Transmaternal exposure to bisphenol a modulates the development of oral tolerance.
Bisphenol A (BPA) is a representative endocrine disruptor that may have adverse effects on human health. Since the development of oral tolerance during infancy may play an important role in the prevention of food allergies, we examined whether transmaternal exposure to BPA influences the development of oral tolerance. To measure antigen-specific responses, female wild-type mice mated with male ovalbumin (OVA)-specific T-cell receptor transgenic (TCR-tg) mice were fed with BPA during pregnancy and while nursing. OVA was administered to OVA-TCR-tg offspring during their weaning period. Oral administration of both high and low doses of OVA suppressed OVA-specific cell proliferation and cytokine production in both BPA-exposed and nonexposed control mice, but the OVA-mediated suppression was significantly more diminished by the BPA exposure. The accumulation of CD4+CD25+Foxp3+ T cells was diminished in the BPA-exposed offspring. Moreover, after low dose OVA administration, serum OVA-specific IgG1 and IgG2a levels were higher in the BPA-exposed offspring than in nonexposed ones. Taken together, our results indicate that transmaternal exposure to BPA seems to modulate the mechanisms underlying tolerance induction; therefore, BPA may partially interrupt the development of oral tolerance.


Predicting Post-Transplant Recurrence of IgA Nephropathy: The Importance of Crescents.
Most studies that have assessed the predictors of recurrent IgA nephropathy (IgAN) in the renal allograft have focused on post-transplant features. Identifying high-risk pre-transplant features of IgAN is useful for counseling patients and may help in tailoring post-transplant immunosuppression. We investigated the pre-transplant clinical and biopsy features of 62 patients with IgAN who received transplants at Columbia University Medical Center from 2001 to 2012 and compared the characteristics and outcomes of patients with IgAN recurrence to those without recurrence. The primary outcome was time to recurrent IgAN. Secondary outcomes were a composite of doubling of creatinine or allograft failure, and recurrent IgAN as a cause of allograft dysfunction. Of the 62 patients, 14 had recurrent IgAN in the allograft. Mean time to recurrence was 2.75 years. Those with recurrent disease were younger at the time of native kidney biopsy (29 vs. 41 years, p < 0.0009). Black race and Hispanic ethnicity composed a higher proportion of the recurrent disease group. On multivariable analysis, significant predictors of recurrent IgAN included age at diagnosis (hazards ratio (HR) 0.911, 95% CI 0.85-0.98), burden of crescents on native biopsy (HR 1.21 per 10% increase in crescents, 95% CI 1.00-1.47) and allograft rejection (HR 3.59, 95% CI 1.10-11.7). Features of native IgAN can help predict the risk of recurrent disease in the renal allograft. In particular, immunologically active disease represented by earlier age of onset and greater burden of crescents on native biopsy is more likely to recur after transplant.


SPR-based fragment screening with neurotensin receptor 1 generates novel small molecule ligands.
The neurotensin receptor 1 represents an important drug target involved in various diseases of the central nervous system. So far, the full exploitation of potential therapeutic activities has been compromised by the lack of compounds with favorable physicochemical and pharmacokinetic properties which efficiently penetrate the blood-brain barrier. Recent progress in the generation of stabilized variants of solubilized neurotensin receptor 1 and its subsequent purification and successful structure determination presents a solid starting point to apply the approach of fragment-based screening to extend the chemical space of known neurotensin receptor 1 ligands. In this report, surface plasmon resonance was used as primary method to screen 6369 compounds. Thereby 44 hits were identified and confirmed in competition as well as dose-response experiments. Furthermore, 4 out of 8 selected hits were validated using nuclear magnetic resonance spectroscopy as orthogonal biophysical method. Computational analysis of the compound structures, taking the known crystal structure of the endogenous peptide agonist into consideration, gave insight into the potential fragment-binding location and interactions and inspires chemistry efforts for further exploration of the fragments.


Parenteral and Enteral Nutrition-From Hospital to Home: Will It Be Covered?
With scientific advances allowing for the safe delivery of parenteral and enteral nutrition in the home setting, challenges have risen with determining how this will be financially feasible for patients. In the United States, the government is one of the major payers for home parenteral and enteral nutrition (HPEN). Thus, it is important for nutrition providers to have an understanding of the Medicare criteria that must be met in order for these services to be covered. It can be difficult for clinicians to sift through these requirements and decipher for whom and when HPEN is covered. As our nutrition science knowledge and delivery continue to grow and evolve, potential barriers to this coverage may arise. This article provides background on those currently on HPEN in the United States, the current Medicare HPEN coverage criteria, and challenges we may face in the future.


Structural Versatility of Bicellar Systems and Their Possibilities as Colloidal Carriers.
Bicellar systems are lipid nanostructures formed by long- and short-chained phospholipids dispersed in aqueous solution. The morphological transitions of bicellar aggregates due to temperature, composition and time variations have been revised in this work. To this end, two bicellar systems have been considered; one formed by dimyristoyl-phosphatidylcholine (DMPC) and dihexanoyl- phosphatidylcholine (DHPC) and another formed by dipalmitoyl-phosphatidylcholine (DPPC) and DHPC. The relationship between the magnetic alignment, the morphology of the aggregates and the phase transition temperature (Tm) of lipids is discussed. In general terms, the non-alignable samples present rounded objects at temperature below the Tm. Above this temperature, an increase of viscosity is followed by the formation of large elongated aggregates. Alignable samples presented discoidal objects below the Tm. The best alignment was achieved above this temperature with large areas of lamellar stacked bilayers and some multilamellar vesicles. The effect of the inclusion of ceramides with different chain lengths in the structure of bicelles is also revised in the present article. A number of physical techniques show that the bicellar structures are affected by both the concentration and the type of ceramide. Systems are able to incorporate 10% mol of ceramides that probably are organized forming domains. The addition of 20% mol of ceramides promotes destabilization of bicelles, promoting the formation of mixed systems that include large structures. Bicellar systems have demonstrated to be morphologically stable with time, able to encapsulate different actives and to induce specific effects on the skin. These facts make bicellar systems good candidates as colloidal carriers for dermal delivery. However, water dilution induces structural changes and formation of vesicular structures in the systems; stabilization strategies have been been explored in recent works and are also updated here.


Follow-up of patients after revascularisation for peripheral arterial diseases: a consensus document from the European Society of Cardiology Working Group on Aorta and Peripheral Vascular Diseases and the European Society for Vascular Surgery.
Peripheral arterial diseases comprise different clinical presentations, from cerebrovascular disease down to lower extremity artery disease, from subclinical to disabling symptoms and events. According to clinical presentation, the patient's general condition, anatomical location and extension of lesions, revascularisation may be needed in addition to best medical treatment. The 2017 European Society of Cardiology guidelines in collaboration with the European Society for Vascular Surgery have addressed the indications for revascularisation. While most cases are amenable to either endovascular or surgical revascularisation, maintaining long-term patency is often challenging. Early and late procedural complications, but also local and remote recurrences frequently lead to revascularisation failure. The rationale for surveillance is to propose the accurate implementation of preventive strategies to avoid other cardiovascular events and disease progression and avoid recurrence of symptoms and the need for redo revascularisation. Combined with vascular history and physical examination, duplex ultrasound scanning is the pivotal imaging technique for identifying revascularisation failures. Other non-invasive examinations (ankle and toe brachial index, computed tomography scan, magnetic resonance imaging) at regular intervals can optimise surveillance in specific settings. Currently, optimal revascularisation surveillance programmes are not well defined and systematic reviews addressing long-term results after revascularisation are lacking. We have systematically reviewed the literature addressing follow-up after revascularisation and we propose this consensus document as a complement to the recent guidelines for optimal surveillance of revascularised patients beyond the perioperative period.


Quantifying reputation and success in art.
In areas of human activity where performance is difficult to quantify in an objective fashion, reputation and networks of influence play a key role in determining access to resources and rewards. To understand the role of these factors, we reconstructed the exhibition history of half a million artists, mapping out the coexhibition network that captures the movement of art between institutions. Centrality within this network captured institutional prestige, allowing us to explore the career trajectory of individual artists in terms of access to coveted institutions. Early access to prestigious central institutions offered life-long access to high-prestige venues and reduced dropout rate. By contrast, starting at the network periphery resulted in a high dropout rate, limiting access to central institutions. A Markov model predicts the career trajectory of individual artists and documents the strong path and history dependence of valuation in art.


The impact of music on the bioelectrical oscillations of the brain.
In this article we conclude the main scientific studies into the changes in the bioelectrical brainwave activity that occur while listening to music. A brainwave spectral analysis, derived from findings of electroencephalograms, is a powerful tool to obtain deep and objective insights into the effects of music on the brain. This capacity is being investigated in various contexts. Starting with a healthy population, studies also seek to determine the impact of music in such conditions as disorders of consciousness, psychiatric diseases, and chronic conditions, as well as to further explore the role of music for rehabilitation purposes. Supplemental investigations in this field are needed not only to deepen the knowledge of general neurophysiology of listening to music, but also to possibly open new perspectives for its broader use in clinical practices.


Correct timing of dnaA transcription and initiation of DNA replication requires trans translation.
The trans translation pathway for protein tagging and ribosome release has been found in all bacteria and is required for proliferation and differentiation in many systems. Caulobacter crescentus mutants that lack the trans translation pathway have a defect in the cell cycle and do not initiate DNA replication at the correct time. To determine the molecular basis for this phenotype, effects on events known to be important for initiation of DNA replication were investigated. In the absence of trans translation, transcription from the dnaA promoter and an origin-proximal promoter involved in replication initiation is delayed. Characterization of the dnaA promoter revealed two cis-acting elements that have dramatic effects on dnaA gene expression. A 5' leader sequence in dnaA mRNA represses gene expression by >15-fold but does not affect the timing of dnaA expression. The second cis-acting element, a sequence upstream of the -35 region, affects both the amount of dnaA transcription and the timing of transcription in response to trans translation. Mutations in this promoter element eliminate the transcription delay and partially suppress the DNA replication phenotype in mutants lacking trans translation activity. These results suggest that the trans translation capacity of the cell is sensed through the dnaA promoter to control the timing of DNA replication initiation.


Metabolic syndrome in subjects at high risk for type 2 diabetes: the genetic, physiopathology and evolution of type 2 diabetes (GENFIEV) study.
We evaluated the relationship between insulin resistance (IR) and insulin secretion with the metabolic syndrome (MS) in 885 subjects (377 men/508 women, age 49±11 years, BMI 29±5.2kgm(-2)) at risk of diabetes enrolled in the genetics, pathophysiology and evolution of type 2 diabetes (GENFIEV) study. All subjects underwent a 75-g oral glucose tolerance test (OGTT) for the estimation of plasma levels of glucose and C-peptide, as well as fasting insulin and lipid profile. IR was arbitrarily defined as HOMA-IR value above the 75th centile of normal glucose tolerance (NGT) subjects. Overall MS prevalence (National Cholesterol Treatment Panel-Adult Treatment Panel (NCEP-ATPIII) criteria) was 33%, 19% in subjects with NGT, 42% in impaired fasting glucose (IFG), 34% in impaired glucose tolerance (IGT), 74% in IFG+IGT subjects, and 56% in newly diagnosed diabetic patients. Prevalence was slightly higher with IDF criteria. MS prevalence was >50% in subjects with 2h glucose >7.8mmoll(-1), independently of fasting plasma glucose. IR prevalence was higher in subjects with MS than in those without (63% vs. 23%; p<0.0001) and increased from 54% to 73% and 88% in the presence of three, four or five traits, respectively. IR occurred in 42% of subjects with non-diabetic alterations of glucose homeostasis, being the highest in those with IFG+IGT (IFG+IGT 53%, IFG 45%, IGT 38%; p<0.0001). Individuals with MS were more IR irrespective of glucose tolerance (p<0.0001) with no difference in insulinogenic index. Hypertriglyceridaemia (OR: 3.38; Confidence Interval, CI: 2.294.99), abdominal obesity (3.26; CI: 2.18-4.89), hyperglycaemia (3.02; CI: 1.80-5.07) and hypertension (1.69; CI: 1.12-2.55) were all associated with IR. These results show that in subjects with altered glucose tolerance (in particular IFG+IGT) MS prevalence is high and is generally associated to IR. Some combinations of traits of MS may significantly contribute to identify subjects with IR.


Using cephalometry to evaluate maxillomandibular relationships in complete denture construction.
Long-term denture wearers undergo facial changes as a result of occlusal wear of the dentures and residual ridge resorption. This study examined 12 such patients, presenting with a clinical appearance of Angle's Class III occlusal relationships, to evaluate a clinical method of determining the correct mandibular position. Complete dentures were fabricated for each patient using standard clinical procedures, but acrylic resin blocks were left on the mandibular posterior bases instead of denture teeth. Ensuing changes in maxillomandibular relationships were recorded. After the stabilization of the mandibular relationship, the dentures were completed using mandibular posterior teeth. Patients were evaluated using cephalometric analysis before and after treatment. Results show that a careful procedure of denture fabrication allows the determination of the correct mandibular relationship, even in patients who have experienced extreme facial collapse.


Associations of School Day Sedentary Behavior and Physical Activity With Gross Motor Skills: Use of Compositional Data Analysis
To examine the relationships among school day sedentary times (SED), light physical activity (LPA), and moderate to vigorous physical activity (MVPA) with gross motor skills in children using Compositional Data Analysis. Participants were 409 children (mean age = 8.4 [1.8] y) recruited across 5 low-income schools. Gross motor skills were assessed using the test for gross motor development—third edition (TGMD-3), and physical activity was assessed using accelerometers. Isometric log-ratio coordinates were calculated by quantifying the relative proportion of percentage of the school day spent in SED, LPA, and MVPA. The associations of the isometric log-ratio coordinates with the TGMD-3 scores were estimated using general linear mixed-effects models adjusted for age, body mass index, estimated aerobic capacity, and school affiliation. A higher proportion of the school day spent in %MVPA relative to %SED and %LPA was significantly associated with higher TGMD-3 total scores (γMVPA = 14.44, P = .01). This relationship was also observed for the ball skills subtest scores (γMVPA = 16.12, P = .003). Replacing %SED and %LPA with %MVPA during school hours may be an effective strategy for improving gross motor skills, specifically ball skills, in low-income elementary school-aged children.


Diet-induced obesity prevents the development of acute traumatic coagulopathy.
Obesity and hemorrhagic shock following trauma are predictors of mortality but have conflicting effects on coagulation. Following hemorrhage, tissue injury and hypoperfusion lead to acute traumatic coagulopathy (ATC), producing a hypocoagulable state. Inversely, obesity promotes clotting and impairs fibrinolysis to yield a hypercoagulable state. High rates of venous thromboembolism, organ failure, and early mortality may be caused by hypercoagulability in obese patients. We hypothesize that obesity prevents the development of ATC following injury-induced hemorrhagic shock. Male Sprague-Dawley rats (250-275 g) were fed a high-fat diet (32%kcal from fat) for 4 weeks to 6 weeks and diverged into obesity-resistant (OR, n = 9) and obesity-prone (OP, n = 9) groups. Age-matched control (CON) rats were fed normal diet (10% kcal from fat, n = 9). Anesthetized rats were subjected to an uncontrolled hemorrhage by a Grade V splenic injury to a mean arterial pressure (MAP) of 40 mm Hg. Hypotension (MAP, 30-40 mm Hg) was maintained for 30 minutes to induce shock. MAP, heart rate, lactate, base excess, cytokines, blood loss, and thrombelastography (TEG) parameters were measured before and after hemorrhagic shock. At baseline, OP rats exhibited a shorter time to 20-mm clot (K), and higher rate of clot formation (α angle), clot strength (maximal amplitude), and coagulation index, compared with the CON rats (p < 0.05), indicating enhanced coagulation. Physiologic parameters following shock were similar between groups. In the CON and OR rats, shock prolonged the time to clot initiation (R) and K and decreased α angle and coagulation index (all p < 0.05 vs. baseline). In contrast, shock had no effect on these TEG parameters in the OP rats. Maximal amplitude was the only TEG parameter affected by shock in the OP rats, which was decreased in all groups. Obesity prevents the development of ATC following hemorrhage shock. Complications associated with obesity following hemorrhagic shock may be attributed to the preserved hypercoagulable state.


Breastfeeding and immunity to intestinal infections.
The purpose of this study was to compare immune response in breast and non breastfed children presenting with diarrhoea at Paediatric Observation Ward, Kenyatta National Hospital (KNH-POW) and Maternal and Child Health Clinic, Pumwani Maternity Hospital (PMH-MCH). Blood and stool samples were collected from the first four consecutive children aged 5 years and below per day, presenting with or without diarrhoea from January to December, 1992. The stools were tested for total IgA by single radial immunodiffusion (SRID) and specific IgA by enzyme linked immunosorbent assay (ELISA). Peripheral blood CD4 and CD8 enumeration was done by flow cytometry. Stools were cultured for bacteria on selective media while ova and cysts of parasites were identified by wet preparation microscopy. A total of 457 children were enrolled into the study, 69.6% of whom presented with diarrhoea. Breastfed children tended to have a shorter duration of diarrhoea than either mixed fed or bottle fed (8.3 vs 9.8 vs 11.2 days, p = 0.2). In general, E. coli were more commonly isolated from breastfed than mixed fed or bottle fed (56.7% vs 43.9% vs 28.9%, p = 0.004) while intestinal parasites were mostly in bottle fed than mixed or breastfed children (28.8% vs 8.2 vs 0.8, p < 0.004). However, when children with diarrhoea were considered, E. coli was more frequently isolated from bottle fed children who presented with diarrhoea than without (26.7% vs 7.7%, p = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)


Immunogenicity evaluation of a lipidic amino acid-based synthetic peptide vaccine for Chlamydia trachomatis.
Lipidic amino acid-based synthetic peptides derived from the variable domains (VD) of Chlamydia trachomatis outer membrane protein 1 were evaluated as potential candidate sequences in a vaccine. A peptide sequence designated P2 from the VD IV of serovar B contained a B cell epitope capable of eliciting antibodies binding to serovar B elementary bodies (EB) and a T helper site capable of presentation by multiple H-2 alleles. Polymerization of the P2 into polylysine to form lipid core peptides (LCP) significantly enhanced immunogenicity compared with P2 monomer alone. The LCP system incorporates lipidic amino acids into the polylysine system and enhances lipophobicity and membrane binding effects of the peptide. A second peptide sequence derived from the VD I of serovar C was cosynthesized with P2 into lipidic polylysine LCP and was designated LCP-H1. Antibodies to this construct reacted at high titer with EB of the three major trachoma causing C. trachomatis serovars A, B, and C. LCP-H1 was immunogenic among four of five murine H-2 alleles. Pepscan analysis showed that the fine specificity of antibodies generated to LCP-H1 were directed to the predetermined neutralizing epitope sequences. An in vitro HAK cell neutralization assay showed that LCP-H1 elicited neutralizing antibodies to serovars A, B, and C, but these were of low titer. Because LCP-H1 antibodies bound to the peptide sequence with 10-100-fold higher titer than to EB, the low neutralization titers most likely result from conformational differences between the synthetic peptide and antigenic sites on the native organism. Modification of LCP-H1 to incorporate a predefined conformation may result in improved antigenic properties.


Respiratory muscle fatigue: a cause of respiratory failure?
1. The question whether respiratory muscle fatigue ever causes respiratory failure is over 40 years old, but we still have no definitive answer to this question. Skeletal muscle fatigue occurs when the rate of energy consumption of the muscle is greater than the energy supplied, so that energy stores are utilized and eventually become depleted. 2. Five factors which are important in the development of muscle fatigue (a, the tension developed by the muscle; b, the maximum tension the muscle can develop; c, the energy stored within the muscle; d, the energy supplied to the muscle; e, the efficiency of the muscle). These can be affected in many diseases, so disposing to fatigue, thus respiratory muscle fatigue is likely to be a common occurrence. 3. Respiratory muscle fatigue can in principle easily be diagnosed at the bedside by application of a simple electromyographic technique used to detect fatigue in other skeletal muscles.


Protective effects of Chinese propolis and its component, chrysin, against neuronal cell death via inhibition of mitochondrial apoptosis pathway in SH-SY5Y cells.
Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of neurodegenerative and ischemic disorders. The purpose of this study was to evaluate the effects of Chinese propolis and its constituents [chrysin, galangin, pinocembrin, caffeic acid, and caffeic acid phenethyl ester (CAPE)] against tunicamycin-induced neuronal cell death in SH-SY5Y cells. Both Chinese propolis and chrysin concentration-dependently inhibited such cell death, the tunicamycin-induced activation of caspase-3, and the effects of tunicamycin on mitochondria [release of cytochrome c into the cytosol and disruption of the mitochondrial membrane potential (DeltaPsim)]. Furthermore, Chinese propolis and chrysin each inhibited staurosporine-induced cell death. These findings indicate that the inhibitory effects of Chinese propolis against neuronal cell death induced by ER stress or staurosporine may be exerted primarily by chrysin. Moreover, the mechanism underlying the protective effects may, at least partly, involve inhibitions of caspase-3 activity and the mitochondrial apoptotic pathway.


Unexpected phenotype of mice lacking Shcbp1, a protein induced during T cell proliferation.
T cell development and activation are highly regulated processes, and their proper execution is important for a competent immune system. Shc SH2-domain binding protein-1 (Shcbp1) is an evolutionarily conserved protein that binds to the adaptor protein ShcA. Studies in Drosophila and in cell lines have strongly linked Shcbp1 to cell proliferation, embryonic development, growth factor signaling, and tumorigenesis. Here we show that Shcbp1 expression is strikingly upregulated during the β-selection checkpoint in thymocytes, and that its expression tightly correlates with proliferative stages of T cell development. To evaluate the role for Shcbp1 during thymic selection and T cell function in vivo, we generated mice with global and conditional deletion of Shcbp1. Surprisingly, the loss of Shcbp1 expression did not have an obvious effect during T cell development. However, in a mouse model of experimental autoimmune encephalomyelitis (EAE), which depends on CD4(+) T cell function and mimics multiple features of the human disease multiple sclerosis, Shcbp1 deficient mice had reduced disease severity and improved survival, and this effect was T cell intrinsic. These data suggest that despite the striking upregulation of Shcbp1 during T cell proliferation, loss of Shcbp1 does not directly affect T cell development, but regulates CD4(+) T cell effector function in vivo.


The Role of Curcumin Administration in Patients with Major Depressive Disorder: Mini Meta-Analysis of Clinical Trials.
Major depression is a common, recurrent, and chronic disease that negatively affects the quality of life and increases the risk of mortality. Several studies have demonstrated that curcumin, the yellow-pigmented substance of the turmeric, possesses antidepressant properties. The aim of this review is to meta-analytically assess the antidepressant effect of curcumin in patients with major depressive disorders. We extensively searched the literature until August 2015. The random-effect model was used to calculate the pooled standardized difference of means (SMD). Subgroup analyses were also performed to examine the effect of different study characteristics on the overall model. Six clinical trials met the inclusion criteria. Overall, curcumin administration showed a significantly higher reduction in depression symptoms [SMD = -0.34; 95% confidence interval (CI) = -0.56, -0.13; p = 0.002]. Subgroup analyses showed that curcumin had the highest effect when given to middle-aged patients (SMD = -0.36; 95% CI = -0.59; -0.13; p = 0.002), for longer duration of administration (SMD = -0.40; 95% CI = -0.64, -0.16; p = 0.001), and at higher doses (SMD = -0.36; 95% CI = -0.59, -0.13; p = 0.002). The administration of new formulation of curcumin (BCM-95) had non-significantly higher effect on depression as compared with the conventional curcumin-piperine formula. We conclude that there is supporting evidence that curcumin administration reduces depressive symptoms in patients with major depression.


Multiple interactions recruit MLL1 and MLL1 fusion proteins to the HOXA9 locus in leukemogenesis.
MLL1 fusion proteins activate HoxA9 gene expression and cause aggressive leukemias that respond poorly to treatment, but how they recognize and stably bind to HoxA9 is not clearly understood. In a systematic analysis of MLL1 domain recruitment activity, we identified an essential MLL1 recruitment domain that includes the CXXC domain and PHD fingers and is controlled by direct interactions with the PAF elongation complex and H3K4Me2/3. MLL1 fusion proteins lack the PHD fingers and require prebinding of a wild-type MLL1 complex and CXXC domain recognition of DNA for stable HoxA9 association. Together, these results suggest that specific recruitment of MLL1 requires multiple interactions and is a precondition for stable recruitment of MLL1 fusion proteins to HoxA9 in leukemogenesis. Since wild-type MLL1 and oncogenic MLL1 fusion proteins have overlapping yet distinct recruitment mechanisms, this creates a window of opportunity that could be exploited for the development of targeted therapies.


An evaluation of an high temperature blackbody as a working standard of spectral radiance.
For those interested in measuring the spectral radiance of high-intensity arcs, especially in the ultraviolet region, the 3000 degrees C blackbody has several advantages over the conventional tungsten ribbon filament standard of spectral radiance. At a wavelength of 250 nm, it is between two and three orders of magnitude more intense and could have 30% to 40% less uncertainty in its spectral radiance. Moreover, by using the blackbody, measurements could be extended to wavelengths shorter than 250 nm. On the other hand, the intensity advantage of the blackbody can be nearly eliminated by operating and calibrating a tungsten standard-type lamp well over its rated current. Tests have shown that the stability of these lamps operated at 45 A and 50 A is suitable for calibration purposes.


Hybrid nanorod-polymer solar cells.
We demonstrate that semiconductor nanorods can be used to fabricate readily processed and efficient hybrid solar cells together with polymers. By controlling nanorod length, we can change the distance on which electrons are transported directly through the thin film device. Tuning the band gap by altering the nanorod radius enabled us to optimize the overlap between the absorption spectrum of the cell and the solar emission spectrum. A photovoltaic device consisting of 7-nanometer by 60-nanometer CdSe nanorods and the conjugated polymer poly-3(hexylthiophene) was assembled from solution with an external quantum efficiency of over 54% and a monochromatic power conversion efficiency of 6.9% under 0.1 milliwatt per square centimeter illumination at 515 nanometers. Under Air Mass (A.M.) 1.5 Global solar conditions, we obtained a power conversion efficiency of 1.7%.


A new measure of group decision-making efficiency.
It has widely been accepted that aggregating group-level decisions is superior to individual decisions. As compared to individuals, groups tend to show a decision advantage in their response accuracy. However, there has been a lack of research exploring whether group decisions are more efficient than individual decisions with a faster information-processing speed. To investigate the relationship between accuracy and response time (RT) in group decision-making, we applied systems' factorial technology, developed by Townsend and Nozawa (Journal of Mathematical Psychology 39, 321-359, 1995) and regarded as a theory-driven methodology, to study the information-processing properties. More specifically, we measured the workload capacity CAND(t), which only considers the correct responses, and the assessment function of capacity AAND(t), which considers the speed-accuracy trade-off, to make a strong inference about the system-level processing efficiency. A two-interval, forced-choice oddball detection task, where participants had to detect which interval contains an odd target, was conducted in Experiment 1. Then, in Experiment 2, a yes/no Gabor detection task was adopted, where participants had to detect the presence of a Gabor patch. Our results replicated previous findings using the accuracy-based measure: Group detection sensitivity was better than the detection sensitivity of the best individual, especially when the two individuals had similar detection sensitivities. On the other hand, both workload capacity measures, CAND(t) and AAND(t), showed evidence of supercapacity processing, thus suggesting a collective benefit. The ordered relationship between accuracy-based and RT-based collective benefit was limited to the AAND(t) of the correct and fast responses, which may help uncover the processing mechanism behind collective benefits. Our results suggested that AAND(t), which combines both accuracy and RT into inferences, can be regarded as a novel and diagnostic tool for studying the group decision-making process.


Impact of fibromyalgia pain on health-related quality of life before and after treatment with tramadol/acetaminophen.
To assess health-related quality of life (HRQOL) in patients with moderate-to-severe fibromyalgia pain compared with the general population, and to assess the relationship between pain severity and HRQOL before and after treatment with an analgesic. Data were obtained from a randomized, double-blind study of patients with moderate-to-severe fibromyalgia pain. Patients received either tramadol/acetaminophen or placebo 4 times/day as needed for 91 days. HRQOL was measured with the Short Form 36 Health Survey (SF-36) and the Fibromyalgia Impact Questionnaire (FIQ). Baseline HRQOL scores were compared with a national sample of noninstitutionalized adults and a sample of patients with impaired HRQOL due to congestive heart failure. Patients with fibromyalgia were divided into tertiles by change in pain severity, and SF-36 scores were compared across the tertiles. Mean changes in SF-36 and FIQ scores were compared between treatment groups. Patients with fibromyalgia scored lower than the US norm on all SF-36 scales (P < 0.0001) and lower than patients with congestive heart failure on most scales. More severe pain was associated with greater impairment of HRQOL compared with less severe pain (P < 0.0001). Patients in the highest tertile for improved pain severity had greater improvement in HRQOL scores than patients in the lower tertiles. Compared with patients who received placebo (n = 157), patients treated with tramadol/acetaminophen (n = 156) showed greater improvement on SF-36 physical functioning, role physical, bodily pain, and physical summary scales, as well as FIQ scales for ability to do job, pain, and stiffness (P < 0.01). Moderate-to-severe fibromyalgia pain significantly impairs HRQOL, and effective pain relief in these patients significantly increases HRQOL.


Integration of spatial and single-cell transcriptomic data elucidates mouse organogenesis.
Molecular profiling of single cells has advanced our knowledge of the molecular basis of development. However, current approaches mostly rely on dissociating cells from tissues, thereby losing the crucial spatial context of regulatory processes. Here, we apply an image-based single-cell transcriptomics method, sequential fluorescence in situ hybridization (seqFISH), to detect mRNAs for 387 target genes in tissue sections of mouse embryos at the 8-12 somite stage. By integrating spatial context and multiplexed transcriptional measurements with two single-cell transcriptome atlases, we characterize cell types across the embryo and demonstrate that spatially resolved expression of genes not profiled by seqFISH can be imputed. We use this high-resolution spatial map to characterize fundamental steps in the patterning of the midbrain-hindbrain boundary (MHB) and the developing gut tube. We uncover axes of cell differentiation that are not apparent from single-cell RNA-sequencing (scRNA-seq) data, such as early dorsal-ventral separation of esophageal and tracheal progenitor populations in the gut tube. Our method provides an approach for studying cell fate decisions in complex tissues and development.


Global evolutionary analysis of chronic hepatitis C patients revealed significant effect of baseline viral resistance, including novel non-target sites, for DAA-based treatment and retreatment outcome.
Direct-acting antivirals (DAAs) have proven highly effective against chronic hepatitis C virus (HCV) infection. However, some patients experience treatment failure, associated with resistance-associated substitutions (RASs). Our aim was to investigate the complete viral coding sequence in hepatitis C patients treated with DAAs to identify RASs and the effects of treatment on the viral population. We selected 22 HCV patients with sustained virologic response (SVR) to match 21 treatment-failure patients in relation to HCV genotype, DAA regimen, liver cirrhosis and previous treatment experience. Viral-titre data were compared between the two patient groups, and HCV full-length open reading frame deep-sequencing was performed. The proportion of HCV NS5A-RASs at baseline was higher in treatment-failure (82%) than matched SVR patients (25%) (p = .0063). Also, treatment failure was associated with slower declines in viraemia titres. Viral population diversity did not differ at baseline between SVR and treatment-failure patients, but failure was associated with decreased diversity probably caused by selection for RAS. The NS5B-substitution 150V was associated with sofosbuvir treatment failure in genotype 3a. Further, mutations identified in NS2, NS3-helicase and NS5A-domain-III were associated with DAA treatment failure in genotype 1a patients. Six retreated HCV patients (35%) experienced 2nd treatment failure; RASs were present in 67% compared to 11% with SVR. In conclusion, baseline RASs to NS5A inhibitors, but not virus population diversity, and lower viral titre decline predicted HCV treatment failure. Mutations outside of the DAA targets can be associated with DAA treatment failure. Successful DAA retreatment in patients with treatment failure was hampered by previously selected RASs.


Large hemorrhagic pericardial effusion.
Establishing the etiology of a large pericardial effusion is of crucial importance since it is likely the result of a serious underlying disease. However, there is a paucity of literature on the diagnostic management of patients with large hemorrhagic effusions. To analyze the management of patients with large hemorrhagic pericardial effusion. We reviewed seven cases of large hemorrhagic pericardial effusions hospitalized in Soroka University Medical Center in 2010. All seven patients underwent a comprehensive evaluation followed by pericardiocentesis. Six of the seven cases demonstrated echocardiographic signs oftamponade. Large amounts of hemorrhagic pericardial effusion (> 600 ml) were aspirated from each patient. A pericardial window was performed in two of the seven patients. The causes for the hemorrhagic effusions were malignancy, streptococcal infection, familial Mediterranean fever exacerbation, and idiopathic. Four patients completely recovered. The condition of one patient improved after initiation of chemotherapy for lung cancer, and two patients with progressive malignancies passed away shortly after discharge. Two cases of massive pulmonary embolism were diagnosed and resolved spontaneously without anticoagulation therapy after the effusion was treated. All cases of pericardial effusion resolved after rapid diagnosis and initiation of specific treatment. Pulmonary embolism in situ may be a complication of large pericardial effusions that does not require anticoagulation treatment after the effusion resolves.


Dimensionality of object representations in monkey inferotemporal cortex.
We have calculated the intrinsic dimensionality of visual object representations in anterior inferotemporal (AIT) cortex, based on responses of a large sample of cells stimulated with photographs of diverse objects. Because dimensionality was dependent on data set size, we determined asymptotic dimensionality as both the number of neurons and number of stimulus image approached infinity. Our final dimensionality estimate was 93 (SD: ± 11), indicating that there is basis set of approximately 100 independent features that characterize the dimensions of neural object space. We believe this is the first estimate of the dimensionality of neural visual representations based on single-cell neurophysiological data. The dimensionality of AIT object representations was much lower than the dimensionality of the stimuli. We suggest that there may be a gradual reduction in the dimensionality of object representations in neural populations going from retina to inferotemporal cortex as receptive fields become increasingly complex.


A strategy to identify de novo mutations in common disorders such as autism and schizophrenia.
There are several lines of evidence supporting the role of de novo mutations as a mechanism for common disorders, such as autism and schizophrenia. First, the de novo mutation rate in humans is relatively high, so new mutations are generated at a high frequency in the population. However, de novo mutations have not been reported in most common diseases. Mutations in genes leading to severe diseases where there is a strong negative selection against the phenotype, such as lethality in embryonic stages or reduced reproductive fitness, will not be transmitted to multiple family members, and therefore will not be detected by linkage gene mapping or association studies. The observation of very high concordance in monozygotic twins and very low concordance in dizygotic twins also strongly supports the hypothesis that a significant fraction of cases may result from new mutations. Such is the case for diseases such as autism and schizophrenia. Second, despite reduced reproductive fitness(1) and extremely variable environmental factors, the incidence of some diseases is maintained worldwide at a relatively high and constant rate. This is the case for autism and schizophrenia, with an incidence of approximately 1% worldwide. Mutational load can be thought of as a balance between selection for or against a deleterious mutation and its production by de novo mutation. Lower rates of reproduction constitute a negative selection factor that should reduce the number of mutant alleles in the population, ultimately leading to decreased disease prevalence. These selective pressures tend to be of different intensity in different environments. Nonetheless, these severe mental disorders have been maintained at a constant relatively high prevalence in the worldwide population across a wide range of cultures and countries despite a strong negative selection against them(2). This is not what one would predict in diseases with reduced reproductive fitness, unless there was a high new mutation rate. Finally, the effects of paternal age: there is a significantly increased risk of the disease with increasing paternal age, which could result from the age related increase in paternal de novo mutations. This is the case for autism and schizophrenia(3). The male-to-female ratio of mutation rate is estimated at about 4-6:1, presumably due to a higher number of germ-cell divisions with age in males. Therefore, one would predict that de novo mutations would more frequently come from males, particularly older males(4). A high rate of new mutations may in part explain why genetic studies have so far failed to identify many genes predisposing to complexes diseases genes, such as autism and schizophrenia, and why diseases have been identified for a mere 3% of genes in the human genome. Identification for de novo mutations as a cause of a disease requires a targeted molecular approach, which includes studying parents and affected subjects. The process for determining if the genetic basis of a disease may result in part from de novo mutations and the molecular approach to establish this link will be illustrated, using autism and schizophrenia as examples.


Founder mutation in dystonin-e underlying autosomal recessive epidermolysis bullosa simplex in Kuwait.
Only two homozygous nonsense mutations in the epidermal isoform of the dystonin gene, DST-e, have been reported previously in autosomal recessive epidermolysis bullosa simplex (EBS); the affected pedigrees were Kuwaiti and Iranian. This subtype of EBS is therefore considered to be a rare clinicopathological entity. In this study, we identified four seemingly unrelated Kuwaiti families in which a total of seven individuals had predominantly acral trauma-induced blistering since infancy. All affected individuals were homozygous for the mutation p.Gln1124* in DST-e, the same mutation that was identified in the originally reported family from Kuwait. Haplotype analysis in the five pedigrees (including the previous case) revealed a shared block of ~60 kb of genomic DNA across the site of the mutation, consistent with a founder effect. Most heterozygotes had no clinical abnormalities although one subject had mild transient skin fragility during childhood, an observation noted in the previously reported Iranian pedigree, suggesting that the condition may also be semidominant in some pedigrees rather than purely autosomal recessive. Our study reveals propagation of a mutant ancestral allele in DST-e throughout Kuwait, indicating that this subtype of EBS may be more common in Kuwait, and perhaps other Middle Eastern countries, than is currently appreciated.


Antimicrobial efficacy of chlorhexidine digluconate alone and in combination with eucalyptus oil, tea tree oil and thymol against planktonic and biofilm cultures of Staphylococcus epidermidis.
Effective skin antisepsis and disinfection of medical devices are key factors in preventing many healthcare-acquired infections associated with skin microorganisms, particularly Staphylococcus epidermidis. The aim of this study was to investigate the antimicrobial efficacy of chlorhexidine digluconate (CHG), a widely used antiseptic in clinical practice, alone and in combination with tea tree oil (TTO), eucalyptus oil (EO) and thymol against planktonic and biofilm cultures of S. epidermidis. Antimicrobial susceptibility assays against S. epidermidis in a suspension and in a biofilm mode of growth were performed with broth microdilution and ATP bioluminescence methods, respectively. Synergy of antimicrobial agents was evaluated with the chequerboard method. CHG exhibited antimicrobial activity against S. epidermidis in both suspension and biofilm (MIC 2-8 mg/L). Of the essential oils thymol exhibited the greatest antimicrobial efficacy (0.5-4 g/L) against S. epidermidis in suspension and biofilm followed by TTO (2-16 g/L) and EO (4-64 g/L). MICs of CHG and EO were reduced against S. epidermidis biofilm when in combination (MIC of 8 reduced to 0.25-1 mg/L and MIC of 32-64 reduced to 4 g/L for CHG and EO, respectively). Furthermore, the combination of EO with CHG demonstrated synergistic activity against S. epidermidis biofilm with a fractional inhibitory concentration index of <0.5. The results from this study suggest that there may be a role for essential oils, in particular EO, for improved skin antisepsis when combined with CHG.


The nuclear migration protein NUDF/LIS1 forms a complex with NUDC and BNFA at spindle pole bodies.
Nuclear migration depends on microtubules, the dynein motor complex, and regulatory components like LIS1 and NUDC. We sought to identify new binding partners of the fungal LIS1 homolog NUDF to clarify its function in dynein regulation. We therefore analyzed the association between NUDF and NUDC in Aspergillus nidulans. NUDF and NUDC directly interacted in yeast two-hybrid experiments via NUDF's WD40 domain. NUDC-green fluorescent protein (NUDC-GFP) was localized to immobile dots in the cytoplasm and at the hyphal cortex, some of which were spindle pole bodies (SPBs). We showed by bimolecular fluorescence complementation microscopy that NUDC directly interacted with NUDF at SPBs at different stages of the cell cycle. Applying tandem affinity purification, we isolated the NUDF-associated protein BNFA (for binding to NUDF). BNFA was dispensable for growth and for nuclear migration. GFP-BNFA fusions localized to SPBs at different stages of the cell cycle. This localization depended on NUDF, since the loss of NUDF resulted in the cytoplasmic accumulation of BNFA. BNFA did not bind to NUDC in a yeast two-hybrid assay. These results show that the conserved NUDF and NUDC proteins play a concerted role at SPBs at different stages of the cell cycle and that NUDF recruits additional proteins specifically to the dynein complex at SPBs.


Typing of Staphylococcus aureus by pulsed-field gel electrophoresis, zymotyping, capsular typing, and phage typing: resolution of clonal relationships.
Sixty-nine Staphylococcus aureus isolates from two epidemiologically unrelated sources were typed by pulsed-field gel electrophoresis after SmaI digestion of chromosomal DNA (genome typing), and the results were compared with those obtained by other typing methods: phage typing with the international set of phages, capsular serotyping with monoclonal antibodies against capsular polysaccharides type 5 and 8, and zymotyping by polyacrylamide agarose electrophoresis for esterase polymorphism. A good correlation of S. aureus types was found by these four typing methods. Differentiation increased in the order capsular typing < zymotyping < phage typing < genome typing, yielding 2, 10, 20, and 26 different S. aureus types, respectively. Five of the 26 genome types were further divided into several subtypes revealing clonal relationships. When 36 French S. aureus isolates were compared with 33 German S. aureus isolates, 3 strains representing clonal populations were identical in both groups. S. aureus isolates from patients with cystic fibrosis were also typed at the beginning and the end of a 4-week summer camp for these patients. The results suggested a possible strain transmission during the summer camp. We conclude that genome typing by pulsed-field gel electrophoresis is a powerful tool not only for strain identification but also for the resolution of the clonal relationships of S. aureus strains.


A cognitive analysis of server intervention policies: perceptions of bar owners and servers.
The present study examined the underlying psychological variables relevant to alcohol server intervention policies. The focus of the research was the theoretical examination of college bar owners' and servers' attitudes and beliefs about server intervention policies. Owners (n = 185) and servers (n = 185) of college bars were asked about their attitudes and perceived cognitive outcomes regarding server intervention policies. Although the findings revealed no statistical differences between owners and servers on their attitudes toward the different server intervention policies, statistical differences were found between the different policies (p < .05). Favorable policies focused on providing services to customers, whereas unfavorable policies focused on limiting the sales of alcohol. Finally, structural equation modeling revealed perceived cognitive outcomes related to the attitudes toward different server intervention policies. According to the present study's theoretical orientation, the attitudes are likely to have a direct influence on the adoption of policies or, on the part of the server, compliance with the policies. These attitudes toward the policies were found to be a function of the perceived hassle of implementing the policies and how effective the policy was in preventing driving under the influence.


Impairing both HMA4 homeologs is required for cadmium reduction in tobacco.
In tobacco, the heavy metal P1B-ATPases HMA4.1 and HMA4.2 function in root-to-shoot zinc and cadmium transport. We present greenhouse and field data that dissect the possibilities to impact the two homeologous genes in order to define the best strategy for leaf cadmium reduction. In a first step, both genes were silenced using an RNAi approach leading to >90% reduction of leaf cadmium content. To modulate HMA4 function more precisely, mutant HMA4.1 and HMA4.2 alleles of a Targeting Induced Local Lesions IN Genomes (TILLING) population were combined. As observed with RNAi plants, knockout of both homeologs decreased cadmium root-to-shoot transfer by >90%. Analysis of plants with segregating null and wild-type alleles of both homeologs showed that one functional HMA4 allele is sufficient to maintain wild-type cadmium levels. Plant development was affected in HMA4 RNAi and double knockout plants that included retarded growth, necrotic lesions, altered leaf morphology and increased water content. The combination of complete functional loss (nonsense mutation) in one homeologous HMA4 gene and the functional reduction in the other HMA4 gene (missense mutation) is proposed as strategy to limit cadmium leaf accumulation without developmental effects.


Referral patterns of children with poor growth in primary health care.
To promote early diagnosis and treatment of short stature, consensus meetings were held in the mid nineteen nineties in the Netherlands and the UK. This resulted in guidelines for referral. In this study we evaluate the referral pattern of short stature in primary health care using these guidelines, comparing it with cut-off values mentioned by the WHO. Three sets of referral rules were tested on the growth data of a random sample (n = 400) of all children born between 01-01-1985 and 31-12-1988, attending school doctors between 1998 and 2000 in Leiden and Alphen aan den Rijn (the Netherlands): the screening criteria mentioned in the Dutch Consensus Guideline (DCG), those of the UK Consensus Guideline (UKCG) and the cut-off values mentioned in the WHO Global Database on Child growth and Malnutrition. Application of the DCG would lead to the referral of too many children (almost 80%). The largest part of the referrals is due to the deflection of height, followed by distance to target height and takes primarily place during the first 3 years. The deflection away from the parental height would also lead to too many referrals. In contrast, the UKCG only leads to 0.3% referrals and the WHO-criteria to approximately 10%. The current Dutch consensus guideline leads to too many referrals, mainly due to the deflection of length during the first 3 years of life. The UKCG leads to far less referrals, but may be relatively insensitive to detect clinically relevant growth disorders like Turner syndrome. New guidelines for growth monitoring are needed, which combine a low percentage of false positive results with a good sensitivity.


Neuropathologic applications of immunohistochemical fiber typing in the non-neoplastic muscle biopsy.
The determination of fiber types is routinely accomplished in skeletal muscle biopsy specimens by enzymatic histochemical analysis, which detects adenosine triphosphatase (ATPase) activity on cryostat sections. This study assesses postmortem antigen degradation, the effects of fixation and processing, and the neuropathologic applications of MY-32, a monoclonal antibody to fast twitch skeletal myosin. Formalin-fixed, paraffin-embedded sections of skeletal muscle biopsy specimens obtained from the quadriceps femoris were immunoreacted with this antibody. Cryostat sections of the same muscle biopsy specimens were examined after brief fixation in either acetone or formalin. Parallel cryostat sections of frozen muscle were also assessed with ATPase preparations at pH 9.4 and 4.3. To evaluate the effect of postmortem interval and autolysis on antigen degradation, skeletal muscle samples obtained at 12 hours postmortem were immunoreacted after 12, 24, or 36 additional hours. These specimens were examined as immunoreacted cryostat sections and compared with parallel sections reacted for ATPase at pH 9.4 and 4.3. Representative sections from each time point were also fixed in formalin, routinely processed, paraffin embedded, and immunoreacted. Selected muscle biopsy specimens with a range of neuropathologic diagnoses, including fiber type grouping, Type II atrophy, and congenital fiber type disproportion, were also assessed for immunoreactivity. Our results indicate that the MY-32 monoclonal antibody specifically reacts with Type II (fast twitch) fibers. Immunoreactivity is most intense in cryostat sections immersion fixed in acetone, but moderately intense, specific immunoreactivity can be clearly identified in formalin-fixed (frozen or paraffin-embedded) tissue obtained even 48 hours after death. Application of this nonenzymatic method for fiber type determinations in the neuropathologic evaluation of skeletal muscle biopsies is presented.


Stories of weight management: factors associated with successful and unsuccessful weight maintenance.
Although behavioural interventions are successful in achieving short-term weight loss, most individuals regain most or all of their weight within a few years. Our aim was to investigate factors that can help in long-term weight maintenance. Qualitative interviews were conducted in order to elicit experiences, successes, and difficulties associated with weight control over the lifespan. Participants were 20 adult volunteers (aged 30-67) including lifelong weight maintainers, active weight maintainers who have maintained weight loss, and weight gainers. Thematic analysis was used to highlight differences between weight groups. Successful weight maintainers adopt a staged approach to weight management, including monitoring weight fluctuations and having a clear alarm signal for weight gain that triggers immediate action. They have several behavioural strategies for weight control, comprising relatively small adjustments to diet and/or exercise behaviour and also have clear strategies for coping with lifestyle interruptions. In contrast, unsuccessful weight maintainers display negative cognitive factors, including erratic or inconsistent weight vigilance, failure to respond to warning signs of weight gain, and failure to restrict weight unless in a positive mindset. Further, their coping strategies for weight gain or failed actions are poor. The results suggest that successful weight maintainers, irrespective of current weight band, adopt a staged behavioural approach to weight management that allows them to maintain a fairly stable weight. Encouraging the use of such strategies in those who typically regain weight after dieting may aid them in maintaining weight loss.


KDM5 histone demethylases repress immune response via suppression of STING.
Cyclic GMP-AMP (cGAMP) synthase (cGAS) stimulator of interferon genes (STING) senses pathogen-derived or abnormal self-DNA in the cytosol and triggers an innate immune defense against microbial infection and cancer. STING agonists induce both innate and adaptive immune responses and are a new class of cancer immunotherapy agents tested in multiple clinical trials. However, STING is commonly silenced in cancer cells via unclear mechanisms, limiting the application of these agonists. Here, we report that the expression of STING is epigenetically suppressed by the histone H3K4 lysine demethylases KDM5B and KDM5C and is activated by the opposing H3K4 methyltransferases. The induction of STING expression by KDM5 blockade triggered a robust interferon response in a cytosolic DNA-dependent manner in breast cancer cells. This response resulted in resistance to infection by DNA and RNA viruses. In human tumors, KDM5B expression is inversely associated with STING expression in multiple cancer types, with the level of intratumoral CD8+ T cells, and with patient survival in cancers with a high level of cytosolic DNA, such as human papilloma virus (HPV)-positive head and neck cancer. These results demonstrate a novel epigenetic regulatory pathway of immune response and suggest that KDM5 demethylases are potential targets for antipathogen treatment and anticancer immunotherapy.


Deep neck abscess in neonatal period: case report and review of literature.
Deep neck abscess is very rare in neonatal period. We reported a deep neck abscess caused by methicillin-sensitive Staphylococcus aureus infection (MSSA) in a neonate. A 10-day male infant was admitted to our neonatal unit with the complaints of fever, irritability, and refused to food intake. Ultrasonography and magnetic resonance imaging revealed as an abscess in the neck. Needle aspiration from abscess revealed pus. Antibiotics and drainage were applied. We also reviewed the neonatal deep neck abscess reported in English literature and clinical presentation, risk factors, causing microorganisms, treatment, complication and outcome of deep neck abscesses were discussed.


Intake of micronutrients among Danish adult users and non-users of dietary supplements.
To evaluate the intake of micronutrients from the diet and from supplements in users and non-users of dietary supplements, respectively, in a representative sample of the Danish adult population. A specific objective was to identify the determinants of supplement use. A cross-sectional representative national study of the intake of vitamins and minerals from the diet and from dietary supplements. The Danish National Survey of Dietary Habits and Physical Activity, 2000-2004. Participants (n=4,479; 53% females) aged 18-75 years gave information about the use of dietary supplements in a personal interview. The quantification of the micronutrient contribution from supplements was estimated from a generic supplement constructed from data on household purchases. Nutrient intakes from the diet were obtained from a self-administered 7-day pre-coded dietary record. Median intakes of total nutrients from the diets of users and non-users of supplements were analysed using the Wilcoxon rank-sum test. Sixty percent of females and 51% of males were users of supplements. With the exception of vitamin D, the intake of micronutrients from the diet was adequate at the group level for all age and gender groups. Among females in the age group 18-49 years, the micronutrient intake from the diet was significantly higher compared with the non-users of dietary supplements. The use of dietary supplements increased with age and with 'intention to eat healthy.' Intake of micronutrients from the diet alone was considered adequate for both users and non-users of dietary supplements. Younger females who were supplement users had a more micronutrient-dense diet compared to non-users.


Expression of platelet-derived growth factor receptors is induced on connective tissue cells during chronic synovial inflammation.
The tissue distribution of the receptor for platelet-derived growth factor (PDGF) was investigated by immunohistochemistry on frozen sections from normal and inflamed synovial tissue using monoclonal antibodies to the receptor. Non-inflamed synovial tissue showed no staining, indicating that PDGF receptor expression is low or absent in normal tissue. In contrast, tissue from synovitis with prominent neovascularization showed a strong staining in the tunica media of the proliferating blood vessels as well as on connective tissue cells in the stroma. Tissue from synovitis with prominent proliferation of synovial lining showed intense staining for PDGF receptors in fibroblast-like cells of the lining and a less intense staining on vascular and connective tissue cells deeper in the stroma. Staining for PDGF receptors was also intense in the pannus tissue close to infiltrated bone and cartilage. In all these forms of synovitis, PDGF receptor staining was associated with increased HLA-DR staining and infiltration of macrophages and T lymphocytes. The finding that PDGF receptor expression is induced in conjunction with the chronic synovial inflammation associated with rheumatoid arthritis and some other forms of arthritides suggests that PDGF may play a role in the stimulation of mesenchymal cell proliferation that often accompanies chronic inflammatory disease.


Does normal developmental expression of psychosis combine with environmental risk to cause persistence of psychosis? A psychosis proneness-persistence model.
Research suggests that low-grade psychotic experiences in the general population are a common but transitory developmental phenomenon. Using two independent general population samples, the hypothesis was examined that common, non-clinical developmental expression of psychosis may become abnormally persistent when synergistically combined with developmental exposures that may impact on behavioural and neurotransmitter sensitization such as cannabis, trauma and urbanicity. The amount of synergism was estimated from the additive statistical interaction between baseline cannabis use, childhood trauma and urbanicity on the one hand, and baseline psychotic experiences on the other, in predicting 3-year follow-up psychotic experiences, using data from two large, longitudinal, random population samples from the Netherlands [The Netherlands Mental Health Survey and Incidence Study (NEMESIS)] and Germany [The Early Developmental Stages of Psychopathology (EDSP) study]. The 3-year persistence rates of psychotic experiences were low at 26% in NEMESIS and 31% in EDSP. However, persistence rates were progressively higher with greater baseline number of environmental exposures in predicting follow-up psychotic experiences (chi2=6.9, df=1, p=0.009 in NEMESIS and chi2=4.2, df=1, p=0.04 in EDSP). Between 21% and 83% (NEMESIS) and 29% and 51% (EDSP) of the subjects exposed to both environmental exposures and psychotic experiences at baseline had persistence of psychotic experiences at follow-up because of the synergistic action of the two factors. The findings suggest that environmental risks for psychosis act additively, and that the level of environmental risk combines synergistically with non-clinical developmental expression of psychosis to cause abnormal persistence and, eventually, need for care.


PPARgamma regulates adipocyte cholesterol metabolism via oxidized LDL receptor 1.
In addition to its role in energy storage, adipose tissue also accumulates cholesterol. Concentrations of cholesterol and triglycerides are strongly correlated in the adipocyte, but little is known about mechanisms regulating cholesterol metabolism in fat cells. Here we report that antidiabetic thiazolidinediones (TZDs) and other ligands for the nuclear receptor PPARgamma dramatically upregulate oxidized LDL receptor 1 (OLR1) in adipocytes by facilitating the exchange of coactivators for corepressors on the OLR1 gene in cultured mouse adipocytes. TZDs markedly stimulate the uptake of oxidized LDL (oxLDL) into adipocytes, and this requires OLR1. Increased OLR1 expression, resulting either from TZD treatment or adenoviral gene delivery, significantly augments adipocyte cholesterol content and enhances fatty acid uptake. OLR1 expression in white adipose tissue is increased in obesity and is further induced by PPARgamma ligand treatment in vivo. Serum oxLDL levels are decreased in both lean and obese diabetic animals treated with TZDs. These data identify OLR1 as a novel PPARgamma target gene in adipocytes. While the physiological role of adipose tissue in cholesterol and oxLDL metabolism remains to be established, the induction of OLR1 is a potential means by which PPARgamma ligands regulate lipid metabolism and insulin sensitivity in adipocytes.


A monoclonal antibody specific for the cellular receptor for the group B coxsackieviruses.
A 50-kilodalton receptor protein (Rp-a) for the group B coxsackieviruses (CB) was isolated in a virus-receptor complex from detergent-solubilized HeLa cells (J. E. Mapoles, D. L. Krah, and R. L. Crowell, J. Virol. 55:560-566, 1985). It was used as an immunogen for preparation of a mouse monoclonal antibody (RmcB) which protected HeLa cells and Buffalo green monkey kidney cells from infection by all six serotypes of CB. RmcB did not protect HeLa cells from infection by poliovirus, echovirus 6, or coxsackievirus A18. This monoclonal antibody differed in receptor epitope specificity from a previously isolated antibody (RmcA) (R. L. Crowell, A. K. Field, W. A. Schleif, W. L. Long, R. J. Colonno, J. E. Mapoles, and E. A. Emini, J. Virol. 57:438-445, 1986) which blocked receptors only for type 1 CB (CB1), CB3, CB5, and echovirus 6. RmcA and RmcB recognized two distinct saturable receptors on HeLa cells, designated HR2 and HR1, respectively. Human rhabdomyosarcoma (RD) cells have the HR2 receptor for CB3-RD (a variant of CB3), but lack the HR1 receptor for CB3. Therefore, RD cells were resistant to infection by CB3. Although binding of CB3-RD to the HR2 receptor on RD cells can lead to infection, binding of CB3-RD to the HR2 receptor on HeLa cells did not lead to infection. Apparently, both CB3 and CB3-RD use only the HR1 receptor for infection of HeLa cells. Thus, a given virus may use two distinct receptors to bind to cells when only one virus-receptor interaction leads to infection.


Prediction of heart failure by amino terminal-pro-B-type natriuretic peptide and C-reactive protein in subjects with cerebrovascular disease.
B-type natriuretic peptide (BNP) and C-reactive protein (CRP) are elevated in persons at risk for congestive heart failure (CHF). However, limited data are available directly comparing BNP-related peptides and CRP in persons at risk of CHF. To evaluate amino terminal-pro-BNP (NT-proBNP) and CRP, separately and together, for assessment of risk of CHF, we performed a nested case-control study of the 6105 participants of the Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS), a placebo-controlled study of a perindopril-based blood pressure-lowering regimen among individuals with previous stroke or transient ischemic attack (TIA). Each of 258 subjects who developed CHF resulting in death, hospitalization, or withdrawal of randomized therapy during a mean follow-up of 3.9 years was matched to 1 to 3 control subjects. NT-proBNP and CRP predicted CHF; the odds ratio for subjects in the highest compared with the lowest quarter was 4.5 (95% confidence interval, 2.7 to 7.5) for NT-proBNP and 2.9 (confidence interval, 1.9 to 4.7) for CRP, and each remained a predictor of CHF after adjustment for all other predictors. Screening for both markers provided better prognostic information than screening for either alone. Elevation of NT-proBNP above 50 pmol/L and CRP above 0.84 mg/L predicted CHF with sensitivity of 64% and specificity of 66%. NT-proBNP and CRP predicted CHF in subjects receiving perindopril-based therapy. We conclude that NT-proBNP and CRP are independent predictors of CHF risk after stroke or TIA. Moreover, NT-proBNP and CRP may be markers of mechanisms of CHF pathogenesis distinct from those responsive to angiotensin-converting enzyme inhibitor-based therapy.


ESCMID* guideline for the diagnosis and management of Candida diseases 2012: developing European guidelines in clinical microbiology and infectious diseases.
The process to develop a guideline in a European setting remains a challenge. The ESCMID Fungal Infection Study Group (EFISG) successfully achieved this endeavour. After two face-to-face meetings, numerous telephone conferences, and email correspondence, an ESCMID task force (basically composed of members of the Society's Fungal Infection Study Group, EFISG) finalized the ESCMID diagnostic and management/therapeutic guideline for Candida diseases. By appreciating various patient populations at risk for Candida diseases, four subgroups were predefined, mainly ICU patients, paediatric, HIV/AIDS and patients with malignancies including haematopoietic stem cell transplantation. Besides treatment recommendations, the ESCMID guidelines provide guidance for diagnostic procedures. For the guidelines, questions were formulated to phrase the intention of a given recommendation, for example, outcome. The recommendation was the clinical intervention, which was graded by a score of A-D for the 'Strength of a recommendation'. The 'level of evidence' received a score of I-III. The author panel was approved by ESCMID, European Organisation for Research and Treatment of Cancer, European Group for Blood and Marrow Transplantation, European Society of Intensive Care Medicine and the European Confederation of Medical Mycology. The guidelines followed the framework of GRADE and Appraisal of Guidelines, Research, and Evaluation. The drafted guideline was presented at ECCMID 2011 and points of discussion occurring during that meeting were incorporated into the manuscripts. These ESCMID guidelines for the diagnosis and management of Candida diseases provide guidance for clinicians in their daily decision-making process.


Physical Activity in Stage III Colon Cancer: CALGB/SWOG 80702 (Alliance).
To determine the specific types, durations, and intensities of recreational physical activity associated with the greatest improvements in disease-free survival (DFS) of patients with colon cancer. We conducted a prospective cohort study nested within a randomized multicenter trial of stage III colon cancer that compared 3 versus 6 months of fluorouracil, leucovorin, and oxaliplatin with or without celecoxib. We measured recreational physical activity in the first 3 months of chemotherapy and again 6 months after completion of chemotherapy. The primary end point was DFS. During a median follow-up of 5.9 years, 457 of 1,696 patients experienced disease recurrence or death. For total recreational physical activity volume, the 3-year DFS was 76.5% with < 3.0 metabolic equivalent task hours per week (MET-h/wk) and 87.1% with ≥ 18.0 MET-h/wk (risk difference [RD], 10.6%; 95% CI, 4.7 to 19.4; P < .001). For light-intensity to moderate-intensity activities, the 3-year DFS was 65.7% with 0.0 h/wk and 87.1% with ≥ 1.5 h/wk (RD, 21.4%; 95% CI, 9.2 to 37.1; P < .001). For vigorous-intensity activity, the 3-year DFS was 76.0% with 0.0 h/wk and 86.0% with ≥ 1.0 h/wk (RD, 10.0%; 95% CI, 4.5 to 18.9; P < .001). For brisk walking, the 3-year DFS was 81.7% with < 1.0 h/wk and 88.4% with ≥ 3.0 h/wk (RD, 6.7%; 95% CI, 3.0 to 13.8; P < .001). For muscle strengthening activity, the 3-year DFS was 81.8% with 0.0 h/wk and 88.8% for ≥ 0.5 h/wk (RD, 7.0%; 95% CI, 3.1 to 14.2; P = .003). Among patients with stage III colon cancer enrolled in a trial of postoperative treatment, larger volumes of recreational physical activity, longer durations of light- to moderate-intensity aerobic physical activity, or any vigorous-intensity aerobic physical activity were associated with the greatest improvements in DFS.


Positional cloning utilizing genomic DNA microarrays: the Niemann-Pick type C gene as a model system.
A major obstacle in positional cloning is identifying the specific mutated gene from within a large physical contig. Here we describe the application of DNA microarray technology to a defined genomic region (physical map) to identify: (i) exons without a priori sequence data and (ii) the disease gene based on differential gene expression in a recessive disorder. The feasibility was tested using resources from the positional cloning of the Neimann-Pick Type C (NP-C) disease gene, NPC1. To identify NPC1 exons and optimize the technology, an array was generated from genomic fragments of the 110-kb bacterial artificial chromosome, 108N2, which encodes NPC1. First, as a test case for blindly identifying exons, fluorescently labeled NPC1 cDNA identified 108N2 fragments that contained NPC1 exons, many of which also contained intronic sequences and could be used to determine part of the NPC1 genomic structure. Second, to demonstrate that the NPC1 disease gene could be identified based upon differential gene expression, subarrays of 108N2 fragments were hybridized with fluorescently labeled cDNA probes generated from total RNA from hamster cell lines differentially expressing NPC1. A probe derived from the NP-C cell line CT60 did not detect NPC1 exons or other genomic fragments from 108N2. In contrast, several NPC1 exons were detected by a probe generated from the non-NP-C cell line 911D5A13, which was derived from CT60, and expressed NPC1 as a consequence of stable transduction with a YAC that contains NPC1 and encompasses 108N2. Thus, the array technology identified NPC1 as a candidate gene based on a physical contig and differential NPC1 expression between NP-C and non-NP-C cells. This technique should facilitate gene identification when a physical contig exists for a region of interest and mutations result in changes in the mRNA level of the disease gene or portions thereof.


[The impact of complaints on clinicians].
Most clinicians will sooner or later make mistakes, and occasionally it leads to litigation. One of the rationales of complaint systems like the Danish one is to contribute to the quality improvement of healthcare provision. Still, there is unsatisfactory evidence to support this while some studies point to negative aftermaths in terms of secondary victimisation, defensive medicine, etc. Further research is required on the effects of complaint measures and on reasonable ways to promote their constructive purpose.


Differences in antiretroviral scale up in three South African provinces: the role of implementation management.
South Africa's antiretroviral programme is governed by defined national plans, establishing treatment targets and providing funding through ring-fenced conditional grants. However, in terms of the country's quasi-federal constitution, provincial governments bear the main responsibility for provision of health care, and have a certain amount of autonomy and therefore choice in the way their HIV/AIDS programmes are implemented. The paper is a comparative case study of the early management of ART scale up in three South African provincial governments--Western Cape, Gauteng and Free State--focusing on both operational and strategic dimensions. Drawing on surveys of models of ART care and analyses of the policy process conducted in the three provinces between 2005 and 2007, as well as a considerable body of grey and indexed literature on ART scale up in South Africa, it draws links between implementation processes and variations in provincial ART coverage (low, medium and high) achieved in the three provinces. While they adopted similar chronic disease care approaches, the provinces differed with respect to political and managerial leadership of the programme, programme design, the balance between central standardisation and local flexibility, the effectiveness of monitoring and evaluation systems, and the nature and extent of external support and programme partnerships. This case study points to the importance of sub-national programme processes and the influence of factors other than financing or human resource capacity, in understanding intervention scale up.


Microhomologies are prevalent at Cas9-induced larger deletions.
The CRISPR system is widely used in genome editing for biomedical research. Here, using either dual paired Cas9D10A nickases or paired Cas9 nuclease we characterize unintended larger deletions at on-target sites that frequently evade common genotyping practices. We found that unintended larger deletions are prevalent at multiple distinct loci on different chromosomes, in cultured cells and mouse embryos alike. We observed a high frequency of microhomologies at larger deletion breakpoint junctions, suggesting the involvement of microhomology-mediated end joining in their generation. In populations of edited cells, the distribution of larger deletion sizes is dependent on proximity to sgRNAs and cannot be predicted by microhomology sequences alone.


Age-related trends in the treatment and outcomes of ruptured cerebral aneurysms: a study of the nationwide inpatient sample 2001-2009.
Patient age substantially influences treatment decisions for ruptured cerebral aneurysms. It would be useful to understand national age-related trends of treatment techniques and outcomes in patients treated for ruptured cerebral aneurysm in the United States. Using the US Nationwide Inpatient Sample, we evaluated trends in treatment technique (clipping versus coiling) and discharge status of patients undergoing clipping or coiling of ruptured cerebral aneurysms between 2001 and 2009. Outcomes were evaluated in relation to 4 age strata: 1) younger than 50 years of age, 2) 50-64 years of age, 3) 65-79 years of age, and 4) patients 80 years or older. We compared outcomes between treatment groups for patients treated between 2001-2004 with those treated between 2005-2009. A significant increase in the proportion of patients undergoing endovascular coiling between 2001 and 2009 was noted for all age groups (P < .0001). For both clipped and coiled patients, mortality and the proportion of patients discharged to long-term facilities increased with age. Overall mortality for patients clipped and coiled decreased modestly for all age groups, and overall proportions of patients discharged home increased modestly (P < .01) for all age groups except those older than 80 years of age. Between 2001 and 2009, there has been a significant increase in the proportion of patients with ruptured aneurysms undergoing endovascular coiling rather than aneurysm clipping. This increase was more pronounced in older patients. Mortality from aneurysmal subarachnoid hemorrhage decreased during the past decade, regardless of aneurysm treatment technique.


A synthesis of bacterial and archaeal phenotypic trait data.
A synthesis of phenotypic and quantitative genomic traits is provided for bacteria and archaea, in the form of a scripted, reproducible workflow that standardizes and merges 26 sources. The resulting unified dataset covers 14 phenotypic traits, 5 quantitative genomic traits, and 4 environmental characteristics for approximately 170,000 strain-level and 15,000 species-aggregated records. It spans all habitats including soils, marine and fresh waters and sediments, host-associated and thermal. Trait data can find use in clarifying major dimensions of ecological strategy variation across species. They can also be used in conjunction with species and abundance sampling to characterize trait mixtures in communities and responses of traits along environmental gradients.


Management of osteoarthritis of the knee in the active patient.
Total knee arthroplasty has been extremely successful in elderly patients with osteoarthritis. However, there is considerable controversy regarding how best to treat the younger, athletic patient with advanced arthritis. Treatment options range from nonsurgical management with exercise and nonsteroidal anti-inflammatory drugs, to joint arthroplasty with activity modification. When properly indicated, arthroscopic débridement, high tibial osteotomy, unicondylar knee arthroplasty, and total knee arthroplasty allow younger patients with arthritis to maintain an active, healthy lifestyle.


Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD.
Most guidelines recommend either a long-acting beta-agonist (LABA) plus an inhaled glucocorticoid or a long-acting muscarinic antagonist (LAMA) as the first-choice treatment for patients with chronic obstructive pulmonary disease (COPD) who have a high risk of exacerbations. The role of treatment with a LABA-LAMA regimen in these patients is unclear. We conducted a 52-week, randomized, double-blind, double-dummy, noninferiority trial. Patients who had COPD with a history of at least one exacerbation during the previous year were randomly assigned to receive, by inhalation, either the LABA indacaterol (110 μg) plus the LAMA glycopyrronium (50 μg) once daily or the LABA salmeterol (50 μg) plus the inhaled glucocorticoid fluticasone (500 μg) twice daily. The primary outcome was the annual rate of all COPD exacerbations. A total of 1680 patients were assigned to the indacaterol-glycopyrronium group, and 1682 to the salmeterol-fluticasone group. Indacaterol-glycopyrronium showed not only noninferiority but also superiority to salmeterol-fluticasone in reducing the annual rate of all COPD exacerbations; the rate was 11% lower in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group (3.59 vs. 4.03; rate ratio, 0.89; 95% confidence interval [CI], 0.83 to 0.96; P=0.003). The indacaterol-glycopyrronium group had a longer time to the first exacerbation than did the salmeterol-fluticasone group (71 days [95% CI, 60 to 82] vs. 51 days [95% CI, 46 to 57]; hazard ratio, 0.84 [95% CI, 0.78 to 0.91], representing a 16% lower risk; P<0.001). The annual rate of moderate or severe exacerbations was lower in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group (0.98 vs. 1.19; rate ratio, 0.83; 95% CI, 0.75 to 0.91; P<0.001), and the time to the first moderate or severe exacerbation was longer in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group (hazard ratio, 0.78; 95% CI, 0.70 to 0.86; P<0.001), as was the time to the first severe exacerbation (hazard ratio, 0.81; 95% CI, 0.66 to 1.00; P=0.046). The effect of indacaterol-glycopyrronium versus salmeterol-fluticasone on the rate of COPD exacerbations was independent of the baseline blood eosinophil count. The incidence of adverse events and deaths was similar in the two groups. The incidence of pneumonia was 3.2% in the indacaterol-glycopyrronium group and 4.8% in the salmeterol-fluticasone group (P=0.02). Indacaterol-glycopyrronium was more effective than salmeterol-fluticasone in preventing COPD exacerbations in patients with a history of exacerbation during the previous year. (Funded by Novartis; FLAME ClinicalTrials.gov number, NCT01782326.).


Adeno-associated virus-targeted disruption of the CFTR gene in cloned ferrets.
Somatic cell gene targeting combined with nuclear transfer cloning presents tremendous potential for the creation of new, large-animal models of human diseases. Mouse disease models often fail to reproduce human phenotypes, underscoring the need for the generation and study of alternative disease models. Mice deficient for CFTR have been poor models for cystic fibrosis (CF), lacking many aspects of human CF lung disease. In this study, we describe the production of a CFTR gene-deficient model in the domestic ferret using recombinant adeno-associated virus-mediated gene targeting in fibroblasts, followed by nuclear transfer cloning. As part of this approach, we developed a somatic cell rejuvenation protocol using serial nuclear transfer to produce live CFTR-deficient clones from senescent gene-targeted fibroblasts. We transferred 472 reconstructed embryos into 11 recipient jills and obtained 8 healthy male ferret clones heterozygous for a disruption in exon 10 of the CFTR gene. To our knowledge, this study represents the first description of genetically engineered ferrets and describes an approach that may be of substantial utility in modeling not only CF, but also other genetic diseases.


Printed Flexible Thermoelectric Nanocomposites Based on Carbon Nanotubes and Polyaniline.
A new era of composite organic materials, nanomaterials, and printed electronics is emerging to the applications of thermoelectric generators (TEGs). Special attention is focused on carbon nanomaterials and conducting polymers, and the possibility to form pastes and inks for various low-cost deposition techniques. In this work, we present a novel approach to the processing of composite materials for screen-printing based on carbon nanotubes (CNTs) and polyaniline (PANI), supported with a dielectric polymer vehicle. Three different types of such tailor-made materials were prepared, with a functional phase consisted of carbon nanotubes and polyaniline composites fabricated with two methods: dry mixing of PANI CNT powders and in situ polymerisation of PANI with CNT. These materials were printed on flexible polymer substrates, exhibiting outstanding mechanical properties. The best parameters obtained for elaborated materials were σ=405.45 S·m-1, S=15.4 μV·K-1, and PF=85.2 nW·m-1K-2, respectively.


Land-bridge calibration of molecular clocks and the post-glacial Colonization of Scandinavia by the Eurasian field vole Microtus agrestis.
Phylogeography interprets molecular genetic variation in a spatial and temporal context. Molecular clocks are frequently used to calibrate phylogeographic analyses, however there is mounting evidence that molecular rates decay over the relevant timescales. It is therefore essential that an appropriate rate is determined, consistent with the temporal scale of the specific analysis. This can be achieved by using temporally spaced data such as ancient DNA or by relating the divergence of lineages directly to contemporaneous external events of known time. Here we calibrate a Eurasian field vole (Microtus agrestis) mitochondrial genealogy from the well-established series of post-glacial geophysical changes that led to the formation of the Baltic Sea and the separation of the Scandinavian peninsula from the central European mainland. The field vole exhibits the common phylogeographic pattern of Scandinavian colonization from both the north and the south, however the southernmost of the two relevant lineages appears to have originated in situ on the Scandinavian peninsula, or possibly in the adjacent island of Zealand, around the close of the Younger Dryas. The mitochondrial substitution rate and the timescale for the genealogy are closely consistent with those obtained with a previous calibration, based on the separation of the British Isles from mainland Europe. However the result here is arguably more certain, given the level of confidence that can be placed in one of the central assumptions of the calibration, that field voles could not survive the last glaciation of the southern part of the Scandinavian peninsula. Furthermore, the similarity between the molecular clock rate estimated here and those obtained by sampling heterochronous (ancient) DNA (including that of a congeneric species) suggest that there is little disparity between the measured genetic divergence and the population divergence that is implicit in our land-bridge calibration.


Restrictive Immigration Law and Birth Outcomes of Immigrant Women.
Unauthorized immigration is one of the most contentious policy issues in the United States. In an attempt to curb unauthorized migration, many states have considered restrictive laws intended to make life so difficult for unauthorized immigrants that they would choose to leave the country. Arizona's Senate Bill 1070, enacted in 2010, was a pioneering example of these efforts. Using population-level natality data and causal inference methods, we examined the effect of SB1070 on infants exposed before birth in Arizona. Prenatal exposure to the bill resulted in lower birth weight among Latina immigrant women, but not among US-born white, black, or Latina women. The decline in birth weight resulted from exposure to the bill being signed into law, rather than from its (limited) implementation. The findings indicate that the threat of a punitive law, even in the absence of implementation, can have a harmful effect on the birth outcomes of the next generation.


Cyclin-dependent kinase inhibitors, roscovitine and purvalanol, induce apoptosis and autophagy related to unfolded protein response in HeLa cervical cancer cells.
Roscovitine (Rosc) and purvalanol (Pur) are competitive inhibitors of cyclin-dependent kinases (CDKs) by targeting their ATP-binding pockets. Both drugs are shown to be effective to decrease cell viability and dysregulate the ratio of pro- and anti-apoptotic Bcl-2 family members, which finally led to apoptotic cell death in different cancer cell lines in vitro. It was well established that Bcl-2 family members have distinct roles in the regulation of other cellular processes such as endoplasmic reticulum (ER) stress. The induction of ER stress has been shown to play critical role in cell death/survival decision via autophagy or apoptosis. In this study, our aim was to investigate the molecular targets of CDK inhibitors on ER stress mechanism related to distinct cell death types in time-dependent manner in HeLa cervical cancer cells. Our results showed that Rosc and Pur decreased the cell viability, cell growth and colony formation, induced ER stress-mediated autophagy or apoptosis in time-dependent manner. Thus, we conclude that exposure of cells to CDK inhibitors induces unfolded protein response and ER stress leading to autophagy and apoptosis processes in HeLa cervical cancer cells.


Epigallocatechin-3-Gallate Regulates Anti-Inflammatory Action Through 67-kDa Laminin Receptor-Mediated Tollip Signaling Induction in Lipopolysaccharide-Stimulated Human Intestinal Epithelial Cells.
Inflammatory bowel disease (IBD) is a condition that involves chronic inflammation in all or part of the digestive tract. Often painful and debilitating, IBD can lead to life-threatening complications and increase the risk for colon cancer. In this study, we investigated the epigallocatechin-3-gallate (EGCG) mediated anti-inflammation response in lipopolysaccharide (LPS)-stimulated human colorectal cells through the negative regulator of Toll-like receptor (TLR) signaling. human intestinal epithelial cells (HT-29) were used in all experiments. Cell cytotoxicity and nitric oxide (NO) were evaluated by WST-1 and the Griess reagent. Western blot analysis and ELISA were used to determine inflammatory mediators and 67-kDa laminin receptor (67LR)-mediated Tollip signaling pathways. Treatment of EGCG and LPS did not affect the cytotoxicity in HT-29 cells. LPS treatment dose-dependently increased the pro-inflammatory cytokine, such as interleukin (IL)-8, whereas EGCG significantly reduced the LPS-stimulated IL-8 production. Additionally, EGCG treatment markedly increased the Toll-interacting protein (Tollip) expression, which negatively regulates the TLR signaling in a dose and time-dependent manner. In particular, in the result from an RNA interference-mediated assay, our finding showed that silencing of Tollip resulted in abrogation of the inhibitory action of EGCG on LPS-induced production of pro-inflammatory mediators (inducible nitric oxide synthase-mediated NO/COX2, and IL-8) and activation of MAPKs and NF-κB signaling pathways. Interestingly, we also found that Tollip expression induced by EGCG could be modulated through 67LR expressed on the surface of HT-29 cells. Our novel finding indicates that 67LR and Tollip signaling activated by EGCG treatment is essential for inhibition of inflammation in human intestinal epithelial cells.


Altered membrane sodium transport and the presence of a plasma ouabain-like inhibitory factor in acute myeloid leukaemia.
1. Sodium transport studies were performed in erythrocytes from normal subjects and from patients with acute myeloid leukaemia. Sodium influx and efflux rates were increased in erythrocytes from leukaemic patients. 2. The ouabain-sensitive component of sodium efflux was increased in leukaemic erythrocytes. 3. The high sodium efflux from leukaemic erythrocytes was decreased when the incubation media contained leukaemic plasma, suggesting the presence of an ouabain-like factor in the plasma. Paired experiments failed to show the presence of a similar factor in normal plasma. 4. Leukaemic erythrocytes showed a significantly greater ouabain uptake than the normal cells. 5. The results are discussed in relation to the wide-spread electrolyte disturbances in acute myeloid leukaemia.


Second European Round Table on the Future Management of HIV: 10-11 October 2014, Barcelona, Spain.
The Second European Round Table on the Future Management of HIV took place in Barcelona, 10-11 October 2014 and focused on the HIV-1 reservoir, strategies for HIV cure and primary HIV infection (PHI). Important issues in the HIV-1 reservoir research field are the validity of reservoir measurement techniques and the potential of new drugs to target latently infected cells. Current HIV-1 cure concepts are based on theoretical assumptions of biologically plausible mechanisms, supported by several clinical observations. Three main potential strategies are under investigation in order to achieve a sterilising cure or maintain HIV-1 remission: latency reversal resulting in antigen expression and viral cytolysis or immune targeted cell-death; immunological control of the reservoir; or replacement of the complete autologous haematopoietic and lymphoid stem-cell repertoire by transplantation. An interesting opportunity for restricting the size of the reservoir entails the early initiation of antiretroviral treatment (ART) during PHI. In terms of the reservoir, early treatment limits its size, alters its composition, and restricts the genetic variability of integrated proviral HIV-1 DNA. The challenges ahead involve the identification of patients undergoing seroconversion to HIV-1 and the prompt initiation of treatment. How the seemingly beneficial impact of early treatment will make cure more feasible, and whether the positive effects of the cure efforts outweigh the potentially negative impact of life-long ART, are important aspects of future collaborative research prospects.


Genotypic identification and characterization of species and strains within the genus Candida by using random amplified polymorphic DNA.
Random amplified polymorphic DNA (RAPD) was used to better characterize the genotypic relatedness among medically important Candida species. By using short oligomer primers (10-mers) with arbitrarily chosen sequences in the polymerase chain reaction, distinctive and reproducible sets of polymerase chain reaction products were observed for isolates of C. albicans, C. lusitaniae, C. tropicalis, and Torulopsis (Candida) glabrata. The RAPD analysis differentiated a physiologically homogeneous panel of C. parapsilosis into three distinct groups and showed genetic diversity within C. haemulonii. Intraspecies DNA-length polymorphisms were seen for RAPD profiles derived from different isolates of each species. Analysis of RAPDs from a panel of C. albicans, which included 16 laboratory derivatives of two reference strains, showed that the profiles of unrelated strains differed and that the derivatives of each reference strain were identifiable. Minor differences in the RAPD profiles, suggestive of mutations that had occurred during the long-term maintenance of the strains, were detected. Because of its ease and reliability, RAPD analysis should be useful in providing genotypic characters for taxonomic descriptions, for confirming the identities of stock isolates, for typing Candida species in epidemiologic investigations, and for use in the rapid identification of pathogenic fungi.