The R403Q myosin mutation implicated in familial hypertrophic cardiomyopathy causes disorder at the actomyosin interface.
Mutations in virtually all of the proteins comprising the cardiac muscle sarcomere have been implicated in causing Familial Hypertrophic Cardiomyopathy (FHC). Mutations in the beta-myosin heavy chain (MHC) remain among the most common causes of FHC, with the widely studied R403Q mutation resulting in an especially severe clinical prognosis. In vitro functional studies of cardiac myosin containing the R403Q mutation have revealed significant changes in enzymatic and mechanical properties compared to wild-type myosin. It has been proposed that these molecular changes must trigger events that ultimately lead to the clinical phenotype. Here we examine the structural consequences of the R403Q mutation in a recombinant smooth muscle myosin subfragment (S1), whose kinetic features have much in common with slow beta-MHC. We obtained three-dimensional reconstructions of wild-type and R403Q smooth muscle S1 bound to actin filaments in the presence (ADP) and absence (apo) of nucleotide by electron cryomicroscopy and image analysis. We observed that the mutant S1 was attached to actin at highly variable angles compared to wild-type reconstructions, suggesting a severe disruption of the actin-myosin interaction at the interface. These results provide structural evidence that disarray at the molecular level may be linked to the histopathological myocyte disarray characteristic of the diseased state.


Kidney Disease Caused by Dysregulation of the Complement Alternative Pathway: An Etiologic Approach.
Kidney diseases caused by genetic or acquired dysregulation of the complement alternative pathway (AP) are traditionally classified on the basis of clinical presentation (atypical hemolytic uremic syndrome as thrombotic microangiopathy), biopsy appearance (dense deposit disease and C3 GN), or clinical course (atypical postinfectious GN). Each is characterized by an inappropriate activation of the AP, eventuating in renal damage. The clinical diversity of these disorders highlights important differences in the triggers, the sites and intensity of involvement, and the outcome of the AP dysregulation. Nevertheless, we contend that these diseases should be grouped as disorders of the AP and classified on an etiologic basis. In this review, we define different pathophysiologic categories of AP dysfunction. The precise identification of the underlying abnormality is the key to predict the response to immune suppression, plasma infusion, and complement-inhibitory drugs and the outcome after transplantation. In a patient with presumed dysregulation of the AP, the collaboration of the clinician, the renal pathologist, and the biochemical and genetic laboratory is very much encouraged, because this enables the elucidation of both the underlying pathogenesis and the optimal therapeutic approach.


Conceptualizing the health and well-being impacts of social enterprise: a UK-based study.
Social enterprises-businesses that work for social benefit rather than for the maximization of financial returns to shareholders or owners-could potentially prove to be an innovative and sustainable way of tackling 'upstream' social determinants of health. However, empirical work focusing upon how, and to what extent, social enterprise-led activity may impact upon health and well-being is still relatively scarce. This study examines how social enterprises portray their impact, and how such impacts may be considered in health and well-being terms. Through analysing evaluative reports of the work of social enterprises in Scotland (n = 17) utilizing a 'process coding' method, we investigate both the self-reported impacts of the work of social enterprises and the mechanisms by which these are said to be derived. Revisiting previous conceptualizations in the extant literature, this work allows us to present an 'empirically-informed' conceptual model of the health and well-being impacts of social enterprise-led activity, and thus presents a significant advance on previous hypothetical, theoretically-based conceptualizations. It is considered that these findings further improve our overall knowledge of ways in which social enterprise and other parts of the third sector could be considered as potentially valuable 'non-obvious' public health actors.


Predictors of breastfeeding duration: evidence from a cohort study.
To report the duration of breastfeeding among a population of Australian women and to identify factors that are associated with the duration of full breastfeeding to 6 months and any breastfeeding to 12 months. Participants were 587 women who were recruited from 2 maternity hospitals in Perth and completed a baseline questionnaire just before or shortly after discharge from the hospital. Women were followed up by telephone interview at 4, 10, 16, 22, 32, 40, and 52 weeks postpartum. Data collected included sociodemographic, biomedical, hospital-related, and psychosocial factors associated with the initiation and the duration of breastfeeding. Cox's proportional hazards model was used to identify factors that were associated with the risk for discontinuing full breastfeeding before 6 months and any breastfeeding before 12 months. At 6 months of age, fewer than one half of infants were receiving any breast milk (45.9%), and only 12% were being fully breastfed. By 12 months, only 19.2% of infants were still receiving any breast milk. Breastfeeding duration was independently, positively associated with maternal infant feeding attitudes and negatively associated with breastfeeding difficulties in the first 4 weeks, maternal smoking, introduction of a pacifier, and early return to work. Relatively few women achieved the international recommendations for duration of full and overall breastfeeding. Women should receive anticipatory guidance while still in the hospital on how to prevent or manage common breastfeeding difficulties and should be discouraged from introducing a pacifier before 10 weeks, if at all. Improved maternity leave provisions and more flexible working conditions may help women to remain at home with their infants longer and/or to combine successfully breastfeeding with employment outside the home.


Protocol: systematic review of the association between socio-economic status and survival in adult head and neck cancer.
Head and neck cancer incidence is increasing worldwide. Despite overall improvements in survival, numerous studies suggest worse survival in more disadvantaged populations; however, this literature has not been systematically reviewed. The aim of this review is to investigate whether lower compared to higher socioeconomic status (SES) influences survival in head and neck squamous cell cancer (HNSCC) and explore possible explanations for any relationship found. A systematic strategy will be used to identify articles, appraise their quality and extract data. Online databases including MEDLINE, Web of Knowledge, ESBCO Host and Scopus will be used to locate observational studies of adults with a primary diagnosis of head and neck cancer in EU15+ countries (15 members of the EU, Australia, Canada, Norway, USA and New Zealand) where the outcomes report associations between SES and survival. This will be augmented by searching for grey literature and through reference lists. Data will be extracted using a standardised form. Study quality will be assessed using the Newcastle Ottawa scale and where possible meta-analysis of the pooled data will be conducted. This review will quantify the association between SES and survival outcomes for adult head and neck cancer patients in developed countries. The results will help identify gaps in the literature and therefore direct further novel research in the field. Ultimately, this will inform public policy and strategies to reduce the inequalities in HNSCC survival. PROSPERO CRD42016037019 .


[Patient's relationship with the medical prescription - an observational study in urban populations in the ambulatory setting of General Practice/Family Medicine in the centre of Portugal].
The vast majority of General Practice/Family Medicine appointments end with a pharmacological prescription. It is therefore important to study the expectations facing the reasons to treat and the value attributed to the prescribed medicines, by patients. To know the expectations of patients facing the decision to treat and the therapeutic value attributed to prescribed medicines, by gender, academic grading, profession and age groups. In an observational study using a validated questionnaire, a non probabilistic convenience population representing, by gender and age groups, the universe of the urban attendants of a Primary Care facility in central Portugal, was studied. The questionnaire was applied, after informed consent, in an interview with a psychologist, for anonymous self-fulfillment. Descriptive and inferential statistics were performed. A population of 180 individuals was studied, mean age 47,3 ± 17,0 years (ns by gender) median 45 years, mode 29, being 85 males (47,2%). No differences were found by gender, profession and age groups. There is a clear preference for the treatment of the diseases the doctor has diagnosed. A frequency of 2,8% would prefer to define the medical prescription. Patients think that prescribed medicines aim to increase health (79,5%) and to treat the diagnosed diseases (67,6%). Older and non actives agree that prescribed medicines are targeted to the problems they presented, while younger ones medicines are targeted for their diseases. For the active ones prescribed medicines are to improve health. Patient's expectations about the decision of treating are technically oriented and medicines are thought of as a tool for healing and also as a mean to increase health. These two perspectives urge general practitioners/family doctors to make good patients medicines information and to define therapeutical objectives with patients. The knowledge of the patients' expectation on pharmacological therapy can help increase its results, once patients wish to be treated of the diseases doctors diagnose and think that medicines cure diseases and increase health.


Molecular identification and cellular localisation of GSH synthesis, uptake, efflux and degradation pathways in the rat ciliary body.
The aim of this study is to determine the contribution of the ciliary epithelium to glutathione (GSH) levels in the aqueous by mapping GSH metabolism and transport pathways in the rat ciliary body. Using a combination of molecular and immunohistochemical techniques, we screened and localised enzymes and transporters involved in GSH synthesis, uptake, efflux and degradation. Our findings indicate that both the pigmented epithelial (PE) and the non-pigmented epithelial (NPE) cell layers are capable of accumulating precursor amino acids for GSH synthesis, but only the NPE cells appear to be involved in the direct uptake of precursor amino acids from the stroma. The localisation of GSH efflux transporters to the PE cell and PE-NPE interface indicates that GSH and potentially GSH-S conjugates can be removed from the ciliary epithelium into the stroma, while the location of GSH efflux transporters to the basolateral membrane of the NPE indicates that these cells can mediate GSH secretion into the aqueous. GSH secreted by the ciliary into the aqueous would remain largely intact due to the absence of the GSH degradation enzymes γ-glutamyltranspeptidase (γ-GGT) labelling at the basolateral membrane of the NPE. Therefore, it appears that the ciliary epithelium contains the molecular machinery to mediate GSH secretion into the aqueous.


Elevated serum creatine kinase after neurosurgeries in lateral position with intraoperative neurophysiological monitoring is associated with OP duration, BMI and age.
Elevated serum levels of creatine kinase (CK) reflect skeletal muscle injury, which may lead to renal dysfunction following surgery. High CK levels are known to occur after neurosurgical interventions, especially following lateral positioning, but a consensus on possible risk factors is still lacking. Here we investigate risk factors for postoperative CK excess in a patient population at high risk (lateral position) with a special focus on the influence of intraoperative neurophysiological monitoring (IONM), particularly Motor Evoked Potentials (MEPs). We analyzed patient charts from elective surgeries in lateral position between 2010 and 2012 and where IONM was performed and where postoperative CK-levels were available. In these patients, the anesthesia regimen excluded muscle relaxants. Patient charts were reviewed retrospectively for patient characteristics, CK levels and indicators of renal dysfunction. The MEP response intensity was measured. These patients were compared to a matched (age, BMI, surgery duration) control group of patients operated with IONM, but operated in prone or supine position. We included 96 patients (55 female, mean age 50years). The maximal CK level (CKmax) occurred on postoperative days 2 or 3 (mean 1763U/L). In a multivariate linear regression model, log(CKmax) correlated positively with duration of surgery (p<0.001) and BMI (p=0.007), and negatively with age (p=0.007), but not with MEP response intensity (p=0.481). We did not observe impaired renal function. CK excess following neurosurgical procedures in lateral position correlated positively with duration of surgery and BMI and negatively with age. MEP stimulations of the muscles at risk did not cause further CK elevation. In patients undergoing long neurosurgeries without muscle relaxants, we recommend special care regarding positioning and perioperative management.


Speckle coherence of piecewise-stationary stochastic targets.
The van Cittert-Zernike (VCZ) theorem describes the propagation of spatial covariance from an incoherent source distribution, such as backscatter from stochastic targets in pulse-echo imaging. These stochastic targets are typically assumed statistically stationary and spatially incoherent with uniform scattering strength. In this work, the VCZ theorem is applied to a piecewise-stationary scattering model. Under this framework, the spatial covariance of the received echo data is demonstrated as the linear superposition of covariances from distinct spatial regions. This theory is analytically derived from fundamental physical principles, and validated through simulation studies demonstrating superposition and scaling. Simulations show that linearity is preserved over various depths and transmit apodizations, and in the presence of noise. These results provide a general framework to decompose spatial covariance into contributions from distinct regions of interest, which may be applied to advanced imaging methods. While the simulation tools used for validation are specific to ultrasound, this analysis is generally applicable to other coherent imaging applications involving stochastic targets. This covariance decomposition provides the physical basis for a recently described imaging method, Multi-covariate Imaging of Sub-resolution Targets.


Otic topical agents.
Ototopical preparations are available for the treatment of obstruction, dermatitis, pain, and infection of the ear canal and the mastoid and tympanic structures. Most preparations contain alcohol and some type of mild acid, both of which provide nonspecific antiseptic activity against fungi and bacteria. For bacterial infections the combination of neomycin and polymyxin offers the best therapeutic spectrum against common pathogens. Ototoxicity from topical use in man is a theoretic possibility but not a practical problem. Chloramphenicol (otic) is an alternative in infections caused by bacteroides, but not by the more common P aeruginosa. When otic preparations are too painful for application through a tympanic perforation, an ophthalmic preparation may be more acceptable.


Insulin regulation of Na/K pump activity in rat hepatoma cells.
Insulin rapidly increases Na/K pump activity in HTC rat hepatoma cells in tissue culture, as measured by the ouabain-sensitive influx of the potassium analogue 86Rb+. Increased influx is observed within minutes and is maximal (70% above control) within 1-2 h. The effect appears to be mediated by the insulin receptors, as: the concentration dependence on insulin is identical to that for insulin induction of tyrosine aminotransferase and stimulation of 2-aminoisobutyric acid transport, proinsulin is 6% as potent as insulin, and the effect is blocked by anti-receptor antibodies. The early stimulation of potassium influx is not blocked by cycloheximide and is not associated with an increased number of pump sites as measured by 3H-ouabain binding. The insulin effect is blocked by amiloride, which blocks sodium influx, and is mimicked by the sodium ionophore monensin, which increases sodium influx and intracellular accumulation. Insulin also rapidly increases the initial rate of 22Na+ influx, suggesting that insulin may enhance Na/K pump activity, in part, by increasing intracellular sodium concentration. Incubation of HTC cells with insulin for 24 h causes complete unresponsiveness to the insulin induction of transaminase and stimulation of amino acid transport, a phenomenon mediated by postbinding mechanisms. In contrast, similar incubation with insulin does not cause unresponsiveness to the insulin stimulation of Na/K pump activity. Therefore, the site of regulation of responsiveness to insulin must be distal to, or separate from, those events causing stimulation of ion fluxes.


Comparative surgical resection of the ligamentum teres hepatis in a cadaveric model and a patient with ovarian cancer
Resection of all tumor implants with the aim of maximal cytoreduction is the main predictor of overall survival in ovarian carcinoma. However, there are high risk sites of tumor recurrence, and the perihepatic region, especially the point where the ligamentum teres hepatis enters the liver parenchyma under the hepatic bridge (pont hepatique), is one of them. This video demonstrates the resection of the ligamentum teres hepatis both in a cadaveric model and in a patient with ovarian cancer.


An Improved High-Throughput Data Processing Based on Combinatorial Materials Chip Approach for Rapid Construction of Fe-Cr-Ni Composition-Phase Map.
The combinatorial materials chip approach is vastly superior to the conventional one that characterizes one sample at a time in the efficiency of composition-phase map construction. However, the resolution of its high-throughput characterization and the correct rate of automated composition-phase mapping are often affected by inherent experimental limitations and imperfect automated analyses, respectively. Therefore, effective data preprocessing and refined automated analysis methods are required to automatically process huge amounts of experiment data to score a higher correct rate. In this work, the pixel-by-pixel structural and compositional characterization of the Fe-Cr-Ni combinatorial materials chip annealed at 750 °C was performed by microbeam X-ray at a synchrotron light source and by electron probe microanalysis, respectively. The severe baseline drift and system noise in the X-ray diffraction patterns were successfully eliminated by the three-step automated preprocessing (baseline drift removal, noise elimination, and baseline correction) proposed, which was beneficial to the subsequent quantitative analysis of the patterns. Through the injection of human experience, hierarchy clustering analyses, based on three dissimilarity measures (the cosine, Pearson correlation coefficient, and Jenson-Shannon divergence), were further accelerated by the simplified vectorization of the preprocessed X-ray diffraction patterns. As a result, a correct rate of 91.15% was reached for the whole map built automatically in comparison with the one constructed manually, which confirmed that the present data processing could assist humans to improve and expedite the processing of X-ray diffraction patterns and was feasible for composition-phase mapping. The constructed maps were generally consistent with the corresponding isothermal section of the Fe-Cr-Ni ternary alloy system in the ASM Alloy Phase Diagram Database except the inexistence of the σ phase under insufficient annealing.


dnaB gene of Escherichia coli K-12 affects superinfection inhibition between F' plasmids.
F' Escherichia coli K-12 strains bearing the chromosomal mutation dnaB43 offer significantly less resistance to the conjugational introduction of a second F' plasmid than do nonmutant strains. Both the entry exclusion and incompatibility components of superinfection inhibition are altered. This action of dnaB43 occurs regardless of the presence of a recA-minus mutation in matings in liquid cultures and on membrane filters and is not limited to a particular set of F' plasmids. These effects are co-transducible by phage P1 with the temperature sensitivity conferred by dnaB43. The effects also occur with a strain carrying dnaB107. In the double F' strains that arise, the two plasmids exist as units autonomous of one another and the chromosome.


Effects of indomethacin in utero on the pulmonary vasculature of the newborn lambs.
Exposure of the fetus to indomethacin and the resultant closure of the ductus arteriosus in utero has been suggested to be one possible cause of persistent pulmonary hypertension of the newborn (PPHN). We examined whether or not closing the ductus arteriosus of fetal lambs by the administration of in-domethacin to the fetus and ewe could produce the functional and structural changes of PPHN. Three treated and four non-treated lambs were delivered by cesarean section. Postnatal hemodynamics were studied in two of the treated lambs. Pulmonary arterial pressure gradually decreased after delivery and did not reveal features compatible with PPHN, while the blood gases remained within the physiological range. However, acute hypoxemia produced a re-elevation in pulmonary arterial pressure. Morphometric analysis showed the medial thickening of normally fully-muscularized pulmonary arteries, but there was no abnormal extension of fully-muscularized arteries to the intraacinar level in the treated lambs. In conclusion, we could not reproduce functional and structural changes of PPHN in newborn lambs by the administration of indomethacin in utero. However, our experimental animal model with excessive muscularization of the pulmonary vasculature appears to be useful for studying vasoconstriction in response to hypoxemia.


Positive surgical margins in robot-assisted partial nephrectomy: a multi-institutional analysis of oncologic outcomes (leave no tumor behind).
Expanding indications for robot-assisted partial nephrectomy raise major oncologic concerns for positive surgical margins. Previous reports showed no correlation between positive surgical margins and oncologic outcomes. We report a multi-institutional experience with the oncologic outcomes of positive surgical margins on robot-assisted partial nephrectomy. Pathological and clinical followup data were reviewed from an institutional review board approved, prospectively maintained joint database from 5 institutions. Tumors with malignant pathology were isolated and statistically analyzed for demographics and oncologic followup. The log rank test was used to compare recurrence-free and metastasis-free survival between patients with positive and negative surgical margins. The proportional hazards method was used to assess the influence of multiple factors, including positive surgical margins, on recurrence and metastasis. A total of 943 robot-assisted partial nephrectomies for malignant tumors were successfully completed. Of the patients 21 (2.2%) had positive surgical margins on final pathological assessment, resulting in 2 groups, including the 21 with positive surgical margins and 922 with negative surgical margins. Positive surgical margin cases had higher recurrence and metastasis rates (p<0.001). As projected by the Kaplan-Meier method in the population as a whole at followup out to 63.6 months, 5-year recurrence-free and metastasis-free survival was 94.8% and 97.5%, respectively. There was a statistically significant difference in recurrence-free and metastasis-free survival between patients with positive and negative surgical margins (log rank test<0.001), which favored negative surgical margins. Positive surgical margins showed an 18.4-fold higher HR for recurrence when adjusted for multiple tumors, tumor size, tumor growth pattern and pathological stage. Positive surgical margins on final pathological evaluation increase the HR of recurrence and metastasis. In addition to pathological and molecular tumor characteristics, this should be considered to plan appropriate management.


Colour stability of denture teeth submitted to different cleaning protocols and accelerated artificial aging.
Acrylic resin is widely used for artificial teeth manufacturing due to several important characteristics; however, this material do not present acceptable colour stability over the course of time. This study evaluated the effect of different cleaning protocols and accelerated artificial aging on colour stability of denture teeth made of acrylic resin. Sixty denture teeth in dark and light shades were used, and separated according to the treatment to which they were submitted. Results demonstrated that colour stability of artificial teeth is influenced by the cleaning solution and artificial aging, being dark teeth more susceptible to colour alteration than lighter ones.


Membrane permeability: cation selectivity reversibly altered by salicylate.
The effect of salicylate on the relative cation permeability of a membrane was investigated in large, identified molluscan neurons, with the use of intracellular recording techniques. Salicylate caused a reversible, dose-dependent decrease in the permeability of rubidium, cesium, sodium, and lithium ions relative to that of potassium ions. The results suggest that the changes in cation selectivity result from the adsorption of salicylate anions to the membrane with a subsequent increase in the density and field strength of anionic sites in the membrane.


Application of N-doped graphene modified carbon ionic liquid electrode for direct electrochemistry of hemoglobin.
Nitrogen-doped graphene (NG) was synthesized and used for the investigation on direct electrochemistry of hemoglobin (Hb) with a carbon ionic liquid electrode as the substrate electrode. Due to specific characteristics of NG such as excellent electrocatalytic property and large surface area, direct electron transfer of Hb was realized with enhanced electrochemical responses appearing. Electrochemical behaviors of Hb on the NG modified electrode were carefully investigated with the electrochemical parameters calculated. The Hb modified electrode exhibited excellent electrocatalytic reduction activity toward different substrates, such as trichloroacetic acid and H2O2, with wider dynamic range and lower detection limit. These findings show that NG can be used for the preparation of chemically modified electrodes with improved performance and has potential applications in electrochemical sensing.


Unveiling Online Suicide Behavior: What Can We Learn About Mental Health from Suicide Survivors of Reddit?
Suicide is a growing public health concern in online communities. In this paper, we analyze online communications on the topic of suicide in the social networking platform, Reddit. We combine lexical text characteristics with semantic information to identify comments with features of suicide attempts and methods. Then, we develop a set of machine learning methods to automatically extract suicide methods and classify the user comments. Our classification methods performance varied between suicide experiences, with F1-scores up to 0.92 for "drugs" and greater than 0.82 for "hanging" and "other methods". Our exploratory analysis reveals that the most frequent reported suicide methods are drug overdose, hanging, and wrist-cutting.


Strategies for workplace learning used by entry-level physician assistants.
Physician assistants (PAs) play an increasingly important role in medicine. While PAs have strong basic science and clinical training in school, typically they don't participate in postgraduate training and are expected to expand their generalists' competencies through continuing professional education. The purpose of this study was to investigate the methods PAs use during their initial phase of workplace learning and determine which methods are deemed most effective by PAs. This large, cross-sectional study of PAs within the first 2 years of practice consisted of a survey of PAs investigating the methods used for assessment of educational needs, instruction, and assessment of learning. The results revealed that PAs generally found that employers are well aware of their learning needs and their supervising physicians play an essential role in their learning. PAs themselves often recognized their learning needs based on perceived gaps in competencies noted with patient encounters. Though many PAs reported having an orientation period, most PAs said that this orientation was not well adapted to their unique learning needs. A variety of methods were used during workplace learning, with those related to real patient problems deemed most helpful by PAs. Although PAs reported that their learning was assessed, review of patient outcome data was uncommon. Consistent with principles of adult learning theory, these findings suggest that PAs find active forms of learning most valuable. Employers and supervising physicians should consider these findings and the available literature on adult learning in developing an environment that is supportive of continuing professional development.


White and gray matter contributions to executive function recovery after traumatic brain injury.
We investigated the association between regional white and gray matter volume loss and performance on executive functions (EFs) in patients with penetrating traumatic brain injury (pTBI). We studied 164 pTBI patients and 43 healthy controls from the Vietnam Head Injury Study. We acquired CT scans for pTBI patients and divided them according to lesion localization (left and right prefrontal cortex [PFC]). We administered EF tests (Verbal Fluency, Trail Making, Twenty Questions) and used voxel-based lesion symptom mapping (VLSM) and group-based correlational and multiple regression analyses to examine the relative influence of gray and white matter lesions on EF recovery. The VLSM analysis revealed that white and gray white matter lesions were associated with impaired EFs. In the left PFC lesion group, damage to the PFC gray matter, anterior corona radiata, and superior longitudinal fasciculus (SLF) were most correlated with functional recovery. Verbal Fluency, which involves a broad fronto-temporo-parietal network, was best predicted by SLF lesion volume. Trail Making and Twenty Questions, which is associated with more focal left frontal damage, was better predicted by PFC lesions. Our results indicated that white matter volume loss can be a superior predictor of recovery and a crucial factor driving clinical outcome in functions involving a broad network such as Verbal Fluency. White matter damage may place additional burden on recovery by deteriorating signal transmission between cortical areas within a functional network.


A case of hypermucoviscous Klebsiella pneumoniae liver abscess syndrome in an Iraqi male.
A 53-year-old man presented with fevers, productive cough and decreased appetite. He emigrated from Iraq 4 years ago. Chest x-ray revealed a left lung consolidation. Respiratory cultures and two sets of blood cultures grew out pan-susceptible Klebsiella pneumoniae Liver ultrasound revealed a 6.4-cm complex lesion in the left hepatic lobe. A biopsy of the liver lesion produced bloody purulent aspirate; abscess cultures yielded a highly viscous pan-susceptible K. pneumoniae Klebsiella pneumoniae liver abscess syndrome is a newly described invasive syndrome due to a hypermucoviscous phenotype associated with serotypes K1 and K2 of Klebsiella. Although it is more commonly endemic to the Asian-Pacific region, it has been increasingly reported as an emerging global disease. We present the first case of this syndrome in a patient of middle-eastern descent. We also present pictorial evidence of the microbe's unique viscous, muculent texture grown on agar.


Multiple congenital ocular defects in the Akita dog.
Microphthalmia, congenital cataracts, posterior lenticonus, and retinal dysplasia were observed in members of 3 litters of Akita puppies thought to be related to a common male ancestor. The electroretinograms of 3 clinically affected puppies were normal. Histological examination of 6 microphthalmic animals revealed nuclear and cortical cataract with multiple retinal folds and rosettes predominantly overlying the tapetum lucidum. Posterior lenticonus was observed histologically in 3 of the 6 puppies.


Community-based surveillance and case management for suicide prevention: an American Indian tribally initiated system.
The National Strategy for Suicide Prevention highlights the importance of improving the timeliness, usefulness, and quality of national suicide surveillance systems, and expanding local capacity to collect relevant data. This article describes the background, methods, process data, and implications from the first-of-its-kind community-based surveillance system for suicidal and self-injurious behavior developed by the White Mountain Apache Tribe with assistance from Johns Hopkins University. The system enables local, detailed, and real-time data collection beyond clinical settings, with in-person follow-up to facilitate connections to care. Total reporting and the proportion of individuals seeking treatment have increased over time, suggesting that this innovative surveillance system is feasible, useful, and serves as a model for other communities and the field of suicide prevention.


Adherence barriers to chronic dialysis in the United States.
Hemodialysis patients often do not attend their scheduled treatment session. We investigated factors associated with missed appointments and whether such nonadherence poses significant harm to patients and increases overall health care utilization in an observational analysis of 44 million hemodialysis treatments for 182,536 patients with ESRD in the United States. We assessed the risk of hospitalization, emergency room visit, or intensive-coronary care unit (ICU-CCU) admission in the 2 days after a missed treatment relative to the risk for patients who received hemodialysis. Over the 5-year study period, the average missed treatment rate was 7.1 days per patient-year. In covariate adjusted logistic regression, the risk of hospitalization (odds ratio [OR], 3.98; 95% confidence interval [95% CI], 3.93 to 4.04), emergency room visit (OR, 2.00; 95% CI, 1.87 to 2.14), or ICU-CCU admission (OR, 3.89; 95% CI, 3.81 to 3.96) increased significantly after a missed treatment. Overall, 0.9 missed treatment days per year associated with suboptimal transportation to dialysis, inclement weather, holidays, psychiatric illness, pain, and gastrointestinal upset. These barriers also associated with excess hospitalization (5.6 more events per patient-year), emergency room visits (1.1 more visits), and ICU-CCU admissions (0.8 more admissions). In conclusion, poor adherence to hemodialysis treatments may be a substantial roadblock to achieving better patient outcomes. Addressing systemic and patient barriers that impede access to hemodialysis care may decrease missed appointments and reduce patient morbidity.


Targeted enzyme prodrug therapies.
The cure of cancer is still a formidable challenge in medical science. Long-known modalities including surgery, chemotherapy and radiotherapy are successful in a number of cases; however, invasive, metastasized and inaccessible tumors still pose an unresolved and ongoing problem. Targeted therapies designed to locate, detect and specifically kill tumor cells have been developed in the past three decades as an alternative to treat troublesome cancers. Most of these therapies are either based on antibody-dependent cellular cytotoxicity, targeted delivery of cytotoxic drugs or tumor site-specific activation of prodrugs. The latter is a two-step procedure. In the first step, a selected enzyme is accumulated in the tumor by guiding the enzyme or its gene to the neoplastic cells. In the second step, a harmless prodrug is applied and specifically converted by this enzyme into a cytotoxic drug only at the tumor site. A number of targeting systems, enzymes and prodrugs were investigated and improved since the concept was first envisioned in 1974. This review presents a concise overview on the history and latest developments in targeted therapies for cancer treatment. We cover the relevant technologies such as antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT) as well as related therapies such as clostridial- (CDEPT) and polymer-directed enzyme prodrug therapy (PDEPT) with emphasis on prodrug-converting enzymes, prodrugs and drugs.


Effects of Morphology vs. Cell-Cell Interactions on Endothelial Cell Stiffness.
Biological processes such as atherogenesis, wound healing, cancer cell metastasis, and immune cell transmigration rely on a delicate balance between Cell-Cell and cell-substrate adhesion. Cell mechanics have been shown to depend on substrate factors such as stiffness and ligand presentation, while the effects of Cell-Cell interactions on the mechanical properties of cells has received little attention. Here, we use atomic force microscopy to measure the Young's modulus of live human umbilical vein endothelial cells (HUVECs). In varying the degree of Cell-Cell contact in HUVECs (single cells, groups, and monolayers), we observe that increased cell stiffness correlates with an increase in cell area. Further, we observe that HUVECs stiffen as they spread onto a glass substrate. When we weaken Cell-Cell junctions (i.e., through a low dose of cytochalasin B or treatment with a VE-cadherin antibody), we observe that cell-substrate adhesion increases, as measured by focal adhesion size and density, and the stiffness of cells within the monolayer approaches that of single cells. Our results suggest that while morphology can roughly be used to predict cell stiffness, Cell-Cell interactions may play a significant role in determining the mechanical properties of individual cells in tissues by careful maintenance of cell tension homeostasis.


Circ_0001175 Promotes Hepatocellular Carcinoma Cell Proliferation and Metastasis by Regulating miR-130a-5p.
Many aberrantly expressed circular RNAs (circRNAs) play important roles in the development and progression of hepatocellular carcinoma (HCC). However, the exact function of circ_0001175 in HCC cells is unknown. Our study aimed to investigate the expression characteristics of circ_0001175 in HCC and its effects on the proliferation, migration and invasion of HCC cells, and to explore the potential mechanism. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were carried out to detect circ_0001175, microRNA-130a-5p (miR-130a-5p) and sorting nexin 5 (SNX5) expressions in HCC tissues and cells; cell counting kit-8 (CCK-8), BrdU and Transwell assays were conducted to detect the proliferation, migration and invasion of HCC cells. A lung metastasis model in nude mice was used to examine the effect of circ_0001175 on the metastasis of HCC cells in vivo. Bioinformatics prediction, luciferase reporter gene experiment, Ago2-RIP experiment and RNA pull-down assay were adopted to identify the binding relationships among circ_0001175, miR-130a-5p and SNX5. Circ_0001175 and SNX5 expressions were up-regulated in HCC tissues and cell lines, while miR-130a-5p expression was down-regulated. Abnormal expressions of circ_0001175, miR-130a-5p and SNX5 were associated with poor clinicopathological features of HCC patients; circ_0001175 facilitated HCC cell proliferation, migration and invasion in vitro and promoted lung metastasis in vivo; miR-130a-5p inhibited the above malignant biological behaviors of HCC cells, and it could reverse the function of circ_0001175. SNX5 was identified as a target gene of miR-130a-5p, and circ_0001175 could sponge miR-130a-5p and up-regulate the expression of SNX5 in HCC cells. Circ_0001175 is highly expressed in HCC and facilitates HCC progression through regulating miR-130a-5p/SNX5 axis.


Complications from percutaneous-left ventricular assist devices versus intra-aortic balloon pump in acute myocardial infarction-cardiogenic shock.
There are limited data on the complications with a percutaneous left ventricular assist device (pLVAD) vs. intra-aortic balloon pump (IABP) in acute myocardial infarction-cardiogenic shock (AMI-CS). To assess the trends, rates and predictors of complications. Using a 17-year AMI-CS population from the National Inpatient Sample, AMI-CS admissions receiving pLVAD and IABP support were evaluated for vascular, lower limb amputation, hematologic, neurologic and acute kidney injury (AKI) complications. In-hospital mortality, hospitalization costs and length of stay in pLVAD and IABP cohorts with complications was studied. Of 168,645 admissions, 7,855 (4.7%) receiving pLVAD support. The pLVAD cohort had higher comorbidity, cardiac arrest (36.1% vs. 29.7%) and non-cardiac organ failure (74.7% vs. 56.9%) rates. Complications were higher in pLVAD compared to IABP cohort-overall 69.0% vs. 54.7%; vascular 3.8% vs. 2.1%; lower limb amputation 0.3% vs. 0.3%; hematologic 36.0% vs. 27.7%; neurologic 4.9% vs. 3.5% and AKI 55.4% vs. 39.1% (all p<0.001 except for amputation). Non-White race, higher comorbidity, organ failure, and extracorporeal membrane oxygen use were predictors of complications for both cohorts. The pLVAD cohort with complications had higher in-hospital mortality (45.5% vs. 33.1%; adjusted odds ratio 1.65 [95% confidence interval 1.55-1.75]), shorter duration of hospital stay, and higher hospitalization costs compared to the IABP cohort with complications (all p<0.001). These results were consistent in propensity-matched pairs. AMI-CS admissions receiving pLVAD had higher rates of complications compared to the IABP, with worse in-hospital outcomes in the cohort with complications.


Hypervolemia is associated with increased mortality among hemodialysis patients.
Among chronic hemodialysis patients, 217 hospitalizations per 1000 patient-years are attributed to congestive heart failure; some are attributable to unrecognized hypervolemia. Hypervolemia can be detected by relative plasma volume (RPV) monitoring. The purpose of this study was to examine among 308 patients on long-term hemodialysis the value of slope of RPV compared with either ultrafiltration (UF) volume or UF rate index in determining all-cause mortality. RPV slopes were calculated by least-squares regression. These slopes were related to all-cause mortality in unadjusted and adjusted Cox proportional hazards models. Over a median follow-up of 30 months (interquartile range: 14 to 54 months) 96 patients (31%) died, yielding a crude mortality rate of 113/1000 patient-years. We found the following: (1) RPV slope measurements were of prognostic significance (hazard ratio of flatter slopes [>1.39%/h]: 1.72; P=0.01); (2) the UF volume alone was not prognostically informative (hazard ratio of higher UF volume [>2.7 L of dialysis]: 0.78; P=0.23); (3) the UF rate index alone was also not prognostically informative (hazard ratio of higher UF rate index [>8.4 mL/kg per hour]: 0.89; P=0.6); and (4) the prognostic relationship of RPV slope to mortality was independent of conventional and unconventional cardiovascular risk factors including the UF volume, UF rate, or UF volume per kilogram of postweight. RPV monitoring yields information that is prognostically important and independent of several risk factors including UF volume, aggressiveness of UF, and interdialytic ambulatory blood pressure. Its use to assess excess volume-related morbidity among chronic hemodialysis patients should be tested in randomized, controlled trials.


[The influence of the attachment dimensions "anxiety" and "avoidance" on psychosomatic complaints].
In contemporary literature, insecure attachment styles have been identified as nonspecific vulnerability factors for psychosomatic disorders. Further, they are also associated with aggravation of the assessment of complaints (Maunder and Hunter 2001; Strauß and Schwark 2007). The present study investigates the extent to which attachment-related anxiety and avoidance are related with the intensity of psychosomatic complaints. Prior to an initial diagnostic interview, 166 patients from a psychosomatic outpatient department were tested with the questionnaires ECR-RD and SCL-90-R. A model of two latent attachment dimensions, fear (BANG) and avoidance (BVER) in close relationships, underlying the scales of the ECR-RD, was used (Ehrenthal et al. 2009). The GSI was chosen as a good validated, global value from SCL-90-R (Franke 2002) for measuring the psychosomatic pressure caused by complaints. As expected, our results demonstrate strong positive correlations between BANG and GSI, whereas BVER and GSI showed a moderate, positive connection. Thus, both attachment dimensions were able to predict a significant ratio of GSI in a multiple regression analysis. This study confirmed a systematic relationship between insecure attachment representations and psychosomatic complaints, although some limitations must be noted due to the heterogeneous answer patterns of the BVER-scale. However, in our view, the ECR-RD measure should be used in other clinical studies, the goal being to become a diagnostic standard screening tool for assessing the influence of patients' attachment style on their presentation of psychosomatic complaints.


Molecular detection and phylogenetic analysis of tick-borne encephalitis virus in rodents captured in the transdanubian region of Hungary.
Abstract Tick-borne encephalitis virus (TBEV) infection is a common zoonotic disease affecting humans in Europe and Asia. To determine whether TBEV is present in small mammalian hosts in Hungary, liver samples of wild rodents were tested for TBEV RNA. Over a period of 7 years, a total of 405 rodents were collected at five different geographic locations of the Transdanubian region. TBEV nucleic acid was identified in four rodent species: Apodemus agrarius, A. flavicollis, Microtus arvalis, and Myodes glareolus. Out of the 405 collected rodents, 17 small mammals (4.2%) were positive for TBEV. The present study provides molecular evidence and sequence data of TBEV from rodents in Hungary.


Congenital multiple plaque-like glomangiomyoma.
Congenital glomus tumor is a rare clinical variant of glomus tumor, and glomangiomyoma is the least frequent histologic type of glomus tumor. We report a case of congenital multiple plaque-like glomangiomyoma in a 38-year-old man with multiple nodules and plaques on his left arm and forearm. Histopathologic study showed an angiomatous, nonencapsulated tumor with numerous highly folded dilated vascular lumina scattered throughout the dermis. The lumina were lined by a single layer of flat endothelial cells, and one to several rows of glomus cells were observed adjacent to the endothelial cells. Around large vessels, there was a gradual transition from glomus cells to elongated mature smooth muscle cells with thin and long "blunt-ended" nuclei. Immunohistochemically, there were strong positive reactions for cytoplasmic alpha-smooth muscle actin in glomus cells and smooth muscle cells, vimentin in glomus cells and endothelial cells, and desmin in the smooth muscle cells only. To our knowledge, this is the first case report of congenital multiple plaque-like glomus tumor with the microscopic appearance of a glomangiomyoma.


Diminished PRRX1 Expression Is Associated With Increased Risk of Atrial Fibrillation and Shortening of the Cardiac Action Potential.
Atrial fibrillation (AF) affects over 33 million individuals worldwide. Genome-wide association studies have identified at least 30 AF loci, but the mechanisms through which individual variants lead to altered disease risk have remained unclear for the majority of these loci. At the 1q24 locus, we hypothesized that the transcription factor PRRX1 could be a strong candidate gene as it is expressed in the pulmonary veins, a source of AF in many individuals. We sought to identify the molecular mechanism, whereby variation at 1q24 may lead to AF susceptibility. We sequenced a ≈158 kb region encompassing PRRX1 in 962 individuals with and without AF. We identified a broad region of association with AF at the 1q24 locus. Using in silico prediction and functional validation, we identified an enhancer that interacts with the promoter of PRRX1 in cells of cardiac lineage. Within this enhancer, we identified a single-nucleotide polymorphism, rs577676, which alters enhancer activity in a mouse atrial cell line and in embryonic zebrafish and differentially regulates PRRX1 expression in human left atria. We found that suppression of PRRX1 in human embryonic stem cell-derived cardiomyocytes and embryonic zebrafish resulted in shortening of the atrial action potential duration, a hallmark of AF. We have identified a functional genetic variant that alters PRRX1 expression, ultimately resulting in electrophysiological alterations in atrial myocytes that may promote AF.


Blastogenic suppression and alloantibody activity of sera from renal allograft recipients.
To evaluate whether immunological enhancement plays a role in adaptation to renal allografts, we studied sera from transplant recipients to determine whether those which suppressed mixed leukocyte culture (MLC) responses in vitro contained alloantibodies reactive with donor cells. Sera from five of nine renal transplant recipients consistently and specifically suppressed autologous autologous MLC responses to donor cells without impairing the blastogenic responses to third-party leukocytes, soluble antigens, or nonspecific mitogenic agents. In three of the five cases the suppressive activity of the serum was striking; in two cases the effect was less marked but still readily demonstrable in studies designed to evaluate the dose of serum which provided optimal suppression of MLC responses. Serum from one of the recipients nonspecifically suppressed blastogenic activity both to donor cells and other stimuli. No alloantibody reactive with donor leukocytes was found in any of the sera which exhibited suppressive activity in MLC, whereas in one patient, serum which contained antibody reactive with donor cells did not suppress MLC response to that donor. These findings suggest that, if the serum factors which suppress MLC responses in vitro are enhancing antibodies, they are not detectable even with very sensitive techniques either because they are present in very low concentrations, belong to immunoglobulin classes other than IgA, IgG, or IgM, or are complexed with donor antigen in such a way that their ability to react with fresh donor cells in vitro is blocked.


[Role of computerized tomography in the diagnosis of cirrhotic pulmonary tuberculosis].
Computed tomography (CT) revealed cirrhotic tuberculosis in 52 patients. In most patients, cirrhosis resulted from infiltrative and fibrocavernous tuberculosis, less frequently from tuberculous bronchoadenitis, disseminated and focal tuberculosis, caseous pneumonia. Segmental cirrhosis was present in 15 patients, multisegmental and lobar cirrhosis in 19, and bilateral lung cirrhosis in 2. In 8 patients, pulmonary cirrhosis was accompanied by tuberculous empyema; in 8 more patients lobar cirrhosis was the metatuberculous syndrome of fibrocavernous tuberculosis. Evaluation of the diagnostic potentialities of CT in cirrhotic pulmonary tuberculosis revealed that the major CT semiotics of this clinical type was identical to the basic skialogic signs of routine X-ray study. However, unlike the latter that assesses mainly indirect X-ray signs of the cirrhotic transformation of lung tissue, such as reduced lung volumes, chest deformity, CT objectively detects morphological changes in cirrhosis, the presence and magnitude of specific and metatuberculous changes, interprets clinical and X-ray variants of this form of tuberculosis and its related pulmonary vascular alterations.


Cadaveric renal transplants in children under 6 years of age.
Thirty-nine cadaveric renal allografts were performed in 28 children under 6 years of age. Common primary renal diseases were glomerulonephritis, dysplasia/hypoplasia, and reflux/obstructive nephropathy. After a mean follow-up of 40 months of patients with surviving grafts, 19 patients had functioning grafts, 3 had returned to dialysis, and 6 had died. These children required an extraordinary amount of care postoperatively because of anorexia, diarrhea, and ileus. Their psychomotor and physical development was retarded prior to transplant; this reversed dramatically after transplant, but catch-up growth occurred in only 4 patients. Many patients were noticeably more active and distractible for 1 to 2 years post-transplant. Major causes of graft failure were primary nonfunction of 5 donor kidneys (4 from donors under 1 year old) and renal vessel thrombosis in 5 recipients (3 with native kidneys in place who received kidneys from donors over 10 years old). Other causes were recurrence of hemolytic uremic syndrome and Wilms tumor, rejection, and sepsis. Kidneys from donors under 1 year old proved unsatisfactory, and large donor kidneys in small children tended to thrombose, especially when native kidneys with high urine output were left in situ.


Diapause in tardigrades: a study of factors involved in encystment.
Stressful environmental conditions limit survival, growth and reproduction, or these conditions induce resting stages indicated as dormancy. Tardigrades represent one of the few animal phyla able to perform both forms of dormancy: quiescence and diapause. Different forms of cryptobiosis (quiescence) are widespread and well studied, while little attention has been devoted to the adaptive meaning of encystment (diapause). Our goal was to determine the environmental factors and token stimuli involved in the encystment process of tardigrades. The eutardigrade Amphibolus volubilis, a species able to produce two types of cyst (type 1 and type 2), was considered. Laboratory experiments and long-term studies on cyst dynamics of a natural population were conducted. Laboratory experiments demonstrated that active tardigrades collected in April produced mainly type 2 cysts, whereas animals collected in November produced mainly type 1 cysts, indicating that the different responses are functions of the physiological state at the time they were collected. The dynamics of the two types of cyst show opposite seasonal trends: type 2 cysts are present only during the warm season and type 1 cysts are present during the cold season. Temperature represents the environmental factor involved in induction, maintenance and termination of the cyst. We also obtained evidence that A. volubilis is able to perform both diapause and cryptobiosis, even overlapping the two phenomena. The induction phase of tardigrade encystment can be compared to the induction phase of insect diapause, also indicating an involvement of endogenous factors in tardigrade encystment. As in insect diapause, tardigrade encystment can be considered a diapausing state controlled by exogenous and endogenous stimuli.


Patterns of hemopoietic reconstitution in nonobese diabetic mice: dichotomy of allogeneic resistance versus competitive advantage of disease-resistant marrow.
Complete replacement of the immune system via allogeneic bone marrow transplantation is sufficient to prevent diabetes in the nonobese diabetic (NOD) mouse model. In the present study we examined whether mixed allogeneic reconstitution would be sufficient to interrupt the autoimmune process with respect to occurrence of overt diabetes, as well as preexisting autoimmune insulitis. NOD mice were lethally irradiated and reconstituted with a mixture of NOD and B10.BR marrow. A relative resistance to allogeneic bone marrow engraftment was noted in NOD recipients of the mixed bone marrow inoculum, compared with disease-resistant controls. Moreover, unlike disease-resistant controls, all animals that initially repopulated as mixed donor/host chimeras became predominantly allogeneic by 4 mo, suggesting a competitive advantage for long term engraftment for disease-resistant marrow. All but one mouse in the group that engrafted with allogeneic marrow remained free of diabetes for the entire follow-up period (n = 22). Moreover, in all animals examined, virtually all islets were free of insulitis. In contrast, 74% of NOD mice that received similar conditioning and failed to engraft with donor marrow developed acute diabetes and intra-islet insulitis was present in all animals examined. These data suggest that NOD mice exhibit a relative resistance to engraftment compared with disease-resistant recipients. Conversely, animals that initially repopulated as a mixture of syngeneic and donor marrow become converted to virtually all donor by 4 mo. These data provide additional support that a defective stem cell is responsible for autoimmune diabetes in this experimental model.


Evolving concepts in the diagnosis, pathogenesis, and treatment of chronic hepatic allograft rejection.
Chronic hepatic allograft rejection is characterized by the histological findings of ductopenia and a decreased number of hepatic arteries in portal tracts in the presence of foam cell (obliterative) arteriopathy. Recent studies have extended the histological spectrum of chronic rejection to include the presence of biliary epithelial atrophy or pyknosis involving the majority of small ducts present in the liver biopsy specimen. Overall, the incidence of chronic rejection in adults appears to be decreasing and is currently approximately 4%. However, the incidence of chronic rejection in pediatric liver transplant recipients has been more stable and ranges from 8% to 12% in most studies. Clinical risk factors associated with chronic rejection include: underlying liver disease, HLA donor-recipient matching, positive lymphocytotoxic cross-match, cytomegalovirus infection, recipient age, donor-recipient ethnic origin, male donor into female recipient, number of acute rejection episodes, histological severity of acute rejection episodes, low cyclosporine trough levels, and retransplantation for chronic rejection. Chronic rejection, once diagnosed, frequently leads to graft failure; however, a number of reports indicated 20% to 30% of the patients with this diagnosis may respond to additional immunosuppressive therapy or even resolve spontaneously receiving baseline immunosuppression. Newer immunosuppressive agents, such as tacrolimus and mycophenolate, may successfully reverse chronic rejection, particularly when it is diagnosed in its early histological stages.


Serological study of a population of alpine chamois (Rupicapra r rupicapra) affected by an outbreak of respiratory disease.
A serological survey of respiratory virus infections was carried out from 1998 to 2001 in Lecco province, Italy, as part of a health monitoring programme in a population of alpine chamois, many of which died of pneumonia in autumn and winter 2000 to 2001; 194 carcases of all age classes were found over a short period and in a small area. Eighteen of them, which were examined postmortem, consistently showed signs of severe fibrinous lobar pneumonia or catarrhal bronchopneumonia. Samples of serum from 145 chamois collected from hunted animals and carcases were tested by a virus neutralisation test against bovine respiratory syncytial virus (BRSV), bovine viral diarrhoea virus, bovine herpesvirus type 1 and parainfluenzavirus type 3. Positive results were detected only for BRSV. The area was divided into two subunits on the basis of the distribution of deaths; in the areas where fatalities were observed there was a significant increase of BRSV titres at the beginning of the outbreak. Furthermore, during the 2000 and 2001 hunting seasons antibody titres to BRSV were significantly higher in the areas where mortality occurred. The roe deer living in the same area were not affected by pneumonia and had a low prevalence of titres to BRSV which did not vary during the period of the study.


Are spondyloarthropathies as common as rheumatoid arthritis worldwide? A review.
The high-range estimate of 1.3% by the National Arthritis Data Workgroup for the prevalence of the entire spectrum of spondyloarthropathies (SpAs) suggests that SpAs may be more prevalent than rheumatoid arthritis (RA) in the United States. Recent surveys from many European countries using the same sample population have also found SpA to be at least as common as RA in most of the studied populations, including Finnish, Swedish, Lithuanian, French, Italian, and Turkish. Among Asian populations, China has the highest prevalence of SpA, with reported estimates generally higher than that of RA. In Thailand and Vietnam, the two diseases are probably equally common, whereas RA seems to be more prevalent than SpA in the rest of Asia, the Pacific Region, and Latin America, as indicated by studies following the COPCORD (Community-Oriented Program for the Control of Rheumatic Diseases) protocol. Both rheumatic disorders are rare in Africa, but SpA is less common than RA.


Head-to-head comparison between the EQ-5D-5L and the EQ-5D-3L in general population health surveys.
The EQ-5D has been frequently used in national health surveys. This study is a head-to-head comparison to assess how expanding the number of levels from three (EQ-5D-3L) to five in the new EQ-5D-5L version has improved its distribution, discriminatory power, and validity in the general population. A representative sample (N = 7554) from the Catalan Health Interview Survey 2011-2012, aged ≥18, answered both EQ-5D versions, and we evaluated the response redistribution and inconsistencies between them. To assess validity of this redistribution, we calculated the mean of the Visual Analogue Scale (VAS), which measures perceived health. The discriminatory power was examined with Shannon Indices, calculated for each dimension separately. Spanish preference value sets were applied to obtain utility indices, examining their distribution with statistics of central tendency and dispersion. We estimated the proportion of individuals reporting the best health state in EQ-5D-5L and EQ-5D-3L within groups of specific chronic conditions and their VAS mean. A very small reduction in the percentage of individuals with the best health state was observed, from 61.8% in EQ-5D-3L to 60.8% in EQ-5D-5L. In contrast, a large proportion of individuals reporting extreme problems in the 3 L version moved to severe problems (level 4) in the 5 L version, particularly for pain/discomfort (75.5%) and anxiety/depression (66.4%). The average proportion of inconsistencies was 0.9%. The pattern of the perceived health VAS mean confirmed the hypothesis established a priori, supporting the validity of the observed redistribution. Shannon index showed that absolute informativity was higher in the 5 L version for all dimensions. The means (SD) of the Spanish EQ-5D-3L and EQ-5D-5L indices were 0.87 (0.25) and 0.89 (0.22). The proportion of individuals with the best health state within each specific chronic condition was very similar, regardless of the EQ-5D version (≤ 30% in half of the 28 chronic conditions). Although the proportion of individuals with the best possible health state is still very high, our findings support that the increase of levels provided by the EQ-5D-5L contributed to the validity and discriminatory power of this new version to measure health in general population, as in the national health surveys.


Growth and auto-oxidation of Pd on single-layer AgOx/Ag(111).
We investigated the growth and auto-oxidation of Pd deposited onto a AgOx single-layer on Ag(111) using scanning tunneling microscopy (STM) and X-ray photoelectron spectroscopy (XPS). Palladium initially grows as well-dispersed, single-layer clusters that adopt the same triangular shape and orientation of Agn units in the underlying AgOx layer. Bi-layer clusters preferentially form upon increasing the Pd coverage to ∼0.30 ML (monolayer) and continue to develop until aggregating and forming a nearly conformal Pd bi-layer at a coverage near 2 ML. Analysis of the STM images provides quantitative evidence of a transition from single to bi-layer Pd growth on the AgOx layer, and a continuation of bi-layer growth with increasing Pd coverage from ∼0.3 to 2 ML. XPS further demonstrates that the AgOx layer efficiently transfers oxygen to Pd at 300 K, and that the fraction of Pd that oxidizes is approximately equal to the local oxygen coverage in the AgOx layer for Pd coverages up to at least ∼0.7 ML. Our results show that oxygen in the initial AgOx layer mediates the growth and structural properties of Pd on the AgOx/Ag(111) surface, enabling the preparation of model PdAg surfaces with uniformly distributed single or bi-layer Pd clusters. Facile auto-oxidation of Pd by AgOx further suggests that oxygen transfer from Ag to Pd could play a role in promoting oxidation chemistry of adsorbed molecules on PdAg surfaces.


Rising incidence of psychiatric disorders before diagnosis of immune-mediated inflammatory disease.
After the diagnosis of immune-mediated inflammatory diseases (IMID) such as inflammatory bowel disease (IBD), multiple sclerosis (MS) and rheumatoid arthritis (RA), the incidence of psychiatric comorbidity is increased relative to the general population. We aimed to determine whether the incidence of psychiatric disorders is increased in the 5 years before the diagnosis of IMID as compared with the general population. Using population-based administrative health data from the Canadian province of Manitoba, we identified all persons with incident IBD, MS and RA between 1989 and 2012, and cohorts from the general population matched 5 : 1 on year of birth, sex and region to each disease cohort. We identified members of these groups with at least 5 years of residency before and after the IMID diagnosis date. We applied validated algorithms for depression, anxiety disorders, bipolar disorder, schizophrenia, and any psychiatric disorder to determine the annual incidence of these conditions in the 5-year periods before and after the diagnosis year. We identified 12 141 incident cases of IMID (3766 IBD, 2190 MS, 6350 RA) and 65 424 matched individuals. As early as 5 years before diagnosis, the incidence of depression [incidence rate ratio (IRR) 1.54; 95% CI 1.30-1.84) and anxiety disorders (IRR 1.30; 95% CI 1.12-1.51) were elevated in the IMID cohort as compared with the matched cohort. Similar results were obtained for each of the IBD, MS and RA cohorts. The incidence of bipolar disorder was elevated beginning 3 years before IMID diagnosis (IRR 1.63; 95% CI 1.10-2.40). The incidence of psychiatric comorbidity is elevated in the IMID population as compared with a matched population as early as 5 years before diagnosis. Future studies should elucidate whether this reflects shared risk factors for psychiatric disorders and IMID, a shared final common inflammatory pathway or other aetiology.


Multiplex immunohistochemistry defines two cholesterol metabolism patterns predicting immunotherapeutic outcomes in gastric cancer.
The role of cholesterol metabolism in gastric cancer (GC) and its implications for tumor characteristics and immunotherapy response remain poorly understood. In this study, our aim was to investigate this role, identify associated metabolic subtypes, and assess their clinical implications in GC. We conducted a comprehensive analysis of cholesterol metabolism genes (CMGs) using transcriptomic data from TCGA and GEO. Based on 23 representative CMGs, we classified GC into metabolic subtypes. We evaluated clinical features and immune cell infiltration between these subtypes. Additionally, we identified a CMG signature and assessed its clinical relevance in GC. We retrospectively enrolled thirty-five GC patients receiving chemotherapy plus a PD-1 inhibitor to assess the CMG signature using multiplex immunohistochemistry. Our analysis revealed two cholesterol metabolism subtypes in GC: Cholesterol Metabolism Type 1 (CMT1) and Cholesterol Metabolism Type 2 (CMT2). These subtypes exhibited distinct patterns: CMT1 indicated heightened cholesterol biosynthesis, while CMT2 showed abnormal cholesterol transport. CMT2 was associated with unfavorable clinical features, enriched malignant pathways, and a pro-tumor immune microenvironment. Furthermore, we developed a five-CMG prognostic signature (ABCA1, NR1H3, TSPO, NCEH1, and HMGCR) that effectively predicted the prognosis of patients with GC and their response to chemotherapy plus a PD-1 inhibitor. This signature was validated in a clinical cohort using multiplex immunohistochemistry. Our results highlight the effectiveness of cholesterol metabolism patterns as biomarkers for predicting the prognosis and immunotherapy response in GC. The expression of cholesterol metabolism genes and the assessment of cholesterol metabolism patterns have the potential to predict the outcome of immunotherapy and guide treatment strategies.


New resting energy expenditure prediction equations for patients with rheumatoid arthritis.
Resting energy expenditure (REE), one of the main components of total energy expenditure, can be measured via indirect calorimetry and/or predicted from equations. The latter may be misleading in RA, as they do not take into account the metabolic alterations occurring in RA. The objectives of this study are to evaluate the accuracy of widely used REE-predictive equations in RA patients against measured REE and to develop RA-specific equations. We assessed REE (via indirect calorimetry and several predictive equations), fat-free mass (FFM; via bioelectrical impedance) and disease activity (CRP) in RA patients and healthy controls. Data from 60 RA patients (experimental group) were used to assess the accuracy of existing REE equations and to develop new equations. The new equations were validated in an independent cross-validation group of 22 RA patients. These two groups were merged and two final equations were developed. All equations significantly under-predicted measured REE (from 15% to 18.2%, all at P < 0.001) in the RA experimental group, but not in the control group. After both equations demonstrated a high validity in the cross-validation group, the new final REE prediction equations developed from the total RA sample (n = 82) were: Model 1: REE (kcal/day) = 126.1 x FFM(0.638) x CRP(0.045) (R(2) = 0.70) and Model 2: REE (kcal/day) = 598.8 x weight(0.47) x age(-0.29) x CRP(0.066) (R(2) = 0.62). The new equations provide an accurate prediction of REE in RA patients and could be used for clinical monitoring of resting metabolism of these patients without the requirement for specialized personnel.


The Impact of Auditory Spectral Resolution on Listening Effort Revealed by Pupil Dilation.
This study measured the impact of auditory spectral resolution on listening effort. Systematic degradation in spectral resolution was hypothesized to elicit corresponding systematic increases in pupil dilation, consistent with the notion of pupil dilation as a marker of cognitive load. Spectral resolution of sentences was varied with two different vocoders: (1) a noise-channel vocoder with a variable number of spectral channels; and (2) a vocoder designed to simulate front-end processing of a cochlear implant, including peak-picking channel selection with variable synthesis filter slopes to simulate spread of neural excitation. Pupil dilation was measured after subject-specific luminance adjustment and trial-specific baseline measures. Mixed-effects growth curve analysis was used to model pupillary responses over time. For both types of vocoder, pupil dilation grew with each successive degradation in spectral resolution. Within each condition, pupillary responses were not related to intelligibility scores, and the effect of spectral resolution on pupil dilation persisted even when only analyzing trials in which responses were 100% correct. Intelligibility scores alone were not sufficient to quantify the effort required to understand speech with poor resolution. Degraded spectral resolution results in increased effort required to understand speech, even when intelligibility is at 100%. Pupillary responses were a sensitive and highly granular measurement to reveal changes in listening effort. Pupillary responses might potentially reveal the benefits of aural prostheses that are not captured by speech intelligibility performance alone as well as the disadvantages that are overcome by increased listening effort.


Molecular Mechanisms Underlying Pathological and Therapeutic Roles of Pericytes in Atherosclerosis.
Pericytes are multipotent mesenchymal stromal cells playing an active role in angiogenesis, vessel stabilisation, maturation, remodelling, blood flow regulation and are able to trans-differentiate into other cells of the mesenchymal lineage. In this review, we summarised recent data demonstrating that pericytes play a key role in the pathogenesis and development of atherosclerosis (AS). Pericytes are involved in lipid accumulation, inflammation, growth, and vascularization of the atherosclerotic plaque. Decreased pericyte coverage, endothelial and pericyte dysfunction is associated with intraplaque angiogenesis and haemorrhage, calcification and cholesterol clefts deposition. At the same time, pericytes can be used as a novel therapeutic target to promote vessel maturity and stability, thus reducing plaque vulnerability. Finally, we discuss recent studies exploring effective AS treatments with pericyte-mediated anti-atherosclerotic, anti-inflammatory and anti-apoptotic effects.


Bronchopulmonary dysplasia: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases.
Bronchopulmonary dysplasia (BPD) is the most common complication of extreme preterm birth. Infants who develop BPD manifest aberrant or arrested pulmonary development and can experience lifelong alterations in cardiopulmonary function. Despite decades of promising research, primary prevention of BPD has proven elusive. This workshop report identifies current barriers to the conduct of primary prevention studies for BPD and causal pathways implicated in BPD pathogenesis. Throughout, we highlight promising areas for research to improve understanding of normal and aberrant lung development, distinguish BPD endotypes, and ascertain biomarkers for more targeted therapeutic approaches to prevention. We conclude with research recommendations and priorities to accelerate discovery and promote lung health in infants born preterm.


Comments on ``digital step edges from zero crossings of second directional derivatives''.
In a recent paper,1 Haralick published an edge detection scheme that was supported, in part, by an evaluation against the Prewitt and the Marr-Hildreth (¿2G) operators. This evaluation led to the conclusion that Haralick's method performed the best, and the ¿2G operator performed the worst. The implementation of the ¿2G operator, on which this evaluation was based, differed significantly from that used by Marr and Hildreth. Evaluation of the performance of the Marr-Hildreth implementation of the ¿2G operator on similar images shows that this edge detection method in fact performs comparably to the Prewitt and Haralick operators.


Extracellular protease ADAMTS9 suppresses esophageal and nasopharyngeal carcinoma tumor formation by inhibiting angiogenesis.
ADAMTS metalloprotease family member ADAMTS9 maps to 3p14.2 and shows significant associations with the aerodigestive tract cancers esophageal squamous cell carcinoma (ESCC) and nasopharyngeal carcinoma (NPC). However, the functional impact of ADAMTS9 on cancer development has not been explored. In this study, we evaluated the hypothesized antiangiogenic and tumor-suppressive functions of ADAMTS9 in ESCC and NPC, in stringent tumorigenicity and Matrigel plug angiogenesis assays. ADAMTS9 activation suppressed tumor formation in nude mice. Conversely, knockdown of ADAMTS9 resulted in clones reverting to the tumorigenic phenotype of parental cells. In vivo angiogenesis assays revealed a reduction in microvessel numbers in gel plugs injected with tumor-suppressive cell transfectants. Similarly, conditioned medium from cell transfectants dramatically reduced the tube-forming capacity of human umbilical vein endothelial cells. These activities were associated with a reduction in expression levels of the proangiogenic factors MMP9 and VEGFA, which were consistently reduced in ADAMTS9 transfectants derived from both cancers. Taken together, our results indicate that ADAMTS9 contributes an important function in the tumor microenvironment that acts to inhibit angiogenesis and tumor growth in both ESCC and NPC.


Controlling uncoupled resonances in photonic crystals through breaking the mirror symmetry.
We show that modes in a photonic crystal slab that are uncoupled to outside radiation in a symmetric structure can be excited by breaking the mirror symmetry through introducing a protrusion on the side of the photonic crystal holes. We show that coupling to these resonances can be controlled by the strength of this asymmetry, and that it is also possible to choose among modes to couple to, through the shape of the asymmetry introduced. We provide simple theoretical arguments that explain the effect, and present eigenmode simulations and time-domain simulations. We confirm this predicted behavior with measurements on a photonic crystal with a broken mirror symmetry that exhibits an additional sharp resonant feature with a linewidth of 0.5 nm, in agreement with both calculated and simulated predictions.


Ubiquitinated proteins in exosomes secreted by myeloid-derived suppressor cells.
We provide evidence at the molecular level that ubiquitinated proteins are present in exosomes shed by myeloid-derived suppressor cells (MDSC). Ubiquitin was selected as a post-translational modification of interest because it is known to play a determinant role in the endosomal trafficking that culminates in exosome release. Enrichment was achieved by two immunoprecipitations, first at the protein level and subsequently at the peptide level. Fifty ubiquitinated proteins were identified by tandem mass spectrometry filtering at a 5% spectral false discovery rate and using the conservative requirement that glycinylglycine-modified lysine residues were observed in tryptic peptides. Thirty five of these proteins have not previously been reported to be ubiquitinated. The ubiquitinated cohort spans a range of protein sizes and favors basic pI values and hydrophobicity. Five proteins associated with endosomal trafficking were identified as ubiquitinated, along with pro-inflammatory high mobility group protein B1 and proinflammatory histones.


Retrieval-balloon-assisted enterography for ERCP after Billroth II gastroenterostomy and Braun anastomosis.
To describe an optimal route to the Braun anastomosis including the use of retrieval-balloon-assisted enterography. Patients who received a Billroth II gastroenterostomy (n = 109) and a Billroth II gastroenterostomy with Braun anastomosis (n = 20) between January 2009 and May 2013 were analyzed in this study. Endoscopic retrograde cholangiopancreatography (ERCP) was performed under fluoroscopic control using a total length of 120 cm oblique-viewing duodenoscope with a 3.7-mm diameter working channel. For this procedure, we used a triple-lumen retrieval balloon catheter in which a 0.035-inch guidewire could be inserted into the "open-channel" guidewire lumen while the balloon could be simultaneously injected and inflated through the other 2 lumens. For the patients with Billroth II gastroenterostomy and Braun anastomosis, successful access to the papilla was gained in 17 patients (85%) and there was therapeutic success in 16 patients (80%). One patient had afferent loop perforation, but postoperative bleeding did not occur. For Billroth II gastroenterostomy, there was failure in accessing the papilla in 15 patients (13.8%). ERCP was unsuccessful because of tumor infiltration (6 patients), a long afferent loop (9 patients), and cannulation failure (4 patients). The papilla was successfully accessed in 94 patients (86.2%), and there was therapeutic success in 90 patients (82.6%). Afferent loop perforation did not occur in any of these patients. One patient had hemorrhage 2 h after ERCP, which was successfully managed with conservative treatment. Retrieval-balloon-assisted enterography along an optimal route may improve the ERCP success rate after Billroth II gastroenterostomy and Braun anastomosis.


Psychological factors associated with the intention to choose for risk-reducing mastectomy in family cancer clinic attendees.
Women seeking counseling because of familial breast cancer occurrence face difficult decisions, such as whether and when to opt for risk-reducing mastectomy (RRM) in case of BRCA1/2 mutation. Only limited research has been done to identify the psychological factors associated with the decision for RRM. This study investigated which psychological factors are related to the intention to choose for RRM. A cohort of 486 cancer-unaffected women with a family history of breast cancer completed the following questionnaires prior to genetic counseling: the Cancer Worry Scale, Positive And Negative Affect Scale, Perceived Personal Control Scale, Hospital Anxiety and Depression Scale and State Anxiety Scale and questions regarding socio-demographic characteristics, family history, risk perception and RRM intention. Multivariate logistic regression was used to analyze the relation between psychological factors and women's intention to choose for RRM. Factors associated with RRM intention were high positive affect (OR = 1.86, 95%CI = 1.12-3.08), high negative affect (OR = 2.52, 95%CI = 1.44-4.43), high cancer worry (OR = 1.65, 95%CI = 1.00-2.72), high perceived personal control (OR = 3.58, 95%CI = 2.18-5.89), high risk-perception (OR = 1.85, 95%CI = 1.15-2.95) and having children (OR = 2.06, 95%CI = 1.21-3.50). Negative and positive affects play an important role in the intention for RRM. Furthermore, perceived personal control over the situation is associated with an intention for RRM. In addition to focusing on accurate risk communication, counseling should pay attention to the influence of perceived control and emotions to facilitate decision-making.


Simultaneous determination of seven major isosteroidal alkaloids in bulbs of Fritillaria by gas chromatography.
The present paper describes the development of a most simple, sensitive, and specific gas chromatographic method to date, for the direct determination of seven major bioactive isosteroidal alkaloids, namely ebeiedine, ebeiedinone, ebeienine, hupehenine, isoverticine, verticine, verticinone and imperialine, in Fritillaria species, a commonly used antitussive traditional Chinese medicinal (TCM) herb. In the present study, a commercially available Supelco SAC-5 capillary column (30 m x 0.25 mm, 0.25 microm) specifically designed for the analysis of steroids was utilized for the direct determination of Fritillaria alkaloids. Calibration curves were obtained by spiking authentic compounds and the internal standard (solanidine) into herbal samples prior to extraction. Extraction was conducted simply by shaking the pre-alkalized diethyl ether solution (5.0 ml) containing dried herb (0.1 g) for 2 h. All calibration curves showed good linear regressions (r2>0.995) within test ranges. The assay was reproducible and accurate with the overall intra- and inter-day variation and accuracy of less than 10% and more than 90%, respectively. The developed GC method was successfully utilized to analyze seven major bioactive alkaloids in seven Fritillaria species, and the results demonstrate that this direct GC analytical method is suitable for the quality control of this commonly used antitussive TCM herb.


Macrophage migration inhibitory factor (MIF) modulates trophic signaling through interaction with serine protease HTRA1.
Macrophage migration inhibitory factor (MIF), a small conserved protein, is abundant in the immune- and central nervous system (CNS). MIF has several receptors and binding partners that can modulate its action on a cellular level. It is upregulated in neurodegenerative diseases and cancer although its function is far from clear. Here, we report the finding of a new binding partner to MIF, the serine protease HTRA1. This enzyme cleaves several growth factors, extracellular matrix molecules and is implicated in some of the same diseases as MIF. We show that the function of the binding between MIF and HTRA1 is to inhibit the proteolytic activity of HTRA1, modulating the availability of molecules that can change cell growth and differentiation. MIF is therefore the first endogenous inhibitor ever found for HTRA1. It was found that both molecules were present in astrocytes and that the functional binding has the ability to modulate astrocytic activities important in development and disease of the CNS.


Earthquake size-frequency statistics in a forest-fire model of individual faults.
The earthquake size-frequency distribution of individual seismic faults commonly differs from the Gutenberg-Richter law of regional seismicity by the presence of an excess of large earthquakes. Here we present a cellular automaton of the forest-fire model type that is able to reproduce several size-frequency distributions depending on the number and location of asperities on the fault plane. The model describes a fault plane as a two-dimensional array of cells where each cell can be either a normal site or a trigger site. Earthquakes start on trigger sites. Asperities appear as the dual entities of the trigger sites. We study the effect that the number and distribution of asperities (the dual of the set of trigger sites), the earthquake rate, and the aspect ratio of the fault have on the size-frequency distribution. Size-frequency distributions have been grouped into subcritical, critical, and supercritical, and the relationship between the model parameters and these three kinds of distributions is presented in the form of phase maps for each of the five asperity types tested. We also study the connection between the model parameters and the aperiodicity of the large earthquakes. For this purpose the concept of aperiodicity spectrum is introduced. The aperiodicity in the recurrence of the large earthquakes in a fault shows an interesting variability that can be potentially useful for prediction purposes.


Nutritional support during oncologic treatment of patients with gastrointestinal cancer: who could benefit?
In patients with gastrointestinal (GI) cancer, severe malnutrition is associated with increased morbidity and mortality, reduction of treatment efficacy, and increased length of hospital stay. Therefore, systematic screening and care of malnutrition is mandatory. Data for this review were identified by searches of Medline with and without MeSH database and Cancerlit. Studies were selected only if they were randomised clinical trials or historical reports. References were also identified from reference lists in relevant previously published articles. Recent guidelines and meta-analyses were included. Only articles published in English were taken into consideration. For surgical patients, practical information such as weight loss or subjective global assessment would provide a better basis for deciding whether or not to delay surgery. At least 10 days of nutritional support is recommended in severely malnourished patients before major digestive surgery. In non-severely malnourished patients, preoperative oral immunonutrition is associated with a 50% decrease in postoperative complications. The benefit of immune-enhancing diets in severely malnourished patients remains to be proven. For patients undergoing radiochemotherapy, dietary counselling should be proposed to all patients. In cases of severely malnourished patients or if dietary counselling suffers a setback, enteral nutrition should be recommended. Parenteral nutrition should be reserved for patients with severe digestive intolerance when enteral nutrition is not possible. Propose an adaptive nutritional support at each step of a multimodal GI oncological treatment is essential. These recommendations should be used in daily practice but should also be included in all clinical research protocols.


Standardized protocols for photocarcinogenesis safety testing.
Solar ultraviolet radiation (UVR) is recognized as a major cause of non-melanoma skin cancer in man. Skin cancer occurs most frequently in the most heavily exposed areas and correlates with degree of outdoor exposure. The incidence of skin cancer is also increased by contact with photosensitizing drugs and chemicals such as psoralens, coal tars and petroleum stocks. Other substances which do not act as photosensitizers, such as immunosuppressants taken by organ transplant recipients, also increase the risk of skin cancer. The U.S. Food and Drug Administration requests, on a case-by-case basis, that risk of enhanced photocarcinogenesis is assessed for many classes of drugs. Health Canada's Therapeutic Products Programme has issued a Notice of Intent to regulate pharmaceutical products which may enhance carcinogenicity of the skin induced by ultraviolet radiation. Other national regulatory agencies review such data when they exist, but their own requirements emphasize batteries of short-term in vitro and in vivo tests. While they may support drug development strategies, short-term tests have yet to be validated as predictors of the ability of drugs or chemicals to enhance photocarcinogenesis. Published protocols now describe study designs and procedures capable of determining whether test agents enhance the rate of formation of UVR-induced skin tumors.


Probing the stability of the SpCas9-DNA complex after cleavage.
CRISPR-Cas9 is a ribonucleoprotein complex that sequence-specifically binds and cleaves double-stranded DNA. Wildtype Cas9 and its nickase and cleavage-incompetent mutants have been used in various biological techniques due to their versatility and programmable specificity. Cas9 has been shown to bind very stably to DNA even after cleavage of the individual DNA strands, inhibiting further turnovers and considerably slowing down in-vivo repair processes. This poses an obstacle in genome editing applications. Here, we employed single-molecule magnetic tweezers to investigate the binding stability of different Streptococcus pyogenes Cas9 variants after cleavage by challenging them with supercoiling. We find that different release mechanisms occur depending on which DNA strand is cleaved. After initial target strand cleavage, supercoils are only removed after the collapse of the R-loop. We identified several states with different stabilities of the R-loop. Most importantly, we find that the post-cleavage state of Cas9 exhibits a higher stability than the pre-cleavage state. After non-target strand cleavage, supercoils are immediately but slowly released by swiveling of the non-target strand around Cas9 bound to the target strand. Consequently, Cas9 and its non-target strand nicking mutant stay stably bound to the DNA for many hours even at elevated torsional stress.


Memristors Based on 2D Materials as an Artificial Synapse for Neuromorphic Electronics.
The memristor, a composite word of memory and resistor, has become one of the most important electronic components for brain-inspired neuromorphic computing in recent years. This device has the ability to control resistance with multiple states by memorizing the history of previous electrical inputs, enabling it to mimic a biological synapse in the neural network of the human brain. Among many candidates for memristive materials, including metal oxides, organic materials, and low-dimensional nanomaterials, 2D layered materials have been widely investigated owing to their outstanding physical properties and electrical tunability, low-power-switching capability, and hetero-integration compatibility. Hence, a large number of experimental demonstrations on 2D material-based memristors have been reported showing their unique memristive characteristics and novel synaptic functionalities, distinct from traditional bulk-material-based systems. Herein, an overview of the latest advances in the structures, mechanisms, and memristive characteristics of 2D material-based memristors is presented. Additionally, novel strategies to modulate and enhance the synaptic functionalities of 2D-memristor-based artificial synapses are summarized. Finally, as a foreseeing perspective, the potentials and challenges of these emerging materials for future neuromorphic electronics are also discussed.


Living with breast cancer: care givers' perceptions in a surgical ward.
Caring for women with breast cancer has potential for increasing care giver distress and anxiety. Knowledge of the threats implicit in the disease and treatment as well as overidentification with the patient form the basis for this outcome. In order to describe perceptions of breast cancer as an illness, semistructured interviews were carried out with 37 care givers at a surgical department. The interviews were tape-recorded and transcribed verbatim. An analysis was then carried out of the stories told by the care givers about breast cancer as an illness. The results indicated that breast cancer as an illness gave rise to predominantly negative and dark associations among the care givers. Their experiences of caring for women in critical stages of the illness over many years appear to have had a negative influence on them. Death itself, and even more so the process leading to the end, were very tangible in their stories. The article concludes that care givers on a surgical ward have a fragmented picture of the patients and need to be given opportunities to follow the total care process. Those care givers who were able to follow the women's stages of illness throughout more often had a positive picture.


Sex-dependent and race-dependent association of XPNPEP2 C-2399A polymorphism with angiotensin-converting enzyme inhibitor-associated angioedema.
Angioedema is a rare adverse effect of angiotensin-converting enzyme (ACE) inhibitors, which occurs more commonly in women and black Americans. Angioedema is thought to result from decreased degradation of vasoactive peptides. During ACE inhibition, bradykinin is primarily inactivated by aminopeptidase P (APP). Earlier studies have provided conflicting data with regard to serum APP activity in patients with a history of ACE inhibitor-associated angioedema. A single nucleotide polymorphism, -2399C>A (rs3788853, C-2399A), in XPNPEP2, the X-linked gene that encodes membranous APP, has been reported to associate with APP activity. To test the hypothesis that the relationship between XPNPEP2 C-2399A genotype and APP activity or ACE inhibitor-associated angioedema is sex-dependent and race-dependent. We compared C-2399A genotype frequencies in 169 cases with a history of ACE inhibitor-associated angioedema and 397 ACE inhibitor-exposed controls. Controls were prespecified to be 50% white, 50% black, and 50% women. Cases and controls were group matched for age and smoking. XPNPEP2 C-2399A genotype associated with serum APP activity in both men and women. Serum APP activity was lower in men than in women, independent of genotype. XPNPEP2 -2399 A/ genotype was associated with an increased risk of angioedema in men [odds ratio 2.17 (1.09-4.32), P=0.03] in multivariate analysis. The A/ genotype was associated with angioedema in black men (P=0.03) but not in white men. APP activity is lower in men and the XPNPEP2 C-2399A polymorphism associates with ACE inhibitor-associated angioedema in men but not women.


Cramér-Rao bound analysis of echo time selection for (1)H-MR spectroscopy.
The choice of echo time (TE) is a complicated and controversial issue in proton MR spectroscopy, and represents a balancing act between signal-to-noise ratio and signal complexity. The TE values used in previous literature were selected either heuristically or based on limited empirical studies. In this work, we reconsider this problem from an estimation theoretic perspective. Specifically, we analyze the Crame r-Rao lower bound on estimated spectral parameters as a function of TE, which serves as a metric to quantify the reliability of the estimation procedure. This analysis reveals that a good choice of TE often depends on the particular metabolite of interest, and is a function of both the coupling properties of the metabolites and the general complexity of the spectrum.


[Certain physical parameters of cerebroside and phospholipid-cerebroside membranes].
Study of some electric properties of bilayer membranes made of cerebrosides and phospholipid-cerebroside mixture has shown that the capacity of cerebroside film is lower than that of lecithin-cerebroside and phospholipid-cerebroside ones (0.22 +/- 0.01 mkf/cm2 and 0.28 +/- 0.01 mkf/cm2 respectively). The membranes had small cation selectivity. It is stated that conductivity of cations of mixed phospholipid-cerebroside membrane is two orders, and of cerebroside three orders higher than that of phospholipid bilayers. Conductivity of the films under study depends on the medium pH. By means of fluorescent probes cerebrosides were found capable of changing the conformation of phospholipid membranes.