Melatonin in the treatment of fibromyalgia symptoms: A systematic review.
The available pharmacological modalities for the treatment of fibromyalgia (FM) are associated with a variety of adverse effects and limited benefits. In this study, we systematically reviewed the impact of melatonin in the treatment of FM. Interventional studies, either controlled or uncontrolled and randomized or non-randomized, were included. PubMed, EMBASE, Scopus, Web of Science, and the Cochrane Library were searched without time limitation. Primary outcome measures were the effect of melatonin on the disease impact, pain, sleep quality, tender point count, fatigue, anxiety, stiffness, and depression in FM patients. Four studies, reporting the effect of melatonin on 98 patients, were eligible to include. All the studies reported the positive effect of melatonin on the FM symptoms. No major adverse event was reported. A significant level of heterogeneity was observed between the studies. Therefore, further high-quality controlled clinical trials are needed to understand the role of melatonin in FM treatment fully.


Breaking the hierarchy--a new cluster selection mechanism for hierarchical clustering methods.
Hierarchical clustering methods like Ward's method have been used since decades to understand biological and chemical data sets. In order to get a partition of the data set, it is necessary to choose an optimal level of the hierarchy by a so-called level selection algorithm. In 2005, a new kind of hierarchical clustering method was introduced by Palla et al. that differs in two ways from Ward's method: it can be used on data on which no full similarity matrix is defined and it can produce overlapping clusters, i.e., allow for multiple membership of items in clusters. These features are optimal for biological and chemical data sets but until now no level selection algorithm has been published for this method. In this article we provide a general selection scheme, the level independent clustering selection method, called LInCS. With it, clusters can be selected from any level in quadratic time with respect to the number of clusters. Since hierarchically clustered data is not necessarily associated with a similarity measure, the selection is based on a graph theoretic notion of cohesive clusters. We present results of our method on two data sets, a set of drug like molecules and set of protein-protein interaction (PPI) data. In both cases the method provides a clustering with very good sensitivity and specificity values according to a given reference clustering. Moreover, we can show for the PPI data set that our graph theoretic cohesiveness measure indeed chooses biologically homogeneous clusters and disregards inhomogeneous ones in most cases. We finally discuss how the method can be generalized to other hierarchical clustering methods to allow for a level independent cluster selection. Using our new cluster selection method together with the method by Palla et al. provides a new interesting clustering mechanism that allows to compute overlapping clusters, which is especially valuable for biological and chemical data sets.


Aging, Depression, and Wisdom: A Pilot Study of Life-Review Intervention and PTSD Treatment With Two Groups of Vietnam Veterans.
Vietnam War veterans are a sometimes overlooked subgroup of the aging baby boomer generation. Forty years after the war ended, war veterans still seek out VA or Vet Center counselors to assist with traumatic stress symptoms. However, there currently are no specific age-related protocols for treating older war veterans suffering from posttraumatic stress disorder (PTSD), nor have established PTSD interventions incorporated gerontology content for these older trauma survivors. This pilot study juxtaposed life review within regular PTSD group counseling for 12 Vietnam veterans at a community-based Vet Center using a partial crossover design. The Life Review and Experiencing Form (LREF) structured the delivery of the life review component. T-tests and repeated measures ANOVA were used to examine depression and self-assessed wisdom outcomes using measures previously tested with older adults. Findings suggest that life review prior to PTSD group therapy has clinical benefits for reducing symptoms of depression and increasing self-assessed wisdom. The study illuminates the possible relationship of traumatic stress symptom effects on the natural reminiscing process for older veterans and provides insights into methods for more age-appropriate treatment for trauma survivors participating in Vet Center and VA programs nationwide.


Induction of metalloproteinases by glomerular mesangial cells stimulated by proteins of the extracellular matrix.
Human glomerular mesangial cells (HMC) are embedded in the mesangial matrix (MM) and control its turnover through a dynamic equilibrium between synthesis and degradation. Degradation is controlled by matrix metalloproteinases (MMP), whose activity has been causally implicated in the progression of glomerular disease. In other systems, MMP secretion may be directly affected by exposure to specific matrix proteins. The present study, therefore, investigated the effect of different matrix components on the adherence of HMC and on their secretion and activation of the gelatinases MMP2 and MMP9. HMC adhered strongly (quantified using crystal violet staining) to collagen IV and collagen I (P < 0.01, relative to binding to control, bovine serum albumin (BSA)-coated wells) and to a lesser extent to gelatin IV and fibronectin (P < 0.05). Binding to vitronectin and laminin was not statistically different to control wells. After the addition of these matrix proteins (0.1 microg/ml to 100 microg/ml) to growth-arrested HMC for 72 h, zymography of the conditioned medium established that only fibronectin and collagens I and IV dose-dependently increased latent (72 kD) MMP2 secretion and activation. Fibronectin, however, also induced the secretion of MMP9. Membranes from HMC that had been co-cultured with fibronectin for 72 h were prepared to investigate whether the activation of MMP2 in this system was due to the action of membrane-type (MT)-MMP. When incubated with latent MMP2 for times up to 24 h, these membranes activated the enzyme in a time- and dose-dependent manner. The results demonstrate that specific matrix components increased the secretion of MMP2 and MMP9 from HMC. In addition, MT-MMP activity, selectively induced by fibronectin, was implicated in the activation of the secreted proteinases.


Penile Reconstructive Surgery in Peyronie Disease: Challenges in Restoring Normal Penis Size, Shape, and Function.
To provide an overview of current approaches to penile reconstructive surgery in Peyronie disease (PD), and to discuss the challenges in restoring normal penile size and function. A systematic literature search was conducted to identify the published literature relevant to PD and penile reconstructive surgery. A summary of the published guidelines from major organisations is included in this review paper. Penile plication is simple and minimally invasive, and tends to preserve potency in most patients. However, plication invariably results in penile length loss and may, in fact, worsen the existing hour-glass or hinge effect. In contrast, graft reconstructive surgery can address issues relating to the loss of penile length and complex penile deformities, but long-term data highlight the risks of altered glans sensation, recurrent curvature, and/or loss of penile length from graft contracture, as well as the development of erectile dysfunction. Complex penile reconstruction with the concurrent placement of a penile prosthesis and/or graft material is a demanding operation that should be performed by surgeons with extensive prosthetic and reconstructive experience, as the risk of sensory loss, glans ischemia/necrosis, prosthesis-related complications, and failure to gain any meaningful length are serious concerns and cannot be underestimated. While surgical approaches remain the standard of care, they pose considerable risks and require prolonged postoperative rehabilitation. Obtaining proper informed consent and establishing realistic outcome expectations are imperative for successful postoperative outcomes.


A left MCA territory infarction during intravenous recombinant tissue plasminogen activator therapy for right MCA territory ischaemic stroke.
An 81 year old man with a history of hypertension received intravenous recombinant tissue plasminogen activator (tPA) for right middle cerebral artery (MCA) infarction. He had not had stroke or arrhythmia previously. The initial National Institute of Health Stroke Scale (NIHSS) score was 8. However, a left MCA territory infarction developed 2 minutes after the full course of tPA therapy was completed, and 24 hours after tPA infusion, NIHSS score was 17. The subsequent magnetic resonance imaging scan confirmed an extensive left MCA territory infarction and a small right MCA territory infarction. Although the intracerebral haemorrhage after tPA therapy is relatively more common, tPA infusion may result in an ischaemic cerebral stroke in rare cases.


Fluid catalytic cracking: recent developments on the grand old lady of zeolite catalysis.
Fluid catalytic cracking (FCC) is one of the major conversion technologies in the oil refinery industry. FCC currently produces the majority of the world's gasoline, as well as an important fraction of propylene for the polymer industry. In this critical review, we give an overview of the latest trends in this field of research. These trends include ways to make it possible to process either very heavy or very light crude oil fractions as well as to co-process biomass-based oxygenates with regular crude oil fractions, and convert these more complex feedstocks in an increasing amount of propylene and diesel-range fuels. After providing some general background of the FCC process, including a short history as well as details on the process, reactor design, chemical reactions involved and catalyst material, we will discuss several trends in FCC catalysis research by focusing on ways to improve the zeolite structure stability, propylene selectivity and the overall catalyst accessibility by (a) the addition of rare earth elements and phosphorus, (b) constructing hierarchical pores systems and (c) the introduction of new zeolite structures. In addition, we present an overview of the state-of-the-art micro-spectroscopy methods for characterizing FCC catalysts at the single particle level. These new characterization tools are able to explain the influence of the harsh FCC processing conditions (e.g. steam) and the presence of various metal poisons (e.g. V, Fe and Ni) in the crude oil feedstocks on the 3-D structure and accessibility of FCC catalyst materials.


Are articular cartilage lesions and meniscus tears predictive of IKDC, KOOS, and Marx activity level outcomes after anterior cruciate ligament reconstruction? A 6-year multicenter cohort study.
Identifying risk factors for inferior outcomes after anterior cruciate ligament reconstruction (ACLR) is important for prognosis and future treatment. Articular cartilage lesions and meniscus tears/treatment would predict International Knee Documentation Committee (IKDC) score, Knee injury and Osteoarthritis Outcome Score (KOOS) (all 5 subscales), and Marx activity level at 6 years after ACLR. Cohort study (prognosis); Level of evidence, 1. Between 2002 and 2004, a total of 1512 ACLR patients were prospectively enrolled and followed longitudinally, with the IKDC, KOOS, and Marx activity score completed at entry, 2 years, and 6 years. A logistic regression model was built incorporating variables from patient demographics, surgical technique, articular cartilage injuries, and meniscus tears/treatment to determine the predictors (risk factors) of IKDC and KOOS scores and Marx activity level at 6 years. A minimum follow-up on 86% (1307/1512) of the cohort was completed at 6 years. The cohort was 56% male and had a median age of 23 years at the time of enrollment, with 76% reporting a noncontact injury mechanism. Incidence of concomitant injury at the time of surgery consisted of the following: articular cartilage (medial femoral condyle [MFC], 25%; lateral femoral condyle [LFC] 20%; medial tibial plateau [MTP], 6%; lateral tibial plateau [LTP], 12%; patella, 20%; trochlear, 9%) and meniscus (medial, 38%; lateral, 46%). Both articular cartilage lesions and meniscus tears were significant predictors of 6-year outcomes on the IKDC and KOOS. Grade 3 or 4 articular cartilage lesions (excluding patella) significantly reduced IKDC and KOOS scores at 6 years. The IKDC demonstrated worse outcomes with the presence of a grade 3 or 4 chondral lesion on the MFC, MTP, and LFC. Likewise, the KOOS score was negatively affected by cartilage injury. The sole significant predictor of reduced Marx activity level was the presence of a grade 4 lesion on the MFC. Lateral meniscus repairs did not correlate with inferior results, but medial meniscus repairs predicted worse IKDC and KOOS scores. Lateral meniscus tears left alone significantly improved prognosis. Small partial meniscectomies (<33%) on the medial meniscus fared worse; conversely, larger excisions (>50%) on either the medial or lateral menisci improved prognosis. Analogous to previous studies, other significant predictors of lower outcome scores were lower baseline scores, higher body mass index, lower education level, smoking, and anterior cruciate ligament revisions. Both articular cartilage injury and meniscus tears/treatment at the time of ACLR were significant predictors of IKDC and KOOS scores 6 years after ACLR. Similarly, having a grade 4 MFC lesion significantly reduced a patient's Marx activity level score at 6 years.


Three thiacalix[4]arene-based Cu(i) coordination polymers: catalytic activities for azide-alkyne cycloaddition reactions and luminescence properties.
Three new coordination polymers, [Cu2(CN)(L)(OCH3)]·CH3OH·3H2O (1), [Cu3(Br)3(L)] (2) and [Cu(I)(L)]·1.5H2O (3), have been solvothermally prepared by reacting L (5,11,17,23-tetra-tert-butyl-25,26,27,28-tetra[(3-pyridylmethyl)oxy]-2,8,14,20-tetrathiacalix[4]arene) with Cu(i) halide. 1 and 2 exhibit layers. 3 displays a chain, a supramolecular layer constructed by hydrogen bonds. The performance of 1-3 was examined as heterogeneous catalysts for azide-alkyne cycloaddition reactions. Most strikingly, 1 and 2 show predominant efficiency with high regioselectivity and excellent recyclability. Remarkably, solids 1-3 all have luminescence characteristics under irradiation with a UV lamp.


Metabolic rescue in pluripotent cells from patients with mtDNA disease.
Mitochondria have a major role in energy production via oxidative phosphorylation, which is dependent on the expression of critical genes encoded by mitochondrial (mt)DNA. Mutations in mtDNA can cause fatal or severely debilitating disorders with limited treatment options. Clinical manifestations vary based on mutation type and heteroplasmy (that is, the relative levels of mutant and wild-type mtDNA within each cell). Here we generated genetically corrected pluripotent stem cells (PSCs) from patients with mtDNA disease. Multiple induced pluripotent stem (iPS) cell lines were derived from patients with common heteroplasmic mutations including 3243A>G, causing mitochondrial encephalomyopathy and stroke-like episodes (MELAS), and 8993T>G and 13513G>A, implicated in Leigh syndrome. Isogenic MELAS and Leigh syndrome iPS cell lines were generated containing exclusively wild-type or mutant mtDNA through spontaneous segregation of heteroplasmic mtDNA in proliferating fibroblasts. Furthermore, somatic cell nuclear transfer (SCNT) enabled replacement of mutant mtDNA from homoplasmic 8993T>G fibroblasts to generate corrected Leigh-NT1 PSCs. Although Leigh-NT1 PSCs contained donor oocyte wild-type mtDNA (human haplotype D4a) that differed from Leigh syndrome patient haplotype (F1a) at a total of 47 nucleotide sites, Leigh-NT1 cells displayed transcriptomic profiles similar to those in embryo-derived PSCs carrying wild-type mtDNA, indicative of normal nuclear-to-mitochondrial interactions. Moreover, genetically rescued patient PSCs displayed normal metabolic function compared to impaired oxygen consumption and ATP production observed in mutant cells. We conclude that both reprogramming approaches offer complementary strategies for derivation of PSCs containing exclusively wild-type mtDNA, through spontaneous segregation of heteroplasmic mtDNA in individual iPS cell lines or mitochondrial replacement by SCNT in homoplasmic mtDNA-based disease.


Stimulation of active and passive sodium absorption by sugars in the human jejunum.
The effects of glucose and fructose on water and sodium absorption in the human jejunum were compared to assess the relative contribution of active and passive sugar stimulation of sodium transport. The effect of fructose is assumed to be entirely passive, and the difference between the effects of fructose and glucose is assumed to be a measure of sugar-stimulated, active sodium absorption. Water and sodium movement with mannitol was the base line. Three sets of test solutions with differing sugar concentrations were studied. Fructose stimulated 66-100 per cent as much net sodium and water absorption as glucose. Fructose stimulated potassium absorption, whereas glucose stimulated potassium secretion. Urea absorption was stimulated by both sugars. Glucose and fructose stimulated sodium absorption when chloride was the major anion, but they had relatively little effect on net sodium movement when chloride was replaced by bicarbonate or sulfate. It is concluded that glucose stimulates passive and active sodium transport in the human jejunum. Stimulated active sodium absorption generates an electrical potential across the mucosa that causes sodium (and potassium) secretion and partly or completely nullifies the effect of active sodium transport on net sodium movement. Net sodium absorption sitmulated by glucose is mainly (66-100 per cent) the passive consequence of solvent flow. The accompanying anion determines the degree to which sugars stimulate sodium absorption (C1 greater than SO-4 greater than HCO3). The effects of bicarbonate and sugars on jejunal sodium absorption are not additive.


SOAP: short oligonucleotide alignment program.
We have developed a program SOAP for efficient gapped and ungapped alignment of short oligonucleotides onto reference sequences. The program is designed to handle the huge amounts of short reads generated by parallel sequencing using the new generation Illumina-Solexa sequencing technology. SOAP is compatible with numerous applications, including single-read or pair-end resequencing, small RNA discovery and mRNA tag sequence mapping. SOAP is a command-driven program, which supports multi-threaded parallel computing, and has a batch module for multiple query sets. http://soap.genomics.org.cn.


Adipokine dysregulation and adipose tissue inflammation in human obesity.
Obesity, a worldwide epidemic, confers increased risk for multiple serious conditions, including type 2 diabetes, cardiovascular diseases, nonalcoholic fatty liver disease and cancer. Adipose tissue is considered one of the largest endocrine organs in the body as well as an active tissue for cellular reactions and metabolic homeostasis rather than an inert tissue for energy storage. The functional pleiotropism of adipose tissue relies on its ability to synthesize and release a large number of hormones, cytokines, extracellular matrix proteins and growth and vasoactive factors, collectively termed adipokines that influence a variety of physiological and pathophysiological processes. In the obese state, excessive visceral fat accumulation causes adipose tissue dysfunctionality that strongly contributes to the onset of obesity-related comorbidities. The mechanisms underlying adipose tissue dysfunction include adipocyte hypertrophy and hyperplasia, increased inflammation, impaired extracellular matrix remodelling and fibrosis together with an altered secretion of adipokines. This review describes how adipose tissue becomes inflamed in obesity and summarizes key players and molecular mechanisms involved in adipose inflammation.


Co-depletion of cathepsin B and uPAR induces G0/G1 arrest in glioma via FOXO3a mediated p27 upregulation.
Cathepsin B and urokinase plasminogen activator receptor (uPAR) are both known to be overexpressed in gliomas. Our previous work and that of others strongly suggest a relationship between the infiltrative phenotype of glioma and the expression of cathepsin B and uPAR. Though their role in migration and adhesion are well studied the effect of these molecules on cell cycle progression has not been thoroughly examined. Cathepsin B and uPAR single and bicistronic siRNA plasmids were used to downregulate these molecules in SNB19 and U251 glioma cells. FACS analysis and BrdU incorporation assay demonstrated G0/G1 arrest and decreased proliferation with the treatments, respectively. Immunoblot and immunocyto analysis demonstrated increased expression of p27(Kip1) and its nuclear localization with the knockdown of cathepsin B and uPAR. These effects could be mediated by alphaVbeta3/PI3K/AKT/FOXO pathway as observed by the decreased alphaVbeta3 expression, PI3K and AKT phosphorylation accompanied by elevated FOXO3a levels. These results were further confirmed with the increased expression of p27(Kip1) and FOXO3a when treated with Ly294002 (10 microM) and increased luciferase expression with the siRNA and Ly294002 treatments when the FOXO binding promoter region of p27(Kip1) was used. Our treatment also reduced the expression of cyclin D1, cyclin D2, p-Rb and cyclin E while the expression of Cdk2 was unaffected. Of note, the Cdk2-cyclin E complex formation was reduced significantly. Our study indicates that cathepsin B and uPAR knockdown induces G0/G1 arrest by modulating the PI3K/AKT signaling pathway and further increases expression of p27(Kip1) accompanied by the binding of FOXO3a to its promoter. Taken together, our findings provide molecular mechanism for the G0/G1 arrest induced by the downregulation of cathepsin B and uPAR in SNB19 and U251 glioma cells.


Therapeutic MK2 inhibition blocks pathological vascular smooth muscle cell phenotype switch.
Vascular procedures, such as stenting, angioplasty, and bypass grafting, often fail due to intimal hyperplasia (IH), wherein contractile vascular smooth muscle cells (VSMCs) dedifferentiate to synthetic VSMCs, which are highly proliferative, migratory, and fibrotic. Previous studies suggest MAPK-activated protein kinase 2 (MK2) inhibition may limit VSMC proliferation and IH, although the molecular mechanism underlying the observation remains unclear. We demonstrated here that MK2 inhibition blocked the molecular program of contractile to synthetic dedifferentiation and mitigated IH development. Molecular markers of the VSMC contractile phenotype were sustained over time in culture in rat primary VSMCs treated with potent, long-lasting MK2 inhibitory peptide nanopolyplexes (MK2i-NPs), a result supported in human saphenous vein specimens cultured ex vivo. RNA-Seq of MK2i-NP-treated primary human VSMCs revealed programmatic switching toward a contractile VSMC gene expression profile, increasing expression of antiinflammatory and contractile-associated genes while lowering expression of proinflammatory, promigratory, and synthetic phenotype-associated genes. Finally, these results were confirmed using an in vivo rabbit vein graft model where brief, intraoperative treatment with MK2i-NPs decreased IH and synthetic phenotype markers while preserving contractile proteins. These results support further development of MK2i-NPs as a therapy for blocking VSMC phenotype switch and IH associated with cardiovascular procedures.


The Influence of Pore Structure and Acidity on the Hydrodesulfurization of Dibenzothiophene over NiMo-Supported Catalysts.
A series of mesoporous materials of SBA-16 were in situ incorporated into ZSM-5 crystallites via a two-step self-assemble method, and hydrodesulfurization (HDS) catalysts were prepared on the corresponding ZSM-5/SBA-16 (ZS) composites. The characterization results indicated that ZSM-5 nanoseeds were fabricated into the silica framework of the ZS composites, and the three-dimensional Im3m cubic structure of SBA-16 was retained simultaneously. In addition, the ZS series materials possessed open pores and large surfaces, which would facilitate the diffusion of reactants in the mesoporous channels. Moreover, the introduction of ZSM-5 seeds into composites could enhance the acidities of supports. As a result, the NiMo/ZS series catalysts exhibited high activities for DBT HDS processes. The NiMo/ZS-160 catalyst exhibited the highest catalytic efficiency (96.5%), which was apparently attributed to the synergistic contributions of the physicochemical properties of ZS supports and the dispersion states of active metals. Correspondingly, DBT HDS reactions over the NiMo/ZS series catalysts mainly proceeded via a hydrogenation desulfurization route that benefitted from the enhanced acidities especially the total Brønsted acid.


Identification of kit-ligand a as the Gene Responsible for the Medaka Pigment Cell Mutant few melanophore.
The body coloration of animals is due to pigment cells derived from neural crest cells, which are multipotent and differentiate into diverse cell types. Medaka (Oryzias latipes) possesses four distinct types of pigment cells known as melanophores, xanthophores, iridophores, and leucophores. The few melanophore (fm) mutant of medaka is characterized by reduced numbers of melanophores and leucophores. We here identify kit-ligand a (kitlga) as the gene whose mutation gives rise to the fm phenotype. This identification was confirmed by generation of kitlga knockout medaka and the findings that these fish also manifest reduced numbers of melanophores and leucophores and fail to rescue the fm mutant phenotype. We also found that expression of sox5, pax7a, pax3a, and mitfa genes is down-regulated in both fm and kitlga knockout medaka, implicating c-Kit signaling in regulation of the expression of these genes as well as the encoded transcription factors in pigment cell specification. Our results may provide insight into the pathogenesis of c-Kit-related pigmentation disorders such as piebaldism in humans, and our kitlga knockout medaka may prove useful as a tool for drug screening.


Polygenic autoimmune traits: Lyn, CD22, and SHP-1 are limiting elements of a biochemical pathway regulating BCR signaling and selection.
A B lymphocyte hyperactivity syndrome resembling systemic lupus erythematosus characterizes mice lacking the src-family kinase Lyn. Lyn is not required to initiate B cell antigen receptor (BCR) signaling but is an essential inhibitory component. lyn-/- B cells have a delayed but increased calcium flux and exaggerated negative selection responses in the presence of antigen and spontaneous hyperactivity in the absence of antigen. As in invertebrates, genetic effects of loci with only one functional allele can be used to analyze signaling networks in mice, demonstrating that negative regulation of the BCR is a complex quantitative trait in which Lyn, the coreceptor CD22, and the tyrosine phosphatase SHP-1 are each limiting elements. The biochemical basis of this complex trait involves a pathway requiring Lyn to phosphorylate CD22 and recruit SHP-1 to the CD22/BCR complex.


Stan: A Probabilistic Programming Language.
Stan is a probabilistic programming language for specifying statistical models. A Stan program imperatively defines a log probability function over parameters conditioned on specified data and constants. As of version 2.14.0, Stan provides full Bayesian inference for continuous-variable models through Markov chain Monte Carlo methods such as the No-U-Turn sampler, an adaptive form of Hamiltonian Monte Carlo sampling. Penalized maximum likelihood estimates are calculated using optimization methods such as the limited memory Broyden-Fletcher-Goldfarb-Shanno algorithm. Stan is also a platform for computing log densities and their gradients and Hessians, which can be used in alternative algorithms such as variational Bayes, expectation propagation, and marginal inference using approximate integration. To this end, Stan is set up so that the densities, gradients, and Hessians, along with intermediate quantities of the algorithm such as acceptance probabilities, are easily accessible. Stan can be called from the command line using the cmdstan package, through R using the rstan package, and through Python using the pystan package. All three interfaces support sampling and optimization-based inference with diagnostics and posterior analysis. rstan and pystan also provide access to log probabilities, gradients, Hessians, parameter transforms, and specialized plotting.


Adipose-Derived Stem Cell Transplant Technique for Degenerative Joint Disease.
The treatment of mild to moderate osteoarthritis can be a challenging problem for orthopaedic surgeons. As new research and treatment strategies have emerged, stem cell therapy has risen in popularity for the management of degenerative joint conditions. In this article, we describe a stepwise technical approach with tips and pearls to performing adipose-derived stem cell transplantation for degenerative joint disease of the knee.


Risk Factors for Cutaneous Squamous Cell Carcinoma Recurrence, Metastasis, and Disease-Specific Death: A Systematic Review and Meta-analysis.
To date, the magnitude of association and the quality of evidence for cutaneous squamous cell carcinoma (cSCC) and risk factors for outcomes have not been reviewed and analyzed systematically. To systematically analyze all published data on risk factors for recurrence, metastasis, and disease-specific death (DSD) of cSCC. Comprehensive search of Ovid MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus, from each database's inception to May 14, 2015. Inclusion criteria were studies of at least 10 patients, comparative data for at least 1 cSCC risk factor, and an outcome of interest. Exclusion criteria were noncutaneous squamous cell carcinoma (SCC), anogenital SCC, inability to extract cSCC data from other malignancy data, SCC in situ, Marjolin ulcer, and genetic disorders predisposing to cSCC. Two reviewers independently abstracted the data. Meta-analysis was performed using the random-effects model. Risk of bias was assessed by the Newcastle-Ottawa Scale. A priori outcomes were recurrence, metastasis, and DSD. Thirty-six studies (17 248 patients with 23 421 cSCCs) were included. Significant risk factors for recurrence were the following: Breslow thickness exceeding 2 mm (risk ratio [RR], 9.64; 95% CI, 1.30-71.52), invasion beyond subcutaneous fat (RR, 7.61; 95% CI, 4.17-13.88), Breslow thickness exceeding 6 mm (RR, 7.13; 95% CI, 3.04-16.72), perineural invasion (RR, 4.30; 95% CI, 2.80-6.60), diameter exceeding 20 mm (RR, 3.22; 95% CI, 1.91-5.45), location on the temple (RR, 3.20; 95% CI, 1.12-9.15), and poor differentiation (RR, 2.66; 95% CI, 1.72-4.14). Significant risk factors for metastasis were: invasion beyond subcutaneous fat (RR, 11.21; 95% CI, 3.59-34.97), Breslow thickness exceeding 2 mm (RR, 10.76; 95% CI, 2.55-45.31), Breslow thickness exceeding 6 mm (RR, 6.93; 95% CI, 4.02-11.94), diameter exceeding 20 mm (RR, 6.15; 95% CI, 3.56-10.65), poor differentiation (RR, 4.98; 95% CI, 3.30-7.49), perineural invasion (RR, 2.95; 95% CI, 2.31-3.75), immunosuppression (RR, 1.59; 95% CI, 1.07-2.37), and location on the temple (RR, 2.82; 95% CI, 1.72-4.63), ear (RR, 2.33; 95% CI, 1.67-3.23), or lip (RR, 2.28; 95% CI, 1.54-3.37). Significant risk factors for DSD were: diameter exceeding 20 mm (RR, 19.10; 95% CI, 5.80-62.95), poor differentiation (RR, 5.65; 95% CI, 1.76-18.20), location on the ear (RR, 4.67; 95% CI, 1.28-17.12) or lip (RR, 4.55; 95% CI, 1.41-14.69), invasion beyond subcutaneous fat (RR, 4.49; 95% CI, 2.05-9.82), and perineural invasion (RR, 4.06; 95% CI, 3.10-5.32). Evidence quality was considered low to moderate. Tumor depth is associated with the highest RR of local recurrence and metastasis of cSCC, and tumor diameter exceeding 20 mm is associated with the highest RR of DSD. Unified, consistent collection and reporting of risk factors in a prospective, multicentered effort are needed to further understand the increasing incidence of cSCC.


In situ vascularization of injectable fibrin/poly(ethylene glycol) hydrogels by human amniotic fluid-derived stem cells.
One of the greatest challenges in regenerative medicine is generating clinically relevant engineered tissues with functional blood vessels. Vascularization is a key hurdle faced in designing tissue constructs larger than the in vivo limit of oxygen diffusion. In this study, we utilized fibrin-based hydrogels to serve as a foundation for vascular formation, poly(ethylene glycol) (PEG) to modify fibrinogen and increase scaffold longevity, and human amniotic fluid-derived stem cells (AFSC) as a source of vascular cell types (AFSC-EC). AFSC hold great potential for use in regenerative medicine strategies, especially those involving autologous congenital applications, and we have shown previously that AFSC-seeded fibrin-PEG hydrogels have the potential to form three-dimensional vascular-like networks in vitro. We hypothesized that subcutaneously injecting these hydrogels in immunodeficient mice would both induce a fibrin-driven angiogenic host response and promote in situ AFSC-derived neovascularization. Two weeks postinjection, hydrogels were sectioned, and the following was demonstrated: the average maximum invasion distance of host murine cells into the subcutaneous fibrin/PEG scaffold was 147 ± 90 µm after 1 week and 395 ± 138 µm after 2 weeks; the average number of cell-lined lumen per square millimeter was significantly higher in hydrogels seeded with stem cells or cocultures containing stem cells (MSC, 36.5 ± 11.4; AFSC, 47.0 ± 18.9; AFSC/AFSC-EC, 32.8 ± 11.6; and MSC/HUVEC, 43.1 ± 25.1) versus endothelial cell types alone (AFSC-EC, 9.7 ± 6.1; HUVEC, 14.2 ± 8.8); and a subset of these lumen were characterized by the presence of red blood cells. Select areas of cell-seeded hydrogels contained CD31(+) lumen surrounded by α-smooth muscle cell support cells, whereas control hydrogels with no cells only showed infiltration of α-smooth muscle cell-positive host cells.


Serine protease of pestiviruses: determination of cleavage sites.
The single-stranded genomic RNA of pestiviruses is of positive polarity and encompasses one large open reading frame of about 4,000 codons. The resulting polyprotein is processed co- and posttranslationally by virus-encoded and host cell proteases to give rise to the mature viral proteins. A serine protease residing in the nonstructural (NS) protein NS3 (p80) has been shown to be essential for the release of the NS proteins located downstream of NS3. In this report the NS3 serine protease-dependent cleavage sites for bovine viral diarrhea virus (BVDV) strain CP7 are described. Proteins used for analysis were generated in Escherichia coli or in eukaryotic cells by the use of the T7 vaccinia virus system. The N termini of NS4A, NS4B, NS5A, and NS5B were determined by protein sequencing. Analysis of the data obtained showed that leucine at P1 is the only position conserved for all cleavage sites. At P1' alanine is found at the NS4A-NS4B site, whereas serine resides at this position at the NS3-NS4A, NS4B-NS5A, and NS5A-NS5B cleavage sites. For all cleavage sites the amino acids found at P1 and P1' are conserved for different genotypes of pestiviruses, despite the high degree of sequence variation found between these viruses. It is therefore assumed that the cleavage sites determined for BVDV CP7 are representative of those for all pestiviruses.


Description of the SAGhE Cohort: A Large European Study of Mortality and Cancer Incidence Risks after Childhood Treatment with Recombinant Growth Hormone.
The long-term safety of growth hormone treatment is uncertain. Raised risks of death and certain cancers have been reported inconsistently, based on limited data or short-term follow-up by pharmaceutical companies. The SAGhE (Safety and Appropriateness of Growth Hormone Treatments in Europe) study assembled cohorts of patients treated in childhood with recombinant human growth hormone (r-hGH) in 8 European countries since the first use of this treatment in 1984 and followed them for cause-specific mortality and cancer incidence. Expected rates were obtained from national and local general population data. The cohort consisted of 24,232 patients, most commonly treated for isolated growth failure (53%), Turner syndrome (13%) and growth hormone deficiency linked to neoplasia (12%). This paper describes in detail the study design, methods and data collection and discusses the strengths, biases and weaknesses consequent on this. The SAGhE cohort is the largest and longest follow-up cohort study of growth hormone-treated patients with follow-up and analysis independent of industry. It forms a major resource for investigating cancer and mortality risks in r-hGH patients. The interpretation of SAGhE results, however, will need to take account of the methods of cohort assembly and follow-up in each country.


A pilot study of an electronic, adolescent version of the quick inventory of depressive symptomatology.
Adolescent depression assessments are time-intensive, often requiring separate interviews with an adolescent and a parent/ informant. In adults, a self-rated, interactive voice response (IVR) version of the Quick Inventory of Depressive Symptomatology (QIDS-IVR) has been shown to be reliable, valid, and sensitive to change. An adolescent version of the QIDS (QIDS-A-IVR) was created using speaker-independent voice recognition technology. An informant version, QIDS-P-IVR, collects ratings from parents or other knowledgeable adults. The study included 27 adolescents ranging from 12 to 17 years of age, 48% of whom were female. During a single office visit, adolescents completed the QIDS-A-IVR and parents completed the QIDS-P-IVR. A clinician completed the clinician-rated adult version of the QIDS separately for adolescents (QIDS-C-A) and parents (QIDS-C-P) and the Children's Depression Rating Scale-Revised (CDRS-R). The study was conducted from October 2005 to April 2006. Cronbach alpha of the QIDS-A-IVR was .85. The QIDS-A-IVR correlated significantly with the QIDS-C-A (r = 0.95) and the CDRS-R (r = 0.76), both p < .01. Conversely, the correlations of the QIDS-A-IVR with the QIDS-P-IVR and the QIDS-C-P were small and nonsignificant. The QIDS-A-IVR required adolescents a mean of 6 minutes and 31 seconds to complete (SD = 41 seconds). The voice recognition technology correctly identified the adolescents' spoken words in 92% of the 483 spoken responses. The system recognized a response from all adolescents on all items. This study supports the reliability and validity of the QIDS-A-IVR as an adolescent depression measure. The QIDS-A-IVR may provide clinicians and researchers with a sound, technology-based method of assessing adolescent depression. Future research is needed on the informational value of parent ratings of adolescent depression.


Association of Disease Recurrence With Survival Outcomes in Patients With Cutaneous Squamous Cell Carcinoma of the Head and Neck Treated With Multimodality Therapy.
It has previously been demonstrated that immunosuppressed patients with cutaneous squamous cell cancer of the head and neck (cSCC-HN) treated with surgery and postoperative radiotherapy have significantly inferior disease-related outcomes compared with immunocompetent patients, but data on outcomes after disease recurrence are limited. To report survival outcomes in patients with cSCC-HN after disease recurrence after surgery and postoperative radiotherapy and to investigate the association of immune status with disease-related outcomes. A multi-institutional study of 205 patients treated at the Cleveland Clinic, Washington University in St Louis, and the University of California, San Francisco, in which patients who underwent surgical resection and postoperative radiotherapy for primary or recurrent stage I to IV (nonmetastatic) cSCC-HN between January 1, 1995, and December 31, 2014, were identified. Patients with any disease recurrence, defined as local, regional, and/or distant failure, were included. Patients were categorized as immunosuppressed if they received a diagnosis of chronic hematologic malignant neoplasm or HIV or AIDS, or were treated with immunosuppressive therapy for organ transplantation 6 months or more before diagnosis. Statistical analysis was conducted from January 1, 1995, to December 31, 2015. Overall survival calculated using the Kaplan-Meier method and compared using the log-rank test. Of the 205 patients in the original cohort, 72 patients (63 men and 9 women; median age, 71 years [range, 43-91 years]) developed disease recurrence after surgery and postoperative radiotherapy. Forty patients (55.6%) were immunosuppressed, and 32 patients (44.4%) were immunocompetent. Locoregional recurrence was the most common first pattern of failure for both groups (31 immunosuppressed patients [77.5%]; 21 immunocompetent patients [65.6%]). After any recurrence, 1-year overall survival was 43.2% (95% CI, 30.9%-55.4%), and median survival was 8.4 months. For patients for whom information on salvage treatment was available (n = 45), those not amenable to surgical salvage had significantly poorer median cumulative incidence of survival compared with those who were amenable to surgical salvage (4.7 months; 95% CI, 3.7-7.0 months vs 26.1 months; 95% CI, 6.6 months to not reached; P = .01), regardless of their immune status. Results of this study suggest that patients with cSCC-HN who experience disease recurrence after definitive treatment with surgery and postoperative radiotherapy have poor survival, irrespective of immune status. Survival rates are low for patients with recurrent disease that is not amenable to surgical salvage. The low rate of successful salvage underscores the importance of intensifying upfront treatment to prevent recurrence.


Estimating resource utilization demands in implementing statewide screening, brief intervention, and referral to treatment for alcohol-impaired drivers.
The Alcohol Use Disorders Identification Test (AUDIT) is used to assess the level of alcohol use/misuse and to inform the intensity of intervention delivered within screening, brief intervention, and referral to treatment (SBIRT) programs. Policy initiatives are recommending delivery of SBIRT within health care settings to reduce alcohol misuse and prevent alcohol-impaired driving. Recent reports are considering extending delivery of SBIRT to criminal justice settings. One consideration in implementing SBIRT delivery is the question of resource utilization; the amount of effort required in delivering the 4 different intensities of intervention in SBIRT: Alcohol education, simple advice, brief counseling and continued monitoring, and brief counseling and referral to specialist (from least to most intense in terms of delivery time, the skill level of the provider, and personnel resources). In order to inform expectations about intervention intensity, this article describes the AUDIT scores from 982 adults recently arrested for alcohol-impaired driving. The distribution of scores is extrapolated to state rates for individuals arrested for alcohol-impaired driving by intervention level. Though alcohol education was the most common intervention category, about one quarter of the sample scored in a range corresponding with the more intensive interventions using the brief counseling, continued monitoring for ongoing alcohol use, and/or referral to specialist for diagnostic evaluation and treatment. This article provides local distribution of AUDIT scores and state estimates for the number of individuals scoring in each level of risk (AUDIT risk zone) and corresponding intervention type. Routine criminal justice practice is well positioned to deliver alcohol screening, education, simple advice, and continued alcohol monitoring, making delivery of SBIRT feasible for the majority of alcohol-impaired drivers. Challenges to implementing the full range of SBIRT services include resource demands of brief counseling, identifying the appropriate providers within a criminal justice context, and availability of community providers for referral to diagnostic and specialty care. Solutions may vary by state due to differences in population density and incidence rates of alcohol-impaired driving.


Periodotopy in the gerbil inferior colliculus: local clustering rather than a gradient map.
Periodicities in sound waveforms are widespread, and shape important perceptual attributes of sound including rhythm and pitch. Previous studies have indicated that, in the inferior colliculus (IC), a key processing stage in the auditory midbrain, neurons tuned to different periodicities might be arranged along a periodotopic axis which runs approximately orthogonal to the tonotopic axis. Here we map out the topography of frequency and periodicity tuning in the IC of gerbils in unprecedented detail, using pure tones and different periodic sounds, including click trains, sinusoidally amplitude modulated (SAM) noise and iterated rippled noise. We found that while the tonotopic map exhibited a clear and highly reproducible gradient across all animals, periodotopic maps varied greatly across different types of periodic sound and from animal to animal. Furthermore, periodotopic gradients typically explained only about 10% of the variance in modulation tuning between recording sites. However, there was a strong local clustering of periodicity tuning at a spatial scale of ca. 0.5 mm, which also differed from animal to animal.


Mechanically Biomimetic Gelatin-Gellan Gum Hydrogels for 3D Culture of Beating Human Cardiomyocytes.
To promote the transition of cell cultures from 2D to 3D, hydrogels are needed to biomimic the extracellular matrix (ECM). One potential material for this purpose is gellan gum (GG), a biocompatible and mechanically tunable hydrogel. However, GG alone does not provide attachment sites for cells to thrive in 3D. One option for biofunctionalization is the introduction of gelatin, a derivative of the abundant ECM protein collagen. Unfortunately, gelatin lacks cross-linking moieties, making the production of self-standing hydrogels difficult under physiological conditions. Here, we explore the functionalization of GG with gelatin at biologically relevant concentrations using semiorthogonal, cytocompatible, and facile chemistry based on hydrazone reaction. These hydrogels exhibit mechanical behavior, especially elasticity, which resembles the cardiac tissue. The use of optical projection tomography for 3D cell microscopy demonstrates good cytocompatibility and elongation of human fibroblasts (WI-38). In addition, human-induced pluripotent stem cell-derived cardiomyocytes attach to the hydrogels and recover their spontaneous beating in 24 h culture. Beating is studied using in-house-built phase contrast video analysis software, and it is comparable with the beating of control cardiomyocytes under regular culture conditions. These hydrogels provide a promising platform to transition cardiac tissue engineering and disease modeling from 2D to 3D.


A Bio-Inspired Hybrid Thermal Management Approach for 3-D Network-on-Chip Systems.
3-D network-on-chip (NoC) systems are getting popular among the integrated circuit (IC) manufacturer because of reduced latency, heterogeneous integration of technologies on a single chip, high yield, and consumption of less interconnecting power. However, the addition of functional units in the -direction has resulted in higher on-chip temperature and appearance of local hotspots on the die. The increase in temperature degrades the performance, lifetime, and reliability, and increases the maintenance cost of 3-D ICs. To keep the heat within an acceptable limit, floorplanning is the widely accepted solution. Proper arrangement of functional units across different layers can lead to uniform thermal distribution in the chip. For systems with high density of elements, few hotspots cannot be eliminated in the floorplanning approach. To overcome, liquid microchannel cooling technology has emerged as an efficient and scalable solution for 3-D NoC. In this paper, we propose a novel hybrid algorithm combining both floorplanning, and liquid microchannel placement to alleviate the hotspots in high-density systems. A mathematical model is proposed to deal with heat transfer due to diffusion and convention. The proposed approach is independent of topology. Three different topologies: 3-D stacked homogeneous mesh architecture, 3-D stacked heterogeneous mesh architecture, and 3-D stacked ciliated mesh architecture are considered to check the effectiveness of the proposed algorithm in hotspot reduction. A thermal comparison is made with and without the proposed thermal management approach for the above architectures considered. It is observed that there is a significant reduction in on-chip temperature when the proposed thermal management approach is applied.


Depletion of the Ras association domain family 1, isoform A-associated novel microtubule-associated protein, C19ORF5/MAP1S, causes mitotic abnormalities.
Ras association domain family 1, isoform A (RASSF1A) is a novel tumor suppressor gene that is found to be inactivated in more than 40 types of sporadic cancers. In addition, mouse Rassf1a knockout models have an increased frequency of spontaneous and induced tumors. The mechanisms by which RASSF1A exerts its tumor suppression activities or the pathways it can regulate are not yet fully understood. Using yeast two-hybrid system, we have previously identified C19ORF5/MAP1S as the major RASSF1A-interacting protein. C19ORF5 has two conserved microtubule-associated regions and may function to anchor RASSF1A to the centrosomes. In this study, we have analyzed the cellular functions of C19ORF5. By using small interfering RNA-mediated depletion and time-lapse video microscopy, we show that C19ORF5 knockdown causes mitotic abnormalities that consist of failure to form a stable metaphase plate, premature sister chromatid separation, lagging chromosomes, and multipolar spindles. We also show that a fraction of C19ORF5 localizes to the spindle microtubules. Additionally, we show here that C19ORF5 localizes to the microtubule-organizing centers during microtubule regrowth after nocodazole washout. Knockdown of C19ORF5 disrupts the microtubule-organizing center and results in microtubule nucleation from several sites. Whereas the localization of pericentrin is not affected, alpha- and gamma-tubulin localization and sites of nucleation are greatly altered by C19ORF5 depletion. This may indicate that C19ORF5 plays a role in anchoring the microtubule-organizing center to the centrosomes. In addition, we show that the NH2 terminus of C19ORF5 is essential for this process. This novel role for C19ORF5 could explain the resulting mitotic abnormalities that occur on its depletion and can potentially provide an underlying mechanism for the frequent centrosome and microtubule abnormalities detected in several cancers.


Human THAP7 is a chromatin-associated, histone tail-binding protein that represses transcription via recruitment of HDAC3 and nuclear hormone receptor corepressor.
The identities of signal transducer proteins that integrate histone hypoacetylation and transcriptional repression are largely unknown. Here we demonstrate that THAP7, an uncharacterized member of the recently identified THAP (Thanatos-associated protein) family of proteins, is ubiquitously expressed, associates with chromatin, and represses transcription. THAP7 binds preferentially to hypoacetylated (un-, mono-, and diacetylated) histone H4 tails in vitro via its C-terminal 77 amino acids. Deletion of this domain, or treatment of cells with the histone deacetylase inhibitor TSA, which leads to histone hyperacetylation, partially disrupts THAP7/chromatin association in living cells. THAP7 coimmunoprecipitates with histone deacetylase 3 (HDAC3) and the nuclear hormone receptor corepressor (NCoR) and represses transcription as a Gal4 fusion protein. Chromatin immunoprecipitation assays demonstrate that these corepressors are recruited to promoters in a THAP7 dependent manner and promote histone H3 hypoacetylation. The conserved THAP domain is a key determinant for full HDAC3 association in vitro, and both the THAP domain and the histone interaction domain are important for the repressive properties of THAP7. Full repression mediated by THAP7 is also dependent on NCoR expression. We hypothesize that THAP7 is a dual function repressor protein that actively targets deacetylation of histone H3 necessary to establish transcriptional repression and functions as a signal transducer of the repressive mark of hypoacetylated histone H4. This is the first demonstration of the transcriptional regulatory properties of a human THAP domain protein, and a critical identification of a potential transducer of the repressive signal of hypoacetylated histone H4 in higher eukaryotes.


Structural characterization of melanoidin formed from d-glucose and l-alanine at different temperatures applying FTIR, NMR, EPR, and MALDI-ToF-MS.
The aim of this study was to identify specific chemical bonds and characteristic structures in melanoidins formed from d-glucose and l-alanine between 130 and 200 °C. The results might be used to control the type and amount of melanoidin produced during food processing. For this purpose, complementary techniques, such as FTIR, NMR, EPR, and MALDI-ToF, were employed. At 160 °C color, solubility and UV/Vis absorption change characteristically and consequently, structural transformations could be observed in FTIR and NMR spectra. For example, sharp signals of N-H, C-N, and C-H oscillations in the l-alanine spectrum are prone to inhomogeneous broadening in melanoidins prepared above 150 °C. These changes are caused due to formation of heterogeneous macromolecular structures and occur during condensation reactions that lead to an increasing loss of water from the melanoidins with increasing temperatures. Additionally, MALDI-ToF-MS indicates the polymerization of glyoxal/glyoxylic acid and EPR shows the formation of radical structures.


STOP- a training intervention to optimise treatment for smoking cessation in community pharmacies: cluster randomised controlled trial.
Community pharmacies serve people with high levels of tobacco-related illness, but throughput in NHS Stop Smoking Services in pharmacies remains relatively low. We investigated the effectiveness of a complex intervention to increase service uptake and retention. We randomised 60 pharmacies in England and Wales to the STOP intervention or usual practice in a pragmatic, parallel-group, controlled trial over 11 months. Smokers were blind to the allocation. The intervention was theory-based consultation skills training for pharmacy staff with environmental prompts (badges, calendars and behavioural cues). The primary outcome was the number of smokers attending an initial consultation and setting a quit date. The intervention made no significant difference in setting a quit date, retention or quit rate. A total of 631 adult smokers (service users) enrolled and set a quit date in intervention pharmacies compared to 641 in usual practice pharmacies, a rate ratio of 0.75 (95% CI 0.46 to 1.23) adjusted for site and number of prescriptions. A total of 432 (68%) service users were retained at 4 weeks in intervention and 500 (78%) in usual practice pharmacies (odds ratio 0.80, 0.41 to 1.55). A total of 265 (42%) service users quit smoking at 4 weeks in intervention and 276 (43%) in usual practice pharmacies (0.96, 0.65 to 1.43). The pharmacy staff were positive about the intervention with 90% (56/62) stating that it had improved their skills. Sixty-eight per cent would strongly recommend the training to others although there was no difference in self-efficacy for service delivery between arms. Seventy of 131 (53%) service users did not complete the 6-month follow-up assessment. However, 55/61 (90%) service users who completed follow-up were satisfied or very satisfied with the service. All usual practice arm service users (n = 33) and all but one in the intervention arm (n = 27) would recommend the service to smokers. We found high levels of retention and acceptable quit rates in the NHS pharmacy stop smoking service. Despite pharmacy staff providing positive feedback on the STOP intervention, it made no difference to service throughput. Thus, other factors may currently limit service capacity to help smokers to quit. ISRCTN, ISRCTN16351033 . Retrospectively registered.


Auranofin in the treatment of steroid dependent asthma: a double blind study.
Long term administration of oral corticosteroids in patients with asthma may be associated with serious side effects. Non-steroidal anti-inflammatory drugs, including gold salts, have been shown to reduce the need for systemic corticosteroid treatment in uncontrolled studies. The effect of oral gold (auranofin) on asthma symptoms, lung function, and the need for oral prednisone treatment was investigated. A 26 week randomised, double blind, placebo controlled, parallel group trial of auranofin was performed in 32 patients with moderately severe chronic asthma who required an oral corticosteroid dose of at least 5 mg prednisone a day (or equivalent) or 2.5 mg/day prednisone plus more than 800 micrograms/day inhaled corticosteroids. Auranofin was given orally in a dose of 3 mg twice daily. Asthma symptoms, lung function, and adverse effects were assessed at regular intervals. After 12 weeks of treatment prednisone dosage was tapered down by 2.5 mg every two weeks if the patient was clinically stable. Asthma exacerbations were treated with short courses of high doses of oral steroids. Twenty eight of the 32 patients, 13 in the placebo group and 15 in the auranofin group, completed the study. The total corticosteroid reduction achieved after 26 weeks of treatment was significantly greater (4 mg) in the auranofin group than in the placebo group (0.3 mg). The number of exacerbations requiring an increase of steroids was greater in the placebo group (2.1) than in the active group (0.9). A significant increase in FEV1 of 6.4% predicted occurred in the auranofin group during the study and there was a reduction of asthma symptoms such as wheezing and cough. There was no difference between the groups in peak flow measurements or in the number of asthma attacks. The incidence of side effects of auranofin was low, but exacerbations of constitutional eczema were noticeable. Auranofin provides an effective adjunct to treatment for steroid dependent asthma, leading to a reduction of oral steroid dose.


Comparative genetic diversity in a sample of pony breeds from the U.K. and North America: a case study in the conservation of global genetic resources.
Most species exist as subdivided ex situ daughter population(s) derived from a single original group of individuals. Such subdivision occurs for many reasons both natural and manmade. Traditional British and Irish pony breeds were introduced to North America (U.S.A. and Canada) within the last 150 years, and subsequently equivalent breed societies were established. We have analyzed selected U.K. and North American equivalent pony populations as a case study for understanding the relationship between putative source and derived subpopulations. Diversity was measured using mitochondrial DNA and a panel of microsatellite markers. Genetic signatures differed between the North American subpopulations according to historical management processes. Founder effect and stochastic drift was apparent, particularly pronounced in some breeds, with evidence of admixture of imported mares of different North American breeds. This demonstrates the importance of analysis of subpopulations to facilitate understanding the genetic effects of past management practices and to lead to informed future conservation strategies.


Can rash associated with HER1/EGFR inhibition be used as a marker of treatment outcome?
Rash is a class effect of HER1/epidermal growth factor receptor (EGFR)-targeted agents, and has occurred with high frequency and in a dose-dependent manner in clinical trials of these agents in cancer patients. Analysis of phase II trials of erlotinib (Tarceva) in non-small-cell lung cancer, head and neck cancer, and ovarian cancer shows a significant association between rash severity and objective tumor response. Rash severity was highly significantly associated with survival in patients with non-small-cell lung cancer receiving erlotinib; median survival in patients with no rash was 46.5 days, compared with 257 days in those with grade 1 rash (P < .0001) and 597 days in those with grade 2/3 rash (P < .0001). Similarly, for the combined non-small-cell lung cancer, head and neck cancer, and ovarian cancer studies, median survival in patients with no rash was 103 days, compared with 191 days in those with grade 1 rash (P = .0001) and 266 days in those with grade 2/3/4 rash (P = .0001). Similar findings have been made with cetuximab (Erbitux) and in some settings with gefitinib (Iressa). The strong association of rash severity with response/survival suggests that rash may serve as a marker of response to erlotinib treatment and may be used to guide treatment to obtain optimal response. Dosing erlotinib at the maximum tolerated dose, which is associated with more frequent and more severe rash, may improve response rates and survival durations. Further study of the potentially important association between rash and outcome of treatment with EGFR-targeted agents is needed.


Plectin-1 as a novel biomarker for pancreatic cancer.
We are in great need of specific biomarkers to detect pancreatic ductal adenocarcinoma (PDAC) at an early stage, ideally before invasion. Plectin-1 (Plec1) was recently identified as one such biomarker. However, its suitability as a specific biomarker for human pancreatic cancer, and its usability as an imaging target, remain to be assessed. Specimens of human PDAC, chronic pancreatitis, and normal pancreata were evaluated by immunohistochemistry and Western blot analysis. To validate Plec1 as an imaging target, Plec1-targeting peptides (tPTP) were used as a contrast agent for single photon emission computed tomography in an orthotopic and liver metastasis murine model of PDAC. Plec1 expression was noted to be positive in all PDACs but negative in benign tissues. Plec1 expression increases during pancreatic carcinogenesis. It was found to be misexpressed in only 0% to 3.85% of early PDAC precursor lesions (PanIN I/II) but in 60% of PanIN III lesions. Plec1 expression was further noted to be retained in all metastatic foci assayed and clearly highlighted these metastatic deposits in lymph nodes, liver, and peritoneum. In vivo imaging using tPTP specifically highlighted the primary and metastatic tumors. Biodistribution studies performed after imaging show that the primary pancreatic tumors and liver metastases retained 1.9- to 2.9-fold of tPTP over normal pancreas and 1.7-fold over normal liver. Plec1 is the first biomarker to identify primary and metastatic PDAC by imaging and may also detect preinvasive PanIN III lesions. Strategies designed to image Plec1 could therefore improve detection and staging.


A strongly selected mutation in the HIV-1 genome is independent of T cell responses and neutralizing antibodies.
Mutations rapidly accumulate in the HIV-1 genome after infection. Some of those mutations are selected by host immune responses and often cause viral fitness losses. This study is to investigate whether strongly selected mutations that are not associated with immune responses result in fitness losses. Strongly selected mutations were identified by analyzing 5'-half HIV-1 genome (gag/pol) sequences from longitudinal samples of subject CH0131. The K43R mutation in the gag gene was first detected at day 91 post screening and was fixed in the viral population at day 273 while the synonymous N323tc mutation was first detected at day 177 and fixed at day 670. No conventional or cryptic T cell responses were detected against either mutation sites by ELISpot analysis. However, when fitness costs of both mutations were measured by introducing each mutation into their cognate transmitted/founder (T/F) viral genome, the K43R mutation caused a significant fitness loss while the N323tc mutation had little impact on viral fitness. The rapid fixation, the lack of detectable immune responses and the significant fitness cost of the K43R mutation suggests that it was strongly selected by host factors other than T cell responses and neutralizing antibodies.


Dietary salt restriction is beneficial to the management of autosomal dominant polycystic kidney disease.
The CRISP study of polycystic kidney disease (PKD) found that urinary sodium excretion associated with the rate of total kidney volume increase. Whether sodium restriction slows the progression of Autosomal Dominant PKD (ADPKD) is not known. To evaluate this we conducted a post hoc analysis of the HALT-PKD clinical trials of renin-angiotensin blockade in patients with ADPKD. Linear mixed models examined whether dietary sodium affected rates of total kidney volume or change in estimated glomerular filtration rate (eGFR) in patients with an eGFR over 60 ml/min/1.73 m2 (Study A) or the risk for a composite endpoint of 50% reduction in eGFR, end-stage renal disease or death, or the rate of eGFR decline in patients with an eGFR 25-60 ml/min/1.73 m2 (Study B) all in patients initiated on an under100 mEq sodium diet. During the trial urinary sodium excretion significantly declined by an average of 0.25 and 0.41 mEq/24 hour per month in studies A and B, respectively. In Study A, averaged and time varying urinary sodium excretions were significantly associated with kidney growth (0.43%/year and 0.09%/year, respectively, for each 18 mEq urinary sodium excretion). Averaged urinary sodium excretion was not significantly associated with faster eGFR decline (-0.07 ml/min/1.73m2/year for each 18 mEq urinary sodium excretion). In Study B, the averaged but not time-varying urinary sodium excretion significantly associated with increased risk for the composite endpoint (hazard ratio 1.08 for each 18 mEq urinary sodium excretion) and a significantly faster eGFR decline (-0.09 ml/min/1.73m2/year for each mEq 18 mEq urinary sodium excretion). Thus, sodium restriction is beneficial in the management of ADPKD.


Long-term clinical outcome after epineural coaptation of digital nerves.
This study evaluates the long-term clinical outcome and complication rate after digital nerve repair in adults and aims to identify possible prognostic factors of sensory recovery. End-to-end epineural coaptation was performed under magnification. A total of 93 coapted digital nerves were clinically evaluated with a mean follow-up of 3.5 years (range 1-6 years). The mean two-point discrimination was 10.6 mm (versus 4.4 mm for the contralateral side). Cutaneous pressure threshold tested with Semmes-Weinstein monofilaments showed a mean value of 2.7 (versus 2.2 for the contralateral side). Only 2% of our patients developed painful neuromas. None of our patients recovered normal functional sensibility, however, recovery of protective sensation contributed to a high reported level of satisfaction. No correlation was observed between the sensory outcome and age, smoking, mechanism of injury, lesion to or anastomosis of a digital artery, or time of immobilization. The only identified predictor of the result was the surgeon's level of experience. This highlights the importance of adequate training and practice in the surgical repair of smaller peripheral nerves. IV.


Reverse causality behind the association between reproductive history and MS.
Possible associations between childbearing patterns and multiple sclerosis (MS) risk have been studied for a long time, with conflicting results. We aimed to investigate the influence of reproductive history on MS risk. Using a Swedish population-based case-control study involving incident cases of MS (1798 cases, 3907 controls), we calculated odds ratios (OR) for MS comparing parents with childless subjects together with 95% confidence intervals (CI) employing logistic regression. Overall, there was an association between having children and reduced MS risk among both sexes. Subjects who had become parents within five years prior to the index year had a substantially reduced risk of developing MS (OR 0.6, 95% CI 0.5-0.8 for women, and OR 0.4, 95% CI 0.3-0.6 for men). No association between having children and MS risk was observed when more than 10 years had passed since the birth of the last child. We found no association between increasing offspring number and MS risk. The observed association between reproductive history and MS risk is restricted to a limited time period preceding the index year, with similar findings in both sexes, which contradicts biologic impact of pregnancy on MS risk and argues in favor of reverse causality, i.e. that fecundity is affected by yet-undiagnosed MS.


Radiation Safety in the Catheterization Laboratory: Current Perspectives and Practices.
There is great variability in radiation safety practices in cardiac catheterization laboratories around the world. We performed an international online survey on radiation safety including interventional cardiologists, electrophysiologists, interventional radiologists, and vascular surgeons. A total of 570 responses were received from various geographic locations, including the United States (77.9%), Asia (7.9%), Europe (6.8%), Canada (2.8%), and Mexico and Central America (2.1%). Most respondents (73%) were interventional cardiologists and 23% were electrophysiologists, with 14.4 ± 10.2 years in practice. Most respondents (75%) were not aware of their radiation dose during the past year and 21.2% had never attended a radiation safety course; 58.9% are "somewhat worried" and 31.5% are "very worried" about chronic radiation exposure. Back pain due to lead use was reported by 43.0% and radiation-related health complications including cataracts and malignancies were reported by 6.3%. Only 37.5% of respondents had an established radiation dose threshold for initiating patient follow-up. When comparing United States operators with the other respondents, the former were more likely to attend radiation safety courses (P<.001), wear dosimeters (P<.001), know their annual personal radiation exposure (P<.001), and have an established patient radiation dose threshold (P<.001). They were also more likely to use the fluoro store function, under-table shields, leaded glasses, ceiling lead glass, and disposable radiation shields, and were more concerned about the adverse effects of radiation. Radiation safety is of concern to catheterization laboratory personnel, yet there is significant variability in radiation protection practices, highlighting several opportunities for standardization and improvement.


Effect of alpha-fluorination of valproic acid on valproyl-S-acyl-CoA formation in vivo in rats.
Studies designed to compare valproic acid (VPA) with its alpha-fluorinated derivative (F-VPA) for their abilities to form acyl-CoA thioester derivatives in vivo are described. Recent studies have shown that alpha-fluorination of a hepatotoxic metabolite of VPA (Delta(4)-VPA) resulted in a nonhepatotoxic derivative. We hypothesize that the decrease in hepatotoxicity may be related to a lack of formation of the intermediary acyl-CoA thioester. To determine the effect of alpha-fluoro substitution on acyl-CoA formation, we synthesized F-VPA and compared it with VPA for its ability to form the acyl-CoA thioester derivative in vivo in rat liver. Thus, after dosing rats with VPA or F-VPA, animals were sacrificed (0.05-, 0.5-, 1-, 2-, and 5-h postadministration) for the analysis of liver tissue. High-performance liquid chromatography (HPLC) and electrospray ionization/tandem mass spectrometry analysis of liver extracts from VPA-dosed rats showed the presence of VPA-CoA that was maximal after 0.5 h (185 nmol/g of liver) and was still measurable 5-h postadministration (90 nmol/g of liver). In agreement with our hypothesis, F-VPA did not form the corresponding acyl-CoA derivative as determined by the absence of F-VPA-CoA upon HPLC analysis of liver extracts from F-VPA-dosed rats. Further examination of liver tissue for the presence of free acids revealed that the differences in acyl-CoA formation cannot be explained by differences in VPA and F-VPA free acid concentrations. From these observations and related studies showing the lack of toxicity due to alpha-fluoro substitution, we propose that metabolism of VPA by acyl-CoA formation may mediate the hepatotoxicity of the drug.


Trans-Metal-Trapping Meets Frustrated-Lewis-Pair Chemistry: Ga(CH2SiMe3)3-Induced C-H Functionalizations.
Merging two topical themes in main-group chemistry, namely, cooperative bimetallics and frustrated-Lewis-pair (FLP) activity, this Forum Article focuses on the cooperativity-induced outcomes observed when the tris(alkyl)gallium compound GaR3 (R = CH2SiMe3) is paired with the lithium amide LiTMP (TMP = 2,2,6,6-tetramethylpiperidide) or the sterically hindered N-heterocyclic carbene (NHC) 1,3-bis(tert-butyl)imidazol-2-ylidene (ItBu). When some previously published work are drawn together with new results, unique tandem reactivities are presented that are driven by the steric mismatch between the individual reagents of these multicomponent reagents. Thus, the LiTMP/GaR3 combination, which on its own fails to form a cocomplex, functions as a highly regioselective base (LiTMP)/trap (GaR3) partnership for the metalation of N-heterocycles such as diazines, 1,3-benzoazoles, and 2-picolines in a trans-metal-trapping (TMT) process that stabilizes the emerging sensitive carbanions. Taking advantage of related steric incompatibility, a novel monometallic FLP system pairing GaR3 with ItBu has been developed for the activation of carbonyl compounds (via C═O insertion) and other molecules with acidic hydrogen atoms such as phenol and phenylacetylene. Shedding new light on how these non-cocomplexing partnerships operate and showcasing the potential of gallium reagents to engage in metalation reactions or FLP activations, areas where the use of this group 13 metal is scant, this Forum Article aims to stimulate more interest and activity toward the advancement of organogallium chemistry.


Muscle-tendon interaction and EMG profiles of world class endurance runners during hopping.
The present study examined the muscle-tendon interaction of ten international level Kenyan runners. Ultrasonography and kinematics were applied together with EMG recordings of lower limb muscles during repetitive hopping performed at maximal level. The ten Kenyans had longer gastro Achilles tendon at rest (p < 0.01) as compared with ten control subjects matched in height. Conversely, the stretching and shortening amplitudes of the tendinous tissues of the medial gastrocnemius (MG) muscle were significantly smaller in the Kenyans than in controls during the contact phase of hopping. This applied also to the fascicle length changes, which were smaller and more homogeneous among Kenyans. These limited musculo-tendinous changes resulted in higher maximal hopping height and in larger power despite their reduced body weight. The associated finding of a greater shortening to stretching ratio of the MG tendinous tissues during contact could imply that the Kenyan MG muscle-tendon unit is optimized to favor efficient storage and recoil of elastic energy, while operating at optimal muscle fascicle working range (plateau region).


Exploiting developments in nanotechnology for the preferential delivery of platinum-based anti-cancer agents to tumours: targeting some of the hallmarks of cancer.
Platinum drugs as anti-cancer therapeutics are held in extremely high regard. Despite their success, there are drawbacks associated with their use; their dose-limiting toxicity, their limited activity against an array of common cancers and patient resistance to Pt-based therapeutic regimes. Current investigations in medicinal inorganic chemistry strive to offset these shortcomings through selective targeting of Pt drugs and/or the development of Pt drugs with new or multiple modes of action. A comprehensive overview showcasing how liposomes, nanocapsules, polymers, dendrimers, nanoparticles and nanotubes may be employed as vehicles to selectively deliver cytotoxic Pt payloads to tumour cells is provided.


Guided resonances in photonic quasicrystals.
In this paper, we report on the first evidence of guided resonances (GRs) in aperiodically-ordered photonic crystals, tied to the concept of "quasicrystals" in solid-state physics. Via a full-wave numerical study of the transmittance response and the modal structure of a photonic quasicrystal (PQC) slab based on a representative aperiodic geometry (Ammann-Beenker octagonal tiling), we demonstrate the possibility of exciting GR modes, and highlight similarities and differences with the periodic case. In particular, we show that, as for the periodic case, GRs arise from the coupling of the incident plane-wave with degenerate modes of the PQC slab that exhibit a matching symmetry in the spatial distribution, and can still be parameterized via a Fano-like model. Besides the phenomenological implications, our results may provide new degrees of freedom in the engineering of GRs, and pave the way for new developments and applications.


Maternal depressive symptoms are adversely associated with prevention practices and parenting behaviors for preschool children.
To determine the relationship between maternal depressive symptoms and select prevention practices and parenting behaviors for older preschool children. A telephone survey of mothers and female guardians of children entering kindergarten in Monroe County, New York, was administered to 400 eligible parents in 2001. The Mental Health Inventory-5 was used to determine maternal depressive symptoms. We examined the impact of maternal depression on well-child care, immunizations, routine dental care, tooth brushing, frequent reading, safe motor vehicle seating location, car seat or booster seat use, discipline consistency, and parenting confidence. A total of 17.7% of mothers had depressive symptoms, with increased rates among women who were poor, less educated, and single parents. Children of mothers with depressive symptoms were more likely to have not received routine dental care in the past year (21.1% vs 8.2%, P = .001), brush their teeth less than twice a day (37.1% vs 25.2%, P = .041), or be read to less than 3 times per week (31.0% vs 13.7%, P < .001) compared with children of mothers without depressive symptoms. In addition, mothers with depressive symptoms were more likely to describe inconsistent discipline practices (36.6% vs 20.1%, P = .005) and less confidence in their parenting (39.4% vs 18.5%, P < .001). All associations remained significant in multivariate analyses controlling for maternal race, ethnicity, education, income, age, and household structure. Maternal depressive symptoms are associated with diminished positive parenting behaviors including dental care, reading, and discipline consistency for older preschoolers. These findings have implications for clinical pediatrics as well as preventive public health efforts.


Evidence for an association between U1 RNA and interspersed repeat single-copy RNAs in the cytoplasm of sea urchin eggs.
Psoralen crosslinking of RNA-RNA intermolecular duplexes in sea urchin egg extracts reveals that some maternal poly(A)+ RNA molecules are complexed with U1 RNA, a cofactor in somatic nuclear pre-mRNA splicing. Reaction of egg extracts with a monoclonal antibody specific for U1 snRNP selects, in addition to U1, RNAs that contain repeated sequences interspersed with single-copy elements. Antibody-selection experiments with nucleate and anucleate egg halves demonstrate that most of the U1 RNA-interspersed RNA complexes are cytoplasmic, as is the egg's store of total U1 snRNP. These results raise the possibility that maternal interspersed RNAs include unprocessed pre-messenger RNA molecules in arrested complexes with splicing cofactors.


c-kit+ stem cells and thymocyte precursors in the livers of adult mice.
Livers of the adult mice contain c-kit+ stem cells that can reconstitute thymocytes, multiple lineage cells, and bone marrow (BM) stem cells. Transfer of 1 x 10(7) hepatic mononuclear cells (MNC) and 5 x 10(4) hepatic c-kit+ cells of BALB/c mice induced DP thymocytes within a week in four Gy-irradiated CB17/-SCID mice, but 2 wk were required for BM cells or BM c-kit+ cells to produce DP thymocytes. Moreover, B cell-depleted BM cells or liver MNC of SCID mice that had been rescued by hepatic MNC of BALB/c mice again reconstituted thymus and B cells of other irradiated SCID mice. CD3- IL-2R beta- populations of both BM cells and hepatic MNC of C57BL/6 (B6) mice could generate T cells with intermediate TCR (mostly NK1.1-) in the liver of irradiated B6 SCID mice before thymic reconstitution (extrathymic T cells). Furthermore, transfer of liver c-kit+ cells of B6-Ly 5.1 mice into irradiated B6 SCID (Ly5.2) mice revealed that liver c-kit+ cells can reconstitute myeloid and erythroid lineage cells. These results strongly suggest that the liver contains pluripotent stem cells and serves an important hematopoietic organ even into adulthood.


Performance of outpatient transvaginal hydrolaparoscopy.
What is the feasibility of performing transvaginal hydrolaparoscopy (THL) in an outpatient setting? It is feasible to perform THL in an outpatient setting, reflected by a low complication and failure rate and a high patients' satisfaction. THL is a safe method to investigate tubal patency and exploring the pelvis in subfertile women. Retrospective cohort study of 1127 subfertile women who underwent THL as primary diagnostic method for testing tubal patency in an outpatient setting. We studied all THL procedures performed as a primary diagnostic tubal patency test in an outpatient setting in subfertile women starting from the initial THL in four large hospitals. Baseline characteristics were obtained, as well as the outcome of the procedures in terms of success, complications and findings by examining medical records. We used a uniform visual analogue scale (VAS) score document to collect data on pain and acceptability prospectively and compared two methods of pain relief. We studied a total of 1103 women who underwent THL. Successful access to the pouch of Douglas was achieved in 1028 women (93.2%), and 1017 women had a complete evaluation (92.2%). Double-sided tubal patency was found in 844 women (83%), unilateral tubal patency in 127 women (12.5%), while in 46 women (4.5%) bilateral occluded tubes were diagnosed. Endometriosis alone was seen in 64 women (6.3%), adhesions alone in 87 women (8.6%) and both endometriosis and adhesions in 42 women (4.1%).Complications occurred in 29 (2.6%) women, including 10 perforations of the rectum (0.9%), 8 perforations of the posterior uterine wall (0.7%) and 5 infections/pelvic inflammatory diseases (PIDs) (0.5%). Bleeding of the vaginal wall requiring intervention and hospital admissions due to pain was seen in 4 (0.4%) and 2 women, respectively (0.2%). The average pain score was rated 4.0 (±2.4 SD) on a VAS from 0 to 10 with 0 meaning no pain at all with no difference in different types of pain relief. Acceptability was rated 1.5 (±2.1 SD). The main limitation of the study is its retrospective character and the fact that only a fourth of the women were asked for pain and acceptability scores. THL can be used as a primary method for tubal assessment in an outpatient setting. Further randomized studies are needed to assess whether THL is superior to other methods and strategies for tubal assessment in terms of prognostic capacity and cost-effectiveness. No external funding was either sought or obtained for this study. The authors have no competing interests to declare.


Altered fronto-striatal fiber topography and connectivity in obsessive-compulsive disorder.
Fronto-striatal circuits are hypothesized to be involved in the pathophysiology of obsessive-compulsive disorder (OCD). Within this circuitry, ventral frontal regions project fibers to the ventral striatum (VS) and dorsal frontal regions to the dorsal striatum. Resting state fMRI research has shown higher functional connectivity between the orbitofrontal cortex (OFC) and the dorsal part of the VS in OCD patients compared to healthy controls (HC). Therefore, we hypothesized that in OCD the OFC predominantly project fibers to the more dorsal part of the VS, and that the structural connectivity between the OFC and VS is higher compared to HC. A total of 20 non-medicated OCD patients and 20 HC underwent diffusion-weighted imaging. Connectivity-based parcellation analyses were performed with the striatum as seed region and the OFC, dorsolateral prefrontal cortex, and dorsal anterior cingulate cortex as target regions. Obtained connectivity maps for each frontal region of interest (ROI) were normalized into standard space, and Z-component (dorsal-ventral) coordinate of center-of-gravity (COG) were compared between two groups. Probabilistic tractography was performed to investigate diffusion indices of fibers between the striatum and frontal ROIs. COG Z-component coordinates of connectivity maps for OFC ROI were located in the more dorsal part of the VS in OCD patients compared to HC. Fractional anisotropy of fibers between the OFC and the striatum was higher in OCD patients compared to HC. Part of the pathophysiology of OCD might be understood by altered topography and structural connectivity of fibers between the OFC and the striatum.


Elite level rhythmic gymnasts have significantly more and stronger pain than peers of similar age: a prospective study.
Rhythmic gymnastics (RG) unites aesthetic, ballet-like motion, and all aspects of gymnastics. To reach elite level, girls begin at early age the intensive training. To date it is unclear if such demanding training influences the incidence and intensity of painful overuse injuries. The purpose of this study is to analyze anatomical painful regions and pain intensity in elite level rhythmic gymnasts (elRG) and compare results with an age-matched control group (CG). This prospective field study was carried out at the European Championship in RG 2013 (218 participating athletes, Vienna, Austria). Volunteering athletes were interviewed according to a preformed questionnaire. As CG secondary school pupils without any competitive sports experience were analyzed accordingly. Overall, 243 young females (144 elRG/66 % of all participants and 99 CG) were observed. ElRGs were significantly (s.) smaller, lighter, and had s. stronger pain (p < 0.001). A total of 72 % of athletes reported to have at least one painful body region compared with 52 % of CG (p < 0.001). ElRG had nearly three times more serious injuries than the CG. In all 23 % off all elRG reported to have had no access to professional medical care. ElRGs were s. more frequently (25 vs 9 %) affected at the lumbar spine and the ankle joint (17.4 vs 7 %). To our knowledge, this trial analyzes the largest cohort of elRG to date. Hence, it is clearly alluded that intensive training in RG is a significant factor causing more and stronger pain than in a CG.


The Drosophila retinoid X receptor homolog ultraspiracle functions in both female reproduction and eye morphogenesis.
Ultraspiracle (usp) encodes the Drosophila cognate of RXR, the human retinoid X receptor. To examine how RXR subfamily members function in development, we have undertaken a phenotypic analysis of usp mutants. usp is required at multiple stages of development for functions that occur in a wide variety of tissues. usp is required in the eye-antennal imaginal disc for normal eye morphogenesis and in the somatic and germline tissues of adult females for fertilization, eggshell morphogenesis and embryonic development. An unusual sunken eye phenotype with marked ventral-dorsal polarity appears to be caused by a lack of usp function in the imaginal disc cells that reside between the eye and antennal anlage. The usp functions include cell autonomous and non-cell autonomous components, suggesting that usp controls the production of factors important for both cell-cell communication and cellular differentiation. These usp signalling pathways have mechanistic parallels to steroid and retinoid action in developing vertebrate tissues.


Testing the Situationism Scale in Europe: Scale validation, self-regulation and regional differences.
The term situationism refers to an individual's belief about the importance of a behaviour's context. This study tested whether the degree of situationism expressed by individuals in various regions of Europe was consistent with self-regulation and cross-cultural theories. The English version of a Situationism Scale (measuring beliefs about the relation between the environment and one's own behaviour) was translated into five additional languages: Dutch, German, Hungarian, Italian and Slovenian. Young adults (N = 1106, MAge = 22.9 years, 79% female) across Europe responded to one of the six language versions of the scale as part of a larger survey. Results indicated that: new language versions were psychometrically valid; there was a positive relation between situationism and the use of situation-control strategies; and situationism was higher for individuals from regions that are Eastern European and relatively more interdependent, compared with individuals from regions that are Western European and relatively less interdependent. As the first evaluation of the Situationism Scale outside America, this study supports the Scale's validity and suggests not only may some effects of situationism be universal, but between- and within-culture differences in situationism exist. Overall, when making judgments and decisions about the self, cultural background and individual differences in situationism may come into play.


Origin of Extended UV Stability of 2D Atomic Layer Titania-Based Perovskite Solar Cells Unveiled by Ultrafast Spectroscopy.
The inherent instability of UV-induced degradation in TiO2-based perovskite solar cells was largely improved by replacing the anatase-phase compact TiO2 layer with an atomic sheet transport layer (ASTL) of two-dimensional (2D) Ti1-δO2. The vital role of microscopic carrier dynamics that govern the UV stability of perovskite solar cells was comprehensively examined in this work by performing time-resolved pump-probe spectroscopy. In conventional perovskite solar cells, the presence of a UV-active oxygen vacancy in compact TiO2 prohibits current generation by heavily trapping electrons after UV degradation. Conversely, the dominant vacancy type in the 2D Ti1-δO2 ASTL is a titanium vacancy, which is a shallow acceptor and is not UV-sensitive. Therefore, it significantly suppresses carrier recombination and extends UV stability in perovskite solar cells with a 2D Ti1-δO2 ASTL. Other carrier dynamics, such as electron diffusion, electron injection, and hot hole transfer processes, were found to be less affected by UV irradiation. Quantitative pump-probe data clearly show a correlation between the carrier dynamics and UV aging of perovskite solar cells, thus providing a profound insight into the factors driving UV-induced degradation in perovskite solar cells and the origin of its performance.


Climate change decreases the cooling effect from postfire albedo in boreal North America.
Fire is a primary disturbance in boreal forests and generates both positive and negative climate forcings. The influence of fire on surface albedo is a predominantly negative forcing in boreal forests, and one of the strongest overall, due to increased snow exposure in the winter and spring months. Albedo forcings are spatially and temporally heterogeneous and depend on a variety of factors related to soils, topography, climate, land cover/vegetation type, successional dynamics, time since fire, season, and fire severity. However, how these variables interact to influence albedo is not well understood, and quantifying these relationships and predicting postfire albedo becomes increasingly important as the climate changes and management frameworks evolve to consider climate impacts. Here we developed a MODIS-derived 'blue sky' albedo product and a novel machine learning modeling framework to predict fire-driven changes in albedo under historical and future climate scenarios across boreal North America. Converted to radiative forcing (RF), we estimated that fires generate an annual mean cooling of -1.77 ± 1.35 W/m2 from albedo under historical climate conditions (1971-2000) integrated over 70 years postfire. Increasing postfire albedo along a south-north climatic gradient was offset by a nearly opposite gradient in solar insolation, such that large-scale spatial patterns in RF were minimal. Our models suggest that climate change will lead to decreases in mean annual postfire albedo, and hence a decreasing strength of the negative RF, a trend dominated by decreased snow cover in spring months. Considering the range of future climate scenarios and model uncertainties, we estimate that for fires burning in the current era (2016) the cooling effect from long-term postfire albedo will be reduced by 15%-28% due to climate change.


A diagnosis of the primary difference between EuroForMix and STRmix™.
There is interest in comparing the output, principally the likelihood ratio, from the two probabilistic genotyping software EuroForMix (EFM) and STRmix™. Many of these comparison studies are descriptive and make little or no effort to diagnose the cause of difference. There are fundamental differences between EFM and STRmix™ that are causative of the largest set of likelihood ratio differences. This set of differences is for false donors where there are many instances of LRs just above or below 1 for EFM that give much lower LRs in STRmix™. This is caused by the separate estimation of parameters such as allele height variance and mixture proportion using MLE under Hp and Ha for EFM. This can result in very different estimations of these parameters under Hp and Ha . It results in a departure from calibration for EFM in the region of LRs just above and below 1.


Horner's syndrome in dogs and cats: 100 cases (1975-1985).
The medical records of 74 dogs and 26 cats with Horner's syndrome (HS) that were admitted to the New York State College of Veterinary Medicine between January 1975 and October 1985 were reviewed. In dogs, but not cats, HS was associated significantly (P less than 0.01) with increasing age. Dogs with hypothyroidism (defined liberally but not rigorously), intracranial neoplasia, or thoracic neoplasia, cats with otitis media/interna (defined liberally), and dogs and cats with brachial plexus root avulsion were at greater risk for developing HS than were animals that were hit by a car. Dogs and cats with otitis externa were at less risk of developing HS than were animals that were hit by a car. The cause of HS could not be determined in 50% of dogs and 42.3% of cats. The results of topical adrenergic drug testing in dogs were inconclusive in localizing lesion site. In dogs and cats, HS appeared to be unassociated with gender, breed, or right vs left side. The important causes of HS in dogs and cats were trauma (hit by car), brachial plexus root avulsion, intracranial and thoracic neoplasia, and otitis media/interna.