Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial.
Recent evidence indicates a potential therapeutic role of fluvoxamine for COVID-19. In the TOGETHER trial for acutely symptomatic patients with COVID-19, we aimed to assess the efficacy of fluvoxamine versus placebo in preventing hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to a tertiary hospital due to COVID-19. This placebo-controlled, randomised, adaptive platform trial done among high-risk symptomatic Brazilian adults confirmed positive for SARS-CoV-2 included eligible patients from 11 clinical sites in Brazil with a known risk factor for progression to severe disease. Patients were randomly assigned (1:1) to either fluvoxamine (100 mg twice daily for 10 days) or placebo (or other treatment groups not reported here). The trial team, site staff, and patients were masked to treatment allocation. Our primary outcome was a composite endpoint of hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to tertiary hospital due to COVID-19 up to 28 days post-random assignment on the basis of intention to treat. Modified intention to treat explored patients receiving at least 24 h of treatment before a primary outcome event and per-protocol analysis explored patients with a high level adherence (>80%). We used a Bayesian analytic framework to establish the effects along with probability of success of intervention compared with placebo. The trial is registered at ClinicalTrials.gov (NCT04727424) and is ongoing. The study team screened 9803 potential participants for this trial. The trial was initiated on June 2, 2020, with the current protocol reporting randomisation to fluvoxamine from Jan 20 to Aug 5, 2021, when the trial arms were stopped for superiority. 741 patients were allocated to fluvoxamine and 756 to placebo. The average age of participants was 50 years (range 18-102 years); 58% were female. The proportion of patients observed in a COVID-19 emergency setting for more than 6 h or transferred to a teritary hospital due to COVID-19 was lower for the fluvoxamine group compared with placebo (79 [11%] of 741 vs 119 [16%] of 756); relative risk [RR] 0·68; 95% Bayesian credible interval [95% BCI]: 0·52-0·88), with a probability of superiority of 99·8% surpassing the prespecified superiority threshold of 97·6% (risk difference 5·0%). Of the composite primary outcome events, 87% were hospitalisations. Findings for the primary outcome were similar for the modified intention-to-treat analysis (RR 0·69, 95% BCI 0·53-0·90) and larger in the per-protocol analysis (RR 0·34, 95% BCI, 0·21-0·54). There were 17 deaths in the fluvoxamine group and 25 deaths in the placebo group in the primary intention-to-treat analysis (odds ratio [OR] 0·68, 95% CI: 0·36-1·27). There was one death in the fluvoxamine group and 12 in the placebo group for the per-protocol population (OR 0·09; 95% CI 0·01-0·47). We found no significant differences in number of treatment emergent adverse events among patients in the fluvoxamine and placebo groups. Treatment with fluvoxamine (100 mg twice daily for 10 days) among high-risk outpatients with early diagnosed COVID-19 reduced the need for hospitalisation defined as retention in a COVID-19 emergency setting or transfer to a tertiary hospital. FastGrants and The Rainwater Charitable Foundation. For the Portuguese translation of the abstract see Supplementary Materials section.


H3.3-G34 mutations impair DNA repair and promote cGAS/STING-mediated immune responses in pediatric high-grade glioma models.
Pediatric high-grade gliomas (pHGGs) are the leading cause of cancer-related deaths in children in the USA. Sixteen percent of hemispheric pediatric and young adult HGGs encode Gly34Arg/Val substitutions in the histone H3.3 (H3.3-G34R/V). The mechanisms by which H3.3-G34R/V drive malignancy and therapeutic resistance in pHGGs remain unknown. Using a syngeneic, genetically engineered mouse model (GEMM) and human pHGG cells encoding H3.3-G34R, we demonstrate that this mutation led to the downregulation of DNA repair pathways. This resulted in enhanced susceptibility to DNA damage and inhibition of the DNA damage response (DDR). We demonstrate that genetic instability resulting from improper DNA repair in G34R-mutant pHGG led to the accumulation of extrachromosomal DNA, which activated the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway, inducing the release of immune-stimulatory cytokines. We treated H3.3-G34R pHGG-bearing mice with a combination of radiotherapy (RT) and DNA damage response inhibitors (DDRi) (i.e., the blood-brain barrier-permeable PARP inhibitor pamiparib and the cell-cycle checkpoint CHK1/2 inhibitor AZD7762), and these combinations resulted in long-term survival for approximately 50% of the mice. Moreover, the addition of a STING agonist (diABZl) enhanced the therapeutic efficacy of these treatments. Long-term survivors developed immunological memory, preventing pHGG growth upon rechallenge. These results demonstrate that DDRi and STING agonists in combination with RT induced immune-mediated therapeutic efficacy in G34-mutant pHGG.


From tall to short: the role of TGFβ signaling in growth and its disorders.
The acromelic dysplasia group is characterized by short stature, short hands and feet, stiff joint, and "muscular" build. Four disorders can now be ascribed to this group, namely Weill-Marchesani syndrome (WMS), geleophysic dysplasia (GD), acromicric dysplasia (AD), and Myhre syndrome (MS). Although closely similar, they can be distinguished by subtle clinical features and their pattern inheritance. WMS is characterized by the presence of dislocation of microspherophakia and has autosomal dominant or recessive mode of inheritance. GD is the more severe one, with a progressive cardiac valvular thickening, tracheal stenosis, bronchopulmonary insufficiency, often leading to an early death. AD has an autosomal dominant mode of inheritance, distinct facial and skeleton features (a hoarse voice and internal notch of the femoral head). Finally, MS is sporadic, characterized by prognathism, deafness, developmental delay, thickened calvarium, and large vertebrae with short and large pedicles. We first identified mutations in Fibrillin-1 (FBN1) in the dominant form of WMS and then mutations in A Disintegrin-like And Metalloproteinase domain with ThromboSpondin type 1 repeats 10 (ADAMTS10) in the recessive form of WMS. The function of ADAMTS10 is unknown but these findings support a direct interaction between ADAMTS10 and FBN1. We then identified mutations in ADAMTSL2 in the recessive form of GD and a hotspot of mutations in FBN1 in the dominant form of GD and in AD (exon 41-42, encoding TGFβ binding protein-like domain 5 (TB5) of FBN1). The function of ADAMTSL2 is unknown. Using a yeast double hybrid screen, we identified latent transforming growth factor-β (TGFβ) binding protein 1 as a partner of ADAMTSL2. We found an increased level of active TGFβ in the fibroblast medium from patients with FBN1 or ADAMTSL2 mutations and an enhanced phosphorylated SMAD2 level, allowing us to conclude at an enhanced TGFβ signaling in GD and AD. Finally, a direct interaction between ADAMTSL2 and FBN1 was demonstrated suggesting a dysregulation of FBN1/ADAMTSL2 interrelationship as the underlying mechanism of the short stature phenotypes. Using exome sequencing in MS probands, we identified de novo SMAD4 missense mutations, all involving isoleucine residue at position 500, in the MH2 domain. In MS fibroblasts, we found decreased ubiquitination level of SMAD4 and increased level of SMAD4 supporting a stabilization of SMAD4 protein. Functional SMAD4 is required for canonical signal transduction through the oligomerization with phosphorylated SMAD2/3 and SMAD1/5/8. We therefore studied the nuclear localization of mutant SMAD complexes and found that the complexes translocate to the nucleus. We finally observed a decreased expression of downstream TGFβ target genes supporting impaired TGFβ driven transcriptional control in MS. Our findings support a direct link between the short stature phenotypes and the TGFβ signaling. However, the finding of enhanced TGFβ signaling in Marfan phenotypes supports the existence of yet unknown mechanisms regulating TGFβ action.


Unraveling nanotubes: field emission from an atomic wire.
Field emission of electrons from individually mounted carbon nanotubes has been found to be dramatically enhanced when the nanotube tips are opened by laser evaporation or oxidative etching. Emission currents of 0.1 to 1 microampere were readily obtained at room temperature with bias voltages of less than 80 volts. The emitting structures are concluded to be linear chains of carbon atoms, Cn, (n = 10 to 100), pulled out from the open edges of the graphene wall layers of the nanotube by the force of the electric field, in a process that resembles unraveling the sleeve of a sweater.


The evolution of distributed association networks in the human brain.
The human cerebral cortex is vastly expanded relative to other primates and disproportionately occupied by distributed association regions. Here we offer a hypothesis about how association networks evolved their prominence and came to possess circuit properties vital to human cognition. The rapid expansion of the cortical mantle may have untethered large portions of the cortex from strong constraints of molecular gradients and early activity cascades that lead to sensory hierarchies. What fill the gaps between these hierarchies are densely interconnected networks that widely span the cortex and mature late into development. Limitations of the tethering hypothesis are discussed as well as its broad implications for understanding critical features of the human brain as a byproduct of size scaling.


Effects of locus coeruleus activation on electroencephalographic activity in neocortex and hippocampus.
Experiments were conducted to examine the hypothesis that increased neuronal discharge activity of noradrenergic neurons of the locus coeruleus (LC) above resting discharge rates can alter forebrain electroencephalographic (EEG) activity. Small infusions (70-135 nl) of the cholinergic agonist bethanechol within 500 microns of the LC were used to activate this nucleus reversibly in halothane-anesthetized rats. A combined recording-infusion probe allowed verification of this electrophysiological activation. Simultaneously, EEG activity was recorded from sites in the frontal cortex and hippocampus and subjected to power-spectrum analyses. The findings were (1) LC activation was consistently followed, within 5 to 30 sec, by a shift from low-frequency, high-amplitude to high-frequency, low-amplitude EEG activity in frontal neocortex and by the appearance of intense theta-rhythm in the hippocampus; (2) forebrain EEG changes followed LC activation with similar latencies whether infusions were made lateral or medial to the LC; (3) infusions placed outside the immediate vicinity of the LC were not followed by these forebrain EEG effects; (4) following infusion-induced activation, forebrain EEG returned to preinfusion patterns with about the same time course as the recovery of LC activity (10-20 min for complete recovery). These infusion-induced effects on EEG activity were blocked or severely attenuated by pretreatment with the alpha 2-agonist clonidine, which inhibits LC discharge and norepinephrine release, or the beta-antagonist propranolol. These observations indicate that enhanced LC discharge activity is the crucial mediating event for the infusion-induced changes in forebrain EEG activity observed under these conditions and suggest that LC activation may be sufficient to induce EEG signs of cortical and hippocampal activation.


Sampling the spatial patterns of cancer: optimized biopsy procedures for estimating prostate cancer volume and Gleason Score.
Prostate biopsy is the current gold-standard procedure for prostate cancer diagnosis. Existing prostate biopsy procedures have been mostly focusing on detecting cancer presence. However, they often ignore the potential use of biopsy to estimate cancer volume (CV) and Gleason Score (GS, a cancer grade descriptor), the two surrogate markers for cancer aggressiveness and the two crucial factors for treatment planning. To fill up this vacancy, this paper assumes and demonstrates that, by optimally sampling the spatial patterns of cancer, biopsy procedures can be specifically designed for estimating CV and GS. Our approach combines image analysis and machine learning tools in an atlas-based population study that consists of three steps. First, the spatial distributions of cancer in a patient population are learned, by constructing statistical atlases from histological images of prostate specimens with known cancer ground truths. Then, the optimal biopsy locations are determined in a feature selection formulation, so that biopsy outcomes (either cancer presence or absence) at those locations could be used to differentiate, at the best rate, between the existing specimens having different (high vs. low) CV/GS values. Finally, the optimized biopsy locations are utilized to estimate whether a new-coming prostate cancer patient has high or low CV/GS values, based on a binary classification formulation. The estimation accuracy and the generalization ability are evaluated by the classification rates and the associated receiver-operating-characteristic (ROC) curves in cross validations. The optimized biopsy procedures are also designed to be robust to the almost inevitable needle displacement errors in clinical practice, and are found to be robust to variations in the optimization parameters as well as the training populations.


Novel role of PELP1 in regulating chemotherapy response in mutant p53-expressing triple negative breast cancer cells.
Triple-negative breast cancer (TNBC), the most aggressive breast cancer subtype, occurs in younger women and is associated with poor prognosis. Gain-of-function mutations in TP53 are a frequent occurrence in TNBC and have been demonstrated to repress apoptosis and up-regulate cell cycle progression. Even though TNBC responds to initial chemotherapy, resistance to chemotherapy develops and is a major clinical problem. Tumor recurrence eventually occurs and most patients die from their disease. An urgent need exists to identify molecular-targeted therapies that can enhance chemotherapy response. In the present study, we report that targeting PELP1, an oncogenic co-regulator molecule, could enhance the chemotherapeutic response of TNBC through the inhibition of cell cycle progression and activation of apoptosis. We demonstrate that PELP1 interacts with MTp53, regulates its recruitment, and alters epigenetic marks at the target gene promoters. PELP1 knockdown reduced MTp53 target gene expression, resulting in decreased cell survival and increased apoptosis upon genotoxic stress. Mechanistic studies revealed that PELP1 depletion contributes to increased stability of E2F1, a transcription factor that regulates both cell cycle and apoptosis in a context-dependent manner. Further, PELP1 regulates E2F1 stability in a KDM1A-dependent manner, and PELP1 phosphorylation at the S1033 residue plays an important role in mediating its oncogenic functions in TNBC cells. Accordingly, depletion of PELP1 increased the expression of E2F1 target genes and reduced TNBC cell survival in response to genotoxic agents. PELP1 phosphorylation was significantly greater in the TNBC tumors than in the other subtypes of breast cancer and in the normal tissues. These findings suggest that PELP1 is an important molecular target in TNBC, and that PELP1-targeted therapies may enhance response to chemotherapies.


The effect of neutrophil migration on epithelial permeability.
To reach an inflammatory lesion, neutrophils must frequently traverse the epithelium of an infected organ. Whether the actual migration of neutrophils alters the epithelial permeability is unknown. Through the use of an in vitro model system it was possible to directly determine the effect of neutrophil emigration on the transepithelial electrical resistance of the monolayer. Human neutrophils (5 X 10(6) cells/ml) were placed in the upper compartment of a combined chemotaxis/resistance chamber and stimulated for 40 min by a gradient of 10(-7) M n-formyl-methionyl-leucyl-phenylalanine to traverse a confluent monolayer of canine kidney epithelial cells grown on micropore filters. Neither the chemoattractant alone (10(-5)-10(-9) M) nor the accumulation of an average of eight neutrophils per millimeter of epithelium lowered the transepithelial electrical resistance. However, under certain conditions the migration of neutrophils temporarily increased the permeability of the monolayer. The resistance fell approximately 48% within 5 min if the migratory cells were stimulated to reverse their migration across the same monolayer. As re-migration continued, the resistance returned to its initial levels within 60 min. Doubling the initial neutrophil concentration to 10 X 10(6) cells/ml resulted in the accumulation of an average of 66 neutrophils per millimeter of epithelium and an average fall in resistance of 46% (r = 0.98; P less than 0.001) in 40 min. If the resistance had fallen less than 45%, removal of the neutrophils remaining in the upper compartment resulted in a return of the transepithelial electrical resistance to its initial level within 65 min. However, when the fall was greater than 45%, the resistance only recovered to 23.5% of its initial levels within the same time frame. Thus, these results suggest that the integrity of an epithelium can, under certain conditions, be affected by the emigration of neutrophils, but that this effect is either completely or partially reversible within 65 min.


Inherited chromosomally integrated human herpesvirus 6 and autoimmune connective tissue diseases.
Entire genome of human herpesvirus 6 (HHV-6) that integrates into human chromosomes is called chromosomally integrated HHV-6 (ciHHV-6). Several viral infections have been suggested to be involved in autoimmune connective tissue diseases (CTDs). Reactivated HHV-6 from the integrated viral genome can induce immune responses against the virus. Thus, it is plausible that ciHHV-6 is associated with autoimmune CTDs. We sought to determine whether the prevalence of ciHHV-6 was significantly higher in patients with autoimmune CTDs than in a healthy population. A total of 846 peripheral blood samples collected from autoimmune CTD patients were analyzed. Since there was a large number of samples, they were pooled into 24 samples per group. Copy numbers of HHV-6 DNA were measured by real-time PCR. The threshold level for distinguishing between ciHHV-6 and active viral infection and the reliability of pooled DNA analysis were examined as initial validation experiments. The threshold level was 1.6 × 10^6 copy/mL in whole blood. The reliability of pooled DNA analysis to identify one ciHHV-6 sample among 23 HHV-6 DNA-negative samples was high. No HHV-6 DNA was detected in any of the pooled DNA samples collected from the patients. The probability of the present study including the 846 autoimmune CTD patient's samples was statistically not different with a healthy Japanese population which was 0.2 % or 0.6 %. There was no significant difference in the prevalence of ciHHV-6 between a healthy population and patients with autoimmune CTDs.


Bragg diffraction from crystallized ion plasmas
Single crystals of a one-component plasma were observed by optical Bragg diffraction. The plasmas contained 10(5) to 10(6) single-positive beryllium-9 ions (9Be+) at particle densities of 10(8) to 10(9) per cubic centimeter. In approximately spherical plasmas, single body-centered cubic (bcc) crystals or, in some cases, two or more bcc crystals having fixed orientations with respect to each other were observed. In some oblate plasmas, a mixture of bcc and face-centered cubic ordering was seen. Knowledge of the properties of one-component plasma crystals is required for models of white dwarfs and neutron stars, which are believed to contain matter in that form.


Polyp morphology: an interobserver evaluation for the Paris classification among international experts.
The Paris classification is an international classification system for describing polyp morphology. Thus far, the validity and reproducibility of this classification have not been assessed. We aimed to determine the interobserver agreement for the Paris classification among seven Western expert endoscopists. A total of 85 short endoscopic video clips depicting polyps were created and assessed by seven expert endoscopists according to the Paris classification. After a digital training module, the same 85 polyps were assessed again. We calculated the interobserver agreement with a Fleiss kappa and as the proportion of pairwise agreement. The interobserver agreement of the Paris classification among seven experts was moderate with a Fleiss kappa of 0.42 and a mean pairwise agreement of 67%. The proportion of lesions assessed as "flat" by the experts ranged between 13 and 40% (P<0.001). After the digital training, the interobserver agreement did not change (kappa 0.38, pairwise agreement 60%). Our study is the first to validate the Paris classification for polyp morphology. We demonstrated only a moderate interobserver agreement among international Western experts for this classification system. Our data suggest that, in its current version, the use of this classification system in daily practice is questionable and it is unsuitable for comparative endoscopic research. We therefore suggest introduction of a simplification of the classification system.


Patients' priorities and expectations on an EU registry for rare bone and mineral conditions.
Understanding the natural history of rare bone and mineral conditions is essential for improving clinical practice and the development of new diagnostics and therapeutics. Recruitment and long-term participation in registries are key challenges for researchers. To understand the user needs, the European Reference Network on Rare Bone Diseases (ERN BOND) and European Patient Advocacy Groups developed and implemented a multinational survey about the patient's preferred database content and functionality through an iterative consensus process. The survey was disseminated by national and international patient groups and healthcare professionals. The findings were analysed using descriptive statistics and multivariate regression. There were 493 eligible responses from 378 adults, 15 children and 100 parents, guardians or carers (PGC) across 22 rare bone and mineral conditions. Osteogenesis imperfecta constituted 53.4% of responses. Contents related to improving treatment and medical services scored the highest and contents about anxiety and socializing scored less highly. Additional content was recommended by 205 respondents. Respondents preferred data entry by their Healthcare Provider (HCP). However, less than 50% of adults received followup from their specialist HCP at least annually and 29% were followed up as needed. This survey of individuals, their family, guardians and carers has prioritised the key components for an EU-based rare bone and mineral condition research database. The survey highlights issues around collecting psychosocial impacts as well as measures of HCP trust. The survey demonstrated that using only specialist centre visits for data collection, while preferred by patients, will miss a substantial number of individuals, limiting generalisability. Combined HCP and patient platforms will be required to collect representative and complete natural history data for this patient group.


Polyherbal formulation: Concept of ayurveda.
Ayurveda is one of the traditional medicinal systems of Indian. The philosophy behind Ayurveda is preventing unnecessary suffering and living a long healthy life. Ayurveda involves the use of natural elements to eliminate the root cause of the disease by restoring balance, at the same time create a healthy life-style to prevent the recurrence of imbalance. Herbal medicines have existed world-wide with long recorded history and they were used in ancient Chinese, Greek, Egyptian and Indian medicine for various therapies purposes. World Health Organization estimated that 80% of the word's inhabitants still rely mainly on traditional medicines for their health care. The subcontinent of India is well-known to be one of the major biodiversity centers with about 45,000 plant species. In India, about 15,000 medicinal plants have been recorded, in which the communities used 7,000-7,500 plants for curing different diseases. In Ayurveda, single or multiple herbs (polyherbal) are used for the treatment. The Ayurvedic literature Sarangdhar Samhita' highlighted the concept of polyherbalism to achieve greater therapeutic efficacy. The active phytochemical constituents of individual plants are insufficient to achieve the desirable therapeutic effects. When combining the multiple herbs in a particular ratio, it will give a better therapeutic effect and reduce the toxicity. This review mainly focuses on important of the polyherbalism and its clinical significance.


Hyperferritinemia and hyperuricemia may be associated with liver function abnormality in obese adolescents.
The iron status in human body and its association with liver function in adolescents was rarely studied. The objective was to investigate the association among the levels of serum ferritin, uric acid and alanine aminotransferase (ALT) in adolescents. A total of 2090 adolescents negative for hepatitis B surface antigen from one junior high school (786, 12-13 years), three senior high schools (973, 15-16 years) and one college (331, 18-19 years) participated in this survey. Anthropometric and biochemical measurements, including complete blood count, ALT, serum ferritin and uric acid were performed. An ALT>42 U/L was defined as elevated, a ferritin level >200 µg/L was defined as hyperferritinemia. A uric acid level >460 µmol/L in males and >340 µmol/L in females was defined as hyperuricemia. The chi-squared test, linear regression and multivariate logistic regression were used for the data analysis. Elevated ALT levels were detected in 76 (3.6%) students and were more prevalent in males than females (6.4% vs. 2.0%, p<0.001). The univariate analysis found gender, age group, body mass index, ferritin level, uric acid level and white blood cell count all to be significantly associated with elevated ALT. Linear regression showed a positive correlation among log(ferritin), uric acid level and ALT level. Elevated ALT occurred more frequently at ferritin level >100 µg/L. The logistic regression analysis found that body mass index, hyperferritinemia and hyperuricemia were significant factors associated with the ALT elevation, but gender, age, and white blood cell count were not. Hyperferritinemia and hyperuricemia are two independently significant factors associated with ALT elevation among obese adolescents. More studies are needed to corroborate any hypothesis related to these phenomena.


[Secretion of niche signal molecules in conditions of osteogenic differentiation of multipotent mesenchymal stromal cells induced by textured calcium phosphate coating].
Secretion of 21 cytokines, chemokines and growth factors (LIF, SCF, SDF-1a, SCGF-b, M-CSF, MCP-3, MIF, MIG, TRAIL, GRO-a; IL-1a, IL-2ra, IL-3, IL-12(p40), IL-16, IL-18, HGF, TNF-b, b-NGF, IFN-a2, CTACK) has been studied in vitro in the culture of human adipose-derived multipotent mesenchymal stromal cells (hAMMSCs) in conditions of its osteogenic differentiation caused by 14-day contact with calcium phosphate (CP) surface with different roughness. Bilateral X-ray amorphous CP coatings were prepared on the samples of commercially pure titanium in the anodal regime using a micro-arc method. An aqueous solution prepared from 20 wt% phosphoric acid, 6 wt% dissolved hydrohyapatite nanopowder (particle diameter 10-30 nm with single agglomerates up to 100 nm), and 9 wt% dissolved calcium carbonate was used to obtain CP coating. hAMMSCs isolated from lipoaspirate were co-cultured after 4 passages with the CP-coated samples at final concentration of 1.5´105 viable karyocytes per 1.5 mL of standard nutrition medium (without osteogenic stimulators) for 14 days (a determination of [CD45,34,14,20], CD73, CD90 и CD105 cell immunophenotype; an analysis of secretory activity) and 21 days (alizarin red S staining of culture) with medium replacement every 3-4 days. Under conditions of in vitro contact with rough CP coating hAMMSCs differentiated into osteoblasts synthesizing the mineralized bone matrix; this was accompanied by 2-3-fold increasing ratio of [CD45,34,14,20]+ hemopoietic cells. The following humoral factors of hemopoietic niches acted as the signal molecules escalating in vitro the hemopoietic base in 14 days of differentiating three-dimensional culture of hAMMSCs: either leukemia inhibitory factor (LIF) and stem cell factor (SCF) cytokines under mean index of CP roughness Ra=2.4-2.6 mm or stromal derived factor-1 (SDF-1a, CXCL12 chemokine) under Ra=3.1-4.4 mm.


Out-of-plane shape determination in generalized fringe projection profilometry.
The out-of-plane shape determination in a generalized fringe projection profilometry is presented. The proposed technique corrects the problems in existing approaches, and it can cope well with the divergent illumination encountered in the generalized profilometry. In addition, the technique can automatically detect the geometric parameters of the experimental setup, which makes the generalized fringe projection profilometry simple and practical. The concept was verified by both computer simulations and actual experiments. The technique can be easily employed for out-of-plane shape measurements with high accuracies.


Thrombopoietin expression in normal and hypobaric hypoxia-induced thrombocytopenic rats.
Thrombopoietin (TPO) is important as the physiologic regulator of platelet production. High-altitude hypoxia is a well-known cause of polycythemia and thrombocytopenia in animals. Fifty-two Wistar rats were housed for 0.5 to 21 days in a mechanical chamber in an environment equivalent to that found at 5500 m to determine (a) the cellular localization of TPO and (b) whether the decreased platelet and megakaryocyte counts in rats exposed to a hypobaric hypoxic environment (HHE) are associated with an altered TPO mRNA expression. In normal rats, there were high levels of TPO mRNA in the liver and kidney, intermediate levels in the brain and large intestine, and low levels in the skeletal muscle and small intestine. TPO mRNA and protein were expressed in Purkinje cells and neuronal cells in the brain, in proximal tubular cells and the mesangial cells of the glomeruli in the kidney, in hepatocytes and biliary duct epithelial cells, in absorptive epithelial cells in the large intestine, in the epidermis, and in the lung. The platelet count in the blood and megakaryocyte counts in the bone marrow and spleen were all decreased significantly after 5 or more days of exposure to HHE. In major producers such as the liver and kidney and in minor producers such as the brain, TPO mRNA levels, which tended to be decreased after 0.5 to 3 days of exposure to HHE, had returned to normal by about Day 5 or 7. Thus, during the HHE period with a decreased platelet count, no changes in TPO mRNA levels were detected in these three organs. In conclusion, we have demonstrated that TPO production occurs in various types of cells. In HHE, however, factors other than TPO may be involved in hypobaric hypoxia-induced thrombocytopenia in rats.


Methylphenidate for attention-deficit/hyperactivity disorder in children and adolescents: Cochrane systematic review with meta-analyses and trial sequential analyses of randomised clinical trials.
Is methylphenidate beneficial or harmful for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents? Electronic databases were searched up to February 2015 for parallel and crossover randomised clinical trials comparing methylphenidate with placebo or no intervention in children and adolescents with ADHD. Meta-analyses and trial sequential analyses (TSA) were conducted. Quality was assessed using GRADE. Teachers, parents, and observers rated ADHD symptoms and general behaviour. The analyses included 38 parallel group trials (n=5111, median treatment duration 49 days) and 147 crossover trials (n=7134, 14 days). The average age across all studies was 9.7 years. The analysis suggested a beneficial effect of methylphenidate on teacher rated symptoms in 19 parallel group trials (standardised mean difference (SMD) -0.77, n=1698), corresponding to a mean difference of -9.6 points on the ADHD rating scale. There was no evidence that methylphenidate was associated with an increase in serious adverse events (risk ratio 0.98, nine trials, n=1532; TSA adjusted intervention effect RR 0.91). Methylphenidate was associated with an increased risk of non-serious adverse events (1.29, 21 trials, n=3132; TSA adjusted RR 1.29). Teacher rated general behaviour seemed to improve with methylphenidate (SMD -0.87, five trials, n=668) A change of 7 points on the child health questionnaire (CHQ) has been deemed a minimal clinically relevant difference. The change reported in a meta-analysis of three trials corresponds to a mean difference of 8.0 points on the CHQ (range 0-100 points), which suggests that methylphenidate may improve parent reported quality of life (SMD 0.61, three trials, n=514). 96.8% of trials were considered high risk of bias trials according to the Cochrane guidelines. All outcomes were assessed very low quality according to GRADE. The results suggest that among children and adolescents with a diagnosis of ADHD, methylphenidate may improve teacher reported symptoms of ADHD and general behaviour and parent reported quality of life. However, given the risk of bias in the included studies, and the very low quality of outcomes, the magnitude of the effects is uncertain. Methylphenidate is associated with an increased risk of non-serious but not serious adverse events. Region Zealand Research Foundation and Copenhagen Trial Unit. Competing interests are given in the full paper on bmj.com. Full data are available in the version of this review published in The Cochrane Library.


A randomized investigator-blind parallel-group study to assess efficacy and safety of azelaic acid 15% gel vs. adapalene 0.1% gel in the treatment and maintenance treatment of female adult acne.
Growing numbers of post-adolescent females are suffering from treatment-resistant or relapsing adult acne forms, therefore requiring the definition of safe and effective treatment options for this burdening disease. To assess the efficacy of azelaic acid 15% gel (AzA) vs. no treatment during maintenance therapy of female adult acne and to compare its efficacy and safety vs. adapalene 0.1% gel (AD) during a 9-month period (3-month treatment and 6-month maintenance treatment). A total of 55 women between 18 and 45 years with adult acne were included in this investigator-blind trial and randomized into three groups receiving AzA gel b.i.d. for 9 months (AzA9M, n = 17) or AzA gel b.i.d. for 3 months followed by a 6-month observational phase (AzA3M, n = 19) or AD gel once daily for 9 months (AD9M, n = 19). Parameters of efficacy, safety and patient-related factors were analysed. The reduction in lesion counts, severity and Dermatology Life Quality Index score was significant (P < 0.05) and comparable between groups during the treatment phase, while dryness and scaling were significantly lower (P < 0.05) in group AzA9M vs. AD9M. During maintenance, AzA9M was superior to AzA3M in the control of inflammatory lesions (P = 0.008) and total lesions (P = 0.014) at week 24. From week 12 to week 36, a mild relative increase in inflammatory lesions could be observed in all groups. In AzA3M, this increase exceeded that of AzA9M by 23.1% (P = 0.109), while the difference of total lesions diverged to 30.8% (P = 0.038). No significant differences could be detected between AzA9M and AD9M. Group AzA9M was non-inferior to AD9M (non-inferiority margin of 50% for the confidence limit for the relative effect) in the control of inflammatory acne lesions. AzA15% gel is a safe and effective treatment and maintenance treatment of female adult acne with non-inferior efficacy to AD 0.1% gel in the control of inflammatory acne.


Deinococcus ruber sp. nov., a radiation-resistant bacterium isolated from soil.
Two gamma- and UVC-resistant bacterial strains, designated JSH3-1T and 9-2-2, were isolated from garden soil in South Korea. Cells were Gram-stain-positive, aerobic, non-motile and spherical. A polyphasic approach was used to study the taxonomic properties of strains JSH3-1T and 9-2-2. Phylogenetic analysis based on nearly full-length 16S rRNA gene sequences of strains JSH3-1T and 9-2-2 indicated highest similarity with Deinococcus radiomollis PO-04-20-132T (94.7 and 94.9 %, respectively); levels of sequence similarity with the type strains of other Deinococcus species were less than 94.0 %. Strains JSH3-1T and 9-2-2 shared relatively high 16S rRNA gene sequence similarity (98.7 %) and had a high DNA reassociation value of 81±0.5 %. Meanwhile, they showed low levels of DNA reassociation (<25 %) with other closely related species of the genus Deinococcus. The two strains showed chemotaxonomic features typical of the genus Deinococcus, with the presence of menaquinone 8 as the respiratory quinone. The predominant fatty acids were iso-C17 : 0, iso-C13 : 0 and anteiso-C13 : 0. The polar lipids comprised phosphoglycolipid, aminophospholipid, glycolipid and unknown aminolipids. The DNA G+C contents of strains JSH3-1T and 9-2-2 were 62.0 and 61.9 mol%, respectively. On the basis of their phenotypic and genotypic characteristics, and phylogenetic distinction, strains JSH3-1T (=KCTC 33790T=JCM 31311T) and 9-2-2 (=KCTC 33789=JCM 31310) should be classified within a novel species of the genus Deinococcus, for which the name Deinococcus ruber sp. nov. is proposed.


A Plasma Biomarker Panel of Four MicroRNAs for the Diagnosis of Prostate Cancer.
Prostate cancer is diagnosed in over 1 million men every year globally, yet current diagnostic modalities are inadequate for identification of significant cancer and more reliable early diagnostic biomarkers are necessary for improved clinical management of prostate cancer patients. MicroRNAs (miRNAs) modulate important cellular processes/pathways contributing to cancer and are stably present in body fluids. In this study we profiled 372 cancer-associated miRNAs in plasma collected before (~60% patients) and after/during commencement of treatment (~40% patients), from age-matched prostate cancer patients and healthy controls, and observed elevated levels of 4 miRNAs - miR-4289, miR-326, miR-152-3p and miR-98-5p, which were validated in an independent cohort. The miRNA panel was able to differentiate between prostate cancer patients and controls (AUC = 0.88). Analysis of published miRNA transcriptomic data from clinical samples demonstrated low expression of miR-152-3p in tumour compared to adjacent non-malignant tissues. Overexpression of miR-152-3p increased proliferation and migration of prostate cancer cells, suggesting a role for this miRNA in prostate cancer pathogenesis, a concept that was supported by pathway analysis of predicted miR-152-3p target genes. In summary, a four miRNA panel, including miR-152-3p which likely targets genes with key roles in prostate cancer pathogenesis, has the potential to improve early prostate cancer diagnosis.


The Headache-Attributed Lost Time (HALT) Indices: measures of burden for clinical management and population-based research.
The burden attributable to headache disorders has multiple components: a simple measure summarising them all does not exist. The Migraine Disability Assessment (MIDAS) instrument has proved useful, estimating productive time lost in the preceding 3 months due to the disabling effect of headache. We developed adaptations of MIDAS for purposes of the Global Campaign against Headache, embracing epidemiological studies and the provision of clinical management aids. We reviewed the structure, content, wording and scoring of MIDAS and made revisions, developing the Headache-Attributed Lost Time (HALT) Indices in three versions. Over 10 years, these were employed in multiple epidemiological and clinical studies in countries worldwide. In the original HALT-90, we made no changes to the structure and scoring of MIDAS, but used wording in questions 1-4 that we believed would be more widely understood and more easily translated into other languages. Of the two alternative versions, HALT-30 kept the same structure, question format and wording except that "3 months" was replaced by "1 month". HALT-7/30 was a variant of HALT-30: focusing only on lost work time for population-based studies of headache-attributed burden, it enquired into lost days in the preceding month (30 days) and week (7 days). Three versions of the HALT Indices serve different purposes as measures of headache-attributed burden, and offer different means of scoring. In studies using HALT as a population measure, there is no need to reflect the states of individuals, whereas a measure over shorter periods than 3 months is likely to be more reliable through better recall. Assessment of individual patients prior to treatment may best estimate impact if enquiry is made into the preceding 90 days, except in cases where headache is highly frequent. Follow-up in clinical management may be better served by assessments over 30 rather than 90 days.


Analysis of MET mRNA expression in gastric cancers using RNA in situ hybridization assay: its clinical implication and comparison with immunohistochemistry and silver in situ hybridization.
We investigated MET mRNA expression status using RNA in situ hybridization (ISH) technique in primary and metastatic lesions of 535 surgically resected gastric carcinoma (GC) cases. We compared the results with those of immunohistochemistry and silver in situ hybridization, and examined the association with clinicopathologic characteristics and prognosis. Among 535 primary GCs, 391 (73.1%) were scored 0, 87 (16.3%) were scored 1, 38 (7.1%) were scored 2, 12 (2.2%) were scored 3 and 7 (1.3%) were scored 4 by RNA ISH. High MET mRNA expression (score ≥3) was associated with lymph node metastasis (P = .014), distant metastasis (P = .001), and higher TNM stage (P<.001). MET mRNA expression was correlated with protein expression (r = 0.398; P<.001) and gene copy number (r = 0.345; P<.001). The patients showing high-MET mRNA in primary or metastatic lesions had shorter overall survival than those showing low-MET mRNA (primary tumors, P = .002; metastatic lymph nodes, P<.001). The patients showing positive conversion of MET mRNA status in metastatic lymph node had shorter overall survival than those with no conversion (P = .011). Multivariate analysis demonstrated that high MET mRNA expression in metastatic lymph node was an independent prognostic factor for overall survival (P = .007). Therefore, this study suggests that MET mRNA expression assessed by RNA ISH could be useful as a potential marker to identify MET oncogene-addicted GC.


Fractal analysis of retinal vessels suggests that a distinct vasculopathy causes lacunar stroke.
Lacunar strokes account for 25% of all ischemic strokes and may represent the cerebral manifestation of a systemic small vessel vasculopathy of unknown etiology. Altered retinal vessel fractal dimensions may act as a surrogate marker for diseased cerebral vessels. We used a cross-sectional study to investigate fractal properties of retinal vessels in lacunar stroke. We recruited patients presenting with lacunar stroke and patients with minor cortical stroke as controls. All patients were examined by a stroke expert and had MRI at presentation. Digital retinal photographs were taken of both eyes. Monofractal and multifractal analyses were performed with custom-written semiautomated software. We recruited 183 patients. Seventeen were excluded owing to poor photographic quality, leaving 166 patients (86 with lacunar and 80 with cortical stroke). The mean age was 67.3 years (SD 11.5 years). The patients with lacunar stroke were younger but the prevalence of diabetes, hypertension, and white matter hyperintensities did not differ between the groups. The mean Dbox (monofractal dimension) was 1.42 (SD 0.02), the mean D0 (multifractal dimension) 1.67 (SD 0.03). With multivariate analysis, decreased Dbox and D0 (both representing decreased branching complexity) were associated with increasing age and lacunar stroke subtype after correcting for hypertension, diabetes, stroke severity, and white matter hyperintensity scores. Lacunar stroke subtype and increasing age are associated with decreased fractal dimensions, suggesting a loss of branching complexity. Further studies should concentrate on longitudinal associations with other manifestations of cerebral small vessel disease.


Order of magnitude improvement of nano-contact spin torque nano-oscillator performance.
Spin torque nano-oscillators (STNO) represent a unique class of nano-scale microwave signal generators and offer a combination of intriguing properties, such as nano sized footprint, ultrafast modulation rates, and highly tunable microwave frequencies from 100 MHz to close to 100 GHz. However, their low output power and relatively high threshold current still limit their applicability and must be improved. In this study, we investigate the influence of the bottom Cu electrode thickness (tCu) in nano-contact STNOs based on Co/Cu/NiFe GMR stacks and with nano-contact diameters ranging from 60 to 500 nm. Increasing tCu from 10 to 70 nm results in a 40% reduction of the threshold current, an order of magnitude higher microwave output power, and close to two orders of magnitude better power conversion efficiency. Numerical simulations of the current distribution suggest that these dramatic improvements originate from a strongly reduced lateral current spread in the magneto-dynamically active region.


Epidemiologic contributions to recent cancer trends among HIV-infected people in the United States.
HIV-infected people have elevated risk for some cancers. Changing incidence of these cancers over time may reflect changes in three factors: HIV population demographic structure (e.g. age distribution), general population (background) cancer rates, and HIV-associated relative risks. We assessed the contributions of these factors to time trends for 10 cancers during 1996-2010. Population-based registry linkage study. We applied Poisson models to data from the U.S. HIV/AIDS Cancer Match Study to estimate annual percentage changes (APCs) in incidence rates of AIDS-defining cancers [ADCs: Kaposi sarcoma, non-Hodgkin lymphoma (NHL), and cervical cancer] and seven non-AIDS-defining cancers (NADCs). We evaluated HIV-infected cancer trends with and without adjustment for demographics, trends in background rates, and trends in standardized incidence ratios (SIRs, to capture relative risk). Cancer rates among HIV-infected people rose over time for anal (APC 3.8%), liver (8.5%), and prostate (9.8%) cancers, but declined for Kaposi sarcoma (1996-2000: -29.3%; 2000-2010: -7.8%), NHL (1996-2003: -15.7%; 2003-2010: -5.5%), cervical cancer (-11.1%), Hodgkin lymphoma (-4.0%), and lung cancer (-2.8%). Breast and colorectal cancer incidence did not change over time. Based on comparison to adjusted models, changing demographics contributed to trends for Kaposi sarcoma and breast, colorectal, liver, lung, and prostate cancers (all P < 0.01). Trends in background rates were notable for liver (APC 5.6%) and lung (-3.2%) cancers. SIRs declined for ADCs, Hodgkin lymphoma (APC -3.2%), and lung cancer (-4.4%). Demographic shifts influenced several cancer trends among HIV-infected individuals. Falling relative risks largely explained ADC declines, while background incidence contributed to some NADC trends.


Cardiopulmonary resuscitation training of family members before hospital discharge using video self-instruction: a feasibility trial.
Bystander cardiopulmonary resuscitation (CPR) is a crucial therapy for sudden cardiac arrest (SCA), yet rates of bystander CPR are low. This is especially the case for SCA occurring in the home setting, as family members of at-risk patients are often not CPR trained. To evaluate the feasibility of a novel hospital-based CPR education program targeted to family members of patients at increased risk for SCA. Prospective, multicenter, cohort study. Inpatient wards at 3 hospitals. Family members of inpatients admitted with cardiac-related diagnoses. Family members were offered CPR training via a proctored video-self instruction (VSI) program. After training, CPR skills and participant perspectives regarding their training experience were assessed. Surveys were conducted one month postdischarge to measure the rate of "secondary training" of other individuals by enrolled family members. At the 3 study sites, 756 subjects were offered CPR instruction; 280 agreed to training and 136 underwent instruction using the VSI program. Of these, 78 of 136 (57%) had no previous CPR training. After training, chest compression performance was generally adequate (mean compression rate 90 ± 26/minute, mean depth 37 ± 12 mm). At 1 month, 57 of 122 (47%) of subjects performed secondary training for friends or family members, with a calculated mean of 2.1 persons trained per kit distributed. The hospital setting offers a unique "point of capture" to provide CPR instruction to an important, undertrained population in contact with at-risk individuals.


The epidemiology of renal cell carcinoma.
Kidney cancer is among the 10 most frequently occurring cancers in Western communities. Globally, about 270 000 cases of kidney cancer are diagnosed yearly and 116 000 people die from the disease. Approximately 90% of all kidney cancers are renal cell carcinomas (RCC). The causes of RCC are not completely known. We have reviewed known aetiologic factors. The data provided in the current review are based on a thorough review of available original and review articles on RCC epidemiology with a systemic literature search using Medline. Smoking, overweight and obesity, and germline mutations in specific genes are established risk factors for RCC. Hypertension and advanced kidney disease, which makes dialysis necessary, also increase RCC risk. Specific dietary habits and occupational exposure to specific carcinogens are suspected risk factors, but results in the literature are inconclusive. Alcohol consumption seems to have a protective effect for reasons yet unknown. Hardly any information is available for some factors that may have a high a priori role in the causation of RCC, such as salt consumption. Large collaborative studies with uniform data collection seem to be necessary to elucidate a complete list of established risk factors of RCC. This is necessary to make successful prevention possible for a disease that is diagnosed frequently in a stage where curative treatment is not possible anymore.


CESAR: conventional ventilatory support vs extracorporeal membrane oxygenation for severe adult respiratory failure.
An estimated 350 adults develop severe, but potentially reversible respiratory failure in the UK annually. Current management uses intermittent positive pressure ventilation, but barotrauma, volutrauma and oxygen toxicity can prevent lung recovery. An alternative treatment, extracorporeal membrane oxygenation, uses cardio-pulmonary bypass technology to temporarily provide gas exchange, allowing ventilator settings to be reduced. While extracorporeal membrane oxygenation is proven to result in improved outcome when compared to conventional ventilation in neonates with severe respiratory failure, there is currently no good evidence from randomised controlled trials to compare these managements for important clinical outcomes in adults, although evidence from case series is promising. The aim of the randomised controlled trial of Conventional ventilatory support vs extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR) is to assess whether, for patients with severe, but potentially reversible, respiratory failure, extracorporeal membrane oxygenation will increase the rate of survival without severe disability ('confined to bed' and 'unable to wash or dress') by six months post-randomisation, and be cost effective from the viewpoints of the NHS and society, compared to conventional ventilatory support. Following assent from a relative, adults (18-65 years) with severe, but potentially reversible, respiratory failure (Murray score >/= 3.0 or hypercapnea with pH < 7.2) will be randomised for consideration of extracorporeal membrane oxygenation at Glenfield Hospital, Leicester or continuing conventional care in a centre providing a high standard of conventional treatment. The central randomisation service will minimise by type of conventional treatment centre, age, duration of high pressure ventilation, hypoxia/hypercapnea, diagnosis and number of organs failed, to ensure balance in key prognostic variables. Extracorporeal membrane oxygenation will not be available for patients meeting entry criteria outside the trial. 180 patients will be recruited to have 80% power to be able to detect a one third reduction in the primary outcome from 65% at 5% level of statistical significance (2-sided test). Secondary outcomes include patient morbidity and health status at 6 months. Analysis will be based on intention to treat. A concurrent economic evaluation will also be performed to compare the costs and outcomes of both treatments.


A prospective controlled study of limited versus subtotal posterior discectomy: short-term outcomes in patients with herniated lumbar intervertebral discs and large posterior anular defect.
Prospective observational study with historical control. The prospective study population consisted of 30 patients undergoing a posterior lumbar subtotal discectomy for lumbar disc herniation. This group was compared to a historical cohort of 46 patients treated with limited discectomy alone. To compare clinical outcomes after limited versus subtotal discectomy for lumbar disc herniations. Large posterior anular defects found at posterior discectomy have been associated with more frequent reherniation when treated with limited discectomy (i.e., removing only extruded or loose intervertebral fragments). A trial of more aggressive discectomy (subtotal) was undertaken to determine if the rate of reherniation could be decreased with this technique. A total of 30 patients undergoing a posterior lumbar discectomy for lumbar disc herniation were treated with an aggressive (subtotal) resection of intervertebral disc material after removal of the extruded or protruded fragments. This group was compared against a historical cohort of 46 patients treated with limited discectomy alone. Reherniation rates and clinical outcomes were determined by independent evaluation at 6, 12, and 24 months after surgery. The reherniation rate in the limited discectomy group was 18% versus 9% in the subtotal discectomy group at follow-up (P = 0.1). However, the back pain (visual analog scale) (P = 0.02) and Oswestry scores (P = 0.06) were worse in the subtotal discectomy group at 12-month follow-up. Time to return to work was longer, and pain medication usage was higher in the subtotal discectomy group at 12-month follow-up. Despite a trend toward a higher reherniation rate, the patient satisfaction at 2-year follow-up was higher in the limited discectomy group. The more aggressive removal of remaining intervertebral disc material may decrease the risk of reherniation, but the overall outcome was less satisfactory, especially during the first year after surgery.


Hexachlorobenzene toxicity in the monkey primordial germ cell without induced porphyria.
Hexachlorobenzene is a persistent chlorinated organic chemical that has been detected in many tissues from a variety of species including human ovary and human ovarian follicular fluid. When administered in high dosage to nonhuman primates, hexachlorobenzene causes destruction of ovarian primordial germ cells in association with systemic toxicity. The purpose of these experiments was to assess relative ovarian germ cell sensitivity at much lower dosages of hexachlorobenzene that do not produce systemic effects and additionally to evaluate oocyte function by means of the response to superovulation, fertilization, and embryo cleavage during a cycle of in vitro fertilization in the cynomolgus monkey. Hexachlorobenzene in dosages of 0.1, 1.0, and 10.0 mg/kg/day was administered orally by gelatin capsule for 90 days. There was a dose-dependent accumulation of HCB in serum and other tissues without any change in the serum estradiol response to human menopausal gonadotropin, oocyte recovery, oocyte maturation, oocyte fertilization in vitro, and early embryo cleavage rate. There was a dose-related toxic effect observed in primordial germ cells at the lowest dose despite no evidence of systemic or hepatic effects. As there were no changes in the urinary porphyrin excretion, the mechanism of hexachlorobenzene ovotoxicity may be distinct from hexachlorobenzene-induced cytochrome P-450-dependent inhibition of uroporphobilinogen decarboxylase in the liver, although such intraovarian metabolism cannot be excluded.


Acetylation of Sirt2 by p300 attenuates its deacetylase activity.
Histone deacetylases (HDACs) are subdivided into three classes--HDAC I, HDAC II, and Sir2. Sirt proteins are mammalian members of the Sir2 family of NAD+ (nicotinamide adenine dinucleotide)-dependent protein deacetylases. The balance between acetylation and deacetylation of histone and non-histone proteins, regulated by protein acetyltransferases and deacetylases, affects the expression of genes involved in a variety of cellular processes. In addition, HDAC1 is acetylated and regulated by p300, a transcriptional co-activator with protein acetyltransferase activity, suggesting that protein acetyltransferases and deacetylases they control the activities of each other. Although the regulation of HDAC1 by p300 is well characterized, the relationship between Sir2 homologs and p300 is not understood. Here, we report that p300 interacts with Sirt2, a member of the Sir2 family, and triggers the acetylation and subsequent down-regulation of the deacetylation activity of Sirt2, and that the acetylation of Sirt2 by p300 relieves the inhibitory effect of Sirt2 on the transcriptional activity of p53. These observations demonstrate that p300 can inactivate Sirt2 by acetylation and that p300 may regulate the activity of p53 indirectly through Sirt2 in addition to its direct modification of p53.


Deletion 6q Drives T-cell Leukemia Progression by Ribosome Modulation.
Deletion of chromosome 6q is a well-recognized abnormality found in poor-prognosis T-cell acute lymphoblastic leukemia (T-ALL). Using integrated genomic approaches, we identified two candidate haploinsufficient genes contiguous at 6q14, SYNCRIP (encoding hnRNP-Q) and SNHG5 (that hosts snoRNAs), both involved in regulating RNA maturation and translation. Combined silencing of both genes, but not of either gene alone, accelerated leukemogeneis in a Tal1/Lmo1/Notch1-driven mouse model, demonstrating the tumor-suppressive nature of the two-gene region. Proteomic and translational profiling of cells in which we engineered a short 6q deletion by CRISPR/Cas9 genome editing indicated decreased ribosome and mitochondrial activities, suggesting that the resulting metabolic changes may regulate tumor progression. Indeed, xenograft experiments showed an increased leukemia-initiating cell activity of primary human leukemic cells upon coextinction of SYNCRIP and SNHG5. Our findings not only elucidate the nature of 6q deletion but also highlight the role of ribosomes and mitochondria in T-ALL tumor progression. SIGNIFICANCE: The oncogenic role of 6q deletion in T-ALL has remained elusive since this chromosomal abnormality was first identified more than 40 years ago. We combined genomic analysis and functional models to show that the codeletion of two contiguous genes at 6q14 enhances malignancy through deregulation of a ribosome-mitochondria axis, suggesting the potential for therapeutic intervention.This article is highlighted in the In This Issue feature, p. 1494.


Field study of pneumonia in vaccinated cattle associated with incorrect vaccination and Pasteurella multocida infection.
This field study used data on the vaccine courses against bovine respiratory disease sold by one pharmaceutical company in conjunction with pharmacovigilance data to explore reported suspected lack of expected efficacy and the reasons for this. The study ran from May 1, 2007, to April 30, 2010, and covered vaccines sold in Scotland and part of Northumberland. In total, 83 groups of cattle reported suspected lack of expected efficacy, representing 1.6 per cent of the 804,618 vaccine courses sold. It was possible to investigate 45 of these outbreaks in depth using a standard questionnaire and diagnostic protocol. Vaccine usage outwith the specific product characteristics (SPC) occurred in 47 per cent of cases (21/45). The proportion of vaccination courses used where a pathogen contained in the vaccine was detected in the diseased cattle and vaccine use was consistent with the SPC was estimated at 0.12 per cent of the courses sold. Pasteurella multocida was the most common pathogen detected and was found in 21 of the outbreaks. For outbreaks where a pathogen contained in the vaccine was detected, P. multocida was found at a significantly greater frequency (P=0.03) where vaccine use was compliant with the SPC (five of six outbreaks) compared with outbreaks where vaccine use had not been compliant with the SPC (one of seven outbreaks). The limitations of the study, including the diagnostic tests employed and definition of vaccination outwith the SPC, are discussed.


Resistance quantitative trait loci originating from Solanum sparsipilum act independently on the sex ratio of Globodera pallida and together for developing a necrotic reaction.
Plant resistance to nematodes is related to the ability of the host to reduce the development of nematode juveniles into females. Resistance to the potato cyst nematode (PCN) Globodera pallida, originating from the wild species Solanum sparsipilum, was dissected by a quantitative trait loci (QTL) approach. Two QTL explained 89% of the phenotypic variation. The QTL GpaV(s)spl on chromosome V displayed the major effect on the cyst number (coefficient of determination [R2] = 76.6%). It restricted G. pallida development to 16.2% of juveniles, 81.5% of males, and 2.3% of females. The QTL GpaXI(s)spl on chromosome XI displayed a lower effect on the cyst number (R2 = 12.7%). It restricted G. pallida development to 13.8% of juveniles, 35.4% of males, and 50.8% of females. Clones carrying both QTL restricted the nematode development to 58.1% juveniles, 41.1% of males, and 0.8% of females. We demonstrated that potato clones carrying both QTL showed a strong necrotic reaction in roots infected by nematodes, while no such reaction was observed in clones carrying a single QTL. This result underlines the importance to introgress together GpaV(s)spl and GpaXI(s)spl into potato cultivars, in order to reduce the density of this quarantine pest in soil and to decrease the risk of selecting overcoming G. pallida subpopulations.


Altered expression of two zinc transporters, SLC30A5 and SLC30A6, underlies a mammary gland disorder of reduced zinc secretion into milk.
Two cases of zinc deficiency in breastfed neonates were investigated where zinc levels in the mothers' milk were reduced by more than 75 % compared to normal. The objective of this study was to find the molecular basis of the maternal zinc deficiency condition. Significant reductions in mRNA expression and protein levels of the zinc transporters SLC30A5 and SLC30A6 were found in maternal tissue, suggesting a causal link to the zinc-deficient milk. Novel splice variants of the SLC30A6 transcript were detected. No modifications were found in coding regions, or in transcription binding sites of promoter regions or in 5' and 3' untranslated regions of both transporters in lymphoblasts and fibroblasts isolated from both mothers. Altered DNA methylation in SLC30A5 at two CpG sites was detected and may account for the reduced levels of SLC30A5 mRNA and protein in lymphoblasts. Reduced SLC30A6 mRNA and protein levels in lymphoblasts may be secondary to reduced SLC30A5 expression, as they function as a heterodimer in zinc transport. In conclusion, two cases of zinc deficiency are linked to low levels of the SLC30A5 and SLC30A6 zinc transporters. These two zinc transporters have not been previously associated with zinc deficiency in milk.


Glycated albumin versus glycated hemoglobin as glycemic indicator in hemodialysis patients with diabetes mellitus: variables that influence.
The significance of glycated albumin (GA) compared with casual plasma glucose (PG) and glycated hemoglobin (HbA1c) was evaluated as an indicator of the glycemic control state in hemodialysis (HD) patients with diabetes. In HD patients with diabetes (n = 25), the mean PG, GA and HbA1c levels were 192.9 + 23 mg/dL, 278.8 + 43 μmol/L and 5.9 + 0.5%, respectively, which were higher by 43.9%, 67.04% and 18%, respectively, compared with HD patients without diabetes (n = 25). HbA1c levels were significantly lower than simultaneous PG and GA values in those patients in comparison with the three parameters in patients who had diabetes without renal dysfunction (n = 25). A significant negative correlation was found between GA and serum albumin (r = 0.21, P <0.05) in HD patients with diabetes, whereas HbA1c correlated positively and negatively with hemoglobin (r = 0.11, P <0.01) and weekly dose of erythropoietin injection (r = -0.19, P < 0.01), respectively. Although PG and GA did not differ significantly between HD patients with diabetes and with and without erythropoietin injection, HbA1c levels were significantly higher in patients without erythropoietin. Categorization of glycemic control into arbitrary quartiles by GA level led to better glycemic control in a significantly higher proportion of HD patients with diabetes than those assessed by HA1c. Multiple regression analysis demonstrated that hemoglobin in addition to PG emerged as an independent factor associated with HbA1c in HD patients with diabetes, while PG, body mass index and albumin were an independent factor associated with GA. it is suggested that GA provides a significantly better measure to estimate glycemic control in HD patients with diabetes and that the assessment of glycemic control by HbA1c in these patients might lead to likely underestimation as a result of the increasing proportion of young erythrocyte by the use of erythropoietin.


Evidence-based clinical practice guideline: Reconstruction after skin cancer resection.
A multi-disciplinary work group involving stakeholders from various backgrounds and societies was convened to develop guidelines for the management of reconstruction after skin cancer resection. The goal was to identify areas of common ground and provide evidence-based recommendations to improve patient care. Given the heterogeneity of reconstructive techniques and clinical scenarios, investigation centered around common elements in the process. In some cases, a distinction was made between treatment options in the office-based setting as opposed to those in the facility setting. A systematic literature review was performed, and an established appraisal process was used to rate the quality of relevant scientific research (Grading of Recommendations Assessment, Development, and Evaluation methodology). Final recommendations are related to concepts concerning the timing of reconstruction, management of anticoagulation, use of antibiotics, methods of pain control, and follow-up assessment. At times, there was insufficient evidence to make high-level recommendations. The literature analysis highlights the need for additional methodologically robust studies in this area, to help guide clinical practice.


A Novel Coronavirus from Patients with Pneumonia in China, 2019.
In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.).


Epidemiological and Mendelian Randomization Studies of Dihydrotestosterone and Estradiol and Leukocyte Telomere Length in Men.
Advancing age is accompanied by an accumulation of ill health and shortening of chromosomal telomeres signifying biological aging. T is metabolized to DHT by 5α-reductase (SRD5A2) and to estradiol (E2) by aromatase (CYP19A1). Telomerase preserves telomeres, and T and E2 regulate telomerase expression and activity in vitro. The objective of the study was to establish whether circulating T or its metabolites, DHT or E2, and single-nucleotide polymorphisms in SRD5A2 or CYP19A1 associate with leucocyte telomere length (LTL) in men. Early-morning serum T, DHT, and E2 were assayed using mass spectrometry, and SRD5A2 and CYP19A1 single-nucleotide polymorphisms and LTL analyzed by PCR in 980 men from the Western Australian Busselton Health Survey who participated in the study. LTL was expressed as the T/S ratio. Men were aged (mean ± SD) 53.7 ± 15.6 years. LTL decreased linearly with age, from the T/S ratio of 1.89 ± 0.41 at younger than 30 years to 1.50 ± 0.49 at 70 to younger than 80 years (r = -0.225, P < .0001). After adjustment for age, DHT and E2 were positively correlated with LTL (DHT, r = 0.069, P = .030; E2, r = 0.068, P = .034). The SRD5A2 rs9282858 polymorphism was associated with serum DHT but not with LTL. Three dominant alleles of CYP19A1 were each associated with lower serum E2 and shorter LTL: rs2899470 T (E2, 59.3 vs 68.6 pmol/L, P < .0001; T/S ratio, 1.54 vs 1.62, P = .045), rs10046 C (60.5 vs 68.1 pmol/L, P = .0005, 1.54 vs 1.62, P = .035), and rs700518 A (59.9 vs 68.9 pmol/L, P < .0001, 1.54 vs 1.63, P = .020). A single-copy haplotype C/T/I/A/T rs10046/rs2899470/rs11575899/rs700518/rs17703883 (52% prevalence) was associated with both lower E2 and shorter LTL. In men, serum DHT and E2 correlate with LTL independently of age. Aromatase gene polymorphisms include three dominant alleles that are associated with both lower serum E2 and shorter LTL. E2 influences telomere length in vivo, thus warranting further studies to examine whether hormonal interventions might slow biological aging in men.


Mechanisms underlying pattern generation in lobster stomatogastric ganglion as determined by selective inactivation of identified neurons. I. Pyloric system.
1. Four factors contribute to pattern generation in the pyloric network of the lobster stomatogastric ganglion. These are: a) endogenously oscillating neurons; b) synaptic network properties; c) nonlinear cellular properties, including the generation of plateau potentials; and d) excitatory input from the commissural ganglia. The roles and relative importance of these factors were investigated with a new technique for inactivating single specific identified neurons. 2. In stomatogastric ganglia in which the excitatory input is left intact, a) pattern generation continues when any cell or pair of cells other than the endogenous bursters are inactivated, b) pattern generation also continues when the endogenous bursters are inactivated, c) pattern generation ceases when the endogenous bursters plus one other particular cell are inactivated. This cell, although not an endogenous burster, displays a strong tendency to generate plateau potentials. 3. In stomatogastric ganglia that have been isolated from excitatory input, a) pattern generation continues when any cell or pair of cells other than the endogenous bursters are inactivated, b) pattern generation ceases when the endogenous bursters are inactivated. 4. Some of the inputs to the stomatogastric ganglion normally fire in bursts. However, their potentiation and acceleration of the output pattern are also produced by tonic stimulation of the nerve. The effect of one of those inputs is mimicked by bath application of dopamine to the stomatogastric ganglion. 5. The roles and importance of the three most important factors were qualitatively summarized in a chart specifying the activity of the network as a function of its intactness.


Daylight saving time as a potential public health intervention: an observational study of evening daylight and objectively-measured physical activity among 23,000 children from 9 countries.
It has been proposed that introducing daylight saving measures could increase children's physical activity, but there exists little research on this issue. This study therefore examined associations between time of sunset and activity levels, including using the bi-annual 'changing of the clocks' as a natural experiment. 23,188 children aged 5-16 years from 15 studies in nine countries were brought together in the International Children's Accelerometry Database. 439 of these children were of particular interest for our analyses as they contributed data both immediately before and after the clocks changed. All children provided objectively-measured physical activity data from Actigraph accelerometers, and we used their average physical activity level (accelerometer counts per minute) as our primary outcome. Date of accelerometer data collection was matched to time of sunset, and to weather characteristics including daily precipitation, humidity, wind speed and temperature. Adjusting for child and weather covariates, we found that longer evening daylight was independently associated with a small increase in daily physical activity. Consistent with a causal interpretation, the magnitude of these associations was largest in the late afternoon and early evening and these associations were also evident when comparing the same child just before and just after the clocks changed. These associations were, however, only consistently observed in the five mainland European, four English and two Australian samples (adjusted, pooled effect sizes 0.03-0.07 standard deviations per hour of additional evening daylight). In some settings there was some evidence of larger associations between daylength and physical activity in boys. There was no evidence of interactions with weight status or maternal education, and inconsistent findings for interactions with age. In Europe and Australia, evening daylight seems to play a causal role in increasing children's activity in a relatively equitable manner. Although the average increase in activity is small in absolute terms, these increases apply across all children in a population. Moreover, these small effect sizes actually compare relatively favourably with the typical effect of intensive, individual-level interventions. We therefore conclude that, by shifting the physical activity mean of the entire population, the introduction of additional daylight saving measures could yield worthwhile public health benefits.


UK consensus definitions for necrotising otitis externa: a Delphi study.
To establish consensus definitions for necrotising otitis externa (NOE) to facilitate the diagnosis and exclusion of NOE in clinical practice and expedite future high-quality study of this neglected condition. The work comprised of a systematic review of the literature, five iterative rounds of consultation via a Delphi process and open discussion within the collaborative. An expert panel analysed the results to produce the final outputs which were shared with and endorsed by national specialty bodies. Secondary care in the UK. UK clinical specialists practising in infection, ear nose and throat (ENT) surgery or radiology. Definitions and statements meeting the following criteria were accepted: (a) minimum of 70% of respondents in agreement or strong agreement with a definition/statement AND (b) <15% of respondents in disagreement or strong disagreement with a definition/statement. Seventy-four UK clinicians specialising in ENT, Infection and Radiology with a special interest in NOE took part in the work which was undertaken between 2019 and 2021. The minimum response rate for a Round was 76%. Consensus criteria for all proposed case definitions, outcome definitions and consensus statements were met in the fifth round. This work distills the clinical opinion of a large group of multidisciplinary specialists from across the UK to create practical definitions and statements to support clinical practice and research for NOE. This is the first step in an iterative process. Further work will seek to validate and test these definitions and inform their evolution.


The use of recombinant activated factor VII in the circumcision operation in the case of a congenital factor VII deficiency.
Congenital factor VII deficiency is a rare autosomal recessive hemorrhagic disorder and surgery is normally the cause of excessive bleeding. In this report, we describe the first case with congenital factor VII deficiency admitted to our clinics for the sunnet operation (circumcision), in which recombinant activated factor VII (rFVIIa; NovoSeven) was used to manage the bleeding. The patient was an 8-year old boy with moderate factor VII deficiency (factor VII level, 4%), and rFVIIa was administered at a dose of 20 microg/kg per dose during the circumcision operation. The same dose was repeated at 2, 4, 6, 9, 12, 15, 18, 21 and 24 h post operation. The circumcision operation could therefore be safely performed in patients with congenital factor VII using rFVIIa.


Zinc compounds inhibit osteoclast-like cell formation at the earlier stage of rat marrow culture but not osteoclast function.
The effect of zinc compounds on osteoclast-like cell formation in rat marrow culture in vitro was investigated. The bone marrow cells were cultured for 7 days in alpha-minimal essential medium containing a well-known bone resorbing hormone (1, 25-dihydroxyvitamin D3 and parathyroid hormone [1-34]). Osteoclast-like cell formation was estimated by staining for tartrate-resistant acid phosphatase (TRACP), a marker enzyme of osteoclasts. The presence of 1, 25-dihydroxyvitamin D3 (10(-8) M) or parathyroid hormone (PTH; 10(-8) M) induced a remarkable increase in osteoclast-like multinucleated cells (MNC). These increases were clearly inhibited by the presence of zinc sulfate or zinc-chelating dipeptide (beta-alanyl-L-histidinato zinc; AHZ) in the concentration range of 10(-7) to 10(-5) M. The inhibitory effect was seen at the earlier stage of osteoclast-like MNC formation. However, zinc compounds (10(-6) M) did not have an effect on PTH (10(-8) M)-induced osteoclast-like cell formation in the presence of EGTA (5 x 10(-4) M), dibucaine (10(-5) M) or staurosporine (10(-9) M). Moreover, when osteoclasts isolated from rat femoral-diaphyseal tissues were cultured for 24 h in the presence of zinc compounds (10(-7) to 10(-5) M), the compounds did not have an effect on cell numbers or lysosomal enzymes activity (acid phosphatase and beta-glucuronidase) in the cells. The present study clearly demonstrates that zinc compounds inhibit osteoclast-like cell formation at the earlier stage with differentiation of marrow cells.


Profoundly abnormal initial physiologic and biochemical data cannot be used to determine futility in massively transfused trauma patients.
Improvements in prehospital care and resuscitation have led to increases in the number of severely injured patients who are salvageable. Massive transfusion has been increasingly used. Patients often present with markedly abnormal physiologic and biochemical data. The purpose of this study was to identify objective data that can be used to identify clinical futility in massively transfused trauma patients to allow for early termination of resuscitative efforts. A multicenter database was used. Initial physiologic and biochemical data were obtained, and mortality was determined for patients in the 5th and 10th percentiles for each variable. Raw data from the extreme outliers for each variable were also examined to determine whether a point of excessive mortality could be identified. Injury scoring data were also analyzed. A classification tree model was used to look for variable combinations that predict clinical futility. The cohort included 704 patients. Overall mortality was 40.2%. The highest mortality rates were seen in patients in the 10th percentile for lactate (77%) and pH (72%). Survivors at the extreme ends of the distribution curves for each variable were not uncommon. The classification tree analysis failed to identify any biochemical and physiologic variable combination predictive of >90% mortality. Patients older than 65 years with severe head injuries had 100% mortality. Consideration should be given to withholding massive transfusion for patients older than 65 years with severe head injuries. Otherwise we did not identify any objective variables that reliably predict clinical futility in individual cases. Significant survival rates can be expected even in patients with profoundly abnormal physiologic and biochemical data.


Exploring the contribution of candidate genes to artemisinin resistance in Plasmodium falciparum.
The reduced in vivo sensitivity of Plasmodium falciparum has recently been confirmed in western Cambodia. Identifying molecular markers for artemisinin resistance is essential for monitoring the spread of the resistant phenotype and identifying the mechanisms of resistance. Four candidate genes, including the P. falciparum mdr1 (pfmdr1) gene, the P. falciparum ATPase6 (pfATPase6) gene, the 6-kb mitochondrial genome, and ubp-1, encoding a deubiquitinating enzyme, of artemisinin-resistant P. falciparum strains from western Cambodia were examined and compared to those of sensitive strains from northwestern Thailand, where the artemisinins are still very effective. The artemisinin-resistant phenotype did not correlate with pfmdr1 amplification or mutations (full-length sequencing), mutations in pfATPase6 (full-length sequencing) or the 6-kb mitochondrial genome (full-length sequencing), or ubp-1 mutations at positions 739 and 770. The P. falciparum CRT K76T mutation was present in all isolates from both study sites. The pfmdr1 copy numbers in western Cambodia were significantly lower in parasite samples obtained in 2007 than in those obtained in 2005, coinciding with a local change in drug policy replacing artesunate-mefloquine with dihydroartemisinin-piperaquine. Artemisinin resistance in western Cambodia is not linked to candidate genes, as was suggested by earlier studies.


Tuning the efficiency of dendritic nanocarriers using conformational constraints.
A series of deoxycholic and cholic acid-derived oligomers were synthesized and their ability to extract hydrophilic dye molecules of different structure, size, and functional groups into nonpolar media was studied. The structure of the dye and "dendritic effect" in the extraction process was examined using absorption spectroscopy and dynamic light scattering (DLS). The efficiency of structurally preorganized oligomers in the aggregation process was evaluated by 1-anilinonaphthalene-8-sulfonic acid (ANS) fluorescence studies. The possible formation of globular structures for higher-generation molecules was investigated by molecular modeling studies and the results were correlated with the anomaly observed in the extraction process with this molecule. The ability of these molecules for selective extraction of specific dyes from blended colors is also reported.


Person-centered care for nursing home residents: the culture-change movement.
The "culture change" movement represents a fundamental shift in thinking about nursing homes. Facilities are viewed not as health care institutions, but as person-centered homes offering long-term care services. Culture-change principles and practices have been shaped by shared concerns among consumers, policy makers, and providers regarding the value and quality of care offered in traditional nursing homes. They have shown promise in improving quality of life as well as quality of care, while alleviating such problems as high staff turnover. Policy makers can encourage culture change and capitalize on its transformational power through regulation, reimbursement, public reporting, and other mechanisms.


Relationship between material properties and transparent heater performance for both bulk-like and percolative nanostructured networks.
Transparent heaters are important for many applications and in the future are likely to be fabricated from thin, conducting, nanostructured networks. However, the electrical properties of such networks are almost always controlled by percolative effects. The impact of percolation on heating effects has not been considered, and the material parameter combinations that lead to efficient performance are not known. In fact, figures of merit for transparent heaters have not been elucidated, either in bulk-like or percolative systems. Here, we develop a simple yet comprehensive model describing the operation of transparent heaters. By considering the balance of Joule heating versus power dissipated by both convection and radiation, we derive an expression for the time-dependent heater temperature as a function of both electrical and thermal parameters. This equation can be modified to describe the relationship between temperature, optical transmittance, and electrical/thermal parameters in both bulk-like and percolative systems. By performing experiments on silver nanowire networks, systems known to display both bulk-like and percolative regimes, we show the model to describe real systems extremely well. This work shows the performance of transparent heaters in the percolative regime to be significantly less efficient compared to the bulk-like regime, implying the diameter of the nanowires making up the network to be critical. The model allows the identification of figures of merit for networks in both bulk-like and percolative regimes. We show that metallic nanowire networks are most promising, closely followed by CVD graphene, with networks of solution-processed graphene and carbon nanotubes being much less efficient.


Gender Differences in Patients with Takotsubo Cardiomyopathy: Multi-Center Registry from Tokyo CCU Network.
The clinical features of gender differences in takotsubo cardiomyopathy (TC) remain to be determined. The aim of this study was to evaluate the differences in clinical characteristics of male and female patients with TC. We obtained the clinical information of 368 patients diagnosed with TC (84 male, 284 female) from the Tokyo CCU Network database collected from 1 January 2010 to 31 December 2012; the Network is comprised of 71 cardiovascular centers in the Tokyo (Japan) metropolitan area. We attempted to characterize clinical differences during hospitalization, comparing male and female patients with TC. There were no significant differences in apical ballooning type, median echocardiography ejection fraction, serious ventricular arrhythmias (such as ventricular tachycardia or fibrillation), or cardiovascular death between male and female patients. Male patients were younger than female patients (median age at hospitalization for male patients was 72 years vs. 76 years for female patients; p = 0.040). Prior physical stress was more common in male than female patients (50.0% vs.31.3%; p = 0.002), while emotional stress was more common in female patients (19.0% vs. 31.0%; p = 0.039). Severe pump failure (defined as Killip Class > III) (20.2% vs. 10.6%; p = 0.020) and cardiopulmonary supportive therapies (28.6% vs. 12.7%, p < 0.001) were more common in male than female patients. Multivariate analysis revealed that male gender (odds ratio = 4.32, 95% CI = 1.41-13.6, p = 0.011) was an independent predictor of adverse composite cardiac events, including cardiovascular death, severe pump failure, and serious ventricular arrhythmia. Cardiac complications in our dataset appeared to be more common in male than female patients with TC during their hospitalization. Further investigation is required to clarify the underlying mechanisms responsible for the observed gender differences.


Host proteins interacting with the Moloney murine leukemia virus integrase: multiple transcriptional regulators and chromatin binding factors.
A critical step for retroviral replication is the stable integration of the provirus into the genome of its host. The viral integrase protein is key in this essential step of the retroviral life cycle. Although the basic mechanism of integration by mammalian retroviruses has been well characterized, the factors determining how viral integration events are targeted to particular regions of the genome or to regions of a particular DNA structure remain poorly defined. Significant questions remain regarding the influence of host proteins on the selection of target sites, on the repair of integration intermediates, and on the efficiency of integration. We describe the results of a yeast two-hybrid screen using Moloney murine leukemia virus integrase as bait to screen murine cDNA libraries for host proteins that interact with the integrase. We identified 27 proteins that interacted with different integrase fusion proteins. The identified proteins include chromatin remodeling, DNA repair and transcription factors (13 proteins); translational regulation factors, helicases, splicing factors and other RNA binding proteins (10 proteins); and transporters or miscellaneous factors (4 proteins). We confirmed the interaction of these proteins with integrase by testing them in the context of other yeast strains with GAL4-DNA binding domain-integrase fusions, and by in vitro binding assays between recombinant proteins. Subsequent analyses revealed that a number of the proteins identified as Mo-MLV integrase interactors also interact with HIV-1 integrase both in yeast and in vitro. We identify several proteins interacting directly with both MoMLV and HIV-1 integrases that may be common to the integration reaction pathways of both viruses. Many of the proteins identified in the screen are logical interaction partners for integrase, and the validity of a number of the interactions are supported by other studies. In addition, we observe that some of the proteins have documented interactions with other viruses, raising the intriguing possibility that there may be common host proteins used by different viruses. We undertook this screen to identify host factors that might affect integration target site selection, and find that our screens have generated a wealth of putative interacting proteins that merit further investigation.


Acute and sub-acute effects of repetitive kicking on hip adduction torque in injury-free elite youth soccer players.
Hip adduction strength is important for kicking and acceleration in soccer players. Changes in hip adduction strength may therefore have an effect on soccer players' athletic performance. The purpose of this study was to investigate the acute and sub-acute effects of a kicking drill session on hip strength, concerning isometric hip adduction, abduction and flexion torque of the kicking leg and the supporting leg. Ten injury-free male elite soccer players, mean ± s age of 15.8 ± 0.4 years participated. All players underwent a specific 20 min kicking drill session, comprising 45 kicks. The players were tested the day before, 15 min after and 24 h after the kicking drill session by a blinded tester using a reliable test procedure. The isometric hip-action and leg-order were randomized. For the kicking leg, hip adduction torque increased from 2.45 (2.19-2.65) Nm ∙ kg(-1), median (25th-75th percentiles), at pre-kicking to 2.65 (2.55-2.81) Nm ∙ kg(-1) (P = 0.024) 24 h post-kicking. This may have implications for the soccer player's ability to maximally activate the hip adductors during kicking and acceleration, and thereby improve performance the day after a kicking drill session.


Complications of minimally invasive calcaneal osteotomy versus open osteotomy.
Calcaneal osteotomy is an established technique for correcting hindfoot deformity. Patients traditionally receive an osteotomy through the open lateral approach to the calcaneus. To reduce the rate of wound complications associated with a direct open lateral approach, a minimally invasive surgical (MIS) technique has been adopted. This uses a low-speed, high-torque burr to perform the same osteotomy under radiographic guidance. We hypothesized that the new MIS calcaneal osteotomy would be a safe alternative to open calcaneal osteotomy while obtaining the same displacement. The safety of the new MIS technique was investigated with a case controlled study on all patients who underwent displacement calcaneal osteotomy at the Nuffield Orthopaedic Centre from 2008 to 2014. The primary outcome measure was 30 day postoperative complication rate. Secondary outcome measures included operating time, duration of stay, fusion rates, and calcaneal displacement. Eighty-one patients underwent calcaneal osteotomy as part of their corrective surgery, 50 in the Open approach group and 31 in MIS group. The average age was 47.7 years (range 16-77) for the Open group and 50.1 (range 21-77) in the MIS group. A mean calcaneal displacement of 9.4 mm (SD = 1.16, 8 to 11 mm) and 10.2 mm (SD = 1.06, 8 to 13 mm) was achieved through the MIS and Open approaches, respectively. There were significantly fewer wound complications in the MIS group (6.45%) compared to the Open group (28%, P = .022). The MIS group was associated with significantly lower rate of wound infection (3% versus 20%, P = .044). Three patients in the Open group experienced sural peripheral neuropathy. The average length of stay was 3.8 days following MIS and 4.3 days following open calcaneal osteotomy. Nonunion occurred in only 1 patient in the MIS group and none in the open group. MIS calcaneal osteotomy was found to be a safe technique. It was technically as effective as calcaneal osteotomy performed through an open lateral approach but was associated with significantly fewer wound complications and fewer nerve complications. Level III, comparative study.


SNARC effects with numerical and non-numerical symbolic comparative judgments: instructional and cultural dependencies.
With English-language readers in an experiment requiring pairwise comparative judgments of the sizes of animals, the nature of the association between the magnitudes of the animal pairs and the left or right sides of response (i.e., the SNARC effect) was reversed depending on whether the participants had to choose either the smaller or the larger member of the pair. In contrast, such a dependence of the direction of the SNARC effect on the form of the comparative instructions was not evident for pairwise comparisons of numerical magnitude made by a similar group of participants. Furthermore, exactly the same configuration of findings was obtained for a single group of Israeli-Palestinian right-to-left reading and writing participants, except that the spatial direction of the SNARC effects for both the animal-size and number comparisons were completely reversed. In a final experiment with English readers, SNARC effects paralleling those for the animal-size comparisons were obtained for pairwise comparative judgments involving the just-learned height relations between 6 imaginary individuals. As will be discussed, such results serve to extend the generality of the SNARC effect far beyond the current modal view that it simply reflects culturally influenced, long-term learned associations between numerical magnitudes and the locations on a fixed mental number line. The implications that these results have for both the Proctor and Cho (2006) polarity correspondence view and the Gevers, Verguts, Reynvoet, Caessens, and Fias (2006) computational model of the SNARC effect will also discussed.


New species of Ehrlichia isolated from Rhipicephalus (Boophilus) microplus shows an ortholog of the E. canis major immunogenic glycoprotein gp36 with a new sequence of tandem repeats.
Ehrlichia species are the etiological agents of emerging and life-threatening tick-borne human zoonoses that inflict serious and fatal infections in companion animals and livestock. The aim of this paper was to phylogeneticaly characterise a new species of Ehrlichia isolated from Rhipicephalus (Boophilus) microplus from Minas Gerais, Brazil. The agent was isolated from the hemolymph of Rhipicephalus (B.) microplus engorged females that had been collected from naturally infested cattle in a farm in the state of Minas Gerais, Brazil. This agent was then established and cultured in IDE8 tick cells. The molecular and phylogenetic analysis was based on 16S rRNA, groEL, dsb, gltA and gp36 genes. We used the maximum likelihood method to construct the phylogenetic trees. The phylogenetic trees based on 16S rRNA, groEL, dsb and gltA showed that the Ehrlichia spp isolated in this study falls in a clade separated from any previously reported Ehrlichia spp. The molecular analysis of the ortholog of gp36, the major immunoreactive glycoproteins in E. canis and ortholog of the E. chaffeensis gp47, showed a unique tandem repeat of 9 amino acids (VPAASGDAQ) when compared with those reported for E. canis, E. chaffeensis and the related mucin-like protein in E. ruminantium. Based on the molecular and phylogenetic analysis of the 16S rRNA, groEL, dsb and gltA genes we concluded that this tick-derived microorganism isolated in Brazil is a new species, named E. mineirensis (UFMG-EV), with predicted novel antigenic properties in the gp36 ortholog glycoprotein. Further studies on this new Ehrlichia spp should address questions about its transmissibility by ticks and its pathogenicity for mammalian hosts.