Association of childhood physical and sexual abuse with intimate partner violence, poor general health and depressive symptoms among pregnant women.
We examined associations of childhood physical and sexual abuse with risk of intimate partner violence (IPV). We also evaluated the extent to which childhood abuse was associated with self-reported general health status and symptoms of antepartum depression in a cohort of pregnant Peruvian women. In-person interviews were conducted to collect information regarding history of childhood abuse and IPV from 1,521 women during early pregnancy. Antepartum depressive symptomatology was evaluated using the Patient Health Questionnaire-9. Multivariable logistic regression procedures were used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (95%CI). Any childhood abuse was associated with 2.2-fold increased odds of lifetime IPV (95%CI: 1.72-2.83). Compared with women who reported no childhood abuse, those who reported both, childhood physical and sexual abuse had a 7.14-fold lifetime risk of physical and sexual IPV (95%CI: 4.15-12.26). The odds of experiencing physical and sexual abuse by an intimate partner in the past year was 3.33-fold higher among women with a history of childhood physical and sexual abuse as compared to women who were not abused as children (95%CI 1.60-6.89). Childhood abuse was associated with higher odds of self-reported poor health status during early pregnancy (aOR = 1.32, 95%CI: 1.04-1.68) and with symptoms of antepartum depression (aOR = 2.07, 95%CI: 1.58-2.71). These data indicate that childhood sexual and physical abuse is associated with IPV, poor general health and depressive symptoms in early pregnancy. The high prevalence of childhood trauma and its enduring effects of on women's health warrant concerted global health efforts in preventing violence.


Rhodium nanoparticles for ultraviolet plasmonics.
The nonoxidizing catalytic noble metal rhodium is introduced for ultraviolet plasmonics. Planar tripods of 8 nm Rh nanoparticles, synthesized by a modified polyol reduction method, have a calculated local surface plasmon resonance near 330 nm. By attaching p-aminothiophenol, local field-enhanced Raman spectra and accelerated photodamage were observed under near-resonant ultraviolet illumination, while charge transfer simultaneously increased fluorescence for up to 13 min. The combined local field enhancement and charge transfer demonstrate essential steps toward plasmonically enhanced ultraviolet photocatalysis.


Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota.
In recent years, several associations between common chronic human disorders and altered gut microbiome composition and function have been reported. In most of these reports, treatment regimens were not controlled for and conclusions could thus be confounded by the effects of various drugs on the microbiota, which may obscure microbial causes, protective factors or diagnostically relevant signals. Our study addresses disease and drug signatures in the human gut microbiome of type 2 diabetes mellitus (T2D). Two previous quantitative gut metagenomics studies of T2D patients that were unstratified for treatment yielded divergent conclusions regarding its associated gut microbial dysbiosis. Here we show, using 784 available human gut metagenomes, how antidiabetic medication confounds these results, and analyse in detail the effects of the most widely used antidiabetic drug metformin. We provide support for microbial mediation of the therapeutic effects of metformin through short-chain fatty acid production, as well as for potential microbiota-mediated mechanisms behind known intestinal adverse effects in the form of a relative increase in abundance of Escherichia species. Controlling for metformin treatment, we report a unified signature of gut microbiome shifts in T2D with a depletion of butyrate-producing taxa. These in turn cause functional microbiome shifts, in part alleviated by metformin-induced changes. Overall, the present study emphasizes the need to disentangle gut microbiota signatures of specific human diseases from those of medication.


Clinic-integrated behavioral intervention for families of youth with type 1 diabetes: randomized clinical trial.
To test the effect on diabetes management outcomes of a low-intensity, clinic-integrated behavioral intervention for families of youth with type 1 diabetes. Families (n = 390) obtaining care for type 1 diabetes participated in a 2-year randomized clinical trial of a clinic-integrated behavioral intervention designed to improve family diabetes management practices. Measurement of hemoglobin A1c, the primary outcome, was obtained at each clinic visit and analyzed centrally. Blood glucose meter data were downloaded at each visit. Adherence was assessed by using a semistructured interview at baseline, mid-study, and follow-up. Analyses included 2-sample t tests at predefined time intervals and mixed-effect linear-quadratic models to assess for difference in change in outcomes across the study duration. A significant overall intervention effect on change in glycemic control from baseline was observed at the 24-month interval (P = .03). The mixed-effect model showed a significant intervention by age interaction (P < .001). Among participants aged 12 to 14, a significant effect on glycemic control was observed (P = .009 for change from baseline to 24-month interval; P = .035 for mixed-effect model across study duration), but there was no effect among those aged 9 to 11. There was no intervention effect on child or parent report of adherence; however, associations of change in adherence with change in glycemic control were weak. This clinic-integrated behavioral intervention was effective in preventing the deterioration in glycemic control evident during adolescence, offering a potential model for integrating medical and behavioral sciences in clinical care.


Constraining timescales of focused magmatic accretion and extension in the Afar crust using lava geochronology.
As continental rift zones mature the tectonic and volcanic processes associated with crustal extension become confined to narrow magmatic rift zones, reminiscent of oceanic spreading ridges. The formation of these rift zones and the development of ocean-ridge type topography is a significant milestone in rift evolution as it signifies the localization of crustal extension and rift-related volcanism. Here we show that lavas, which erupted since ~200 ka along part of the on-land Red Sea rift system in Afar, Ethiopia, have a consistent age-progression from the rift axis outwards, indicating that axial dyke intrusion has been the primary mechanism of segment growth and that focused magmatic accretion and extension in the crust have remained stable here over this period. Our results suggest that as this rift segment has formed, in thinned and intruded continental crust, the time-averaged surface opening rate has closely approximated the total extension rate between Africa and Arabia.


Association of mitochondrial variants and haplogroups identified by whole exome sequencing with Alzheimer's disease.
Findings regarding the association between mitochondrial DNA (mtDNA) variants and Alzheimer's disease (AD) are inconsistent. We developed a pipeline for accurate assembly and variant calling in mitochondrial genomes embedded within whole exome sequences (WES) from 10,831 participants from the Alzheimer's Disease Sequencing Project (ADSP). Association of AD risk was evaluated with each mtDNA variant and variants located in 1158 nuclear genes related to mitochondrial function using the SCORE test. Gene-based tests were performed using SKAT-O. Analysis of 4220 mtDNA variants revealed study-wide significant association of AD with a rare MT-ND4L variant (rs28709356 C>T; minor allele frequency = 0.002; P = 7.3 × 10-5 ) as well as with MT-ND4L in a gene-based test (P = 6.71 × 10-5 ). Significant association was also observed with a MT-related nuclear gene, TAMM41, in a gene-based test (P = 2.7 × 10-5 ). The expression of TAMM41 was lower in AD cases than controls (P = .00046) or mild cognitive impairment cases (P = .03). Significant findings in MT-ND4L and TAMM41 provide evidence for a role of mitochondria in AD.


Ultrastructural features of diseased human atrial muscle cells.
Left atrial myocardial tissues, excised at the time of surgery from 30 Japanese patients, were studied using light and electron microscopy and the freeze-fracture technique. All had mitral valvular disease, and, in 22 (74%) patients, atrial fibrillation also was present. In all patients, most of the left atrial cardiocytes were hypertrophied and surrounded by various amounts of fibrous tissue. Degenerative alterations included large masses of lipofuscin granules and lamellar bodies, disorganized myofibrils, widened Z-line material, selective loss of thick filaments, and prominent tubules of sarcoplasmic reticulum. A high incidence of tubular aggregates was observed in 70% of the cases. Such alterations were seen more often in the mitral regurgitation group as compared to the mitral stenosis group. Atrial cardiocytes were found to be more susceptible to disease processes, such as rheumatic fever and subsequent pressure and/or volume overloading, than ventricular cardiocytes. Human atrial cardiocytes may be utilized in future cytopathological studies to study the effect of processes leading to cardiocyte hypertrophy and degeneration.


Intranasal mupirocin to prevent postoperative Staphylococcus aureus infections.
Patients with nasal carriage of Staphylococcus aureus have an increased risk of surgical-site infections caused by that organism. Treatment with mupirocin ointment can reduce the rate of nasal carriage and may prevent postoperative S. aureus infections. We conducted a randomized, double-blind, placebo-controlled trial to determine whether intranasal treatment with mupirocin reduces the rate of S. aureus infections at surgical sites and prevents other nosocomial infections. Of 4030 enrolled patients who underwent general, gynecologic, neurologic, or cardiothoracic surgery, 3864 were included in the intention-to-treat analysis. Overall, 2.3 percent of mupirocin recipients and 2.4 percent of placebo recipients had S. aureus infections at surgical sites. Of the 891 patients (23.1 percent of the 3864 who completed the study) who had S. aureus in their anterior nares, 444 received mupirocin and 447 received placebo. Among the patients with nasal carriage of S. aureus, 4.0 percent of those who received mupirocin had nosocomial S. aureus infections, as compared with 7.7 percent of those who received placebo (odds ratio for infection, 0.49; 95 percent confidence interval, 0.25 to 0.92; P=0.02). Prophylactic intranasal application of mupirocin did not significantly reduce the rate of S. aureus surgical-site infections overall, but it did significantly decrease the rate of all nosocomial S. aureus infections among the patients who were S. aureus carriers.


Blockade of endoplasmic reticulum stress-induced cell death by Ureaplasma parvum vacuolating factor.
Previously, we found that Ureaplasma parvum internalised into HeLa cells and cytosolic accumulation of galectin-3. U. parvum induced the host cellular membrane damage and survived there. Here, we conducted vesicular trafficking inhibitory screening in yeast to identify U. parvum vacuolating factor (UpVF). U. parvum triggered endoplasmic reticulum (ER) stress and upregulated the unfolded protein response-related factors, including BiP, P-eIF2 and IRE1 in the host cells, but it blocked the induction of the downstream apoptotic factors. MicroRNA library screening of U. parvum-infected cells and UpVF-transfected cells identified miR-211 and miR-214 as the negative regulators of the apoptotic cascade under ER stress. Transient expression of UpVF induced HeLa cell death with intracellular vacuolization; however, some stable UpVF transformant survived. U. parvum-infected cervical cell lines showed resistance to actinomycin D, and UpVF stable transformant cell lines exhibited resistance to X-ray irradiation, as well as cisplatin and paclitaxel. UpVF expressing cervical cancer xenografts in nude mice also acquired resistance to cisplatin and paclitaxel. A mycoplasma expression vector based on Mycoplasma mycoides, Syn-MBA (multiple banded antigen)-UpVF, reduced HeLa cell survival compared with that of Syn-MBA after 72 hr of infection. These findings together suggest novel mechanisms for Ureaplasma infection and the possible implications for cervical cancer malignancy. TAKE AWAYS: • Ureaplasmal novel virulence factor, UpVF, was identified. • UpVF triggered ER stress but suppressed apoptotic cascade via miR-211 and -214. • UpVF conferred resistance to anticancer treatments both in vivo and in vitro. • Dual expression of MBA and UpVF in JCVI-syn3B showed host cell damage.


Excessive gestational weight gain predicts large for gestational age neonates independent of maternal body mass index.
To determine the effects of maternal pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) on large-for-gestational-age (LGA) birth weight (≥90th % ile). We examined 4321 mother-infant pairs from the Ottawa and Kingston (OaK) birth cohort. Multivariate logistic regression (controlling for gestational and maternal age, pre-pregnancy weight, parity, smoking) were performed and odds ratios (ORs) calculated. Prior to pregnancy, a total of 23.7% of women were overweight and 16.2% obese. Only 29.3% of women met GWG targets recommended by the Institute of Medicine (IOM), whereas 57.7% exceeded the guidelines. Adjusting for smoking, parity, age, maternal height, and achieving the IOM's recommended GWG, overweight (OR 1.99; 95%CI 1.17-3.37) or obese (OR 2.64; 95% CI 1.59-4.39) pre-pregnancy was associated with a higher rate of LGA compared to women with normal BMI. In the same model, exceeding GWG guidelines was associated with higher rates of LGA (OR 2.86; 95% CI 2.09-3.92), as was parity (OR 1.49; 95% CI 1.22-1.82). Smoking (OR 0.53; 95%CI 0.35-0.79) was associated with decreased rates of LGA. The adjusted association with LGA was also estimated for women who exceeded the GWG guidelines and were overweight (OR 3.59; 95% CI 2.60-4.95) or obese (OR 6.71; 95% CI 4.83-9.31). Pregravid overweight or obesity and gaining in excess of the IOM 2009 GWG guidelines strongly increase a woman's chance of having a larger baby. Lifestyle interventions that aim to optimize GWG by incorporating healthy eating and exercise strategies during pregnancy should be investigated to determine their effects on LGA neonates and down-stream child obesity.


Virus-vector-host relationships of Aedes stimulans and Jamestown Canyon virus in a northern Indiana enzootic focus.
Collections of hematophagous Diptera at the Kingsbury State Fish and Wildlife Area in northern Indiana between 1982 and 1984 yielded 118,972 mosquitoes from which 5 isolates of Jamestown Canyon virus and 3 isolates of trivittatus virus were obtained. All Jamestown Canyon isolates were from Aedes stimulans, including 1 from a pool of newly emerged males and 2 from pools of newly emerged females. These 3 isolates suggest that Jamestown Canyon virus is transovarially transmitted by Ae. stimulans. All isolates of trivittatus virus came from pools of Ae. trivittatus. No isolates were obtained from greater than 4,000 tabanids collected along with the mosquitoes those years. Transmission trials with field-collected newly emerged adult female Ae. stimulans demonstrated a mean midgut infection rate of 44%, a disseminated infection rate of 16%, and an oral transmission rate of 12% to suckling mice. Precipitin tests of field-collected bloodfed female mosquitoes indicated that white-tailed deer were the preferred host for numerous mosquito species including Ae. stimulans. The results of this study suggest that Ae. stimulans is a primary vector of Jamestown Canyon virus and that transovarial transmission is the probable overwintering mechanism for this California group virus.


Developing a Standardized and Reusable Method to Link Distributed Health Plan Databases to the National Death Index: Methods Development Study Protocol.
Certain medications may increase the risk of death or death from specific causes (eg, sudden cardiac death), but these risks may not be identified in premarket randomized trials. Having the capacity to examine death in postmarket safety surveillance activities is important to the US Food and Drug Administration's (FDA) mission to protect public health. Distributed networks of electronic health plan databases used by the FDA to conduct multicenter research or medical product safety surveillance studies often do not systematically include death or cause-of-death information. This study aims to develop reusable, generalizable methods for linking multiple health plan databases with the Centers for Disease Control and Prevention's National Death Index Plus (NDI+) data. We will develop efficient administrative workflows to facilitate multicenter institutional review board (IRB) review and approval within a distributed network of 6 health plans. The study will create a distributed NDI+ linkage process that avoids sharing of identifiable patient information between health plans or with a central coordinating center. We will develop standardized criteria for selecting and retaining NDI+ matches and methods for harmonizing linked information across multiple health plans. We will test our processes within a use case comprising users and nonusers of antiarrhythmic medications. We will use the linked health plan and NDI+ data sets to estimate the incidences and incidence rates of mortality and specific causes of death within the study use case and compare the results with reported estimates. These comparisons provide an opportunity to assess the performance of the developed NDI+ linkage approach and lessons for future studies requiring NDI+ linkage in distributed database settings. This study is approved by the IRB at Harvard Pilgrim Health Care in Boston, MA. Results will be presented to the FDA at academic conferences and published in peer-reviewed journals. This study will develop and test a reusable distributed NDI+ linkage approach with the goal of providing tested NDI+ linkage methods for use in future studies within distributed data networks. Having standardized and reusable methods for systematically obtaining death and cause-of-death information from NDI+ would enhance the FDA's ability to assess mortality-related safety questions in the postmarket, real-world setting. DERR1-10.2196/21811.


On the single point resolution of on-axis digital holography.
On-axis digital holography (DH) is becoming widely used for its time-resolved three-dimensional (3D) imaging capabilities. A 3D volume can be reconstructed from a single hologram. DH is applied as a metrological tool in experimental mechanics, biology, and fluid dynamics, and therefore the estimation and the improvement of the resolution are current challenges. However, the resolution depends on experimental parameters such as the recording distance, the sensor definition, the pixel size, and also on the location of the object in the field of view. This paper derives resolution bounds in DH by using estimation theory. The single point resolution expresses the standard deviations on the estimation of the spatial coordinates of a point source from its hologram. Cramér-Rao lower bounds give a lower limit for the resolution. The closed-form expressions of the Cramér-Rao lower bounds are obtained for a point source located on and out of the optical axis. The influences of the 3D location of the source, the numerical aperture, and the signal-to-noise ratio are studied.


Released Tryptophanyl-tRNA Synthetase Stimulates Innate Immune Responses against Viral Infection.
Tryptophanyl-tRNA synthetase (WRS) is one of the aminoacyl-tRNA synthetases (ARSs) that possesses noncanonical functions. Full-length WRS is released during bacterial infection and primes the Toll-like receptor 4 (TLR4)-myeloid differentiation factor 2 (MD2) complex to elicit innate immune responses. However, the role of WRS in viral infection remains unknown. Here, we show that full-length WRS is secreted by immune cells in the early phase of viral infection and functions as an antiviral cytokine. Treatment of cells with recombinant WRS protein promotes the production of inflammatory cytokines and type I interferons (IFNs) and curtails virus replication in THP-1 and Raw264.7 cells but not in TLR4-/- or MD2-/- bone marrow-derived macrophages (BMDMs). Intravenous and intranasal administration of recombinant WRS protein induces an innate immune response and blocks viral replication in vivo These findings suggest that secreted full-length WRS has a noncanonical role in inducing innate immune responses to viral infection as well as to bacterial infection.IMPORTANCE ARSs are essential enzymes in translation that link specific amino acids to their cognate tRNAs. In higher eukaryotes, some ARSs possess additional, noncanonical functions in the regulation of cell metabolism. Here, we report a novel noncanonical function of WRS in antiviral defense. WRS is rapidly secreted in response to viral infection and primes the innate immune response by inducing the secretion of proinflammatory cytokines and type I IFNs, resulting in the inhibition of virus replication both in vitro and in vivo Thus, we consider WRS to be a member of the antiviral innate immune response. The results of this study enhance our understanding of host defense systems and provide additional information on the noncanonical functions of ARSs.


Cell penetrating peptide delivery of splice directing oligonucleotides as a treatment for Duchenne muscular dystrophy.
Duchenne muscular dystrophy is a severe, X-linked muscle wasting disorder caused by the absence of an integral structural protein called dystrophin. This is caused by mutations or deletions in the dystrophin gene which disrupt the reading frame, thereby halting the production of a functional protein. A number of potential therapies have been investigated for the treatment of this disease including utrophin upregulation, 'stop-codon read through' aminoglycosides and adeno-associated virus gene replacement as well as stem cell therapy. However, the most promising treatment to date is the use of antisense oligonucleotides which cause exon skipping by binding to a specific mRNA sequence, skipping the desired exon, thereby restoring the reading frame and producing a truncated yet functional protein. The results from recent 2'OMePS and morpholino clinical trials have renewed hope for Duchenne patients; however in vivo studies in a mouse model, mdx, have revealed low systemic distribution and poor delivery of oligonucleotides to affected tissues such as the brain and heart. However a variety of cell penetrating peptides directly conjugated to antisense oligonucleotides have been shown to enhance delivery in Duchenne model systems with improved systemic distribution and greater efficacy compared to 'naked' antisense oligonucleotides. These cell penetrating peptides, combined with an optimised dose and dosing regimen, as well as thorough toxicity profile have the potential to be developed into a promising treatment which may be progressed to clinical trial.


Investigation of the effect of subcutaneous fat on image quality performance of 2D conventional imaging and tissue harmonic imaging.
Tissue harmonic imaging (THI) has been reported to improve contrast resolution, tissue differentiation and overall image quality in clinical examinations. However, a study carried out previously by the authors (Brown et al. 2004) found improvements only in spatial resolution and not in contrast resolution or anechoic target detection. This result may have been due to the homogeneity of the phantom. Biologic tissues are generally inhomogeneous and THI has been reported to improve image quality in the presence of large amounts of subcutaneous fat. The aims of the study were to simulate the distortion caused by subcutaneous fat to image quality and thus investigate further the improvements reported in anechoic target detection and contrast resolution performance with THI compared with 2D conventional imaging. In addition, the effect of three different types of fat-mimicking layer on image quality was examined. The abdominal transducer of two ultrasound scanners with 2D conventional imaging and THI were tested, the 4C1 (Aspen-Acuson, Siemens Co., CA, USA) and the C5-2 (ATL HDI 5000, ATL/Philips, Amsterdam, The Netherlands). An ex vivo subcutaneous pig fat layer was used to replicate beam distortion and phase aberration seen clinically in the presence of subcutaneous fat. Three different types of fat-mimicking layers (olive oil, lard and lard with fish oil capsules) were evaluated. The subcutaneous pig fat layer demonstrated an improvement in anechoic target detection with THI compared with 2D conventional imaging, but no improvement was demonstrated in contrast resolution performance; a similar result was found in a previous study conducted by this research group (Brown et al. 2004) while using this tissue-mimicking phantom without a fat layer. Similarly, while using the layers of olive oil, lard and lard with fish oil capsules, improvements due to THI were found in anechoic target detection but, again, no improvements were found for contrast resolution for any of the layer combinations. Therefore, it was felt that the lack of improvement in contrast resolution performance may be due to the test phantom design and not to whether a layer was present that caused beam distortion and phase aberrations.


National performance on door-in to door-out time among patients transferred for primary percutaneous coronary intervention.
Delays in treatment time are commonplace for patients with ST-segment elevation acute myocardial infarction who must be transferred to another hospital for percutaneous coronary intervention. Experts have recommended that door-in to door-out (DIDO) time (ie, time from arrival at the first hospital to transfer from that hospital to the percutaneous coronary intervention hospital) should not exceed 30 minutes. We sought to describe national performance in DIDO time using a new measure developed by the Centers for Medicare & Medicaid Services. We report national median DIDO time and examine associations with patient characteristics (age, sex, race, contraindication to fibrinolytic therapy, and arrival time) and hospital characteristics (number of beds, geographic region, location [rural or urban], and number of cases reported) using a mixed effects multivariable model. Among 13,776 included patients from 1034 hospitals, only 1343 (9.7%) had a DIDO time within 30 minutes, and DIDO exceeded 90 minutes for 4267 patients (31.0%). Mean estimated times (95% CI) to transfer based on multivariable analysis were 8.9 (5.6-12.2) minutes longer for women, 9.1 (2.7-16.0) minutes longer for African Americans, 6.9 (1.6-11.9) minutes longer for patients with contraindication to fibrinolytic therapy, shorter for all age categories (except >75 years) relative to the category of 18 to 35 years, 15.3 (7.3-23.5) minutes longer for rural hospitals, and 14.4 (6.6-21.3) minutes longer for hospitals with 9 or fewer transfers vs 15 or more in 2009 (all P < .001). Among patients presenting to emergency departments and requiring transfer to another facility for percutaneous coronary intervention, the DIDO time rarely met the recommended 30 minutes.


Developing a Policy Flight Simulator to Facilitate the Adoption of an Evidence-Based Intervention.
While the use of evidence-based interventions (EBIs) has been advocated by the medical research community for quite some time, uptake of these interventions by healthcare providers has been slow. One possible explanation is that it is challenging for providers to estimate impacts of a specific EBI on their particular organization. To address that concern, we developed and evaluated a type of simulation called a policy flight simulator to determine if it could improve the adoption decision about a specific EBI, the transitional care model (TCM). The TCM uses an advanced practice nurse-led model of care to transition older adults with multiple chronic conditions from a hospitalization to home. An evaluation by a National Advisory Committee, made up of senior representatives from various stakeholders in the U.S. healthcare system, found the policy flight simulator to be a useful tool that has the potential to better inform adoption decisions. This paper describes the simulation development effort and documents lessons learned that may be useful to the healthcare modeling community and those interested in using simulation to support decisions based on EBIs.


V. The differential association of adiposity and fitness with cognitive control in preadolescent children.
With the increasing prevalence of sedentary behaviors during childhood, a greater understanding of the extent to which excess adiposity and aerobic fitness relate to cognitive health is of increasing importance. To date, however, the vast majority of research in this area has focused on adiposity or fitness, rather than the possible inter-relationship, as it relates to cognition. Accordingly, this study examined the differential associations between body composition, aerobic fitness, and cognitive control in a sample of 204 (96 female) preadolescent children. Participants completed a modified flanker task (i.e., inhibition) and a switch task (i.e., cognitive flexibility) to assess two aspects of cognitive control. Findings from this study indicate that fitness and adiposity appear to be separable factors as they relate to cognitive control, given that the interaction of fitness and adiposity was observed to be nonsignificant for both the flanker and switch tasks. Fitness exhibited an independent association with both inhibition and cognitive flexibility whereas adiposity exhibited an independent association only with cognitive flexibility. These results suggest that while childhood obesity and fitness appear to both be related to cognitive control, they may be differentially associated with its component processes.


Chromosome segregation defects contribute to aneuploidy in normal neural progenitor cells.
Recent studies based predominantly on nucleotide hybridization techniques have identified aneuploid neurons and glia in the normal brain. To substantiate these findings and address how neural aneuploidy arises, we examined individual neural progenitor cells (NPCs) undergoing mitosis. Here we report the identification of chromosomal segregation defects in normal NPCs of the mouse cerebral cortex. Immunofluorescence in fixed tissue sections revealed the presence of supernumerary centrosomes and lagging chromosomes among mitotic NPCs. The extent of aneuploidy followed the prevalence of supernumerary centrosomes within distinct cell populations. Real-time imaging of live NPCs revealed lagging chromosomes and multipolar divisions. NPCs undergoing nondisjunction were also observed, along with interphase cells that harbored micronuclei or multiple nuclei, consistent with unbalanced nuclear division. These data independently confirm the presence of aneuploid NPCs and demonstrate the occurrence of mitotic segregation defects in normal cells that can mechanistically account for aneuploidy in the CNS.


Guillain-Barré Syndrome After Acute Hepatitis E Infection: A Case Report and Literature Review.
Guillain-Barré syndrome precipitated by hepatitis E virus infection is rare, yet its incidence is increasing. A 57-year-old man was transferred from another facility with fatigue, orange urine, and progressive weakness over 4 to 6 weeks. Initial laboratory results included total bilirubin, 9.0 mg/dL; direct bilirubin, 6.4 mg/dL; aspartate aminotransferase, 1551 U/L; alanine aminotransferase, 3872 U/L; and alkaline phosphatase, 430 U/L. Immunoglobulin M and quantitative polymerase chain reaction test results were positive for hepatitis E virus. Contrast-enhanced magnetic resonance imaging of the brain and spine showed no gross abnormalities. Analysis of cerebrospinal fluid obtained by lumbar puncture revealed the following (reference values in parentheses): total white blood cell count, 15/μL (0-5/μL), with 33% neutrophils and 54% lymphocytes; protein, 0.045 g/dL (0.015-0.045 g/dL); and glucose, 95 mg/dL (within reference range). Neurological examination revealed weakness in both upper extremities, with proximal strength greater than distal strength. The patient could not elevate either lower extremity off the bed and had areflexia and reduced sensation throughout all extremities. Guillain-Barré syndrome secondary to acute hepatitis E virus infection was diagnosed on the basis of clinical characteristics, serum and cerebrospinal fluid analyses, and nerve conduction studies. Nurses and clinicians should obtain a thorough history and consider hepatitis E virus infection as a precipitating factor in patients with sensory and motor disturbances consistent with Guillain-Barré syndrome. The case gives insight into the diagnostic process for Guillain-Barré syndrome and highlights the vital role of bedside nurses in evaluating and treating these patients.


A pilot clinical study of continuous intravenous ascorbate in terminal cancer patients.
Case studies suggest that vitamin C, given intravenously at doses of 10-100 grams/day can improve patient well being and in some cases, reduce tumor size. While ascorbate is generally considered safe, clinical data on high intravenous doses is limited. Twenty-four late stage terminal cancer patients were given continuous infusions of 150 to 710 mg/kg/day for up to eight weeks. Blood chemistry and blood count profiles were obtained at roughly one-week intervals while patient health, adverse events and tumor progression were monitored. The majority of patients were vitamin C deficient prior to treatment. Intravenous infusions increased plasma ascorbate concentrations to a mean of 1.1 mM. The most common adverse events reported were nausea, edema, and dry mouth or skin; and these were generally minor. Two Grade 3 adverse events 'possibly related' to the agent were reported: one patient with a history of renal calculi developed a kidney stone after thirteen days of treatment and another patient experienced hypokalemia after six weeks of treatment. White blood cell counts were stable while hemoglobin and hematocrit levels dropped slightly during treatment, consistent with trends observed prior to therapy. Blood creatinine, BUN, glucose, and uric acid concentrations decreased or remained stable during therapy, suggesting that ascorbate infusions did not adversely affect renal function. One patient had stable disease and continued the treatment for forty-eight weeks. These data suggest that intravenous vitamin C therapy for cancer is relatively safe, provided the patient does not have a history of kidney stone formation.


Copy number variation of the SELENBP1 gene in schizophrenia.
Schizophrenia is associated with rare copy-number (CN) mutations. Screening for such alleles genome-wide, though comprehensive, cannot study in-depth the causality of particular loci, therefore cannot provide the functional interpretation for the disease etiology. We hypothesized that CN mutations in the SELENBP1 locus could associate with the disorder and that these mutations could alter the gene product's activity in patients. We analyzed SELENBP1 CN variation (CNV) in blood DNA from 49 schizophrenia patients and 49 controls (cohort A). Since CN of genes may vary among tissues, we investigated SELENBP1 CN in age- sex- and postmortem interval-matched cerebellar DNA samples from 14 patients and 14 controls (cohort B). Since CNV may either be de-novo or inherited we analyzed CNV of the SELENBP1 locus in blood DNA from 26 trios of schizophrenia probands and their healthy parents (cohort C). SELENBP1 mRNA levels were measured by real-time PCR. In cohort A reduced CN of the SELENBP1 locus was found in four patients but in none of the controls. In cohort B we found reduced CN of the SELENBP1 locus in two patients but in none of the controls. In cohort C three patients exhibited drastic CN reduction, not present in their parents, indicating de-novo mutation. A reduction in SELENBP1 mRNA levels in the postmortem cerebellar samples of schizophrenia patients was found. We report a focused study of CN mutations in the selenium binding-protein1 (SELENBP1) locus previously linked with schizophrenia. We provide evidence for recurrence of decreased CN of the SELENBP1 locus in three unrelated patients' cohorts but not in controls, raising the possibility of functional involvement of these mutations in the etiology of the disease.


[Effects of allitridin on the expression of human cytomegalovirus immediate early antigens-IE72 and IE86 in human embryonic lung cells].
To investigate the effect of allitridin injection on the expression of human cytomegalovirus (HCMV) immediate-early antigens (IEAs including IE72 and IE86) in human embryonic lung cells. HCMV AD 169 Virus strain infected cell model (MOI = 2.5 and 0.25, respectively) were established, and then treated with ICm5 and MTC doses of allitridin. Western blot was used to analyze the of IE72 and IE86 expression after the treatment, ganciclovir(GCV, IC50 and 2.3 x IC50) treatment as control. No matter what kind of MOI was used, both IE86 and IE72 antigens' expression was effectively suppressed by allitridin treatment, and the inhibitory rate of IE86 was almost twice of IE72's. Compared with GCV, allitridin had stronger inhibitory effect on IE86 expressing, although its efficacy on IE72 was weaker than GCV. Allitridin could suppress the expression of IE72 and IE86, especially for IE86 expressing, maybe it is ore of key role in the mechanism of allitridin against HCMV.


Nicotinic Receptor Subunits Atlas in the Adult Human Lung.
Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels responsible for rapid neural and neuromuscular signal transmission. Although it is well documented that 16 subunits are encoded by the human genome, their presence in airway epithelial cells (AECs) remains poorly understood, and contribution to pathology is mainly discussed in the context of cancer. We analysed nAChR subunit expression in the human lungs of smokers and non-smokers using transcriptomic data for whole-lung tissues, isolated large AECs, and isolated small AECs. We identified differential expressions of nAChRs in terms of detection and repartition in the three modalities. Smoking-associated alterations were also unveiled. Then, we identified an nAChR transcriptomic print at the single-cell level. Finally, we reported the localizations of detectable nAChRs in bronchi and large bronchioles. Thus, we compiled the first complete atlas of pulmonary nAChR subunits to open new avenues to further unravel the involvement of these receptors in lung homeostasis and respiratory diseases.


Is the use of psychotropic drugs associated with increased risk of ischemic heart disease?
Earlier reports of associations between panic disorder, depression, and ischemic heart disease have not evaluated the role of the drugs used to treat these conditions. As part of a larger study on reducing cardiovascular disease in an entire community, we estimated the association between psychotropic drugs and ischemic heart disease in a large community-based population using a cohort study design. We defined exposure as current use of psychotropic medications at the time of the health interview. We determined ischemic heart disease by International Classification of Diseases, 9th revision, Clinical Modification, codes and by an epidemiologic algorithm using clinical diagnostic criteria. An elevated risk for clinically significant ischemic cardiac events was moderately associated with benzodiazepine use [relative risk (RR) = 2.0; 90% confidence interval (CI) = 1.1-3.9] and strongly associated with antidepressant use (RR = 5.7; 90% CI = 2.6-12.8), although the latter estimate was based on only six antidepressant users who had an ischemic event.


Topiramate treatment of alcohol use disorder in veterans with posttraumatic stress disorder: a randomized controlled pilot trial.
The course of posttraumatic stress disorder (PTSD) is frequently and severely complicated by co-occurring alcohol use disorder (AUD), yet there are few reports of pharmacologic treatments for these comorbid conditions. The objective of this pilot study was to obtain a preliminary assessment of the efficacy and safety of topiramate in reducing alcohol use and PTSD symptoms in veterans with both disorders. This was a prospective 12-week, randomized, double-blind, placebo-controlled pilot trial of flexible-dose topiramate up to 300 mg/d in 30 veterans with PTSD and AUD. The primary outcome measure was frequency of drinking. Secondary outcomes consisted of other measures of alcohol use and PTSD symptom severity. Within-group analyses showed that topiramate treatment was associated with significant reductions in frequency and amount of alcohol use and alcohol craving from baseline through week 12. Between-group analyses showed that topiramate reduced frequency of alcohol use and alcohol craving significantly more than placebo and tended to reduce drinking amount. Topiramate treatment was also associated with decreased PTSD symptom severity and tended to reduce hyperarousal symptoms compared with placebo. Topiramate transiently impaired learning and memory, with significant recovery by the end of treatment. These preliminary results indicate that in veterans with co-occurring PTSD and AUD, topiramate may be effective in reducing alcohol consumption, alcohol craving, and PTSD symptom severity-particularly hyperarousal symptoms. Topiramate was associated with transient cognitive impairment but was otherwise well tolerated.


Are short training sessions on hand hygiene effective in preventing hospital-acquired MRSA? A time-series analysis.
We tested the impact of short hand hygiene training sessions and bed occupancy rates on the spread of hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA) using a multivariate time-series analysis. According to our model, bed occupancy rates within general ward and intensive care unit settings correlated positively with the incidence of hospital-acquired MRSA, whereas alcohol-based hand rub use and MRSA showed a negative correlation. Furthermore, our model shows that 2 hand hygiene campaigns based on short training sessions effected a long-run reduction in the incidence of hospital-acquired MRSA.


Poor health-related quality of life and proactive primary control strategy may act as risk factors for acute coronary syndrome.
Increasing evidence supports that psychological factors may be related to development of coronary artery disease (CAD). Although psychological well-being, ill-being, and control strategy factors may play a significant role in CAD, rarely have these factors been simultaneously examined previously. We assessed comprehensive psychological factors in patients with acute coronary syndrome (ACS). A total of 85 ACS patients (56 unstable angina, 29 acute myocardial infarction; 52.6±10.2 years; M/F=68/17) and 63 healthy controls (48.7±6.7 years, M/F=43/20) were included. Socio-demographic information, levels of psychological maladjustment, such as anxiety, hostility, and job stress, health-related quality of life (HRQoL), and primary and secondary control strategy use were collected through self-report questionnaires. There was no significant difference between the ACS group and control group in levels of anxiety, hostility, and job stress. However, ACS patients had significantly lower scores on the general health perception and bodily pain subscales of HRQoL than the control group. The ACS group, as compared with the controls, tended to use primary control strategies more, although not reaching statistical significance by univariate analysis. Multivariate logistic regression analysis after adjusting age and gender identified the physical domain of HRQoL {odds ratio (OR)=0.40}, primary control strategy (OR=1.92), and secondary control strategy (OR=0.53) as independent predictors of ACS. Poor HRQoL and primary control strategy, proactive behaviors in achieving ones' goal, may act as risk factors for ACS, while secondary control strategy to conform to current situation may act as a protective factor for ACS.


Long-term effects of weight reduction on the severity of psoriasis in a cohort derived from a randomized trial: a prospective observational follow-up study.
Weight reduction may reduce the severity of psoriasis, but little is known about the long-term effects. We aimed to investigate long-term effects of weight reduction in psoriasis. We previously conducted a randomized trial (n = 60) involving patients with psoriasis who were allocated to a control group or a low-energy diet (LED) group. Here we followed the participants for an additional 48-wk period. In total, 56 patients with psoriasis [mean ± SD body mass index (in kg/m(2)): 34.4 ± 5.3] underwent a 64-wk weight-loss program consisting of an initial 16-wk randomized phase with an LED for 8 wk and 8 wk of normal food intake combined with 2 LED products/d, followed by a 48-wk period of weight maintenance with the latter diet. After the randomization phase, the control group received the same 8 + 8-wk LED intervention, and all patients were then followed for 48 wk while on the weight-loss maintenance diet. The main outcome was the Psoriasis Area and Severity Index (PASI), and secondary outcome was the Dermatology Life Quality Index (DLQI). For the present study, 56 patients were eligible, 38 agreed to participate, and 32 completed. After the 16-wk LED-only period, the mean weight loss was -15.0 kg (95% CI: -16.6, -13.4 kg), and PASI and DLQI were reduced by -2.3 (95% CI: -3.1, -1.5) and -2.3 (95% CI: -3.2, -1.4), respectively. At week 64, the mean weight loss compared with baseline was -10.1 kg (95% CI: -12.0, -8.1 kg), and PASI and DLQI were maintained at -2.9 (95% CI: -3.9, -1.9) and -1.9 (95% CI: -3.0, -0.9), respectively. Long-term weight loss in patients with psoriasis has long-lasting positive effects on the severity of psoriasis. This trial was registered at clinicaltrials.gov as NCT01137188.


Assessing Medical Student Readiness to Navigate Language Barriers in Telehealth: Cross-sectional Survey Study.
The COVID-19 pandemic has greatly increased telehealth usage in the United States. Patients with limited English proficiency (LEP) face barriers to health care, which may be mitigated when providers work with professional interpreters. However, telehealth may exacerbate disparities if clinicians are not trained to work with interpreters in that setting. Although medical students are now involved in telehealth on an unprecedented scale, no educational innovations have been published that focus on digital care across language barriers. The aim of this study is to investigate advanced medical students' confidence in caring for patients with LEP during telehealth encounters. We administered a written survey to medical students on clinical clerkships at one US institution in August and September 2020. We assessed students' overall confidence in working with interpreters; confidence in performing 8 clinical tasks during in-person versus telehealth encounters; and frequency of performing 5 different clinical tasks with patients with LEP compared to English-speaking patients during in-person versus telehealth encounters. Wilcoxon signed-rank tests and chi-square tests were used to compare confidence and task performance frequency, respectively, for patients with LEP versus English-speaking patients during telehealth encounters. Students were also asked to identify barriers to care for patients with LEP. The free-response questions were qualitatively analyzed using open coding to identify key themes. Of 300 medical students surveyed, 121 responded. Furthermore, 72 students answered >50% of questions and were included in the analyses. Compared to caring for patients with LEP during in-person encounters, respondents were less confident in working with interpreters (P<.001), developing trust (P<.001), identifying agenda (P=.005), eliciting preferences for diabetes management (P=.01), and empowering patients in lifestyle modifications (P=.04) during telehealth encounters. During both in-person and telehealth encounters, approximately half of students (40%-78%) reported engaging less frequently in every clinical task with patients with LEP and this was as low as 22% (13/59) for some tasks. Students identified these key barriers to care for patients with LEP: time pressure, interpretation quality and access, technical difficulties, cultural differences, and difficulty with rapport building. Advanced medical students were significantly less confident caring for patients with LEP via telehealth than in person. Broader implementation of training around navigating language barriers is necessary for telehealth care, which has rapidly expanded in the United States. Our study identified potential key areas for curricular focus, including creating patient-centered agendas and management plans within the constraints of virtual settings. These developments must take place simultaneously with systems-level improvements in interpreter infrastructure to ensure high-quality care for linguistically diverse patients.


In vivo and in vitro knockout system labelled using fluorescent protein via microhomology-mediated end joining.
Gene knockout is important for understanding gene function and genetic disorders. The CRISPR/Cas9 system has great potential to achieve this purpose. However, we cannot distinguish visually whether a gene is knocked out and in how many cells it is knocked out among a population of cells. Here, we developed a new system that enables the labelling of knockout cells with fluorescent protein through microhomology-mediated end joining-based knock-in. Using a combination with recombinant adeno-associated virus, we delivered our system into the retina, where the expression of Staphylococcus aureus Cas9 was driven by a retina ganglion cell (RGC)-specific promoter, and knocked out carnitine acetyltransferase (CAT). We evaluated RGCs and revealed that CAT is required for RGC survival. Furthermore, we applied our system to Keap1 and confirmed that Keap1 is not expressed in fluorescently labelled cells. Our system provides a promising framework for cell type-specific genome editing and fluorescent labelling of gene knockout based on knock-in.


Allograft rejection after liver transplantation for autoimmune liver diseases.
Autoimmune liver diseases (AILD) may progress to liver failure, requiring liver transplantation as definitive therapy, and these immune-mediated disorders may predispose the patient to more frequent graft rejection. The objective of this study was to determine the effect of preexisting AILD on the incidence of allograft rejection after liver transplantation. Sixty-three patients who underwent liver transplantation between March 1988 and December 1994 for AILDs that included autoimmune hepatitis (AIH; n = 33) and primary biliary cirrhosis (PBC; n = 30) were retrospectively compared with 47 patients who underwent liver transplantation for alcoholic cirrhosis during the same time period. There was a lower incidence of acute allograft rejection in patients with AILD who received tacrolimus-based compared with cyclosporine-based immunosuppression (50% v 85.5%; P = .02). However, patients with AILDs overall had a higher incidence of acute rejection than patients with alcoholic cirrhosis (81% v 46.8%; P < .001), regardless of the type of immunosuppression. In addition, steroid-resistant rejection occurred more frequently in patients with AILDs than in patients with alcoholic cirrhosis (38.1% v 12.8%; P = .003). There was also a trend toward a higher incidence of chronic rejection in patients with AILDs compared with patients with alcoholic cirrhosis (11.1% v 2.1%), but this difference did not reach statistical significance. Patient and graft survivals at 1 and 3 years were similar between patients with AILDs and alcoholic liver disease. Compared with alcoholic cirrhosis, preexisting AILDs are associated with a higher incidence of acute allograft rejection and a trend toward more frequent chronic rejection.


Thermally driven anomalous Hall effect transitions in FeRh.
Materials exhibiting controllable magnetic phase transitions are currently in demand for many spintronics applications. Here we investigate from first principles the electronic structure and intrinsic anomalous Hall, spin Hall and anomalous Nernst response properties of the FeRh metallic alloy which undergoes a thermally driven antiferromagnetic-to-ferromagnetic phase transition. We show that the energy band structures and underlying Berry curvatures have important signatures in the various Hall effects. Specifically, the suppression of the anomalous Hall and Nernst effects in the AFM state and a sign change in the spin Hall conductivity across the transition are found. It is suggested that the FeRh can be used a spin current detector capable of differentiating the spin Hall effect from other anomalous transverse effects. The implications of this material and its thermally driven phases as a spin current detection scheme are also discussed.


Diabetes mellitus as an independent risk factor for lung cancer: a meta-analysis of observational studies.
Epidemiologic studies have demonstrated inconsistent associations between diabetes mellitus and the risk of lung cancer. To determine whether diabetes mellitus is associated with an increased risk of lung cancer, we performed a meta-analysis of observational studies. PubMed, EMBASE and the Cochrane Library were searched for observational studies conducted prior to September 2012. We included prospective cohort studies that reported relative risks and case-control studies that showed odds ratios in the analysis. The pooled relative risk (RR) with 95% confidence intervals (CIs) was calculated with a random effects model. Sensitivity analysis was performed with studies which controlled for smoking status. Associations were assessed in several subgroups representing different participant and study characteristics. A total of 34 studies from 24 manuscripts (10 case-control studies and 24 cohort studies) were included in the analyses. Diabetes was significantly associated with the increased risk of lung cancer compared with non-diabetic controls when limiting the analysis to studies adjusting for smoking status (RR, 1.11; 95% CI, 1.02-1.20; I(2)=46.1%). By contrast, this association disappeared when the analysis was restricted to studies not adjusting for smoking status (RR, 0.99; 95% CI, 0.88-1.11; I(2)=96.7%). When stratifying by sex, an increased risk of lung cancer was prominent in diabetic women (RR, 1.14; 95% CI, 1.09-1.20; I(2)=0%), while there was no association in diabetic men (RR, 1.07; 95% CI, 0.89-1.28; I(2)=96.6%). Among diabetic women, significantly increased risks of lung cancer were found in the following subgroups: cohort studies (RR, 1.14; 95% CI, 1.08-1.20; I(2)=0%), studies controlling for major confounding variables such as age, smoking and alcohol (RR, 1.19; 95% CI, 1.00-1.43; I(2)=23.1%), studies with long-term follow-up (RR, 1.14; 95% CI, 1.08-1.20; I(2)=0%), and high-quality studies assessed by the Newcastle-Ottawa Scale (RR, 1.14; 95% CI, 1.08-1.20; I(2)=0%). Preexisting diabetes mellitus may increase the risk of lung cancer, especially among female diabetic patients. Further large-scale prospective studies are needed to test specifically the effect of diabetes mellitus on lung cancer risk.


Rapid responses of British butterflies to opposing forces of climate and habitat change.
Habitat degradation and climate change are thought to be altering the distributions and abundances of animals and plants throughout the world, but their combined impacts have not been assessed for any species assemblage. Here we evaluated changes in the distribution sizes and abundances of 46 species of butterflies that approach their northern climatic range margins in Britain-where changes in climate and habitat are opposing forces. These insects might be expected to have responded positively to climate warming over the past 30 years, yet three-quarters of them declined: negative responses to habitat loss have outweighed positive responses to climate warming. Half of the species that were mobile and habitat generalists increased their distribution sites over this period (consistent with a climate explanation), whereas the other generalists and 89% of the habitat specialists declined in distribution size (consistent with habitat limitation). Changes in population abundances closely matched changes in distributions. The dual forces of habitat modification and climate change are likely to cause specialists to decline, leaving biological communities with reduced numbers of species and dominated by mobile and widespread habitat generalists.


Photoperiod effects on the expression of kisspeptin and gonadotropin genes in Atlantic cod, Gadus morhua, during first maturation.
In order to investigate the potential role of the kisspeptin system in the entrainment of reproduction in Atlantic cod, qPCR assays were developed for kiss2 and its receptor kissr4. mRNA expression was monitored in the brain over a full reproductive cycle in 2 populations of males and females: 1) a maturing population (exposed to simulated natural photoperiod, SNP) and 2) a maturation inhibited population (exposed to constant light, LL). Pituitary expression of gonadotropin subunit mRNA (fshβ and lhβ) was also measured. Results from this study indicated no clear temporal pattern in expression of kiss2 or kissr4 mRNAs in either population of cod, however acute elevations were apparent in maturing (SNP) individuals, namely an elevation in kiss2 in vitellogenic females and spermiating males and spikes in kissr4 during early vitellogenesis in females and spermatogenesis in males. Gonadotropin mRNA expression displayed strong amplitudinal changes over time with fshβ and lhβ mRNA expression increasing towards spawning in maturing individuals. No firm conclusions on the role of the kisspeptin system in cod puberty can be drawn at this stage, however mRNA increases in kiss2 and kissr4 may elude to conserved kisspeptin functions in cod and opens up interesting avenues on potential gender specific functions.


GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes.
A genome-wide association study (GWAS) of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific. Putative causal association signals from a GWAS of 945 clinically defined gout cases and 1213 controls from Japanese males were replicated with 1396 cases and 1268 controls using a custom chip of 1961 single nucleotide polymorphisms (SNPs). We also first conducted GWASs of gout subtypes. Replication with Caucasian and New Zealand Polynesian samples was done to further validate the loci identified in this study. In addition to the five loci we reported previously, further susceptibility loci were identified at a genome-wide significance level (p<5.0×10-8): urate transporter genes (SLC22A12 and SLC17A1) and HIST1H2BF-HIST1H4E for all gout cases, and NIPAL1 and FAM35A for the renal underexcretion gout subtype. While NIPAL1 encodes a magnesium transporter, functional analysis did not detect urate transport via NIPAL1, suggesting an indirect association with urate handling. Localisation analysis in the human kidney revealed expression of NIPAL1 and FAM35A mainly in the distal tubules, which suggests the involvement of the distal nephron in urate handling in humans. Clinically ascertained male patients with gout and controls of Caucasian and Polynesian ancestries were also genotyped, and FAM35A was associated with gout in all cases. A meta-analysis of the three populations revealed FAM35A to be associated with gout at a genome-wide level of significance (p meta =3.58×10-8). Our findings including novel gout risk loci provide further understanding of the molecular pathogenesis of gout and lead to a novel concept for the therapeutic target of gout/hyperuricaemia.


Insights into the structure and stability of the carbonic acid dimer.
In this paper we report the geometries and properties of 40 structural isomers located on the MP2/6-311++G** PES of the carbonic acid dimer. All six possible combinations of carbonic acid monomers were considered. The dimers are divided into six geometrical motifs. Our data suggests that combinations of anti-anti monomers do not necessarily lead to larger stabilization energies in the formation of the dimers. MP2 underestimates the relative binding energies with respect to CCSD(T) by as much as 3.2 kcal mol(-1). At least 3 different dimers which may contribute to the stability of carbonic acid are predicted to have significant populations. Binding energy is only directly related to relative stability when comparing dimers formed from the same monomers. Overall stabilization is mainly dictated by attractive electrostatic interactions via cooperative polarization by virtue of the spatial arrangement of the dipole moment components along the polar bonds. Shorter OH bond distances and larger bond orders predicted for the hydrogen bonds directed towards carbonyl groups make for stronger hydrogen bonding than in O...H bonds directed towards hydroxyl groups.


Spicing up endogenous neural stem cells: aromatic-turmerone offers new possibilities for tackling neurodegeneration.
There is a growing interest in the therapeutic utility of compounds derived from Curcuma longa, an herb of the Zingiberaceae family that has been part of traditional medicine for centuries. Recent reports suggest that bioactive compounds isolated from the rhizome of these plants can address two key aspects of brain injury following stroke that must be dealt with for functional recovery to occur: the moderation of neuroinflammation, and the mobilization of endogenous stem cells resident in the nervous system. Defining their mechanism of action remains a question, but emerging evidence may point towards one shared with more classic modulators of neural stem cell proliferation and survival.


MzrA: a novel modulator of the EnvZ/OmpR two-component regulon.
Analysis of suppressors that alleviate the acute envelope stress phenotype of a DeltabamB DeltadegP strain of Escherichia coli identified a novel protein MzrA and pleiotropic envZ mutations. Genetic evidence shows that overexpression of MzrA--formerly known as YqjB and EcfM--modulates the activity of EnvZ/OmpR similarly to pleiotropic EnvZ mutants and alter porin expression. However, porin expression in strains devoid of MzrA or overexpressing it is still sensitive to medium osmolarity, pH and procaine, all of which modulate EnvZ/OmpR activities. Thus, MzrA appears to alter the output of the EnvZ/OmpR system but not its ability to receive and respond to various environmental signals. Localization and topology experiments indicate that MzrA is a type II membrane protein, with its N-terminus exposed in the cytoplasm and C-terminus in the periplasm. Bacterial two-hybrid experiments determined that MzrA specifically interacts with EnvZ but not with OmpR or the related membrane sensor kinase, CpxA. This and additional genetic and biochemical evidence suggest that the interaction of MzrA with EnvZ would either enhance EnvZ's kinase activity or reduce its phosphatase activity, thus elevating the steady state levels of OmpR approximately P. Furthermore, our data show that MzrA links the two-component envelope stress response regulators, CpxA/CpxR and EnvZ/OmpR.


Acute reductions in haematocrit increase flow-mediated dilatation independent of resting nitric oxide bioavailability in humans.
Changes in haematocrit influence nitric oxide signalling through alterations in shear stress stimuli and haemoglobin scavenging of nitric oxide; these two regulatory factors have not been assessed simultaneously Isovolumic haemodilution led to a marked increase in brachial artery flow-mediated dilatation in humans The increase in flow-mediated dilatation occurred in the face of an unaltered shear stress stimulus for vasodilatation and reduced resting steady-state nitric oxide levels in the blood Collectively, our data point towards haemoglobin scavenging of nitric oxide as a key regulatory factor of brachial flow-mediated dilatation and highlight the importance of the simultaneous consideration of nitric oxide production and inactivation when investigating vascular function in humans ABSTRACT: Haemoglobin (Hb) may impact the transduction of endothelium-dependent and nitric oxide (NO)-mediated vasodilator activity, given its contribution to shear stress stimuli and diverse biochemical reactions with NO. We hypothesized that an acute reduction in [Hb] and haematocrit (Hct) would increase brachial artery flow-mediated dilatation (FMD). In 11 healthy males (28 ± 7 years; 23 ± 2 kg m-2 ), FMD (Duplex ultrasound), arterial blood gases, Hct and [Hb], blood viscosity, and NO metabolites (ozone-based chemiluminescence) were measured before and after isovolumic haemodilution, where ∼20% of whole blood was removed and replaced with 5% human serum albumin. Haemodilution reduced Hct by 18 ± 2% (P < 0.001) and whole blood viscosity by 22 ± 5% (P < 0.001). Plasma nitrite (P = 0.01), S-nitrosothiols (P = 0.03) and total red blood cell NO (P = 0.001) were collectively reduced by ∼15-40%. Brachial artery FMD increased by ∼160% from 3.8 ± 2.1 to 9.7 ± 4.5% (P = 0.004). Statistical covariation for the shear stress stimulus did not alter FMD, indicating that the increase in FMD was not directly related to alterations in whole blood viscosity and the shear stimulus. Collectively, these findings indicate that haemoglobin scavenging of NO appears to be an important factor in the regulation of FMD under normal conditions through constraint of endothelium-dependent NO-mediated vasodilatation in healthy humans.


Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators.
Diabetes mellitus is a strong risk factor for cardiovascular and renal disease. We investigated whether the angiotensin-converting-enzyme (ACE) inhibitor ramipril can lower these risks in patients with diabetes. 3577 people with diabetes included in the Heart Outcomes Prevention Evaluation study, aged 55 years or older, who had a previous cardiovascular event or at least one other cardiovascular risk factor, no clinical proteinuria, heart failure, or low ejection fraction, and who were not taking ACE inhibitors, were randomly assigned ramipril (10 mg/day) or placebo, and vitamin E or placebo, according to a two-by-two factorial design. The combined primary outcome was myocardial infarction, stroke, or cardiovascular death. Overt nephropathy was a main outcome in a substudy. The study was stopped 6 months early (after 4.5 years) by the independent data safety and monitoring board because of a consistent benefit of ramipril compared with placebo. Ramipril lowered the risk of the combined primary outcome by 25% (95% CI 12-36, p=0.0004), myocardial infarction by 22% (6-36), stroke by 33% (10-50), cardiovascular death by 37% (21-51), total mortality by 24% (8-37), revascularisation by 17% (2-30), and overt nephropathy by 24% (3-40, p=0.027). After adjustment for the changes in systolic (2.4 mm Hg) and diastolic (1.0 mm Hg) blood pressures, ramipril still lowered the risk of the combined primary outcome by 25% (12-36, p=0.0004). Ramipril was beneficial for cardiovascular events and overt nephropathy in people with diabetes. The cardiovascular benefit was greater than that attributable to the decrease in blood pressure. This treatment represents a vasculoprotective and renoprotective effect for people with diabetes.


Pneumocystis carinii: inhibition of lung cell growth mediated by parasite attachment.
Pneumocystis carinii pneumonia is a significant cause of mortality in immunocompromised patients. Current concepts suggest that attachment of P. carinii to alveolar epithelium is required for development of pneumonia. We examined the mechanism of P. carinii adherence to cultured A549 cells, a permanent cell line derived from human alveolar epithelium. P. carinii adherence was quantified by measuring attachment of 51Cr-labeled P. carinii to cultured A549 cells. After 8 h of incubation, 37.4 +/- 4.2% of P. carinii were adherent to A549 cells. In the presence of agents known to impair cytoskeletal function, including 10(-5) M cytochalasin B, 10(-5) M colchicine, and 10(-5) M trimethylcolchicinic acid (TMCA), adherence was decreased from 57.4 +/- 4.2% to 9.3 +/- 3.4%, 12.5 +/- 3.6%, and 21.5 +/- 3.6%, respectively (P less than 0.01, all comparisons). Secondly, we examined the effect of P. carinii on the function of A549 cells. P. carinii resulted in significant impairment of A549 cell growth, indicating P. carinii adversely affected the function of target lung cells. A P. carinii:A549 cell ratio of 50:1 resulted in 43.5 +/- 2.9% inhibition of A549 cell growth (P less than 0.001). Additionally, TMCA, which significantly prevented attachment of P. carinii, reversed the impairment of A549 cell growth. These data demonstrate that P. carinii attachment to cultured lung cells can be quantified, is dependent on intact cytoskeletal function and is necessary for impairment of lung cell replication.


Patients with syndrome X have normal transmural myocardial perfusion and oxygenation: a 3-T cardiovascular magnetic resonance imaging study.
The pathophysiology of chest pain in patients with cardiac syndrome X remains controversial. Advances in perfusion imaging with cardiovascular magnetic resonance (CMR) now enable absolute quantification of regional myocardial blood flow (MBF). Furthermore, blood oxygen level-dependent (BOLD) or oxygenation-sensitive CMR provides the unprecedented capability to assess regional myocardial oxygenation. We hypothesized that the combined assessment of regional perfusion and oxygenation with CMR could clarify whether patients with syndrome X show evidence of myocardial ischemia (reduced perfusion and oxygenation) during vasodilator stress compared with normal volunteers. Eighteen patients with syndrome X (chest pain, abnormal exercise treadmill test, normal coronary angiogram without other causes of microvascular dysfunction) and 14 controls underwent CMR scanning at 3 T. Myocardial function, scar, perfusion (2-3 short-axis slices), and oxygenation were assessed. Absolute MBF was measured during adenosine stress (140 μg/kg per minute) and at rest by model-independent deconvolution. For oxygenation, using a T2-prepared BOLD sequence, signal intensity was measured at adenosine stress and rest in the slice matched to the midventricular slice of the perfusion scan. There were no significant differences in MBF at stress (2.35 versus 2.37 mL/min per gram; P=0.91), BOLD signal change (17.3% versus 17.09%; P=0.91), and coronary flow reserve measurements (2.63 versus 2.53; P=0.60) in patients with syndrome X and controls, respectively. Oxygenation and perfusion measurements per coronary territory were also similar between the 2 groups. More patients with syndrome X (17/18 [94%]) developed chest pain during adenosine stress than controls (6/14 [43%]; P=0.004). Patients with syndrome X show greater sensitivity to chest pain compared with controls but no evidence of deoxygenation or hypoperfusion during vasodilatory stress.


Traveling by Private Motorized Vehicle and Physical Fitness in Taiwanese Adults.
Although the time spent sitting in motorized vehicles has been determined to be adversely associated with cardiometabolic health, its association with other health indicators remains unclear. This study examined associations between traveling by private motorized vehicle and 4 indicators of physical fitness in adults. Data from 52,114 Taiwanese adults aged 20 to 65 years who participated in the 2013 National Adults Fitness Survey were used. The examined variables were height, body mass, and performance in modified sit-and-reach (flexibility), bent-leg sit-up (abdominal muscular strength and endurance), and a 3-min step test (cardiorespiratory endurance). Participants were asked on how many days they had used a private car or motorcycle for traveling from place to place and categorized as non-, occasional, and daily private motorized vehicle travelers. Logistic and linear regression models were used to examine associations between the categories of using private motorized vehicles to travel and physical fitness performance. After an adjustment for potential demographic and behavioral confounders, daily traveling by private motorized vehicle was associated with a higher probability of overweight (odds ratio = 1.18), lower performance of abdominal muscular strength and endurance (-0.37 times/min), and lower cardiorespiratory fitness (-0.60 physical fitness index) than was traveling that did not involve private motorized vehicles. The results suggest that in addition to unfavorable cardiorespiratory fitness and a risk of overweight, daily traveling by private motorized vehicle is associated with poor performance in abdominal muscular strength and endurance.


Determinants of tetherin antagonism in the transmembrane domain of the human immunodeficiency virus type 1 Vpu protein.
Tetherin (BST2/CD317) potently restricts the particle release of human immunodeficiency virus type 1 (HIV-1) mutants defective in the accessory gene vpu. Vpu antagonizes tetherin activity and induces its cell surface downregulation and degradation in a manner dependent on the transmembrane (TM) domains of both proteins. We have carried out extensive mutagenesis of the HIV-1 NL4.3 Vpu TM domain to identify three amino acid positions, A14, W22, and, to a lesser extent, A18, that are required for tetherin antagonism. Despite the mutants localizing indistinguishably from the wild-type (wt) protein and maintaining the ability to multimerize, mutation of these positions rendered Vpu incapable of coimmunoprecipitating tetherin or mediating its cell surface downregulation. Interestingly, these amino acid positions are predicted to form one face of the Vpu transmembrane alpha helix and therefore potentially contribute to an interacting surface with the transmembrane domain of tetherin either directly or by modulating the conformation of Vpu oligomers. While the equivalent of W22 is invariant in HIV-1/SIVcpz Vpu proteins, the positions of A14 and A18 are highly conserved among Vpu alleles from HIV-1 groups M and N, but not those from group O or SIVcpz that lack human tetherin (huTetherin)-antagonizing activity, suggesting that they may have contributed to the adaption of HIV-1 to human tetherin.


Ethanol inhibits glutamatergic neurotransmission in nucleus accumbens neurons by multiple mechanisms.
The nucleus accumbens (NAcc) likely plays a role in the rewarding effects of several addictive drugs such as opiates and EtOH. We showed previously that low EtOH concentrations reduced glutamatergic excitatory postsynaptic potentials (EP-SPs) in NAcc neurons. Naloxone inhibited this effect. In the present study we have begun characterizing the receptors involved in the evoked EPSPs and examined the action of EtOH on these receptors by using intracellular recording (voltage- and current-clamp) in the rat NAcc slice. At depolarized membrane potentials, we found 6-cyano-7-nitroquinoxaline-2,3-di-one-resistant EPSPs that were blocked by the N-methyl-D-aspartate (NMDA) receptor antagonist DL-2-amino-5-phosphonovalerate. In 6-cyano-7-nitroquinoxaline-2,3-dione (a non-NMDA glutamate receptor antagonist), EtOH 66 mM decreased these NMDA-EPSPs. Application of exogenous NMDA or non-NMDA [kainate, (R,S)-alpha-amino-3-hydroxy-5-methyli-soxazole-4-propionic acid or quisqualate] glutamate agonists evoked reversible depolarizations or inward currents. The NMDA-induced currents increased with membrane depolarization and were blocked by DL-2-amino-5-phosphonovalerate. EtOH 11 to 200 mM decreased the NMDA currents significantly and dose-dependently, without effect of naloxone. Higher EtOH concentrations (44-66 mM) also reduced slightly kainate-induced currents (again without a naloxone effect), but not (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid or quisqualate currents. These data suggest that NAcc core neurons express both NMDA and non-NMDA glutamate receptors. Because low EtOH concentrations reduce the EPSPs at normal resting potentials, but not responses to non-NMDA glutamate agonists, EtOH probably acts both pre- and postsynaptically: by an opioid-dependent reduction of glutamate release and by postsynaptically reducing NMDA and kainate currents. By virtue of the likely role NAcc plays in alcoholism, these actions could represent major determinants in the intoxicating and reinforcing properties of EtOH.


Trends in use of opioids for non-cancer pain conditions 2000-2005 in commercial and Medicaid insurance plans: the TROUP study.
Opioids are widely prescribed for non-cancer pain conditions (NCPC), but there have been no large observational studies in actual clinical practice assessing patterns of opioid use over extended periods of time. The TROUP (Trends and Risks of Opioid Use for Pain) study reports on trends in opioid therapy for NCPC in two disparate populations, one national and commercially insured population (HealthCore plan data) and one state-based and publicly-insured (Arkansas Medicaid) population over a six year period (2000-2005). We track enrollees with the four most common NCPC conditions: arthritis/joint pain, back pain, neck pain, headaches, as well as HIV/AIDS. Rates of NCPC diagnosis and opioid use increased linearly during this period in both groups, with the Medicaid group starting at higher rates and the HealthCore group increasing more rapidly. The proportion of enrollees receiving NCPC diagnoses increased (HealthCore 33%, Medicaid 9%), as did the proportion of enrollees with NCPC diagnoses who received opioids (HealthCore 58%, Medicaid 29%). Cumulative yearly opioid dose (in mg. morphine equivalents) received by NCPC patients treated with opioids increased (HealthCore 38%, Medicaid 37%) due to increases in number of days supplied rather than dose per day supplied. Use of short-acting Drug Enforcement Administration Schedule II opioids increased most rapidly, both in proportion of NCPC patients treated (HealthCore 54%, Medicaid 38%) and in cumulative yearly dose (HealthCore 95%, Medicaid 191%). These trends have occurred without any significant change in the underlying population prevalence of NCPC or new evidence of the efficacy of long-term opioid therapy and thus likely represent a broad-based shift in opioid treatment philosophy.


Anesthetic management of living transplantation.
Living donor transplantation has helped to partially relieve the refractory shortage of deceased donor grafts. However, living related donation exposes healthy donors to a certain risk of morbidity and even mortality. Anesthetic management of elective live donation surgery with a relatively young and healthy patient is apparently simple; nonetheless, it requires both knowledge and diligence from the anesthesiologist. Some concerns persist regarding the appropriate intraoperative organ protection strategy and potential negative effects of certain surgical maneuvers on graft function. Even when careful attention is paid to maintaining intraoperative cardiorespiratory and metabolic homeostasis, preventing blood loss, preserving renal function, and assuring adequate postoperative analgesia, among other things, these procedures are not completely devoid of some major risks related to anesthesia and surgery. Maximal effort should be applied to minimize the perioperative risks for the donor, every minimal impending complication should be promptly recognized, and a timely treatment implemented. Some anesthetic considerations regarding the most frequently performed living organ transplantations are briefly reported in this article.


Quality of life and audiologic performance through the ability to phone of cochlear implant users.
This study aimed to evaluate the impact of cochlear implantation on quality of life (QoL), using general and cochlear implant (CI) specific questionnaires and to determine the relationship of phone ability with QoL, speech recognition abilities and tinnitus. Twenty-six adult volunteers with a post-lingual profound deafness, unilaterally implanted with a CI, were included in this study. All subjects had used a CI for at least 1 year. The Glasgow benefit inventory (GBI) and Nijmegen cochlear implant questionnaire (NCIQ) were administered to assess QoL. Speech recognition was tested using phonemic Lafon's lists. The subjective tinnitus severity scale (STSS) questionnaire was used to determine the effects of tinnitus. CI users were split into four groups according to their phone ability. There was an improvement in QoL after cochlear implantation. The NCIQ showed significant (p < 0.001) improvements in the total score and in all subdomains after CI. A significant relationship between phone ability, QoL and speech recognition was found. Improving phone ability led to higher QoL (p < 0.05) and speech recognition (p < 0.01) scores. The CI use decreased significantly the occurrence of tinnitus, but its severity was not correlated with QoL. Post-surgery assessment should include speech recognition measures and QoL evaluation. The NCIQ appeared more effective than the GBI in its ability to detect improvements in QoL. Assessing phone ability represents an easy and fast approach to evaluate hearing performances and QoL, and may reflect global outcomes of CI.


Disposition of insanity acquittees in the United States Military.
Recent amendments to the United States Code of Military Justice have essentially adopted the federal mental nonresponsibility rule or insanity defense. The prior standard, as outlined in the American Law Institute's Model Penal Code, has been abandoned. Notably absent is a system to address the disposition of the military insanity acquittee. This raises concerns regarding recidivism and the military's role in mitigating potential dangerousness. Relevant civilian and military law is reviewed, two cases described, and possible remedies proposed.


Biomedical applications of accelerator mass spectrometry-isotope measurements at the level of the atom.
Accelerator mass spectrometry (AMS) is a nuclear physics technique developed about twenty years ago, that uses the high energy (several MeV) of a tandem Van de Graaff accelerator to measure very small quantities of rare and long-lived isotopes. Elements that are of interest in biomedicine and environmental sciences can be measured, often to parts per quadrillion sensitivity, i.e. zeptomole to attomole levels (10(-21)-10(-18) mole) from milligram samples. This is several orders of magnitude lower than that achievable by conventional decay counting techniques, such as liquid scintillation counting (LSC). AMS was first applied to geochemical, climatological and archaeological areas, such as for radiocarbon dating (Shroud of Turin), but more recently this technology has been used for bioanalytical applications. In this sphere, most work has been conducted using aluminium, calcium and carbon isotopes. The latter is of special interest in drug metabolism studies, where a Phase 1 adsorption, distribution, metabolism and excretion (ADME) study can be conducted using only 10 nanoCurie (37 Bq or ca. 0.9 microSv) amounts or less of 14C-labelled drugs. In the UK, these amounts of radioactivity are below those necessary to request specific regulatory approval from the Department of Health's Administration of Radioactive Substances Advisory Committee (ARSAC), thus saving on valuable development time and resources. In addition, the disposal of these amounts is much less an environmental issue than that associated with microCurie quantities, which are currently used. Also, AMS should bring an opportunity to conduct "first into man" studies without the need for widespread use of animals. Centre for Biomedical Accelerator Mass Spectrometry (CBAMS) Ltd. is the first fully commercial company in the world to offer analytical services using AMS. With its high throughput and relatively low costs per sample analysis, AMS should be of great benefit to the pharmaceutical and biotechnology industries as well as other life science areas.


Tracking Mangrove Oil Bioremediation Approaches and Bacterial Diversity at Different Depths in an in situ Mesocosms System.
In this study, oil spills were simulated in field-based mangrove mesocosms to compare the efficiency of bioremediation strategies and to characterize the presence of the alkB, ndo, assA, and bssA genes and the ecological structures of microbial communities in mangrove sediments at two different depths, (D1) 1-10 cm and (D2) 25-35 cm. The results indicated that the hydrocarbon degradation efficiency was higher in superficial sediment layers, although no differences in the hydrocarbon degradation rates or in the abundances of the alkB and ndo genes were detected among the tested bioremediation strategies at this depth. Samples from the deeper layer exhibited higher abundances of the analyzed genes, except for assA and bssA, which were not detected in our samples. For all of the treatments and depths, the most abundant phyla were Proteobacteria, Firmicutes and Bacteroidetes, with Gammaproteobacteria, Flavobacteriales and Clostridiales being the most common classes. The indicator species analysis (ISA) results showed strong distinctions among microbial taxa in response to different treatments and in the two collection depths. Our results indicated a high efficiency of the monitored natural attenuation (MNA) for oil consumption in the tested mangrove sediments, revealing the potential of this strategy for environmental decontamination and suggesting that environmental and ecological factors may select for specific bacterial populations in distinct niches.


Transovarial transmission of St. Louis encephalitis virus by Culex pipiens complex mosquitoes.
Experiments were conducted to determine whether transovarial transmission (TOT) of St. Louis encephalitis (SLE) virus occurs in Culex pipiens complex mosquitoes, the principal vectors of SLE virus in the central-eastern United States. In 1978, field-collected mosquitoes from Memphis, Tennessee, and McLeansboro, Illinois, were used; during 1979, colonized mosquitoes from Chicago, Illinois, and Memphis, Tennessee, were used. Mosquitoes were infected by feeding on viremic chicks inoculated with an SLE virus strain isolated from Cx. pipiens complex mosquitoes collected from Memphis, Tennessee, in 1976. During the 1979 experiments, progeny larval and adult mosquitoes were held at two temperatures, 18 and 25 degrees C. Progeny were tested for virus by plaque assay in duck embryo cell cultures and by inoculation of Aedes albopictus C6/36 cells and examination by immunofluorescence. In 1978, most of the progeny tested were from the first ovarian cycle, and a single occurrence of TOT was documented. In 1979, a single TOT occurred from 46,856 first ovarian cycle progeny, whereas 7 of 9,234 progeny of the second ovarian cycle were infected. The rate of TOT was higher for progeny of Memphis than Chicago mosquitoes, and for mosquitoes held at 18 degrees C than at 25 degrees C; however, these differences were not statistically significant. Four positive pools were females, and three were fed on chicks for transmission attempts. The positive Chicago mosquito pool failed to transmit, but both Memphis pools successfully transmitted virus. The overall rates of TOT of SLE virus in progeny of the first and second ovarian cycle were, respectively, 1/45, 151 and 1/1,460. The significance of these results as they relate to the natural history of SLE virus is discussed.


Stress and the gut: pathophysiology, clinical consequences, diagnostic approach and treatment options.
Stress, which is defined as an acute threat to homeostasis, shows both short- and long-term effects on the functions of the gastrointestinal tract. Exposure to stress results in alterations of the brain-gut interactions ("brain-gut axis") ultimately leading to the development of a broad array of gastrointestinal disorders including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and other functional gastrointestinal diseases, food antigen-related adverse responses, peptic ulcer and gastroesophageal reflux disease (GERD). The major effects of stress on gut physiology include: 1) alterations in gastrointestinal motility; 2) increase in visceral perception; 3) changes in gastrointestinal secretion; 4) increase in intestinal permeability; 5) negative effects on regenerative capacity of gastrointestinal mucosa and mucosal blood flow; and 6) negative effects on intestinal microbiota. Mast cells (MC) are important effectors of brain-gut axis that translate the stress signals into the release of a wide range of neurotransmitters and proinflammatory cytokines, which may profoundly affect the gastrointestinal physiology. IBS represents the most important gastrointestinal disorder in humans, and is characterized by chronic or recurrent pain associated with altered bowel motility. The diagnostic testing for IBS patients include routine blood tests, stool tests, celiac disease serology, abdominal sonography, breath testing to rule out carbohydrate (lactose, fructose, etc.) intolerance and small intestinal bacterial overgrowth. Colonoscopy is recommended if alarming symptoms are present or to obtain colonic biopsies especially in patients with diarrhoea predominant IBS. The management of IBS is based on a multifactorial approach and includes pharmacotherapy targeted against the predominant symptom, behavioural and psychological treatment, dietary alterations, education, reassurance and effective patient-physician relationship. When evaluating for the stress-induced condition in the upper GI tract, the diagnostic testing includes mainly blood tests and gastroscopy to rule out GERD and peptic ulcer disease. The therapy for these conditions is mainly based on the inhibition of gastric acid by proton pump inhibitors and eradication of Helicobacter pylori-infection. Additionally, melatonin an important mediator of brain gut axis has been shown to exhibit important protective effects against stress-induced lesions in the gastrointestinal tract. Finally, probiotics may profoundly affect the brain-gut interactions ("microbiome-gut-brain axis") and attenuate the development of stress-induced disorders in both the upper and lower gastrointestinal tract. Further studies on the brain-gut axis are needed to open new therapeutic avenues in the future.


Emission of coherent THz radiation from superconductors.
Compact solid-state sources of terahertz (THz) radiation are being sought for sensing, imaging, and spectroscopy applications across the physical and biological sciences. We demonstrate that coherent continuous-wave THz radiation of sizable power can be extracted from intrinsic Josephson junctions in the layered high-temperature superconductor Bi2Sr2CaCu2O8. In analogy to a laser cavity, the excitation of an electromagnetic cavity resonance inside the sample generates a macroscopic coherent state in which a large number of junctions are synchronized to oscillate in phase. The emission power is found to increase as the square of the number of junctions reaching values of 0.5 microwatt at frequencies up to 0.85 THz, and persists up to approximately 50 kelvin. These results should stimulate the development of superconducting compact sources of THz radiation.


What are applied ethics?
This paper explores the relationships that various applied ethics bear to each other, both in particular disciplines and more generally. The introductory section lays out the challenge of coming up with such an account and, drawing a parallel with the philosophy of science, offers that applied ethics may either be unified or disunified. The second section develops one simple account through which applied ethics are unified, vis-à-vis ethical theory. However, this is not taken to be a satisfying answer, for reasons explained. In the third section, specific applied ethics are explored: biomedical ethics; business ethics; environmental ethics; and neuroethics. These are chosen not to be comprehensive, but rather for their traditions or other illustrative purposes. The final section draws together the results of the preceding analysis and defends a disunity conception of applied ethics.


Chronic mucocutaneous candidiasis: characterization of a family with STAT-1 gain-of-function and development of an ex-vivo assay for Th17 deficiency of diagnostic utility.
Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent and persistent superficial infections, with Candida albicans affecting the mucous membranes, skin and nails. It can be acquired or caused by primary immune deficiencies, particularly those that impair interleukin (IL)-17 and IL-22 immunity. We describe a single kindred with CMC and the identification of a STAT1 GOF mutation by whole exome sequencing (WES). We show how detailed clinical and immunological phenotyping of this family in the context of WES has enabled revision of disease status and clinical management. Together with analysis of other CMC cases within our cohort of patients, we used knowledge arising from the characterization of this family to develop a rapid ex-vivo screening assay for the detection of T helper type 17 (Th17) deficiency better suited to the routine diagnostic setting than established in-vitro techniques, such as intracellular cytokine staining and enzyme-linked immunosorbent assay (ELISA) using cell culture supernatants. We demonstrate that cell surface staining of unstimulated whole blood for CCR6⁺ CXCR3⁻ CCR4⁺ CD161⁺ T helper cells generates results that correlate with intracellular cytokine staining for IL-17A, and is able to discriminate between patients with molecularly defined CMC and healthy controls with 100% sensitivity and specificity within the cohort tested. Furthermore, removal of CCR4 and CD161 from the antibody staining panel did not affect assay performance, suggesting that the enumeration of CCR6⁺ CXCR3⁻ CD4⁺ T cells is sufficient for screening for Th17 deficiency in patients with CMC and could be used to guide further investigation aimed at identifying the underlying molecular cause.


Mesenchymal stem cell inhibition of T-helper 17 cell- differentiation is triggered by cell-cell contact and mediated by prostaglandin E2 via the EP4 receptor.
Mesenchymal stem cells (MSCs) inhibit T-cell activation and proliferation but their effects on individual T-cell-effector pathways and on memory versus naïve T cells remain unclear. MSC influence on the differentiation of naïve and memory CD4(+) T cells toward the Th17 phenotype was examined. CD4(+) T cells exposed to Th17-skewing conditions exhibited reduced CD25 and IL-17A expression following MSC co-culture. Inhibition of IL-17A production persisted upon re-stimulation in the absence of MSCs. These effects were attenuated when cell-cell contact was prevented. Th17 cultures from highly purified naïve- and memory-phenotype responders were similarly inhibited. Th17 inhibition by MSCs was reversed by indomethacin and a selective COX-2 inhibitor. Media from MSC/Th17 co-cultures contained increased prostaglandin E2 (PGE2) levels and potently suppressed Th17 differentiation in fresh cultures. MSC-mediated Th17 inhibition was reversed by a selective EP4 antagonist and was mimicked by synthetic PGE2 and a selective EP4 agonist. Activation-induced IL-17A secretion by naturally occurring, effector-memory Th17 cells from a urinary obstruction model was also inhibited by MSC co-culture in a COX-dependent manner. Overall, MSCs potently inhibit Th17 differentiation from naïve and memory T-cell precursors and inhibit naturally-occurring Th17 cells derived from a site of inflammation. Suppression entails cell-contact-dependent COX-2 induction resulting in direct Th17 inhibition by PGE2 via EP4.


The new deal: a potential role for secreted vesicles in innate immunity and tumor progression.
Tumors must evade the immune system to survive and metastasize, although the mechanisms that lead to tumor immunoediting and their evasion of immune surveillance are far from clear. The first line of defense against metastatic invasion is the innate immune system that provides immediate defense through humoral immunity and cell-mediated components, mast cells, neutrophils, macrophages, and other myeloid-derived cells that protect the organism against foreign invaders. Therefore, tumors must employ different strategies to evade such immune responses or to modulate their environment, and they must do so prior metastasizing. Exosomes and other secreted vesicles can be used for cell-cell communication during tumor progression by promoting the horizontal transfer of information. In this review, we will analyze the role of such extracellular vesicles during tumor progression, summarizing the role of secreted vesicles in the crosstalk between the tumor and the innate immune system.