifying participants with pain interference by a logistic regression model, with an area under the receiver operating characteristic curve (AUC) of 0.70. The ED survey-based model achieved an AUC of 0.77, and the fusion of research watch and ED survey metrics improved the AUC to 0.79. This work represents the first attempt to predict and classify post-trauma symptoms from passive wearable data using machine learning approaches that leverage the circadian desynchrony in a potential PTSD population.


Widely tunable laser frequency offset lock with 30 GHz range and 5 THz offset.
We demonstrate a simple and versatile method to greatly extend the tuning range of optical frequency shifting devices, such as acousto-optic modulators (AOMs). We use this method to stabilize the frequency of a tunable narrow-band continuous-wave (CW) laser to a transmission maximum of an external Fabry-Perot interferometer (FPI) with a tunable frequency offset. This is achieved through a servo loop which contains an in-loop AOM for simple radiofrequency (RF) tuning of the optical frequency over the full 30 GHz mode-hop-free tuning range of the CW laser. By stabilizing the length of the FPI to a stabilized helium-neon (HeNe) laser (at 5 THz offset from the tunable laser) we simultaneously transfer the ~ 1 MHz absolute frequency stability of the HeNe laser to the entire 30 GHz range of the tunable laser. Thus, our method allows simple, wide-range, fast and reproducible optical frequency tuning and absolute optical frequency measurements through RF electronics, which is here demonstrated by repeatedly recording a 27-GHz-wide molecular iodine spectrum at scan rates up to 500 MHz/s. General technical aspects that determine the performance of the method are discussed in detail.


Immune Alterations in Patients with Anti-Interferon-γ Autoantibodies.
Autoantibodies against interferon-gamma (IFN-γ) can cause immunodeficiency and are associated with various opportunistic infections. In the present study, we investigated other cellular immune parameters for a better understanding of the immunodeficiency condition in the patients. The numbers of WBC, monocytes and NK cells were increased in patients with anti-IFN-γ autoantibodies (AAbs). Upon TCR activation, T cell proliferation and IL-2 receptor of the patients remained intact. Nonetheless, the Th1 cytokine (IFN-γ and TNF-α) production was up-regulated. The production of Th2 (IL-4) and Th17 (IL-17) cytokines was unchanged. We suggest that, in addition to the presence of anti-IFN-γ autoantibodies, alterations in the cellular immune functions may also contribute to this immunodeficiency.


Efficient electrocatalytic hydrogen gas evolution by a cobalt-porphyrin-based crystalline polymer.
Herein, we report a crystalline CoTcPP-based [TcPP = the anion of meso-tetra(4-carboxyphenyl)porphyrin] polymeric system, 1, as a hydrogen evolution reaction (HER) electrocatalyst in acidic aqueous media. The material was characterized by powder X-ray diffraction (p-XRD), Fourier transform infrared (FT-IR) spectroscopy, and energy dispersive X-ray (EDX) analysis and its morphology was probed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Polymer 1 shows a surface area of 441.74 m3 g-1, while the discrete CoTcPP molecule (2) shows a surface area of 3.44 m3 g-1. The HER catalytic performance was evaluated by means of linear sweep voltammetry in the presence of 0.5 M H2SO4 aqueous solution. To achieve 10 mA cm-2 cathodic current density, 1 and 2 respectively require an overpotential of 0.475 V and 0.666 V, providing strong evidence that the extended network of cobalt-based porphyrin leads to enhanced HER efficiency. The polymer also shows great tolerance for HER electrolysis in the presence of an acid remaining active over 10 hours.


Serum Thyroid Stimulating Hormone Levels Are Associated with the Presence of Coronary Atherosclerosis in Healthy Postmenopausal Women.
Menopause is a natural aging process causing estrogen deficiency, accelerating atherogenic processes including dyslipidemia. Prevalence of thyroid dysfunction is also high in postmenopausal women, and it is known to elevate the risk of cardiovascular disease (CVD). Therefore, we are to study on the associations in between serum thyroid stimulating hormone (TSH) and prevalence of CVD in postmenopausal women who have normal thyroid function. We performed a retrospective review of 247 Korean postmenopausal women who visited the health promotion center from January, 2007 to December, 2009. Postmenopausal women with normal serum TSH were included in the study. Coronary atherosclerosis was assessed by 64-row multidetector computed tomography. In multiple linear regression analysis, serum TSH was associated with serum triglyceride (TG) (β = 0.146, P = 0.023). In multiple logistic regression analysis, increasing age and serum TSH were associated with an increased risk of coronary atherosclerosis in euthyroid postmenopausal women (odds ratio [OR] = 1.107 [1.024-1.197], P = 0.011 and OR = 1.303 [1.024-1.658], P = 0.031, respectively). It revealed that significant predictor of serum TSH was serum TG, and increasing age and TSH were found to have associations with an increased risk of coronary atherosclerosis in euthyroid postmenopausal women. Screening and assessing risks for CVD in healthy postmenopausal women would be helpful before atherosclerosis develops.


Slow EEG rhythms and inter-hemispheric synchronization across sleep and wakefulness in the human hippocampus.
Converging data that attribute a central role to sleep in memory consolidation have increased the interest to understand the characteristics of the hippocampal sleep and their relations with the processing of new information. Neural synchronization between different brain regions is thought to be implicated in long-term memory consolidation by facilitating neural communication and by promoting neural plasticity. However, the majority of studies have focused their interest on intra-hippocampal, rhinal-hippocampal or cortico-hippocampal synchronization, while inter-hemispheric synchronization has been so far neglected. To clarify the features of spontaneous human hippocampal activity and to investigate inter-hemispheric hippocampal synchronization across vigilance states, pre-sleep wakefulness and nighttime sleep were recorded from right and left homologous hippocampal loci using stereo-EEG techniques. Hence, quantitative and inter-hemispheric coherence analyses of hippocampal activity across sleep and waking states were carried out. The results showed the presence of delta activity in human hippocampal spontaneous EEG also during wakefulness. The activity in the delta range exhibited a peculiar bimodal distribution, namely a low frequency non-oscillatory activity (up to 2 Hz) synchronized between hemispheres mainly during wake and REM sleep, and a faster oscillatory rhythm (2-4 Hz). The latter was less synchronized between the hippocampi and seemed reminiscent of animal RSA (rhythmic slow activity). Notably, the low-delta activity showed high inter-hemispheric hippocampal coherence during REM sleep and, to a lesser extent, during wakefulness, paralleled by a (unexpected) decrease of coherence during NREM sleep. Therefore, low-delta hippocampal state-dependent synchronization starkly contrasts with neocortical behavior in the same frequency range. Further studies might shed light on the role of these low frequency rhythms in the encoding processes during wakefulness and in the consolidation processes during subsequent sleep.


Management of venous thromboembolism in patients with cancer: role of dalteparin.
Cancer is a major risk factor for the development of venous thromboembolism (VTE). Conventional anticoagulant therapy with a vitamin K antagonist is more problematic in cancer patients due to an increased risk of recurrent VTE, and an increased risk of anticoagulant-related bleeding. In recent years, there has been a shift toward treating cancer patients with VTE with extended duration dalteparin. Dalteparin, a low-molecular-weight heparin, has been shown to be more effective, and as safe as conventional anticoagulant therapy, in cancer patients with VTE. This paper will (a) review the relationship between cancer and VTE, and (b) provide an overview of the role of dalteparin in the management of VTE in patients with cancer.


Neuropsychology of reward learning and negative symptoms in schizophrenia.
We used the Iowa Gambling Test (IGT) to examine the relationship of reward learning to both neuropsychological functioning and symptom formation in 65 individuals with schizophrenia. Results indicated that compared to controls, participants with schizophrenia showed significantly reduced reward learning, which in turn correlated with reduced intelligence, memory and executive function, and negative symptoms. The current findings suggested that a disease-related disturbance in reward learning may underlie both cognitive and motivation deficits, as expressed by neuropsychological impairment and negative symptoms in schizophrenia.


Air pollution and health effects: A study of medical visits among children in Santiago, Chile.
Many epidemiological studies conducted in the last several years have reported associations between exposure to airborne particulate matter, measured as PM10 (<10 microm in diameter), and daily morbidity and mortality. However, much of the evidence involves effects on the elderly population; there is less evidence about the effects of particulates on children, especially those under 2 years of age. To examine these issues, we conducted time-series analyses of 2 years of daily visits to primary health care clinics in Santiago, Chile, where counts were computed for either upper or lower respiratory symptoms and for cohorts of children 3-15 years of age and below age 2. Daily PM10 and ozone measurements and meteorological variables were available from instruments located in downtown Santiago. The multiple regression analysis indicates a statistically significant association between PM10 and medical visits for lower respiratory symptoms in children ages 3-15 and in children under age 2. PM10 is also associated with medical visits related to upper respiratory symptoms in the older cohort, while ozone is associated with visits related to both lower and upper respiratory symptoms in the older cohort. For children under age 2, a 50- microg/m3 change in PM10 (the approximate interquartile range) is associated with a 4-12% increase in lower respiratory symptoms. For children 3-15 years of age, the increase in lower respiratory symptoms ranges from 3 to 9% for a 50- microg/m3 change in PM10 and 5% per 50 ppb change in ozone. These magnitudes are similar to results from studies of children undertaken in Western industrial nations.


The global health and economic impact of low-back pain attributable to occupational ergonomic factors in the working-age population by age, sex, geography in 2019.
Occupational ergonomic factors (OEF) include physical exertion, demanding posture, repetitive work, hand-arm vibration, kneeling or squatting, rising, and climbing, which are risk factors for low-back pain (LBP). This study aimed to examine the prevalence, years lived with disability (YLD), healthcare costs, and productivity losses of LBP attributable to OEF by age, sex, World Health Organization region, and country in 2019. In this cross-sectional study, prevalence and YLD were extracted from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019. Employment statistics were obtained from the International Labor Organization websites. Health and economic impact was estimated for 192 countries and territories using the population attributable fraction method. Globally, OEF were responsible for 126.1 million prevalent cases of LBP and 15.1 million YLD in the working-age population (aged 15-84 years) in 2019, with the Western Pacific region suffering most. OEF-attributable LBP led to $216.1 billion of economic losses worldwide. Of these, $47.0 billion were paid in healthcare costs, with the public sector serving as the largest contributor (59.2%). High-income countries bore >70% of global economic burden, whereas middle-income countries experienced >70% of global YLD. Generally, more prevalent cases and healthcare costs were found among females, whereas more YLD, productivity losses, and total costs were found among males. Globally, OEF-attributable LBP presented a heavy burden on health and economic systems. Exercise together with education, active monitoring, evidence-based medical practices, alternative cost-effective solutions, and prioritizing health policies are needed.


Analysis of aberrant virulence of Gibberella zeae following transformation-mediated complementation of a trichothecene-deficient (Tri5) mutant.
Gibberella zeae causes wheat ear blight and produces trichothecene toxins in infected grain. In previous studies, trichothecene production in this fungus was disabled by specific disruption of the trichodiene synthase gene (Tri5) and was restored by two methods: gene reversion and transformation-mediated mutant complementation. In previous field tests of wheat ear blight, trichothecene-nonproducing mutants were less virulent than the wild-type progenitor strain from which they were derived. Trichothecene-producing revertants also were restored to wild-type levels of virulence. In contrast, in the field test of wheat ear blight reported here, trichothecene-producing strains obtained by Tri5 mutant complementation were not restored to wild-type levels of virulence. The complemented mutants showed a slightly reduced radial growth compared to the wild-type strain, but otherwise appeared normal in morphology, pigmentation and sexual fertility. Genetic analysis indicated that the aberrant virulence of a complemented mutant was likely due to non-target effects that occurred during the process of transforming the trichothecene-nonproducing mutant with Tri5. These results confirm previous findings that trichothecenes contribute to the virulence of G. zeae, but also demonstrate that manipulating this fungus in the laboratory may cause it to undergo subtle changes that reduce its virulence.


Automated Cell Treatment for Competence and Transformation of Escherichia coli in a High-Throughput Quasi-Turbidostat Using Microtiter Plates.
Metabolic engineering and genome editing strategies often lead to large strain libraries of a bacterial host. Nevertheless, the generation of competent cells is the basis for transformation and subsequent screening of these strains. While preparation of competent cells is a standard procedure in flask cultivations, parallelization becomes a challenging task when working with larger libraries and liquid handling stations as transformation efficiency depends on a distinct physiological state of the cells. We present a robust method for the preparation of competent cells and their transformation. The strength of the method is that all cells on the plate can be maintained at a high growth rate until all cultures have reached a defined cell density regardless of growth rate and lag phase variabilities. This allows sufficient transformation in automated high throughput facilities and solves important scheduling issues in wet-lab library screenings. We address the problem of different growth rates, lag phases, and initial cell densities inspired by the characteristics of continuous cultures. The method functions on a fully automated liquid handling platform including all steps from the inoculation of the liquid cultures to plating and incubation on agar plates. The key advantage of the developed method is that it enables cell harvest in 96 well plates at a predefined time by keeping fast growing cells in the exponential phase as in turbidostat cultivations. This is done by a periodic monitoring of cell growth and a controlled dilution specific for each well. With the described methodology, we were able to transform different strains in parallel. The transformants produced can be picked and used in further automated screening experiments. This method offers the possibility to transform any combination of strain- and plasmid library in an automated high-throughput system, overcoming an important bottleneck in the high-throughput screening and the overall chain of bioprocess development.


[Intensive care of patients with acute liver failure].
Acute liver failure and acute decompensated chronic liver failure are two diseases that demand extensive knowledge of etiology and triggering factors, pathophysiology, diagnosis, prognosis and recommended guidelines for treatment. The article defines the diseases, discusses etiological factors, treatment strategies, indications for referral to the transplantation unit at Rikshospitalet and prognostic factors of importance. The basis for this article is literature identified through a non-systematic search in PubMed and the authors' clinical experience and experimental research within the field. In the Western world paracetamol poisoning and toxic reactions to other drugs are the most common triggering factors for acute liver poisoning in adults. Patients can quickly develop multi organ failure requiring advanced intensive care. The most common complications are hepatic encephalopathy, acute renal failure and coagulation disturbances. Acute decompensated chronic liver failure strikes patients with known liver disease and is most often triggered by inflammation, infection, gastrointestinal bleeding, drugs, traumas or disturbances in acid/base/electrolyte balance. Early diagnosing of triggering factors and intensive medical supportive treatment is especially important. Acute renal failure indicates a very bad prognosis. Patients diagnosed with acute liver failure or acute decompensated chronic liver failure remain a clinical challenge. Optimal treatment requires extensive knowledge of pathophysiological mechanisms and treatment strategies.


Thirty-Day Readmission and Cost Analysis in Patients With Cirrhosis: A Nationwide Population-Based Data.
Accurate population-based data are needed on the rate, economic impact, and the long-term outcomes of readmission among patients with cirrhosis. To examine the rates, costs, and 1-year outcomes of patients readmitted within 30 days following their index hospitalization for complications of cirrhosis, we conducted a nationwide, population-based cohort study involving all patients with cirrhosis in Thailand from 2009 through 2013, using data from the National Health Security Office databases, which included those from nationwide hospitalizations. Readmission was captured from hospitals at all health care levels across the country within the Universal Coverage Scheme. For the 134,038 patients hospitalized with cirrhosis, the overall 30-day readmission rate was 17%. Common causes of readmission consisted of complications of portal hypertension (47%) and infections (17%). After adjusting for multiple covariates, predictors of 30-day readmission included hepatocellular carcinoma (odds ratio [OR] 1.95, 95% confidence interval [CI] 1.84-2.06), human immunodeficiency virus-related admission (OR 1.81, 95% CI 1.51-2.17) and cholangiocarcinoma (OR 1.64, 95% CI 1.3-2.05). In all, 2,936 deaths (13%) occurred during readmission, and an additional 14,425 deaths up to 1 year (63.5% total mortality among readmitted patients). Causes of death were mostly from liver-related mortality. Average cost at index admission for those with a 30-day readmission were significantly higher than those readmitted beyond 30 days or not readmitted. Conclusions: Patients hospitalized with cirrhosis complications had high rates of unscheduled 30-day readmission. Average hospitalization costs were high, and only 36.5% of patients readmitted within 30 days survived at 1 year.


Asymptomatic Plasmodium falciparum malaria in pregnant women in the Chittagong Hill Districts of Bangladesh.
Pregnancy is a known risk factor for malaria which is associated with increased maternal and infant mortality and morbidity in areas of moderate-high malaria transmission intensity where Plasmodium falciparum predominates. The nature and impact of malaria, however, is not well understood in pregnant women residing in areas of low, unstable malaria transmission where P. falciparum and P. vivax co-exist. A large longitudinal active surveillance study of malaria was conducted in the Chittagong Hill Districts of Bangladesh. Over 32 months in 2010-2013, the period prevalence of asymptomatic P. falciparum infections was assessed by rapid diagnostic test and blood smear and compared among men, non-pregnant women and pregnant women. A subset of samples was tested for infection by PCR. Hemoglobin was assessed. Independent risk factors for malaria infection were determined using a multivariate logistic regression model. Total of 34 asymptomatic P. falciparum infections were detected by RDT/smear from 3,110 tests. The period prevalence of asymptomatic P. falciparum infection in pregnant women was 2.3%, compared to 0.5% in non-pregnant women and 0.9% in men. All RDT/smear positive samples that were tested by PCR were PCR-positive, and PCR detected additional 35 infections that were RDT/smear negative. In a multivariate logistic regression analysis, pregnant women had 5.4-fold higher odds of infection as compared to non-pregnant women. Malaria-positive pregnant women, though asymptomatic, had statistically lower hemoglobin than those without malaria or pregnancy. Asymptomatic malaria was found to be evenly distributed across space and time, in contrast to symptomatic infections which tend to cluster. Pregnancy is a risk factor for asymptomatic P. falciparum infection in the Chittagong Hill Districts of Bangladesh, and pregnancy and malaria interact to heighten the effect of each on hemoglobin. The even distribution of asymptomatic malaria, without temporal and spatial clustering, may have critical implications for malaria elimination strategies.


Pucotenlimab in patients with advanced mismatch repair-deficient or microsatellite instability-high solid tumors: A multicenter phase 2 study.
We report a multicenter, phase 2 study evaluating the efficacy of pucotenlimab, an anti-PD-1 antibody, in patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumors, and potential biomarkers for response. Overall, 100 patients with previously treated, advanced solid tumors centrally confirmed as dMMR or MSI-H received pucotenlimab at 200 mg every 3 weeks. The most common cancer type is colorectal cancer (n = 71). With a median follow-up of 22.5 months, the objective response rate is 49.0% (95% confidence interval 38.86%-59.20%) as assessed by the independent review committee, while the median progression-free survival and overall survival have not been reached. Grade ≥3 treatment-related adverse events were observed in 18 patients. For the biomarker analysis, responders are enriched in patients with mutations in the KMT2D gene. Pucotenlimab is an effective treatment option for previously treated advanced dMMR/MSI-H solid tumors, and the predictive value of KMT2D mutation warrants further research. This study is registered with ClinicalTrials.gov: NCT03704246.


Synthesis, crystal and electronic structure of the quaternary magnetic EuTAl4Si2 (T = Rh and Ir) compounds.
Single crystals of the quaternary europium compounds EuRhAl4Si2 and EuIrAl4Si2 were synthesized by using the Al-Si binary eutectic as a flux. The structure of the two quaternary compounds has been refined by single crystal X-ray diffraction. Both compounds are stoichiometric and adopt an ordered derivative of the ternary KCu4S3 structure type (tetragonal tP8, P4/mmm). The two compounds reported here represent the first example of a quaternary and truly stoichiometric 1:1:4:2 phase crystallizing with this structure type. In light of our present results, the structure of the BaMg4Si3 compound given in literature as representing a new prototype is actually isotypic with the KCu4S3 structure. Local spin density approximation including the Hubbard U parameter (LSDA + U) calculations show that Eu ions are in the divalent state, with a significant hybridization between the Eu 5d, Rh (Ir) 4d (5d), Si 3p and Al 3p states. Magnetic susceptibility measured along the [001] direction confirms the divalent nature of the Eu ions in EuRhAl4Si2 and EuIrAl4Si2, which order magnetically near ∼11 and ∼15 K, respectively.


Islet cell antibodies in Sulawesi macaques.
Older monkeys of the Sulawesian species Macaca nigra spontaneously develop a lesion in the pancreatic islets of Langerhans in which there is deposition of amyloid and gradual degeneration of all cells, which can lead eventually to development of diabetes mellitus. Islet cell antibodies (ICA), formed in response to the release of cellular antigens, can be used to detect the islet lesion and to monitor the progression of each monkey toward diabetes. Numerous M. nigra and one M. tonkeana in captivity have been tested, but it is unknown whether the islet lesion occurs in monkeys in their natural habitat of Sulawesi. Blood samples collected from M. maurus, M. tonkeana, and hybrid M. maurus/tonkeana were assayed for ICA. When all monkeys were considered together, 33% had ICA positive against beta cells and 14% had ICA positive against alpha and/or D cells. Appearance of ICA in blood of males was virtually the same as in females. These results are similar to those found in M. nigra examined in captivity. Since all Sulawesian species share a common genetic heritage, these results would support the appearance of this lesion in their natural habitat. Cause(s) for formation of the lesion and eventual development of diabetes are unknown. There may be genetic factors or genetic predisposition to environmental factors. If environmental factors are responsible, then they must be present not only in the wild, but either carried with the monkeys or universally available, since M. nigra born in captivity also develop the lesion and diabetes after physical maturity at ca. 7+ years.


Single-file diffusion of particles with long-range interactions: damping and finite-size effects.
We study the single file diffusion of a cyclic chain of particles that cannot cross each other, in a thermal bath, with long-ranged interactions and arbitrary damping. We present simulations that exhibit new behaviors specifically associated with systems of small numbers of particles and with small damping. In order to understand those results, we present an original analysis based on the decomposition of the particles' motion in the normal modes of the chain. Our model explains all dynamic regimes observed in our simulations and provides convincing estimates of the crossover times between those regimes.


Carbonic anhydrase 9 confers resistance to ferroptosis/apoptosis in malignant mesothelioma under hypoxia.
Hypoxia and acidity provide microenvironment for selection under evolutionary pressure and proliferation in cancer cells. Carbonic anhydrases (CAs) are a superfamily of metalloenzymes present in all life kingdoms, equilibrating the reactions among CO2, bicarbonate and H+. CA9, a membrane-associated α-CA, has been a drug target for various cancers. Whereas iron is essential not only for cancer cells but also for all the lives on earth, little is known on the association among hypoxia, iron metabolism, extracellular acidity and redox regulation. Malignant mesothelioma (MM), an aggressive tumor with poor prognosis, is an intriguing model in that asbestos-associated pathogenesis includes excess iron environment during carcinogenesis. Re-analysis of rat asbestos-induced MM model revealed an inverse association between high CA9 expression and survival. Here we used human MMs to identify the molecular events surrounding CA9 from the viewpoint of iron metabolism. CA9 expression was significantly higher in MM cells than in MeT-5A mesothelial cells, which was further amplified under hypoxia (1%O2) with increased catalytic Fe(II). CA9 suppression by inhibitors (S4 and U104) decreased viability and migration of MM cells, accompanied by overexpression of TFRC, IREB1/2 and FPN1(SLC40A1) and by downregulation of FTH/FTL. This expressional pattern was similar to that of erastin-induced ferroptosis in the same cells. Furthermore, we observed mitochondrial fission and enhanced autophagy with increased catalytic Fe(II) in both mitochondria and lysosomes after CA9 inhibition, accompanied by increased peroxides, mitochondrial O2- and lipid peroxidation. The eventual cell death was significantly inhibited by deferoxamine, ferrostatin-1 and Z-VAD-FMK, suggesting a mixed cell death of ferroptosis and apoptosis. Therefore, CA9 plays a role in equilibrating among hypoxia, iron metabolism and redox regulation in MM cells.


Reporting and Staging of Testicular Germ Cell Tumors: The International Society of Urological Pathology (ISUP) Testicular Cancer Consultation Conference Recommendations.
The International Society of Urological Pathology held a conference devoted to issues in testicular and penile pathology in Boston in March 2015, which included a presentation and discussion led by the testis microscopic features working group. This conference focused on controversies related to staging and reporting of testicular tumors and was preceded by an online survey of the International Society of Urological Pathology members. The survey results were used to initiate discussions, but decisions were made by expert consensus rather than voting. A number of recommendations emerged from the conference, including that lymphovascular invasion (LVI) should always be reported and no distinction need be made between lymphatic or blood invasion. If LVI is equivocal, then it should be regarded as negative to avoid triggering unnecessary therapy. LVI in the spermatic cord is considered as category pT2, not pT3, unless future studies provide contrary evidence. At the time of gross dissection, a block should be taken just superior to the epididymis to define the base of the spermatic cord, and direct invasion of tumor in this block indicates a category of pT3. Pagetoid involvement of the rete testis epithelium must be distinguished from rete testis stromal invasion, with only the latter being prognostically useful. Percentages of different tumor elements in mixed germ cell tumors should be reported. Although consensus was reached on many issues, there are still areas of practice that need further evidence on which to base firm recommendations.


Introducing secure modes of operation for optical encryption.
We analyze optical encryption systems using the techniques of conventional cryptography. All conventional block encryption algorithms are vulnerable to attack, and often they employ secure modes of operation as one way to increase security. We introduce the concept of conventional secure modes to optical encryption and analyze the results in the context of known conventional and optical attacks. We consider only the optical system "double random phase encoding," which forms the basis for a large number of optical encryption, watermarking, and multiplexing systems. We consider all attacks proposed to date in one particular scenario. We analyze only the mathematical algorithms themselves and do not consider the additional security that arises from employing these algorithms in physical optical systems.


Different mechanisms of corpus callosum atrophy in Alzheimer's disease and vascular dementia.
Previous neuroimaging studies have indicated that corpus callosum atrophy in Alzheimer's disease (AD) and large vessel occlusive disease (LVOD) is caused by interhemispheric disconnection, namely Wallerian degeneration of interhemispheric commissural nerve fibers originating from pyramidal neurons in the cerebral cortex. However, this hypothesis has not been tested from a neuropathological viewpoint. In the present study, 22 brains with AD (presenile onset, 9; senile onset, 13), 6 brains with Binswanger's disease (BD), a form of vascular dementia and 3 brains with LVOD were compared with 6 non-neurological control brains. White matter lesions in the deep white matter and corpus callosum were quantified as a fiber density score by image analysis of myelin-stained sections. Axonal damage and astrogliosis were assessed by immunohistochemistry for amyloid precursor protein and glial fibrillary acidic protein, respectively.The corpus callosum thickness at the anterior part of the body was decreased in AD and LVOD,but not in BD significantly, as compared with the controls. The corpus callosum thickness correlated roughly with brain weight in AD (R=0.50),and with the severity of deep white matter lesions in BD (R=0.81). Atrophy of the brain and corpus callosum was more marked in presenile onset AD than in senile onset AD. With immunohistochemistry, the corpus callosum showed axonal damage and gliosis with a decreased fiber density score in BD and LVOD, but not in AD. Thus, corpus callosum atrophy was correlated with brain atrophy in AD, which is relevant to the mechanism of interhemispheric disconnection,whereas corpus callosum lesions in BD were secondary to deep white matter lesions. Corpus callosum atrophy in LVOD may indicate interhemispheric disconnection, but focal ischemic injuries may also be involved.


[Multifocal malignant transformation of extreme fibromatosis with pulmonary involvement].
We report on the case of a 40-year old patient with extreme neurofibromatosis with severe kyphoskoliosis and deformation of the thorax. The patient died from malignant transformation which occurred multifocally with extensive pulmonary metastases. The well-known thoracic manifestations of neurofibromatosis are reviewed.