Clinical characteristics and prognosis of optic neuritis in Taiwan - a hospital-based cohort study.
Optic neuritis (ON) is an inflammatory disease of optic nerve. The distinct etiologies of ON significantly influence its clinical manifestation, neuroimaging findings, and visual outcomes. However, the clinical characteristics might be influenced by the racial differences. The purpose of this study is to investigate the clinical characteristics of various types of ON at a Taiwanese tertiary center. This cohort study analyzed 163 patients who received treatment and continued following-up for ON between 2015 and 2022. We selected patients who had been tested for anti-aquaporin-4 antibody (AQP4-Ab) and anti-myelin oligodendrocyte glycoprotein antibody (MOG-Ab). The participants were classified into four groups on the basis of their etiologies, specifically (1) multiple sclerosis (MS)-related, (2) AQP4-Ab-positive, (3) MOG-Ab-positive, or (4) idiopathic ON. The researchers recorded the patients' clinical characteristics, treatment course, magnetic resonance imaging and optical coherence tomography (OCT) findings, and visual outcomes. MOG-Ab-positive group had higher percentages of disk swelling and pain with eye movement. Long optic nerve and perineural enhancement are the hallmarks of MOG-Ab-related ON. The ON relapse rate was higher in AQP4-Ab-positive group. Although members of AQP4-Ab-positive group received immediate steroid pulse therapy, these patients experienced the worst visual outcomes. Moreover, a thinner retinal nerve fiber layer (RNFL) was noted in AQP4-Ab-positive group. MS group had a higher incidence of extra-optic nerve lesions. Multivariate regression identified pretreatment visual acuity and RNFL thickness as the important factors affecting visual outcomes. This cohort study identified the clinical features of different types of ON. Patients with AQP4-Ab-positive ON had poorer visual outcomes, which may be attributed to multiple relapses and profound nerve damage, as revealed by OCT findings. Patients with MOG-Ab-positive ON displayed long optic nerve enhancement but had more favorable prognoses. Thus, antibody-based classification facilitates treatment and prognosis in ON.


Systems metabolic engineering of Corynebacterium glutamicum for the efficient production of β-alanine.
β-Alanine is an important β-amino acid with a growing demand in a wide range of applications in chemical and food industries. However, current industrial production of β-alanine relies on chemical synthesis, which usually involves harmful raw materials and harsh production conditions. Thus, there has been increasing demand for more sustainable, yet efficient production process of β-alanine. In this study, we constructed Corynebacterium glutamicum strains for the highly efficient production of β-alanine through systems metabolic engineering. First, aspartate 1-decarboxylases (ADCs) from seven different bacteria were screened, and the Bacillus subtilis ADC showing the most efficient β-alanine biosynthesis was used to construct a β-alanine-producing base strain. Next, genome-scale metabolic simulations were conducted to optimize multiple metabolic pathways in the base strain, including phosphotransferase system (PTS)-independent glucose uptake system and the biosynthesis of key precursors, including oxaloacetate and L-aspartate. TCA cycle was further engineered for the streamlined supply of key precursors. Finally, a putative β-alanine exporter was newly identified, and its overexpression further improved the β-alanine production. Fed-batch fermentation of the final engineered strain BAL10 (pBA2_tr18) produced 166.6 g/L of β-alanine with the yield and productivity of 0.28 g/g glucose and 1.74 g/L/h, respectively. To our knowledge, this production performance corresponds to the highest titer, yield and productivity reported to date for the microbial fermentation.


Maximizing Sensory Dynamic Range by Tuning the Cortical State to Criticality.
Modulation of interactions among neurons can manifest as dramatic changes in the state of population dynamics in cerebral cortex. How such transitions in cortical state impact the information processing performed by cortical circuits is not clear. Here we performed experiments and computational modeling to determine how somatosensory dynamic range depends on cortical state. We used microelectrode arrays to record ongoing and whisker stimulus-evoked population spiking activity in somatosensory cortex of urethane anesthetized rats. We observed a continuum of different cortical states; at one extreme population activity exhibited small scale variability and was weakly correlated, the other extreme had large scale fluctuations and strong correlations. In experiments, shifts along the continuum often occurred naturally, without direct manipulation. In addition, in both the experiment and the model we directly tuned the cortical state by manipulating inhibitory synaptic interactions. Our principal finding was that somatosensory dynamic range was maximized in a specific cortical state, called criticality, near the tipping point midway between the ends of the continuum. The optimal cortical state was uniquely characterized by scale-free ongoing population dynamics and moderate correlations, in line with theoretical predictions about criticality. However, to reproduce our experimental findings, we found that existing theory required modifications which account for activity-dependent depression. In conclusion, our experiments indicate that in vivo sensory dynamic range is maximized near criticality and our model revealed an unanticipated role for activity-dependent depression in this basic principle of cortical function.


Preparing for selection success: Socio-demographic differences in opportunities and obstacles.
There is a growing drive to improve the heterogeneity of medical school cohorts. However, those from lower socio-economic groups remain under-represented. Understanding the methods used by applicants to prepare for medical school selection, and the challenges they face with respect to opportunities and access, may provide important insights to this lack of diversity. This research considered the influence of socio-demographic background on preparation for medical school selection and on the successful offer of a place. All eligible applicants to a large UK medical school were invited to complete an anonymous online survey (international and mature applicants excluded), detailing demographic data and experiences of preparing for selection and challenges faced (n = 1885). Selection outcomes across all UK medical schools were examined for consenting students (n = 955). Univariate and multivariate analyses explored the associations of preparatory activities and demographic data with subsequent offer of a place at a UK medical school. The survey response rate was 66.4%. Clinical work experience (hospital or general practice), fee-based courses for admissions tests and school preparation courses for interview were activities significantly associated with the offer of a place (P < .05). Those attending independent (private) schools most frequently reported school support and fee-based courses to support preparation (P < .01). Applicants from state non-selective (SNS) schools and lower socio-economic groups more frequently reported challenges in accessing fee-based support, school interview courses and clinical work experience (P ≤ .02). Clinical work experience, commercial courses for admissions tests and school-based support for interview represent areas of preparation that are associated with success. However, they also represent areas that are more challenging to access for demographic groups traditionally under-represented in medicine. Addressing complex issues of fairness in highly selective higher education settings can appear an insurmountable task. These preparatory activities represent key areas for applicants, schools and institutions to explore and address.


Development of chemoreceptor responses in infants.
This paper is devoted to the field of chemoreception and its role in the control of breathing in infants. We use "chemoreception" to refer to the capacity to sense and process changes in P(O2) and P(CO2), and also to react to these changes by adjusting ventilation in order to maintain homeostasis. Functional chemoreceptors are not essential to commence or even to sustain breathing efforts immediately at or after birth; the intense brain activation, which occurs at birth, is sufficient. Over subsequent days to weeks, however, this "neurogenic" drive weakens and drive from the chemoreceptors becomes critical for generating and maintaining a normal breathing rhythm. Failure of the chemoreceptors to develop normally, consequently, becomes an important underlying cause of breathing dysfunction, particularly during sleep. The paper deals with the methods available to study chemoreception in newborn infants and provide an overview of the early postnatal changes and interactions, which influence breathing at rest and under stress. The latter may be described in terms of the threshold and strength as well as the delay/speed with which ventilation changes in response to chemical stimulation. We conclude with a survey of disorders associated with chemoreceptor deficits in infancy.


The DNA damage response and cancer therapy.
Genomic instability is one of the most pervasive characteristics of tumour cells and is probably the combined effect of DNA damage, tumour-specific DNA repair defects, and a failure to stop or stall the cell cycle before the damaged DNA is passed on to daughter cells. Although these processes drive genomic instability and ultimately the disease process, they also provide therapeutic opportunities. A better understanding of the cellular response to DNA damage will not only inform our knowledge of cancer development but also help to refine the classification as well as the treatment of the disease.


Strain-specific modifier genes governing craniofacial phenotypes.
The presence of strain-specific modifier genes is known to modulate the phenotype and pathophysiology of mice harboring genetically engineered mutations. Thus, identification of genetic modifier genes is requisite to understanding control of phenotypic expression. c-Ski is a transcriptional regulator. Ski(-/-) mice on a C57BL6J (B6) background exhibit facial clefting, while Ski(-/-) mice on a 129P3 (129) background present with exencephaly. In the present study, oligonucleotide-based gene expression profiling was used to identify potential strain-specific modifier gene candidates present in wild type mice of B6 and 129 genetic backgrounds. Changes in gene expression were verified by TaqMan quantitative real-time PCR. Steady-state levels of 89 genes demonstrated a significantly higher level of expression, and those of 68 genes demonstrated a significantly lower level of expression in the developing neural tubes from embryonic day (E) 8.5, B6 embryos when compared to expression levels in neural tubes derived from E 8.5, 129 embryos. Based on the results from the current comparative microarray study, and taking into consideration a number of relevant published reports, several potential strain-specific gene candidates, likely to modify the craniofacial phenotypes in various knockout mouse models have been identified.


The role of vagal integrity in gastrin releasing peptide stimulated gastroenteropancreatic hormone release and gastric acid secretion.
The role of the vagus nerve in the control of gastrin releasing peptide (GRP) stimulated gastroenteropancreatic hormone release and gastric acid secretion was investigated in four conscious gastric fistula dogs using a technique of bilateral cryogenic vagal blockade. A 90-min infusion of GRP at a dose of 400 pmol X kg-1. h-1 produced significant elevations in plasma levels of gastrin, motilin, GIP, enteroglucagon, insulin, pancreatic glucagon, pancreatic polypeptide and VIP. Vagal blockade reversibly inhibited the rise of plasma PP and significantly blunted the elevation of plasma VIP. However, the GRP stimulated response of the other hormones investigated was not modified by vagal blockade. Similarly, the substantial secretion of gastric acid observed with GRP was not influenced by vagal blockade. Thus GRP acts predominantly via mechanisms which are independent of vagal integrity, findings that are in support of a major role for the local neuromodulation of hormone release and gastric acid secretion.


The dual processes of health impairment and motivation in international student adjustment in China: insights from a demands-resources model.
China has become one of the leading study abroad destinations worldwide. Recent research also indicates that international students encounter diverse life challenges and mental health issues in China. Therefore, scholars have shown increasing interest in their adjustment in Chinese social and academic settings. Seeking theoretical guidance from the Job Demands-Resources Model with mediation and moderation assumptions, our study aimed to test the dual processes (i.e., the health impairment process and the motivational process) leading to academic, sociocultural, and psychological adjustment, among international students sojourning in China. Using a convenience sampling method, our study recruited 1,001 participants (535 males and 466 females; M age = 22.73; SD = 1.62) who completed an online survey including scales of perceived cultural distance (contextual demands), social support from local members (contextual resources), coping self-efficacy (personal resources), acculturative stress, intercultural engagement, as well as three types of cross-cultural adjustment (academic, sociocultural, and psychological adjustment). Results based on the structural equation modeling (SEM) analyses indicated that perceived cultural distance had indirect relationships with the three types of adjustment through the mediator of acculturative stress. Social support from locals had indirect relationships with the three types of adjustment through the mediators of acculturative stress and intercultural engagement. Coping self-efficacy had indirect relationships with academic and sociocultural adjustment through the mediator of intercultural engagement. Additionally, social support from locals was revealed as a moderator that buffered the relationship between perceived cultural distance and acculturative stress. These mediated and moderated relationships not only confirmed the dual processes underlying international student adjustment, but also added new knowledge of how demands and resources can interplay to predict the dual processes.


The successful use of familial searching in six Hungarian high profile cases by applying a new module in Familias 3.
Commonly DNA profiles obtained from biological samples found at crime scenes or of unknown bodies are searched against a large national or local database of reference and crime scene DNA profiles. The aim is to find a direct match, i.e. an identical profile or in the case of a mixture, at least an overlap of all alleles. Familial searching is, instead, the concept of searching for relatives of a stain donor in the database, i.e. a quest for relatives of the possible perpetrator or an unidentified body. The current paper provides the tool to perform effective searches for relatives of a target DNA profile in a large database. In addition, the algorithm accounts for mixtures which is common in crime stains. Specifically we focus on six high profile Hungarian cases where familial searching has succeeded in providing investigative leads. An implementation of the methods is included in the latest version of the software Familias, freely available at www.familias.no.


Tissue cell differentiation and multicellular evolution via cytoskeletal stiffening in mechanically stressed microenvironments.
Evolution of eukaryotes from simple cells to complex multicellular organisms remains a mystery. Our postulate is that cytoskeletal stiffening is a necessary condition for evolution of complex multicellular organisms from early simple eukaryotes. Recent findings show that embryonic stem cells are as soft as primitive eukaryotes-amoebae and that differentiated tissue cells can be two orders of magnitude stiffer than embryonic stem cells. Soft embryonic stem cells become stiff as they differentiate into tissue cells of the complex multicellular organisms to match their microenvironment stiffness. We perhaps see in differentiation of embryonic stem cells (derived from inner cell mass cells) the echo of those early evolutionary events. Early soft unicellular organisms might have evolved to stiffen their cytoskeleton to protect their structural integrity from external mechanical stresses while being able to maintain form, to change shape, and to move.


"An Environment Built to Include Rather than Exclude Me": Creating Inclusive Environments for Human Well-Being.
Contemporary discourses which challenge the notion of health as the "absence of disease" are prompting changes in health policy and practice. People with disability have been influential in progressing our understanding of the impact of contextual factors in individual and population health, highlighting the impact of environmental factors on functioning and inclusion. The World Health Organization's (WHO) more holistic definition of health as "wellbeing" is now applied in frameworks and legislation, and has long been understood in occupational therapy theory. In practice, however, occupational therapists and other professionals often address only local and individual environmental factors to promote wellbeing, within systems and societies that limit equity in population health and restrict inclusion in communities. This paper presents an in-depth analysis of the supports and accommodations identified by a cohort of individuals (n-100) living with disability. A range of environmental facilitators and barriers were identified in peoples' experience of "inclusive community environs" and found to influence inclusion and wellbeing. The roles and responsibilities of individuals, professionals, and society to enact change in environments are discussed in light of these findings. Recommendations include a focus on the subjective experience of environments, and application of theory from human rights and inclusive economics to address the multiple dimensions and levels of environments in working towards inclusion and wellbeing.


Corticosteroid reduction with tacrolimus (CORRETA) TRIAL: a prospective Brazilian multicenter, randomized trial of early corticosteroid reduction versus regular corticosteroid dosage maintenance on a tacrolimus (Prograf) and mycophenolate mofetil (Cellcept) immunosuppression regimen in kidney transplant recipients: interim analysis.
Corticosteroids are a cornerstone of immunosuppressive therapy in renal transplantation despite their side effects and morbidity. Newer immunosuppressive agents may be more effective to allow corticosteroid sparing. An interim analysis of 60 completed out of 100 planned primary kidney transplant recipients is presented. All patients on tacrolimus (Prograf) and MMF (Cellcept) were randomized into two groups following a 1:1 distribution for early steroid reduction at posttransplant day 7 (G1; n = 31) versus to long-term maintenance steroids (G2; n = 29). Primary efficacy endpoints were composite endpoint of death, graft loss, or severe acute rejection at 6 and 12 months follow-up. Safety evaluation included severity and frequency of diabetes mellitus, hypertension, hyperlipidemia, leukopenia, infection, malignancy, and severe adverse events. Mean age was 39.1 years, with 45.0% males and 66.7% Caucasians. African-Americans were 25.8% in G1 and 27.6% in G2. One death occurred in each group, as well as one case of severe (Banff III) rejection in G1 (P = 1.00). The incidence of rejection episodes between groups was not significant, namely, 41.9% in G1 and 20.7% in G2 (P = .077). There were no differences between groups concerning mean, systolic and diastolic blood pressure, HbA1c, or creatinine at 12 months. This interim analysis showed no evidence of an increased risk of poorer performance among the early steroid reduction or safety differences in kidney transplant recipients versus a regular dosage steroid group of patients. Further analysis of the complete study data is underway.


Phase Separation of P3HT/PMMA Blend Film for Forming Semiconducting and Dielectric Layers in Organic Thin-Film Transistors for High-Sensitivity NO2 Detection.
Formation of the semiconductor/dielectric double-layered films via vertical phase separations from polymer blends is an effective method to fabricate organic thin-film transistors (OTFTs). Here, we introduce a simple one-step processing method for the vertical phase separation of poly(3-hexylthiophene-2,5-diyl) (P3HT) and poly(methyl methacrylate) (PMMA) blends in OTFTs and their applications for high-performance nitrogen dioxide (NO2) sensors. Compared to the conventional two-step coated OTFT sensors, one-step processed devices exhibit a great enhancement of the responsivity from 116 to 1481% for 30 ppm NO2 concentration and a limit of detection of ∼0.7 ppb. Studies of the microstructures of the blend films and the electrical properties of the sensors reveal that the devices formed by the one-step vertical phase separation have better capability for the adsorption of NO2 molecules. Moreover, a careful adjustment of the blend ratio between P3HT and PMMA can further improve the performance of the NO2 sensors, ranging from sensitivity to selectivity and to the ability of recovery. This simple one-step processing method demonstrates a potential possibility for developing high-performance, low-cost, and large-area OTFT gas sensors.


Fast digital 4πβ-4πγ coincidence counting with offline analysis at IRA.
IRA recently launched a project to digitize all the data acquisition systems it uses for primary radionuclide standardizations. It is well-known that the digital approach presents numerous advantages over the traditional analog electronics such as information losslessness, scalability, online and/or offline data processing, and it is also a solution to the growing difficulties to repair or renew ageing modules. As a first step in this wider program, our institute set-up a 4πβ-4πγ digital coincidence counting system, with FPGA (Field Programmable Gate Array)-based commercial boards from National Instruments (NI), to perform data acquisition and offline data analysis. Choosing all components and software from the same supplier provides a full compact and consistent electronic system. To demonstrate and validate the capacity of this system to standardize the activity of radioisotopes, we compare its predictions for the activity concentration of 133Ba, 166mHo and 18F solutions with the results from a coincidence counting system with analog electronics, as well as with the results from other primary methods and a secondary measurement performed with an IG11 ionization chamber (CIR, chambre d'ionization de référence) with an equivalent activity traceable to the Système International de Référence.


Matrix metalloproteinase-12 is an essential mediator of acute and chronic arterial stiffening.
Arterial stiffening is a hallmark of aging and risk factor for cardiovascular disease, yet its regulation is poorly understood. Here we use mouse modeling to show that matrix metalloproteinase-12 (MMP12), a potent elastase, is essential for acute and chronic arterial stiffening. MMP12 was induced in arterial smooth muscle cells (SMCs) after acute vascular injury. As determined by genome-wide analysis, the magnitude of its gene induction exceeded that of all other MMPs as well as those of the fibrillar collagens and lysyl oxidases, other common regulators of tissue stiffness. A preferential induction of SMC MMP12, without comparable effect on collagen abundance or structure, was also seen during chronic arterial stiffening with age. In both settings, deletion of MMP12 reduced elastin degradation and blocked arterial stiffening as assessed by atomic force microscopy and immunostaining for stiffness-regulated molecular markers. Isolated MMP12-null SMCs sense extracellular stiffness normally, indicating that MMP12 causes arterial stiffening by remodeling the SMC microenvironment rather than affecting the mechanoresponsiveness of the cells themselves. In human aortic samples, MMP12 levels strongly correlate with markers of SMC stiffness. We conclude that MMP12 causes arterial stiffening in mice and suggest that it functions similarly in humans.


Role of emotions and stress in the genesis of sudden death.
Emotional arousal induces dramatic endocrine responses through either the sympathetic-adrenal medullary system or pituitary-adrenal cortical system. Many of the known actions of cortisol and catecholamines are atherogenic, cardiotoxic and arrhythmogenic. Emotional stress can produce sudden cardiac death in experimental animals, as can the administration of exogenous catecholamines. Previous studies have found that emotional stress is a common precursor to sudden cardiac death. Thus, acute neuroendocrine arousal, superimposed on a substrate of compromised myocardium and electrical instability, may constitute an important, final inciting event in sudden cardiac death.


Effect of dietary fiber of "Rihane" barley grains and azoxymethane on serum and liver lipid variables in Wistar rats.
The aim of the present study is to evaluate the effects of diet enriched with dietary fiber of barley variety "Rihane" and azoxymethane on serum and liver lipid variables in male rats. Forty male rats were divided into four groups and fed on control diet or experimental diet that contained control enriched with dietary fiber of barley variety "Rihane". Animals were injected with saline (controls) or azoxymethane (20 mg/kg body weight s.c.) at 7 and 8 weeks of age. The experimental diet significantly decreased cholesterol level compared with the control diet. Rats fed with BR diet significantly increased the serum high-density lipoprotein (HDL) cholesterol and significantly decreased low-density lipoprotein (LDL) cholesterol concentrations. The experimental diet decreased the atherogenic index (p < 0.05) compared with the control diet. Whereas the azoxymethane induced a significant increase of liver lipid, serum LDL and triglyceride concentrations, but it caused a significant reduction of HDL. Consequently, the ratio of HDL/TC decreased significantly compared with the control (p < 0.05). Accordingly, these results indicated that the diet enriched with dietary fiber of barley variety "Rihane" could be effective in decreasing the atherogenic risk factors in rats whereas the use of the azoxymethane as colon-specific carcinogen substance altered the lipid metabolism.


Evaluation of the heat sensitivity of Trichophyton rubrum and Trichophyton interdigitale.
Onychomycosis affects up to 50% of patients in the older population. This study aimed to explore heat sensitivity of Trichophyton rubrum and Trichophyton interdigitale as pathogens of onychomycosis. The fungi were heated in sterile saline solution up to 100°C for five or 10 minutes with or without additional previous treatment with 1% ciclopirox solution or chitinase and 1,3 -galactidase or for 45 minutes at 40°C or 60°C with washing powder. Subsequently, the fungi were cultured and regrowth was assessed after one week. After heating T. rubrum for five minutes at 60°C, growth was completely inhibited. After heating T. interdigitale for five minutes at 60°C, all of the samples regrew, and at 95°C, none of the samples regrew. No difference between five and 10-minute heating was observed. Previous incubation with 1% ciclopirox solution for 24 hours inhibited the growth of T. rubrum completely. T. interdigitale was still able to regrow to 100% after five minutes at 40°C, to 33% after 60°C, and to 22% after 80°C. Incubation for 45 minutes with washing powder solution at 40°C or 60°C did not lead to significant growth reduction of T. rubrum or interdigitale. Two hours incubation with -1,3-glucanase and chitinase prior to five minutes of heating to 60°C and 80°C reduced the heat resistance of T. interdigitale; growth was inhibited in 56% and 100% of the samples, respectively. The heat resistance of T. rubrum and interdigitale should be considered using non-medical thermal treatment.


A review on decentralized wastewater treatment systems in India.
Pollution of water resources and a lack of potable water are two important issues that city dwellers in India encounter. The passage of untreated sewage down municipal drains is one of the most significant sources of water resource pollution. In densely populated areas, effective sanitation and wastewater management is becoming increasingly difficult. In many developing nations, centralized sewage and wastewater treatment facilities serve only a section of big cities, and on-site sanitation is frequently insufficient in heavily populated areas. There is a demand for complementary and intermediate solutions. DEWATS (community-managed anaerobic decentralized wastewater treatment systems) is a good option for the possibility of relatively fast sanitation improvements in high-priority neighbourhoods where the local authority is not providing a full sanitation service. The following technical treatment modules are typically seen in DEWATS. The primary treatment consists of sedimentation ponds, settlers, septic tanks or bio digester, secondary treatment consists of anaerobic baffled reactors, anaerobic filters or anaerobic and facultative pond systems, secondary aerobic/facultative treatment consists of horizontal gravel filters and post-treatment consists of aerobic polishing ponds. The experience of India in establishing community-managed DEWATS on a large scale is examined in this review.


Long-term training improves clinical signs of periodontal disease in type 2 diabetic patients: a pilot trial.
Systemic inflammation is related to diabetes mellitus. Periodontal disease may be considered a local manifestation of systemic inflammation in association with diabetes mellitus. Physical activity may have a positive effect on inflammatory diseases. We investigated the effects of exercise training on periodontal inflammation in diabetic patients. Out of 69 diabetic patients with periodontitis, 40 subjects participated in a recreational training, while 29 subjects performed no training. All underwent a periodontal examination before and after 6.14±1.24 months and completed a dental hygiene questionnaire. In the long-term training group the following parameters decreased: hemoglobin A1c from 6.7±1.0% to 6.3±0.7% (P<0.007), papillary bleeding score 3 by 60% (P<0.0003), and the mean of all probing pocket depths 4 - 6 mm by 40% (P<0.0001). No significant weight changes and no improvements in oral health behavior were observed in either of the groups. No correlation between hemoglobin A1c or weight and periodontal parameters was found. A six-months recreational training was independently related to improved clinical signs of periodontal disease in diabetic subjects.


Therapeutic intervention of Ebola virus infection in rhesus macaques with the MB-003 monoclonal antibody cocktail.
Ebola virus (EBOV) remains one of the most lethal transmissible infections and is responsible for high fatality rates and substantial morbidity during sporadic outbreaks. With increasing human incursions into endemic regions and the reported possibility of airborne transmission, EBOV is a high-priority public health threat for which no preventive or therapeutic options are currently available. Recent studies have demonstrated that cocktails of monoclonal antibodies are effective at preventing morbidity and mortality in nonhuman primates (NHPs) when administered as a post-exposure prophylactic within 1 or 2 days of challenge. To test whether one of these cocktails (MB-003) demonstrates efficacy as a therapeutic (after the onset of symptoms), we challenged NHPs with EBOV and initiated treatment upon confirmation of infection according to a diagnostic protocol for U.S. Food and Drug Administration Emergency Use Authorization and observation of a documented fever. Of the treated animals, 43% survived challenge, whereas both the controls and all historical controls with the same challenge stock succumbed to infection. These results represent successful therapy of EBOV infection in NHPs.


Circadian rhythm shifts and alcohol access in adolescence synergistically increase alcohol preference and intake in adulthood in male C57BL/6 mice.
Adolescents have a natural tendency to be night owls, maintaining delayed circadian rhythms, and this rhythm is in direct conflict with the early wake times required during the school year. This leads to 'social jetlag', chronic circadian stress or desynchrony (CD) in which the rhythm of the intrinsic body clock is out of sync with behavior. CD increases alcohol intake in adolescents and adults, yet it is unknown whether adolescent CD also increases long-term addiction risk. The goal of this study was to determine whether adolescent alcohol intake in CD would increase adult alcohol preference and intake in male C57BL/6 J mice. We measured free access alcohol intake, water intake, and wheel-running activity during a normal 12 h (h) baseline photoperiod and then during shifting lighting schedules (Experiment 1) or a shortened circadian day (Experiment 2). In Experiment 1, altered lighting produced a persistent increase in adolescent alcohol intake and in binge-like drinking (drinking at least 5 licks per minute, with no more than a 1 min break in drinking) in adulthood, but only a transient increase in total alcohol intake for the first week after alcohol was reintroduced in adulthood. In Experiment 2, the circadian shift produced a significant increase in alcohol intake in both adolescence and adulthood. Molecular analysis demonstrated changes in plasma corticosterone and neuronal markers of stress and addiction at the conclusion of these experiments in the CD and alcohol-exposed groups. Thus, we conclude that circadian stress during adolescence is sufficient to produce a long-lasting susceptibility to alcohol use.


Renin-angiotensin system in dogs following chronic bile-duct ligation. Relation to vascular reactivity.
The pressor response to angiotensin II, blood volume, angiotensin II in arterial blood, renin substrate, renin concentration, renin activity and aldosterone in venous blood, liver function tests, kidney function tests, glucose, sodium, potassium, plasma osmolality and complete blood count were examined before and 1, 2, 3 and 5 weeks after ligation of bile ducts in nine conscious trained dogs. The pressor response to angiotensin II was markedly suppressed after bile-duct ligation, especially at 1-3 weeks postoperation. A maximal decrease in plasma renin substrate, and maximal increases in plasma renin concentration, plasma renin activity and aldosterone were noted at 1 week postoperatively. Plasma angiotensin II levels were elevated at 1 and 5 weeks postoperatively but were near normal 2 weeks postoperatively despite suppression of the angiotensin II pressor response. Endogenous levels did not correlate with suppression of the pressor response to exogenous angiotensin II.


Perception of effort in isometric and dynamic muscular contraction.
The perception of muscular effort was studied using estimation and production methods in the adductor pollicis and quadriceps. A psychometric scale (percentage magnitude) was used. Static contractions were studied in the adductor pollicis, and both dynamic (isokinetic) and static contractions were studied in quadriceps. Linear and logarithmic equations were fitted for the perceived effort as a percentage of the maximum in relation to the produced percentage maximal force or torque. The logarithmic exponent was around or above 1.0. No significant difference was found between mean exponent and intercept values for the adductor pollicis and the quadriceps, or when estimated or produced values for the two muscles were compared. There was no difference in the same subjects between the equations for static and dynamic contractions with low angular velocity of the quadriceps.


[Recommendations on use of direct oral anticoagulants in the perioperative period].
Because of the characteristics of direct oral anticoagulants (DOA), the lack of an antidote to completely reverse their anticoagulant effects, the absence of standardization in monitoring of their effects, and limited experience of their use, specific recommendations for their management in the perioperative period or in emergencies are required. In elective surgery, in patients with normal renal function and low hemorrhagic/ thrombotic risk, DOA should be withdrawn 2 days before the intervention; when the hemorrhagic/ thrombotic risk is higher, bridge therapy with a low molecular weight hepatin beginning 5 days before the intervention is proposed as an alternative. In emergency surgery, systematic administration of hemostatic drugs as prophylaxis is not recommended. In DOA-related acute hemorrhage, administration of prothrombin complex concentrate, fresh plasma or factor VIIa should be evaluated, and general measures to control bleeding should be implemented.


Pituitary adenomas.
This review highlights various aspects of the new functional classification of pituitary adenomas which is based on detailed immunohistochemical and ultrastructural analysis and correlation with clinical and biochemical findings. In addition, current investigation of the non-hormonal aspects of these tumours is discussed, including the application of flow cytometry in tumour ploidy studies.


Influence of Carbon Nanotubes and Its Derivatives on Tumor Cells In Vitro and Biochemical Parameters, Cellular Blood Composition In Vivo.
The aim of the proposed work was to analyze the toxicity of oxidized carbon nanotubes (CNTox), functionalized by doxorubicin (CNT-Dox) and fluorescein (CNT-FITC) on cell and organism level. The cytotoxic effect of CNTox, CNT-Dox, and CNT-FITC was analyzed on tumor cells in vitro (2-D, 3-D cultures) and on Balb2/c mice model in vivo. As a result, it was demonstrated the possibility of doxorubicin immobilization on the surface of CNT and controlled release of doxorubicin (Dox) from the surface of CNT. Dox immobilization coincident with decreasing cytotoxic effect CNT-Dox compared with free Dox. Breakdown of peptide bonds with CNT surface led to the release of doxorubicin and dose-dependent enhancement of the cytotoxic effect of CNTs and Dox. The combined cytotoxic effect from CNTs, Dox, and trypsin on the survival of tumor cells was shown. At the organism level, it was investigated the effect of the obtained nanostructures on the state of hepatic enzymatic system, the protein metabolism, and cell blood composition of the experimental animals. CNTox influence in vivo model was statistically the same as control. CNT-Dox demonstrated lower total organism toxic effect compared to the pure doxorubicin. Deviations in the cell blood composition indicated a general toxic effect of CNT-Dox, but it was more moderate compared with of pure doxorubicin. From the data obtained, we concluded that binding CNTs with doxorubicin allows reducing toxicity of the doxorubicin on the general biochemical indicators of blood and violations in the blood cells composition in vivo. At the same time, the combined effect of CNTs and doxorubicin after drug release allowed us to achieve greater efficacy in suppressing tumor growth in vitro.


Academic affairs and global health: how global health electives can accelerate progress towards ACGME milestones.
Global health electives (GHEs) have become a standard offering in many residency programs. Residency electives should aid residents in achieving outcomes in the Accreditation Council for Graduate Medical Education (ACGME) competency domains. In this paper, the authors review existing literature and provide expert opinion to highlight how global health electives can complement traditional training programs to assist residents in achieving ACGME milestones, using emergency medicine residency as an example. Recommendations are provided for identifying exemplary global health electives and for the development of institutional global health elective curricula in order to facilitate milestone achievement. Global health electives can advance progress towards ACGME milestones; however, they may vary greatly in terms of potential for learner advancement. Electives should thus be rigorously vetted to ensure they meet standards that will facilitate this process. Given that milestones are a newly introduced tool for assessing resident educational achievement, very little research is available currently to directly determine impacts, and further study will be needed.


Characterization of a novel curcumin analog P1 as potent inhibitor of the NF-κB signaling pathway with distinct mechanisms.
Curcumin has shown promising anticancer activity, which relies on its inhibition on NF-κB pathway. In this study, we characterized the pharmacological profile of a novel curcumin analog P1 and elucidate the related mechanisms. HEK293/NF-κB cells, stably transfected with an NF-κB-responsive luciferase reporter plasmid, were generated for high-throughput screen (HTS). Eight cancer cell lines, including PC3, COLO 205, HeLa cells etc. were tested. Cell viability was assessed using the sulforhodamine B (SRB) assays. Cell apoptosis was evaluated using FACS, immunocytochemistry, and Western blotting. H2-DCFDA and MitoSOX Red were used to detect cellular and mitochondrial reactive oxygen species (ROS). The mitochondrial function was evaluated using mitochondrial oxygen consumption assay. P1, a tropinone curcumin, was found in HTS targeting the NF-κB pathway. Its IC50 value in inhibition of TNF-α-induced NF-κB activation was 0.8 μmol/L, whereas its IC50 values in inhibiting the growth of A549 and HeLa cells were 1.24 and 0.69 μmol/L, respectively, which was 20- to 30-fold more potent than curcumin. The inhibition of P1 on the NF-κB pathway was further addressed in HeLa cells. The compound up to 10 μmol/L did not affect the binding of NF-κB to DNA, but markedly inhibited NF-κB nuclear translocation, IκB degradation and IκB kinase phosphorylation. The compound (1 and 3 μmol/L) concentration-dependently induced ROS generation, whereas curcumin up to 20 μmol/L had no effect. P1-induced ROS generation was mainly localized in mitochondria, and reversed by NAC. Moreover, the compound significantly enhanced TNF-α-induced apoptosis. P1 is a novel curcumin analog with potent anticancer activities, which exerts a distinct inhibition on the NF-κB pathway.


Discovery of four plasmatic biomarkers potentially predicting cardiovascular outcome in peripheral artery disease.
Peripheral artery disease (PAD) patients have an increased cardiovascular risk despite pharmacological treatment strategies. Biomarker research improving risk stratification only focused on known atherothrombotic pathways, but unexplored pathways might play more important roles. To explore the association between a broad cardiovascular biomarker set and cardiovascular risk in PAD. 120 PAD outpatients were enrolled in this observational cohort study. Patients were followed for one year in which the composite endpoint (myocardial infarction, coronary revascularization, stroke, acute limb ischemia and mortality) was assessed. Patient data and blood samples were collected upon inclusion, and citrated platelet-poor plasma was used to analyze 184 biomarkers in Olink Cardiovascular panel II and III using a proximity extension assay. Fifteen patients reached the composite endpoint. These patients had more prior strokes and higher serum creatinine levels. Multivariate analysis revealed increased plasma levels of protease-activated receptor 1 (PAR1), galectin-9 (Gal-9), tumor necrosis factor receptor superfamily member 11A (TNFRSF11A) and interleukin 6 (IL-6) to be most predictive for cardiovascular events and mortality. Positive regulation of acute inflammatory responses and leukocyte chemotaxis were identified as involved biological processes. This study identified IL-6, PAR1, Gal-9, TNFRSF11A as potent predictors for cardiovascular events and mortality in PAD, and potential drug development targets.


Three-dimensional repositioning accuracy of semiadjustable articulator cast mounting systems.
In spite of its importance in prosthesis precision and quality, the 3-dimensional repositioning accuracy of cast mounting systems has not been reported in detail. The purpose of this study was to quantify the 3-dimensional repositioning accuracy of 6 selected cast mounting systems. Five magnetic mounting systems were compared with a conventional screw-on system. Six systems on 3 semiadjustable articulators were evaluated: Denar Mark II with conventional screw-on mounting plates (DENSCR) and magnetic mounting system with converter plates (DENCON); Denar Mark 330 with in-built magnetic mounting system (DENMAG) and disposable mounting plates; and Artex CP with blue (ARTBLU), white (ARTWHI), and black (ARTBLA) magnetic mounting plates. Test casts with 3 high-precision ceramic ball bearings at the mandibular central incisor (Point I) and the right and left second molar (Point R; Point L) positions were mounted on 5 mounting plates (n=5) for all 6 systems. Each cast was repositioned 10 times by 4 operators in random order. Nine linear (Ix, Iy, Iz; Rx, Ry, Rz; Lx, Ly, Lz) and 3 angular (anteroposterior, mediolateral, twisting) displacements were measured with a coordinate measuring machine. The mean standard deviations of the linear and angular displacements defined repositioning accuracy. Anteroposterior linear repositioning accuracy ranged from 23.8 ±3.7 μm (DENCON) to 4.9 ±3.2 μm (DENSCR). Mediolateral linear repositioning accuracy ranged from 46.0 ±8.0 μm (DENCON) to 3.7 ±1.5 μm (ARTBLU), and vertical linear repositioning accuracy ranged from 7.2 ±9.6 μm (DENMAG) to 1.5 ±0.9 μm (ARTBLU). Anteroposterior angular repositioning accuracy ranged from 0.0084 ±0.0080 degrees (DENCON) to 0.0020 ±0.0006 degrees (ARTBLU), and mediolateral angular repositioning accuracy ranged from 0.0120 ±0.0111 degrees (ARTWHI) to 0.0027 ±0.0008 degrees (ARTBLU). Twisting angular repositioning accuracy ranged from 0.0419 ±0.0176 degrees (DENCON) to 0.0042 ±0.0038 degrees (ARTBLA). One-way ANOVA found significant differences (P<.05) among all systems for Iy, Ry, Lx, Ly, and twisting. Generally, vertical linear displacements were less likely to reach the threshold of clinical detectability compared with anteroposterior or mediolateral linear displacements. The overall repositioning accuracy of DENSCR was comparable with 4 magnetic mounting systems (DENMAG, ARTBLU, ARTWHI, ARTBLA). DENCON exhibited the worst repositioning accuracy for Iy, Ry, Lx, Ly, and twisting.


Diurnal variation in norepinephrine-stimulated release of pineal serotonin in vitro.
Adult, male rats were maintained under 12L:12D with lights on at 06.00h. Their pineal glands were incubated at 37 degrees C in the presence or absence of 10(-4)M norepinephrine (NE). 5-HT and various metabolites were quantitated in post-incubation media and pineal glands by high performance liquid chromatography coupled with electrochemical detection. No differences were observed in the quantities of 5-HT released by pineal glands in four hour incubations starting at either 06.00, 13.00 or 18.00 h; however, a highly significant decrease below these levels was observed at 01.00h. NE significantly stimulated 5-HT release at 13.00 and 18.00 h, but was ineffective at 01.00 and 06.00h. These results confirm recently reported stimulatory effects of NE on the release of 5-HT into pineal gland incubation medium and further suggest a diurnal rhythm of pineal gland sensitivity to NE in vitro with maximum stimulation of 5-HT release at midphotophase.


Truncated TSG101 transcripts are present in peripheral blood from both familial breast cancer patients and controls.
TSG101 is a recently identified putative tumour suppressor gene which has been implicated in human breast cancer. To address whether germline disruption of TSG101 predisposes individuals to this disease, we analysed genomic DNA and mRNA isolated from peripheral blood from 20 familial breast cancer cases. No evidence of large intragenic insertions/deletions or point mutations in TSG101 was found by Southern blot analysis and sequence analysis of the entire coding region. However, in 11 of 20 samples, 'aberrant' transcripts were detected. Sequence analysis suggested that these variants were generated by the use of different cryptic splicing sites. Such alternative/aberrant splicing events were not restricted to cancer patients, but were also detected in peripheral blood of non-cancer patients and in normal tissues.


A national survey of endoscopic practice among gynaecologists in Canada.
To assess the current status of endoscopic gynaecological surgery in Canada, as well as the attitudes, perceptions, and educational preferences regarding endoscopy among Canadian obstetrician-gynaecologists. An electronic online survey was sent to 630 obstetrician-gynaecologists in Canada through the Society of Obstetricians and Gynaecologists of Canada electronic mailing list. Survey respondents were asked about demographic variables, level of training and current practice of endoscopic procedures, reasons for and barriers to performing endoscopy, and interest in continuing surgical education in laparoscopy and hysteroscopy. A total of 178 responses (28.3%) were collected and 152 (85.4%) analyzed. The majority of respondents were general obstetrician-gynaecologists (78.0%). More gynaecologic surgeons performed abdominal (92.7%) and vaginal hysterectomies (89.7%) than laparoscopic (68.4%) and robotic hysterectomies (2.2%). Even though 93.2% of respondents selected the endoscopic approach as the preferred approach to surgery for their patients, 38.7% of respondents did not feel that they had adequate training during residency to perform endoscopy. Lack of operating room resources and lack of time and opportunity for further training were frequently selected as major barriers to performing endoscopy. Participants identified weekend continuing medical education courses and trained endoscopic surgeon outreach as preferred methods of acquiring endoscopic skills. This survey provides a contemporary assessment of the current endoscopic practice patterns of Canadian obstetrician-gynaecologists, and it helps to identify some potentially modifiable factors hindering the practice of endoscopy and some possible solutions to overcoming these barriers.


Mucosal neuroma syndrome presenting in a neonate.
A case of multiple mucosal neuromata and a calcitonin-secreting medullary carcinoma of the thyroid is described. Unusual features were the neonatal presentation with large bowel obstruction and severe feeding difficulties associated with giant neuromata of the intestine; severe hypotonia; developmental delay; and the early recognition and treatment of an associated medullary carcinoma of the thyroid.


Diurnal changes of the 2,3-diphosphoglycerate concentration in human red cells and the influence of posture.
The 2,3-diphosphoglycerate (2,3-DPG) concentration, oxygen half saturation pressure at pH 7.4 (P50), pH in plasma and red cells, and mean corpuscular hemoglobin concentration (MCHC) of venous blood were determined during unrestricted daily activity (series I) throughout 24 hrs as well as during prolonged bed rest until noon (series II). In series I almost synchronous dirunal behavior of P50 2,3-DPG, and plasma pH as well as red cell pH became significantly apparent with highest values in the afternoon. The [2,3-DPG] yielded most pronounced alterations, which made up to 13.5% of the average day value. During prolonged recumbency the [2,3-DPG] showed a nonsignificant tendency to decline; the P50 remained unchanged throughout that period. The possible reason for the missing [2,3-DPG] increase is a reduced change of red cell pH in series II. An influence of a posture dependent aldosterone secretion either directly on the 2,3-DPG metabloism of indirectly via mediating the red cell pH and thus ruling the formation of this organic PHOSPHORIS COMPOUND IS DISCUSSED.


Monte Carlo confidence intervals for the indirect effect with missing data.
Missing data is a common occurrence in mediation analysis. As a result, the methods used to construct confidence intervals around the indirect effect should consider missing data. Previous research has demonstrated that, for the indirect effect in data with complete cases, the Monte Carlo method performs as well as nonparametric bootstrap confidence intervals (see MacKinnon et al., Multivariate Behavioral Research, 39(1), 99-128, 2004; Preacher & Selig, Communication Methods and Measures, 6(2), 77-98, 2012; Tofighi & MacKinnon, Structural Equation Modeling: A Multidisciplinary Journal, 23(2), 194-205, 2015). In this manuscript, we propose a simple, fast, and accurate two-step approach for generating confidence intervals for the indirect effect, in the presence of missing data, based on the Monte Carlo method. In the first step, an appropriate method, for example, full-information maximum likelihood or multiple imputation, is used to estimate the parameters and their corresponding sampling variance-covariance matrix in a mediation model. In the second step, the sampling distribution of the indirect effect is simulated using estimates from the first step. A confidence interval is constructed from the resulting sampling distribution. A simulation study with various conditions is presented. Implications of the results for applied research are discussed.


Purification of Bacterial-Enriched Extracellular Vesicle Samples from Feces by Density Gradient Ultracentrifugation.
Commensal microbiota has huge impact on the maintenance of human health, its dysregulation being associated with the development of a plethora of diseases. Release of bacterial extracellular vesicles (BEVs) is a fundamental mechanism of systemic microbiome influence on the host organism. Nevertheless, due to the technical challenges of isolation methods, BEV composition and functions remain poorly characterized. Hereby, we describe the up-to-date protocol for isolation of BEV-enriched samples from human feces. Fecal extracellular vesicles (EVs) are purified through the orthogonal implementation of filtration, size-exclusion chromatography (SEC), and density gradient ultracentrifugation. EVs are first separated from bacteria, flagella, and cell debris by size. In the next steps, BEVs are separated from host-derived EVs by density. The quality of vesicle preparation is estimated via immuno-TEM (transmission electron microscopy) for the presence of vesicle-like structures expressing EV markers and via NTA (nanoparticle tracking analysis) for assaying particle concentration and size. Distribution of EVs of human origin in gradient fractions is estimated using antibodies against human exosomal markers with Western blot and ExoView R100 imaging platform. The enrichment for BEVs in vesicle preparation is estimated by Western blot for the presence of bacterial OMVs (outer membrane vesicles) marker and OmpA (outer membrane protein A). Taken together, our study describes a detailed protocol for EV preparation with enrichment for BEVs from feces with a purity level suitable for bioactivity functional assays.


Fuzhuan Brick Tea Attenuates High-Fat Diet-Induced Obesity and Associated Metabolic Disorders by Shaping Gut Microbiota.
An increasing amount of evidence suggests that the metabolic improvement of high-fat diet (HFD)-induced obese mice by Fuzhuan brick tea (FBT) is associated with gut microbiota. However, the causalities between FBT and gut microbiota have not yet been elucidated and the underlying mechanisms of action remain unclear. To impart direct evidence for the essential role of gut microbiota in the attenuation of obesity by FBT, the effects of FBT on healthy mice and microbiota-depleted mice that were treated with antibiotics were compared in an HFD-induced obesity mouse model. The results showed that FBT dramatically ameliorated obesity, serum lipid parameters, blood glucose homeostasis, hepatic steatosis, adipocyte hypertrophy, and tissue inflammation. However, the microbiota-depleted mice with single bacterium (Escherichia-Shigella) after antibiotic treatment were resistant to FBT-induced antiobesity and metabolic improvement. The beneficial effects of FBT resulted from its shift on gut microbiota composition and structure in mice. HFD-induced increase in the phyla Firmicutes/Bacteroidetes (F/B) ratio was remarkably restored by FBT. Furthermore, FBT-induced increase in abundances of beneficial bacteria Clostridiaceae, Bacteroidales, and Lachnospiraceae and decreases in harmful Ruminococcaceae, Peptococcaceae, Peptostreptococcaceae, and Erysipelotrichaceae were causal antecedents for FBT to reduce obesity and improve metabolic disorders.


The role of hyperbaric oxygen in the management of subarachnoid hemorrhage.
To determine the role of hyperoxic and hyperbaric therapy following experimental subarachnoid hemorrhage (SAH). Prospective, randomized, controlled animal study. Thirty male Wistar rats. Thirty rats were assessed for an initial neurologic status as double-blinded by two different neurosurgeons using a neurologic severity score (NSS) and then underwent an initial angiographic examination. Two days later, 0.3 ml of homologous blood was injected into the cisterna magna to produce a SAH-induced cerebral vasospasm. The NSS and angiographic examination were then repeated. The rats having no spasm or a spasm under 50% (n=8) and 50% or over 50% (n=22) were grouped separately, as groups 1 and 2, respectively. The rats having 50% or more spasm were further divided randomly into group 2A and 2B. The rats in groups 1 and 2A (n=11) underwent a 60-min course of 100% oxygen at the atmospheric pressure 1 atmosphere absolute (ata), and group 2B (n=11) received 100% oxygen at 3 ata for 1 h. Neurologic assessment was repeated on the next day and 7 days later. The animals having no spasm or less than 50% spasm had a better NSS and outcome when compared with the animals having 50% or more spasm. But the animals with 50% or more spasm which underwent hyperbaric therapy were shown to have a better outcome compared to the animals having hyperoxic therapy. Exposure to hyperbaric oxygen therapy seemed to accelerate the recovery of neurologic deficits secondary to experimental SAH.


Differential Expression of Genes for Ubiquitin Ligases in Medulloblastoma Subtypes.
Using publically available datasets on gene expression in medulloblastoma (MB) subtypes, we selected genes for ubiquitin ligases and identified statistically those that best predicted each of the four major MB subgroups as separate disease entities. We identify a gene coding for an ubiquitin ligase, ZNRF3, whose overexpression alone can predict the WNT subgroup for 100% in the Pfister dataset. For the SHH subgroup, we identify a gene for a regulatory subunit of the protein phosphatase 2A (PP2A), PPP2R2C, as the major predictor among the E3 ligases genes. The ubiquitin and ubiquitin-like conjugation database (UUCD) lists PPP2R2C as coding for a Cullin Ring ubiquitin ligase adaptor. For group 3 MBs, the best ubiquitin ligase predictor was PPP2R2B, a gene which codes for another regulatory subunit of the PP2A holoenzyme. For group 4, the best E3 gene predictors were MID2, ZBTB18, and PPP2R2A, which codes for a third PP2A regulatory subunit. Heatmap analysis of the E3 gene data shows that expression of ten genes for ubiquitin ligases can be used to classify MBs into the four major consensus subgroups. This was illustrated by analysis of gene expression of ubiquitin ligases of the Pfister dataset and confirmed in the dataset of Cavalli. We conclude that genes for ubiquitin ligases can be used as genetic markers for MB subtypes and that the proteins coded for by these genes should be investigated as subtype specific therapeutic targets for MB.


Role of the Cys154Arg Substitution in Ribosomal Protein L3 in Oxazolidinone Resistance in Mycobacterium tuberculosis.
We expressed the wild-type rplC and mutated rplC (Cys154Arg) genes, respectively, in Mycobacterium tuberculosis H37Ra and H37Rv in an attempt to delineate the role of rplC (Cys154Arg) regarding oxazolidinone resistance. An increase of the MICs of linezolid (LZD) and sutezolid (PNU-100480, PNU) against the recombinant mycobacteria with overexpressed rplC mutation (Cys154Arg) was found, suggesting the rplC gene is a determinant of bacillary susceptibilities to LZD and PNU.


Optimal saturation recovery time for minimizing the underestimation of arterial input function in quantitative cardiac perfusion MRI.
The purpose of this study was to determine an optimal saturation-recovery time (TS) for minimizing the underestimation of arterial input function (AIF) in quantitative cardiac perfusion MRI without multiple gadolinium injections per subject. We scanned 18 subjects (mean age = 59 ± 14 years, 9/9 males/females) to acquire resting perfusion data and 1 additional subject (age = 38 years, male) to obtain stress-rest perfusion data using a 5-fold accelerated pulse sequence with radial k-space sampling and applied k-space weighted image contrast (KWIC) filters on the same k-space data to retrospectively reconstruct five AIF images with effective TS ranging from 10 to 21.2 ms (2.8 ms steps). Undersampled images were reconstructed using a compressed sensing framework with temporal-total-variation and temporal-principal-component as 2 orthogonal sparsifying transforms. The image processing steps included, same motion correction across five different AIF images, signal normalization by the proton-density-weighted-image, signal-to-T1 conversion using a Bloch equation, T1 -to-gadolinium-concentration conversion assuming fast water exchange, T2 * correction to the AIF, and gadolinium-concentration to myocardial blood flow (MBF) conversion based on a Fermi model. Among five TS values, the shortest TS (10 ms) produced significantly (P < 0.05) higher peak AIF and lower resting MBF (13.73 mM, 0.73 mL g-1 min-1 ) than 12.8 ms (11.24 mM, 0.89 mL g-1 min-1 ), 15.6 ms (9.56 mM, 1.05 mL g-1 min-1 ), 18.4 ms (8.55 mM, 1.17 mL g-1 min-1 ), and 21.2 ms (7.95 mM, 1.27 mL g-1 min-1 ). Similarly, shorter TS reduced underestimation of AIF (or overestimation of MBF) for both during stress and at rest, but this effect was canceled in myocardial-perfusion-reserve (MPR). This study demonstrates that TS of 10 ms reduces the underestimation of AIF and, hence, the overestimation of MBF compared with longer TS values (12.8-21.2 ms).


Laparoscopic conversion of failed gastric banding to Roux-en-Y gastric bypass: short-term follow-up and technical considerations.
The most common bariatric procedure in Australia is laparoscopic adjustable gastric banding (LAGB). Although successful, there is a substantial long-term complication and failure rate. Band removal and conversion to Roux-en-Y gastric bypass (RYGB) can be an effective treatment for complicated or failed bands. There is increasing evidence supporting good weight loss and resolution of band-related complications after conversion. A prospective database of all bariatric procedures is maintained. Patients having revision of LAGB to RYGB between December 2007 and April 2011 were included in this study. Indications for surgery, operative details, morbidity and mortality, weight loss data, and post-operative symptoms were recorded. Eighty-two patients were included. Indications for surgery were inadequate weight loss (n = 42), adverse symptoms (reflux = 8, dysphagia = 2), and band complications (band erosion = 7, band sepsis = 1, band slip = 11, esophageal dilatation = 11). Seventy-eight percent of procedures were completed in a single stage and 96.3% laparoscopically. There was no 30-day mortality. Total morbidity was 46.3% (minor complications = 32.9%, major complications = 13.4%). Median BMI was 43 kg/m(2) pre-RYGB and 34 kg/m(2) after 12 months. All patients with adverse band-related symptoms had resolution. LAGB has a considerable complication and failure rate. Conversion of these patients to RYGB results in further weight loss and resolution of adverse symptoms. This is a challenging procedure, but can usually be performed in a single stage with acceptable morbidity and mortality. These patients should be treated in high-volume, subspecialty bariatric units.


Rationale, Design, and Methods of the Study of Comparison of Canagliflozin vs. Teneligliptin Against Basic Metabolic Risks in Patients with Type 2 Diabetes Mellitus (CANTABILE study): Protocol for a Randomized, Parallel-Group Comparison Trial.
Dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose co-transporter 2 (SGLT2) inhibitors are widely used antidiabetic drugs. However, to date, no studies have directly compared the effects of these two drugs on the components of the metabolic syndrome in patients with type 2 diabetes mellitus (T2DM). The Comparison of Canagliflozin vs. Teneligliptin against Basic Metabolic Risks in Patients with T2DM (CANTABILE) study aims to examine whether the DPP-4 inhibitor (teneligliptin) or the SGLT2 inhibitor (canagliflozin) is the more effective drug for reducing metabolic risk factors as a composite in Japanese patients with T2DM. The CANTABILE study is a prospective, multicenter, open-label, randomized, parallel-group comparison study. A total of 200 patients with T2DM treated with metformin alone or without glucose-lowering agents will be enrolled if they have one or more of the metabolic risk factors, such as obesity, borderline high blood pressure, and dyslipidemia. They will then will be randomized into the Teneligliptin group or the Canagliflozin group and treated for 24 weeks. The primary endpoint is the composite ratio of subjects with one or more improved metabolic risk factors. The secondary endpoints are the changes in each component of the primary endpoint. The CANTABILE study provides valuable evidence to indicate the suitability of SGLT2 inhibitors or DPP-4 inhibitors for Japanese patients with T2DM and metabolic risks. University Hospital Medical Information Network Clinical Trial Registry number: UMIN000030343. Mitsubishi Tanabe Pharma Corporation.


High-density screen of human tumor cell lines for homozygous deletions of loci on chromosome arm 8p.
Tumor cell-specific homozygous deletions coinciding at a particular genetic location may indicate the inactivation of a nearby tumor suppressor gene. Forty-six human cancer cell lines of prostate, pancreatic, lung, liver, and colon origin were screened for homozygous deletions of 139 expressed sequence tag (EST) and sequence-tagged site (STS) loci spanning the entire short arm of chromosome 8. Only one Southern blot-verified homozygous deletion was detected in this set of cell lines. The deletion, in pancreatic tumor cell line MIA-PaCa-2, encompassed two screening loci, D8S549 and D8S1992, and overlapped another previously described homozygous deletion of band 8p22 in a metastatic prostate cancer specimen. Both deletions entirely removed the candidate tumor suppressor gene N33. These data define a consensus homozygous deletion region in chromosome band 8p22.


Extracellular space values and intracellular ionic concentrations in the isolated midgut of Philosamia cynthia and Bombyx mori.
Total extracellular space values have been determined in the midguts of 2 lepidopteran larvae, Philosamia cynthia and Bombyx mori. The values found are 42% and 45% tissue water respectively. Intracellular concentrations of Na+, Ca++ and Mg++ are very low, while K+ concentration is 197,2 mEq/l cell water Philosamia and 180.9 mEq/l cell water in Bombyx.


[Oocyte donation: parents's secrets and lies].
Since 1994, oocyte donation in France must be organized anonymously, in compliance with the bioethics law. The donation is free and any publicity to enrol donors is forbidden. In this system, the recipients are encouraged to incite a donor to visit the recipient's fertility unit. These donors are called "symbolic" donors, since they allow the recipient to be entitred to receive oocytes from another anonymous donor. According to the law, this procedure can be performed both anonymously and non-anonymously. We wanted to study the implication of the anonymous system, focusing on the secret of the child's conception and on the relationship between the recipient family and the "symbolic" donor. We contacted all the patients (n=83) who had children with oocyte donation in our center between 1988 and 1998. These patients participated in an interview conducted with a standardized questionnaire. Fourteen (17.8%) of the couples were lost to follow-up and three declined to participate. Five recipient couples preferred a non-anonymous donation. In all, 70% of the couples had not yet told their child about the donation. They had mentioned the IVF but not the donation despite of the fact that 50% of symbolic donors came from the family of the recipients, 34% from their friends, or 6% from their professional environment; 10% were not related to the recipients. Long after the child's birth, 25% of the recipients had no contact with the symbolic donor but 41% had selected her as the child's godmother and 15% of symbolic donors were the first to be informed of the birth of the child. After the donation, a gift was offered to the "symbolic" donor by 57% of couples, 33% did not know how to thank them (retribution is forbidden by law) and 10% of couples mentioned that their donor refused any gift. Concerning the donor whose oocytes were used, 63% of recipients did not want to know anything about her. 20% would have liked to have medical information and 13% would like to have all kind of information about her. Only 2% of recipients would have liked to know her identity and 2% would have liked to meet her. In agreement with earlier reports in the literature, the majority (70%) of the parents did not inform their child about the oocyte donation even though the symbolic donor was in contact with the child (being his aunt or his godmother for example). The French system has created a double debt: one related to the real donor and another related to the symbolic donor. In the long run, the parents have found a way to humanize this technique: they have given a symbolic place of godmother to the volunteer donor.


Self-efficacy expectations among traumatized adolescents.
Bandura's Multidimensional Scales of Perceived Self-Efficacy (MSPSE) were administered to three matched groups of adolescents. The first group met diagnostic criteria for PTSD. The second had been exposed to qualitatively and quantitatively similar stressors and did not meet criteria for PTSD (traumatized PTSD negatives). The third group consisted of non-traumatized controls. Data analysis revealed that the adolescents with PTSD had appreciably lower self-efficacy ratings on eight of the nine subtests that comprise the MSPSE. Non-significant differences were observed when the MSPSE subtest scores of the traumatized PTSD negatives and controls were compared.


The prospects of flexible natural gas-fired CCGT within a green taxonomy.
Despite increased commitments toward net zero, there will likely be a continued need for natural gas to provide low carbon dispatchable power and blue hydrogen to balance the increased penetration of renewables. We evaluate the CO2 emissions intensity of electricity produced by (i) natural gas-fired combined cycle gas turbine (CCGT) power plants with carbon capture and storage (CCS), and (ii) blue hydrogen CCGT plants which uses steam methane reforming with CCS to supply H2. This study aims to determine whether these assets are able to meet a possible green taxonomy emissions threshold of 100 kg CO2 eq/MWh. Key considerations include methane leakage, CO2 capture rate, and the impacts of start-up and shut down cycles performed by the CCGT-CCS plant. This study suggests that, in order for natural gas to play an enduring role in the transition toward net zero, managing GHG emissions from both the upstream natural gas supply chain and the conversion facility is key.


Ultrasound assessment of the posterior circumflex humeral artery in elite volleyball players: Aneurysm prevalence, anatomy, branching pattern and vessel characteristics.
To determine the prevalence of posterior circumflex humeral artery (PCHA) aneurysms and vessel characteristics of the PCHA and deep brachial artery (DBA) in elite volleyball players. Two-hundred and eighty players underwent standardized ultrasound assessment of the dominant arm by a vascular technologist. Assessment included determination of PCHA aneurysms (defined as segmental vessel dilatation ≥150 %), PCHA and DBA anatomy, branching pattern, vessel course and diameter. The PCHA and DBA were identified in 100 % and 93 % (260/280) of cases, respectively. The prevalence of PCHA aneurysms was 4.6 % (13/280). All aneurysms were detected in proximal PCHA originating from the axillary artery (AA). The PCHA originated from the AA in 81 % of cases (228/280), and showed a curved course dorsally towards the humeral head in 93 % (211/228). The DBA originated from the AA in 73 % of cases (190/260), and showed a straight course parallel to the AA in 93 % (177/190). PCHA aneurysm prevalence in elite volleyball players is high and associated with a specific branching type: a PCHA that originates from the axillary artery. Radiologists should have a high index of suspicion for this vascular overuse injury. For the first time vessel characteristics and reference values are described to facilitate ultrasound assessment. • Prevalence of PCHA aneurysms is 4.6 % among elite volleyball players. • All aneurysms are in proximal PCHA that originates directly from AA. • Vessel characteristics and reference values are described to facilitate US assessment. • Mean PCHA and DBA diameters can be used as reference values. • Radiologists need a high index of suspicion for this vascular overuse injury.


Percutaneous trans-facet screws for supplemental posterior cervical fixation.
Numerous innovative minimally invasive fusion and fixation techniques for the thoracolumbar spine have recently been developed. However, less-invasive approaches for accessing the posterior cervical spine surgery have been more elusive. One promising option for posterior cervical fixation is trans-facet screw placement. This method allows for a screw to be inserted percutaneously through the articular (zygapophyseal) facet joint. This eliminates the need for a connecting rod between segments, which remains a major limitation of longer segment minimally invasive lateral mass screw-rod constructs. Surgery was successfully performed in three consecutive cases with the use of existing small fragment cancellous screws intended for orthopedic applications. In this report we describe an initial clinical experience with cervical trans-facet screws, which we found to be a technically feasible option in the subaxial cervical spine for truly percutaneous spinal fixation. However, until percutaneous bony fusion methods are developed, this approach is limited to the fixation application, such as supplementing an anterior fusion construct.


Author Correction: Competitive endogenous RNA is an intrinsic component of EMT regulatory circuits and modulates EMT.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


Gurvits syndrome: a case of acute esophageal necrosis associated with diabetic ketoacidosis.
Acute esophageal necrosis (AEN), commonly referred to as Gurvits syndrome or "black esophagus", is a rare clinical disease. We present a case of AEN associated with diabetic ketoacidosis (DKA). A 66-year-old male came to our hospital with coffee-ground emesis, dyspnea, and general malaise. He was treated for type 2 diabetes mellitus using insulin and had not been taking his medication, including insulin, for several days. Laboratory analysis revealed severe hyperglycemia (730 mg/dL), normocytic anemia (hemoglobin level, 7.7 g/dL; mean corpuscular volume, 100.4 fL), high serum potassium (7.6 mEq/L), and a high level of blood urea (98.7 mg/dL). Ketones and glucose were detected in the urine, and serum β-hydroxybutyrate was elevated (2132 µmol/L). Arterial blood gas analysis confirmed metabolic acidosis (pH, 7.29; HCO3, 10.5 mmol/L). Collectively, the patient was diagnosed with DKA and upper gastrointestinal bleeding. The patient's condition improved with intravenous fluids, and he received intravenous insulin to treat DKA. According to these findings, the patient was diagnosed with DKA and upper gastrointestinal bleeding. The patient underwent esophagogastroduodenoscopy (EGD) which revealed a circumferential necrosis of the middle and distal esophagus, immediately proximal to the gastroesophageal junction. The patient was then treated with an intravenous proton pump inhibitor. The patient continued to improve with conservative treatment and was subsequently discharged in a stable condition. An EGD repeated 14 days after discharge showed complete healing of the necrotic-like mucosal change without stricture formation of the esophagus. AEN is rare but potentially life-threatening case of upper gastrointestinal bleeding. Therefore, a clinician should be aware of AEN as a potential cause of upper gastrointestinal bleeding in elderly patients with poorly controlled diabetes and significant comorbidities.


Understanding the effects of task-specific practice in the brain: insights from individual-differences analyses.
We used functional magnetic resonance imaging to study practice effects in different mental imagery tasks. The study was designed to address three general questions: First, are the results of standard group-based analyses the same as those of a regression method in which brain activation changes over individual participants are used to predict task performance changes? With respect to the effects of practice, the answer was clear: Group-based analyses produced different results from regression-based individual-differences analyses. Second, are all brain areas that predict practice effects consistently activated across participants? Again, the answer was clear: Most areas that predicted the effects of practice on performance were not activated consistently over participants. Finally, does practice affect different areas in different ways for different people in different tasks? The answer was again clear: The areas that predicted changes in performance with practice varied for the different tasks, but this was more dramatically and clearly revealed by the individual-differences analyses. In short, individual-differences analyses provided insights into the relation between changes in brain activation and changes in accompanying performance, and these insights were not provided by standard group-based analyses.


A qualitative study exploring midlife women's stages of change from domestic violence towards freedom.
Domestic Violence (DV) remains a significant global health problem for women in contemporary society. Existing literature on midlife women's experiences of domestic violence is limited and focuses on health implications. Leaving a violent relationship is a dynamic process that often requires multiple attempts and separations prior to final termination. The aim of this study was to explore the process of leaving a violent relationship for midlife women. This qualitative study involved fifteen women aged between 40-55 who had accessed residential and non-residential community support services for domestic violence within the UK. Community-based support agencies provided these women with access to letters of invitation and participant information sheet explaining the study. The women notified agency staff who contacted the research team to arrange a mutually convenient time to meet within a safe place for both the women and researchers. It was stressed to all potential participants that no identifiable information would be shared with the agency staff. Women were considered survivors of DV if they defined themselves as such. Data were gathered through semi structured interviews, transcribed verbatim and thematically analysed. Midlife women appear to differ from younger women by transitioning quickly though the stages of change, moving rapidly through the breaking free onto the maintenance stage. This rapid transition is the resultant effect of living with long-term violence causing a shift in the women's perception towards the violent partner, with an associated reclamation of power from within the violent relationship. A realisation that rapid departure from the violence may be critical in terms of personal safety, and the realisation that there was something 'wrong' within the relationship, a 'day of dawning' that had not been apparent previously appears to positively affect the trajectory of leaving. Midlife women appeared to navigate through the stages of change in a rapid linear process, forging ahead and exiting the relationship with certainty and without considering options. Whilst these findings appear to differ from younger women's process of leaving, further research is needed to explore and understand the optimum time for intervention and support to maximise midlife women's opportunities to escape an abusive partner, before being reflected appropriately in policy and practice.


Creatine deficiency syndromes.
The lack of creatine in the central nervous system causes a severe but treatable neurological disease. Three inherited defects, AGAT, GAMT, and CrT deficiency, compromising synthesis and transport of creatine have been discovered recently. Together these so-called creatine deficiency syndromes (CDS) might represent the most frequent metabolic disorders with a primarily neurological phenotype. Patients with CDS present with global developmental delays, mental retardation, speech impairment especially affecting active language, seizures, extrapyramidal movement disorder, and autism spectrum disorder. The two defects in the creatine synthesis, AGAT and GAMT, are autosomal recessive disorders. They can be diagnosed by analysis of the creatine, guanidinoacetate, and creatinine in body fluids. Treatment is available and, especially when introduced in infancy, has a good outcome. The defect of creatine transport, CrT, is an X-linked condition and perhaps the most frequent reasons for X-linked mental retardation. Diagnosis is made by an increased ratio of creatine to creatinine in urine, but successful treatment still needs to be explored. CDS are under-diagnosed because easy to miss in standard diagnostic workup. Because CDS represent a frequent cause of cognitive and neurological impairment that is treatable they warrant consideration in the workup for genetic mental retardation syndromes, for intractable seizure disorders, and for neurological diseases with a predominant lack of active speech.


2D (1)H(N), (15)N Correlated NMR Methods at Natural Abundance for Obtaining Structural Maps and Statistical Comparability of Monoclonal Antibodies.
High-resolution nuclear magnetic resonance spectroscopy (NMR) provides a robust approach for producing unique spectral signatures of protein higher order structure at atomic resolution. Such signatures can be used as a tool to establish consistency of protein folding for the assessment of monoclonal antibody (mAb) drug quality and comparability. Using the NIST monoclonal antibody (NISTmAb) and a commercial-sourced polyclonal antibody, both IgG1κ isotype, we apply 2D NMR methods at natural abundance for the acquisition and unbiased statistical analysis of (1)H(N) -(15)N correlated spectra of intact antibody (Ab) and protease-cleaved Fab and Fc fragments. The study demonstrates the feasibility of applying 2D NMR techniques to Abs and the precision with which these methods can be used to map structure and establish comparability between samples at atomic resolution. The statistical analyses suggests that, within the limit of detection, no significant structural differences are observed between the Fab and Fc domains of each respective intact Ab and its corresponding fragments. Discrimination between dissimilar species, such as between the Fab domains of both Abs or between the glycosylated and deglycosylated Fc domains, was further demonstrated. As such, these methods should find general utility for the assessment of mAb higher order structure.


Impact of the current organ allocation system for deceased donor liver transplantation on the outcomes of pediatric recipients: a single center experience in Japan.
The aim of this study was to analyze the outcomes of children added to the waiting list for deceased donor liver transplantation (DDLT) and the results of DDLT in a single Japanese center. Forty-seven children were listed on the organ allocation system for DDLT. The priority points related to the medical status of each patient were evaluated and stratified into four categories; 10, 8, 6, and 3 points. The clinical data were collected from the medical records, and the outcomes were analyzed. There were 10 priority points in 25 patients, 6 points in 13 and 3 points in 9. Ten recipients (21.3 %); 7 patients with 10 points and 3 patients with 6 points, underwent DDLT. Seven out of the 10 recipients received split/reduced liver grafts. The surgical complications consisted of biliary stricture, hepatic venous outflow obstruction, intraabdominal abscess and intraabdominal bleeding. Two recipients, who were critically-ill before DDLT, died due to sepsis. The one-year graft survival rate was 70.0 %, with a median follow-up period of 6.4 months. The initial experience with pediatric DDLT in our series was satisfactory. Split LT of deceased donor organs may have the potential to resolve the serious organ shortage in Japan.


Monoclonal Antibody Drugs for Systemic Lupus Erythematosus.
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease which engages most of the immune cells in its development. Various studies concerning the application of antibodies against TNF-α, BlyS, CD20, CD22, IL-6R and complement factors in treatment of SLE have been recently conducted and in spite of the good results reported by some of them, no definite conclusion on their risk-benefit profile can be drawn. The current review summarizes the results obtained in the field and reveals the perspectives for the development of new and more effective strategies for SLE treatment in combination with other immunomodulating drugs.


Identifying the recharge and salinization mechanisms of the Shekastian saline spring in southern Iran.
To identify the recharge, and the salinization mechanisms of Shekastian saline spring, appearing via thin limestone layers on the Shekastian stream bed, southern Iran, a comprehensive study was conducted using multi-tracing approach. Hydrochemical tracing indicated that the halite dissolution is the main salinity source for Shekastian spring. Similar to surface waters, spring salinity is amplified by evaporation during dry season, indicating that recharge comes from surface waters. The temperature of the spring water varies hourly, which is another sign that surface waters recharge the spring. Applying the discharge tracing method at two low-discharge times in two consecutive years by precise longitudinal discharge monitoring of the Shekastian stream above and below the spring site revealed that the main source of recharge for the Shekastian saline spring is water escape via thin limestone layers, located on a stream bed above the spring site. Results of isotope tracing indicated that Shekastian saline spring is recharged from evaporated surface water, subjecting to CO2 gas along subsurface flow path of recharging water. Geologic/geomorphologic evidences, supported by results of hydrochemical tracing, revealed that halite dissolution of Gachsaran evaporite formation by spring recharging water is the main salinization source for the Shekastian saline spring. To avoid salinization of Shekastian stream by Shekastian saline spring, draining the spring recharging water at downstream vicinity of spring recharging stream by building an underground interceptor drainage system is suggested, in which resulted in flow stopping the spring.


Abdominal wall reconstruction after desmoid type fibromatosis radical resection: Case series from a single institution and review of the literature.
Abdominal wall desmoid type fibromatosis management has been changing over recent years, from an aggressive approach towards a more conservative one. When radical resection is indicated, the surgical team faces the challenge of abdominal wall reconstruction, for which optimal technique is still debated. The present study reports the experience from a single center with abdominal closures after desmoid type fibromatosis resection. Retrospective analysis of patients who underwent abdominal wall closure after sporadic abdominal desmoid type fibromatosis radical resection from 1982 to 2013. Twenty-seven patients were included, mean tumor diameter was 10 + 5.3 cm, and the main choice of abdominal wall reconstruction was midline closure with anterior rectus sheath relaxing incisions and polypropylene onlay mesh (74% of the cases). Only 7% of the cases required more complex procedures for skin closure. Mean follow-up was 5 years and 89% remained disease-free. No grade 4 or 5 complications were observed. High midline fascial closure rate can be achieved after resection of abdominal wall desmoid tumor using relaxing incisions and mesh, with low complication rate.


Involvement of IL-2/IL-2R system activation by parasite antigen in polyclonal expansion of CD4(+)25(+) HTLV-1-infected T-cells in human carriers of both HTLV-1 and S. stercoralis.
The intermediate state of HTLV-1 infection, often found in individuals dually infected with Strongyloides stercoralis (S. stercoralis) and HTLV-1, is assumed to be a preleukemic state of adult T-cell leukemia (ATL). To investigate the effects of S. stercoralis superinfection on the natural history of HTLV-1 infection, we characterized peripheral blood samples of these individuals in Okinawa, Japan, an endemic area for both HTLV-1 and S. stercoralis and we studied effects of the parasite antigen on T-cells. The dually infected individuals showed a significantly higher provirus load and an increase in CD4(+)25(+) T cell population, with a significant, positive correlation. This increase was attributable to polyclonal expansion of HTLV-1-infected cells, as demonstrated by inverse-long PCR analysis of the integration sites. S. stercoralis antigen activated the IL-2 promoter in reporter gene assays, induced production of IL-2 by PBMC in vitro, and supported growth of IL-2 dependent cell lines immortalized by HTLV-1 infection or the transduction of Tax. Taken collectively, these results indicate that S. stercoralis infection induces polyclonal expansion of HTLV-1-infected cells by activating the IL-2/IL-2R system in dually infected carriers, an event which may be a precipitating factor for ATL and inflammatory diseases.


Loss of Diacylglycerol Kinase-Ζ Inhibits Cell Proliferation and Survival in Human Gliomas.
Diacylglycerol kinases ζ (DGKζ) is a critical lipid kinase which is involved in phosphatidic acid (PA) generation via diacylglycerol (DAG) phosphorylation. DGKζ is highly expressed in central nervous system and essential for brain development. Studies have indicated that DGKζ is associated with colon cancer invasion and metastasis. However, the involvement of DGKζ in human glioma development remains elusive. Here, we explored the impact and possible mechanisms of DGKζ knockdown on the proliferation and survival of glioma cells. The relationship between DGKζ expression status and human glioma stages was explored in 111 specimens of human gliomas via immunohistochemistry technology. Then the impact of DGKζ on cell proliferation, cell cycle, survival, and colony formation ability was determined in U-87 MG glioma cell lines via lentiviral-mediated small interfering (shRNA) strategy. The influence of DGKζ knockdown on global gene expression in U-87 MGglioma cell lines was further analyzed by microarray platform to reveal the possible molecular mechanisms underlying DGKζ-mediated glioma development and progression. Immunohistochemistry analysis revealed that DGKζ expression is positively correlated with human gliomagrade. Lentiviral-mediated small interfering (shRNA) strategyefficiently reduced DGKζ expression and DGKζ knockdown impaired cell proliferation, inhibited colony formation ability, and induced cell cycle arrest and cell apoptosis in U-87 MG glioma cells. Finally, microarray analysis revealed that multiple cancer-associated pathways and oncogenes were regulated by DGKζ knockdown, which provides insights into underlying mechansims of DGKζ-associated glioma development and progression. Our results established the positive correlation between DGKζ expression and gliomagrade. Furthermore, DGKζ knockdown in human glioma cell lines U-87 MG impaired cell proliferation, inhibited colony formation ability, and induced cell cycle arrest and apoptosis which microarray analysis showed that DGKζ knockdown interrupted multiple oncogenes and cancer-associated pathways. Taken together, we provided confidential evidence for the causal role of DGKζ in glioma development and progression.


In vitro immunomodulatory properties of gemcitabine alone and in combination with interferon-alpha.
In general, conventional chemotherapy is associated with significant toxicity leading to immunosuppression manifesting mainly in the lymphocyte depletion. This immunosuppression promotes tumor growth and elicits the tumor cell dissemination. However, chemotherapy can be immune stimulative especially in combination with an immunotherapy. In this work, we investigated in vitro effects of gemcitabine alone and in combination with interferon-alpha on splenocytes obtained from healthy and pancreatic carcinoma bearing mice. We showed that gemcitabine alone depletes the regulatory T cells in the splenocyte culture. Gemcitabine in combination with interferon-alpha demonstrated some immunomodulatory features, but these effects were interferon-alpha dependent. We concluded that combination of both drugs induces rather cumulative effects, supposing that these therapeutic could be applied together for a chemo-immunotherapy.


Outcomes of patients with Goodpasture syndrome: A nationwide cohort-based study from the French Society of Hemapheresis.
The overall and renal outcomes of patients with Goodpasture syndrome (GS), a rare autoimmune disorder characterized by circulating anti-GBM antibodies and rapidly progressive glomerulonephritis and/or pulmonary hemorrhage, have mostly been reported in small-sized cohorts or by aggregating patients receiving a variety of therapies that include aggressive (i.e., combined plasma exchanges, corticosteroids, and cyclophosphamide) and less aggressive (i.e., either plasma exchanges or immunosuppressive drugs, or no treatment). To address the prognosis of GS patients with relatively homogeneous management including plasma exchanges, we conducted a multicenter retrospective study on GS patients included in the registry of the French Society of Hemapheresis. 122 patients were included (kidney alone (n = 28), lung alone (n = 5), or combined involvement (n = 89)). All 122 patients received plasma exchanges (median number of sessions: 13 [9-17]), either alone (n = 8) or associated with combined corticosteroids and oral or IV cyclophosphamide (n = 101) or with corticosteroids alone (n = 12) or cyclophosphamide alone (n = 2). One-year survival was 86.9%. 7/16 patients died from severe infection. In multivariate analyses (Cox's regression model), being aged <60 years, and number of plasma exchanges were correlated to overall survival. The use of alternative immunosuppressive drugs (because of refractory or relapsing GS) was correlated to mortality at one year. Superiority of oral cyclophosphamide compared to intravenous intake was close to significant. Using a logistic regression model, renal survival in patients alive at 1 year was only predicted by serum creatinine <500 μmol/L at presentation. This large series describes the predictive factors for overall and renal survival of GS patients treated by plasma exchanges. Interventional studies that compare oral and intravenous cyclophosphamide, as well as testing new immunosuppressive therapies, are warranted.


Structural investigations of a GYF domain covalently linked to a proline-rich peptide.
Protein structure determination of low affinity complexes of interacting macromolecules is often hampered by a lack of observable NOEs between the binding partners. Covalent linkage offers a way to shift the equilibrium of the interaction partners to the bound state. Here we show that a single-chain protein containing the GYF domain of CD2BP2 and the target peptide SHRPPPPGHRV from CD2 allows for the intramolecular association of the binding partners. We obtained NOEs between the GYF domain and the peptide that could define the principal orientation of the peptide in the complex. In conjunction with general recognition rules for proline-rich sequence recognition these NOEs allowed the accurate modeling of the protein-peptide complex.