The two-dimensional coordination polymer poly[[bis(3-methylpyridine)cadmium(II)]-tetra-mu-cyano-nickel(II)].
The title complex, [CdNi(CN)4(C6H7N)2]n, adopts a slightly distorted octahedral geometry around the Cd centre. Four cyanide N atoms occupy the equatorial coordination sites around the Cd centre. The structure consists of corrugated and cyanide-bridged polymeric networks made up of tetracyanonickelate ions coordinated to cadmium, with the Ni ion coordinated by four cyanide ligands in a square-planar arrangement. The Cd and Ni atoms occupy special positions of 2/m site symmetry. The 3-methylpyridine group, except for two methyl H atoms, lies on a crystallographic mirror plane. The 3-methylpyridine molecules, bound to cadmium in trans positions, are located on both sides of the network. The bonding in the networks occurs because of a departure of the Ni-C-N-Cd sequence of atoms from linearity at the C and N atoms.


Interferons direct Th2 cell reprogramming to generate a stable GATA-3(+)T-bet(+) cell subset with combined Th2 and Th1 cell functions.
Current T cell differentiation models invoke separate T helper 2 (Th2) and Th1 cell lineages governed by the lineage-specifying transcription factors GATA-3 and T-bet. However, knowledge on the plasticity of Th2 cell lineage commitment is limited. Here we show that infection with Th1 cell-promoting lymphocytic choriomeningitis virus (LCMV) reprogrammed otherwise stably committed GATA-3(+) Th2 cells to adopt a GATA-3(+)T-bet(+) and interleukin-4(+)interferon-gamma(+) "Th2+1" phenotype that was maintained in vivo for months. Th2 cell reprogramming required T cell receptor stimulation, concerted type I and type II interferon and interleukin-12 signals, and T-bet. LCMV-triggered T-bet induction in adoptively transferred virus-specific Th2 cells was crucial to prevent viral persistence and fatal immunopathology. Thus, functional reprogramming of unfavorably differentiated Th2 cells may facilitate the establishment of protective immune responses. Stable coexpression of GATA-3 and T-bet provides a molecular concept for the long-term coexistence of Th2 and Th1 cell lineage characteristics in single memory T cells.


Prevalence and risk factors for hepatitis C virus, hepatitis B virus, and human immunodeficiency virus in transfused children in Kinshasa.
To determine seroprevalence of hepatitis C virus (HCV), human immunodeficiency virus (HIV), and hepatitis B virus (HBV) and associated factors among transfused children. A multicenter cross-sectional study of transfused children aged between 18 mo and 13 y old was conducted in 4 hospitals in Kinshasa. Blood samples were collected for the detection of Hepatitis B surface antigen (HBsAg) and antibodies to HCV, HIV 1 and 2. A total of 177 (47.7 %) boys and 194 (52.3 %) girls participated in the study. The median age was 59.5 mo (Interquartile range IQR = 60.6). The prevalence rates of HCV, HBV, and HIV infection were 13.5 %, 1.6 %, and 1.3 %, respectively. Frequency of transfusion events were significantly associated with HCV (p < 0.001) and HIV (p < 0.05) infections. HCV infection was by far more frequently identified than HBV and HIV infections among Congolese transfused children. Frequency of transfusion events was the only significant risk factor associated with HCV and HIV infections but not for HBV.


Detecting low penetrance genes in cancer: the way ahead.
The search for the genes responsible for many complex genetic diseases is well under way and has already been successful in some cases. The study of cancer as a complex genetic disease has lagged behind other conditions, largely because of particular problems that are associated with malignant disease. Cancer also, however, presents specific opportunities for gene identification, which are not found in many other diseases. While the methods of genetic mapping and gene cloning used for other complex diseases will be applied to cancer, these must almost certainly be complemented by other methods, such as the study of somatic mutations, cancer associated phenotypes, and modifier genes for Mendelian cancers. Here, we review the strategies available for identifying cancer predisposition genes of low and moderate penetrance.


The health response to the Rohingya refugee crisis post August 2017: Reflections from two years of health sector coordination in Cox's Bazar, Bangladesh.
On August 25 2017, an unprecedented influx of Rohingya refugees began from Rakhine State in Myanmar into Bangladesh's district of Cox's Bazar. The scale and acuteness of this humanitarian crisis was unprecedented and unique globally, requiring strong coordination of a multitude of actors. This paper reflects on the health sector coordination from August 2017 to October 2019, focusing on selected achievements and persisting challenges of the health sector strategic advisory group (HSSAG), and the health sector working groups including epidemiology and case management, sexual and reproductive health, community health, mental health and psychosocial support, and emergency preparedness. In the early days of the response, minimum service standards for primary health care were established, a fundamental initial step which enabled the standardization of services based on critical needs. Similarly, establishing standards for community health outreach was the backbone for capitalizing on this important health workforce. Novel approaches were adopted for infectious disease responses for acute watery diarrhoea and varicella, drawing on inter-sectoral collaborations. Sexual and reproductive health services were prioritized from the initial onset of the crisis and improvements in skilled delivery attendance, gender-based violence services, abortion care and family planning were recorded. Mental health service provision was strengthened through community-based approaches although integration of mental health programmes into primary health care has been limited by availability of specialist psychiatrists. Strong, collaborative and legitimate leadership by the health sector strategic advisory group, drawing on inter-sectoral collaborations and the technical expertise of the different technical working groups, were critical in the response and proved effective, despite the remaining challenges to be addressed. Anticipated reductions in funding as the crisis moves into protracted status threatens the achievements of the health sector in provision of health services to the Rohingya refugees.


A randomized clinical trial of manual therapy and physiotherapy for persistent back and neck complaints: subgroup analysis and relationship between outcome measures.
To study the efficacy of manual therapy and physiotherapy in subgroups of patients with persistent back and neck complaints. The second objective was to determine the correlation between three important outcome measures used in this trial. Randomized clinical trial (subgroup analysis). Primary health care in the Netherlands. Two hundred fifty-six patients with nonspecific back and neck complaints of at least 6 wk duration who had not received physiotherapy or manual therapy in the past 2 yr. At the discretion of the manual therapists, physiotherapists and general practitioners. Physiotherapy consisted of exercises, massage and physical therapy (heat, electrotherapy, ultrasound, shortwave diathermy). Manual therapy consisted of manipulation and mobilization of the spine. Treatment by the general practitioner consisted of drugs (e.g., analgesics), advice about posture, home exercises and (bed)rest. Placebo treatment consisted of detuned shortwave diathermy (10 min) and detuned ultrasound (10 min). Changes in severity of the main complaint and limitation of physical functioning measured on 10-point scales by a blinded research assistant and global perceived effect measured on a 6-point scale by the patients. Improvement in the main complaint was larger with manual therapy (4.3) than with physiotherapy (2.5) for patients with chronic conditions (duration complaint of 1 yr or longer). Also, improvement in the main complaint was larger with manual therapy (5.5) than with physiotherapy (4.0) for patients younger than 40 yr (both were measured after 12-mo follow-up). Labeling of patients by the treating manual therapists as "suitable" or "not suitable" for treatment with manual therapy did not predict differences in outcomes. Generally, there was a moderate to strong correlation between the three outcome measures, although a considerable number of patients gave a relatively low score for perceived benefit, while the research assistant gave a high improvement score for the main complaint and physical functioning. The subgroup analysis suggests better results of manual therapy compared to physiotherapy in chronic patients (duration of present complaints of 1 yr or longer) and in patients younger than 40 yr old). Differences for other subgroups were less clear. The explorative findings of these subgroup analyses have to be investigated in future research.


The risk and extent of neurologic events are equivalent for high-risk patients treated with transcatheter or surgical aortic valve replacement.
This study was designed to characterize the incidence of new clinically detectable neurologic events, or any comparative change in indices of higher cognitive function following transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR) within the framework of a prospective, randomized clinical trial for high-risk patients. High-risk patients (predicted SAVR mortality 15%) with severe aortic stenosis (n = 750) were randomized 1:1 to TAVR or SAVR and underwent evaluation using the National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale assessment at each follow-up and any suspected event. Neurologic outcomes were ascertained by a neurologist and further evaluated by Mini-Mental State Examination (MMSE), visual fields testing, gait assessment, hand function, writing evaluation, and drawing assessment. The 30-day, 1-year, and 2-year stroke rates were 4.9%, 8.7%, and 10.9%, respectively, for TAVR and 6.2%, 12.5%, and 16.6%, respectively, for SAVR (P = .46, .11, and .05, respectively). All-cause mortality in patients with a major stroke was 83.3% for TAVR and 54.5% for SAVR at 2 years (P = .29). Late major stroke was disproportionately higher (23.8% at 2 years) among patients with poor iliofemoral access randomized to SAVR. Peripheral vascular disease and falls within 6 months predicted early stroke, and severe aortic calcification and high Charlson score (≥5) predicted 1-year stroke post-TAVR. NIHSS and MMSE scores trended higher after SAVR than after TAVR. Lack of dual antiplatelet therapy use during and after TAVR was associated with early stroke. This study defines an equivalent postprocedural stroke risk, stroke extent, and degree of cognitive change after TAVR or SAVR in a high-risk population, and also defines several predictors of stroke after TAVR.


Virus recovery is induced in Brome mosaic virus p2 transgenic plants showing synchronous complementation and RNA-2-specific silencing.
Nicotiana benthamiana plants expressing Brome mosaic virus (BMV) p2 protein complemented replication of RNAs1 + 3 but, surprisingly, supported little or no replication of RNA-2. Despite this, the p2 transgenic plants were able to support systemic migration of RNAs-1 and -3. Kinetic analyses showed identical degradation rates for RNAs-2 and -3, greatly detracting from the concept of an induction of an RNA-2-specific degradation system. Deletion analysis identified a 200-nucleotide sequence that may contribute to silencing in a context-specific manner. When R1 progeny of a severely silencing p2 transgenic line were tested for virus resistance, three different classes of reactions were observed. In class 1 and class 3 plants, the virus moved systemically and showed various extents of RNA-2 silencing. However, in class 2 plants, there was a stochastic onset of post-transcriptional silencing in the systemic leaves that was reminiscent of virus recovery. Plants showing recovery tended to have a greater number of transgene loci than did those exhibiting component-specific silencing. The induction of silencing did not appear to be dependent solely on the combined steady state levels of the transgene and viral RNA. Some plants transformed with a p2 frameshift construct showed a complete silencing phenotype, but none showed RNA-2-specific silencing. While the relationship between the two types of silencing remains unclear, we speculate that our observations reflect early events in the induction of virus recovery.


Sacral nerve stimulation for faecal incontinence and constipation in adults.
Faecal incontinence (FI) and constipation are both socially-embarrassing and physically-disabling conditions that impair quality of life. For both, surgery may be required in a minority of people when more conservative measures fail. However, the invasiveness and irreversible nature of direct surgery on bowel and sphincter muscles, poor long-term outcomes and well-established compIications makes such procedures unappealing for these benign conditions. A less-invasive surgical option to treat faecal incontinence and constipation is direct, low-voltage stimulation of the sacral nerve roots, termed sacral nerve stimulation (SNS). SNS has become the first line surgical treatment for FI in people failing conservative therapies. Its value in the treatment of constipation is less clear. To assess the effects of sacral nerve stimulation using implanted electrodes for the treatment of faecal incontinence and constipation in adults. We searched the Cochrane Incontinence Group Specialised Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE In-Process, ClinicalTrials.gov, the World Health Organization (WHO) ICTRP and handsearched journals and conference proceedings (searched 5 February 2015), EMBASE (1 January 1947 to 2015 Week 5), and the reference lists of retrieved relevant articles. All randomised or quasi-randomised trials assessing the effects of SNS for faecal incontinence or constipation in adults. Two review authors independently screened the search results, assessed the methodological quality of the included trials, and undertook data extraction. Six crossover trials and two parallel group trials were included.Six trials assessed the effects of SNS for FI. In the parallel group trial conducted by Tjandra, 53 participants with severe FI in the SNS group experienced fewer episodes of faecal incontinence compared to the control group who received optimal medical therapy (mean difference (MD) -5.20, 95% confidence interval (CI) -9.15 to -1.25 at 3 months; MD -6.30, 95% CI -10.34 to -2.26 at 12 months). Adverse events were reported in a proportion of participants: pain at implant site (6%), seroma (2%) and excessive tingling in the vaginal region (9%).In the parallel group trial carried out by Thin, 15 participants with FI in the SNS group experienced fewer episodes of FI compared with the percutaneous tibial nerve stimulation (PTNS) group (MD -3.00, 95% CI -6.61 to 0.61 at 3 months; MD -3.20, 95% CI -7.14 to 0.74 at 12 months). Adverse events were reported in three participants: mild ipsilateral leg pain during temporary testing (n = 1); and stimulator-site pain following insertion of neurostimulator (n = 2).In the crossover trial by Leroi 7 of 34 recruited participants were excluded from the crossover due mainly to complications or immediate device failure. Twenty-four of the remaining 27 participants while still blinded chose the period of stimulation they had preferred. Outcomes were reported separately for 19 participants who preferred the 'on' and five who preferred the 'off' period. For the group of 19, the median (range) episodes of faecal incontinence per week fell from 1.7 (0 to 9) during the 'off' period to 0.7 (0 to 5) during the 'on' period; for the group of five, however, the median (range) rose from 1.7 (0 to 11) during the 'off' period compared with 3.7 (0 to 11) during the 'on' period. Four of 27 participants experienced an adverse event resulting in removal of the stimulator.In the crossover trial by Sørensen and colleagues, participants did not experience any FI episodes in either the one-week 'on' or 'off' periods.In the crossover trial by Vaizey, participants reported an average of six, and one, episodes of faecal incontinence per week during the 'off' and 'on' periods respectively in two participants with FI. Neither study reported adverse events.In the crossover trial by Kahlke, 14 participants with FI experienced significantly lower episodes of FI per week during the stimulator 'on' (1 (SD, 1.7)) compared with the 'off' period (8.4 (SD, 8.7)). Adverse events reported include: haematoma formation (n = 3); misplacement of tined lead (1); and pain at stimulator site (n = 1).Two trials assessed SNS for constipation. In the Kenefick trial, the two participants experienced an average of two bowel movements per week during the 'off' crossover period, compared with five during the 'on' period. Abdominal pain and bloating occurred 79% of the time during the 'off' period compared with 33% during the 'on' period. No adverse events occurred. In contrast, in the trial by Dinning with 59 participants, SNS did not improve frequency of bowel movements and 73 adverse events were reported, which included pain at site of the implanted pulse generator (32), wound infection (12), and urological (17) events. The limited evidence from the included trials suggests that SNS can improve continence in a proportion of patients with faecal incontinence. However, SNS did not improve symptoms in patients with constipation. In addition, adverse events occurred in some patients where these were reported. Rigorous high quality randomised trials are needed to allow the effects of SNS for these conditions to be assessed with more certainty.


The genome of the soybean cyst nematode (Heterodera glycines) reveals complex patterns of duplications involved in the evolution of parasitism genes.
Heterodera glycines, commonly referred to as the soybean cyst nematode (SCN), is an obligatory and sedentary plant parasite that causes over a billion-dollar yield loss to soybean production annually. Although there are genetic determinants that render soybean plants resistant to certain nematode genotypes, resistant soybean cultivars are increasingly ineffective because their multi-year usage has selected for virulent H. glycines populations. The parasitic success of H. glycines relies on the comprehensive re-engineering of an infection site into a syncytium, as well as the long-term suppression of host defense to ensure syncytial viability. At the forefront of these complex molecular interactions are effectors, the proteins secreted by H. glycines into host root tissues. The mechanisms of effector acquisition, diversification, and selection need to be understood before effective control strategies can be developed, but the lack of an annotated genome has been a major roadblock. Here, we use PacBio long-read technology to assemble a H. glycines genome of 738 contigs into 123 Mb with annotations for 29,769 genes. The genome contains significant numbers of repeats (34%), tandem duplicates (18.7 Mb), and horizontal gene transfer events (151 genes). A large number of putative effectors (431 genes) were identified in the genome, many of which were found in transposons. This advance provides a glimpse into the host and parasite interplay by revealing a diversity of mechanisms that give rise to virulence genes in the soybean cyst nematode, including: tandem duplications containing over a fifth of the total gene count, virulence genes hitchhiking in transposons, and 107 horizontal gene transfers not reported in other plant parasitic nematodes thus far. Through extensive characterization of the H. glycines genome, we provide new insights into H. glycines biology and shed light onto the mystery underlying complex host-parasite interactions. This genome sequence is an important prerequisite to enable work towards generating new resistance or control measures against H. glycines.


Association between PCOS and autoimmune thyroid disease: a systematic review and meta-analysis.
Polycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder affecting women of reproductive age. PCOS has been associated with distinct metabolic and cardiovascular diseases and with autoimmune conditions, predominantly autoimmune thyroid disease (AITD). AITD has been reported in 18-40% of PCOS women, depending on PCOS diagnostic criteria and ethnicity. The aim of this systematic review and meta-analysis was to summarize the available evidence regarding the likelihood of women with PCOS also having AITD in comparison to a reference group of non-PCOS women. We systematically searched EMBASE and MEDLINE for non-interventional case control, cross-sectional, or cohort studies published until August 2017. The Ottawa-Newcastle Scale was used to assess the methodological quality of studies. Statistical meta-analysis was performed with R. Thirteen studies were selected for the present analysis, including 1,210 women diagnosed with PCOS and 987 healthy controls. AITD was observed in 26.03% and 9.72% of PCOS and control groups respectively. A significant association was detected between PCOS and chance of AITD (OR= 3.27, 95%CI 2.32-4.63). Notably, after geographical stratification, the higher risk of AITD in PCOS women persisted for Asians (OR= 4.56, 95%CI 2.47-8.43), Europeans (OR= 3.27, 95%CI 2.07-5.15), and South Americans (OR= 1.86, 95 %CI 1.05-3.29). AIDT is a frequent condition in PCOS patients, and might affect thyroid function. Thus, screening for thyroid function and thyroid-specific autoantibodies should be considered in patients with PCOS even in the absence of overt symptoms. This systematic review and meta-analysis is registered in PROSPERO under number CRD42017079676.


TD-1HNMR measurements show enantioselective dissociation of ribose and glucose in the presence of H2(17)O.
We used Time Domain (1)H Nuclear Magnetic Resonance (NMR) to characterize changes in proton exchange between water and sugar enantiomers at different concentrations of H(2)(17)O (approximately 15-450 mM) and found that dissociation of the (-)-enantiomers of glucose and ribose occurs at significantly higher rates at higher concentrations of H(2)(17)O. The mechanism behind this enantioselective effect is unclear. The hypothesis we propose is that the large magnetic field (B(o) approximately 0.6T) applied during NMR measurements induces electric moments opposite in sign for the D and L-isomers. Because (17)O has a nuclear electric quadrupole moment not = 0, asymmetrically hydrated complexes may form between the B(o)-polarized enantiomers and H(2)(17)O. Either H(2)(17)O is more often hydrating the (+) than the (-)-enantiomers--and consequently pK differences between H(2)(16)O and H(2)(17)O lead to differences in proton exchange between enantiomers and water--or the orientation of H(2)(17)O relative to the B(o)-polarized enantiomers is different, in total or in part, which leads to hydrated complexes with different spatial geometries and different proton exchange properties. This effect is significant for Magneto-Chiral Stereo-Chemistry (MCSC) and astrobiology, and it may help us better understand specific instances of mass independent isotopic fractionation and aid in the development of new technologies for chiral and isotopic separation.


Effects of backhand stroke styles on bone mineral content and density in postmenopausal recreational tennis players: a cross-sectional pilot investigation.
One-handed backhand (OB) and two-handed backhand (TB) styles are commonly used in tennis, but only TB generates loadings on the non-dominant arm and a greater extension torque on the rear leg, leading to a greater axial torque involving rotation of the hip and trunk. The current study investigated whether those effects can further affect bone area (BA), bone mineral content (BMC) and density (BMD) in postmenopausal recreational tennis players. BA, BMC and BMD of the lumbar spine, hip and distal radius were assessed using dual-energy X-ray absorptiometry in TB, OB, and swimmers' group as a control (SG) (all participants self-reported for at least 5 years of exercise history, n = 14 per group). Muscular strength was assessed with a hand dynamometer. Among these three groups, the BA, BMC and BMD of distal radius and muscle strength were assessed using one-way ANOVA, and those of the lumbar region and the hip joint were tested by one-way ANCOVA. TB showed higher BMC and BMD for both lumbar spine and femoral neck than SG (all, p < 0.05). Both OB and TB showed greater BMD inter-trochanter than SG (both, p < 0.05). OB demonstrated greater inter-arm differences in the distal radius, which involved 1/3 distal for BMC and mid-distal radius for BMD compared to the TB and SG (all, p < 0.05). In addition, greater inter-arm asymmetry of grip strength was found in OB compared to TB and SG (both, p < 0.05). For postmenopausal women, performing two-handed backhand strokes, leads to higher BMC and BMD in the non-dominant arm, the lumbar region, and hips, indicating potential benefit to maintain bone health and strength. Whether this result leads to reducing the risk of osteoporosis needs to be investigated in further research.


Inorganic materials for bone repair or replacement applications.
In recent years, excipient systems have been used increasingly in biomedicine in reconstructive and replacement surgery, as bone cements, drug-delivery vehicles and contrast agents. Particularly, interest has been growing in the development and application of controlled pore inorganic ceramic materials for use in bone-replacement and bone-repair roles and, in this context, attention has been focused on calcium-phosphate, bioactive glasses and SiO2- and TiO2-based materials. It has been shown that inorganic materials that most closely mimic bone structure and surface chemistry most closely function best in bone replacement/repair and, in particular, if a substance possesses a macroporous structure (pores and interconnections >100 microm diameter), then cell infiltration, bone growth and vascularization can all be promoted. The surface roughness and micro/mesoporosity of a material have also been observed to significantly influence its ability to promote apatite nucleation and cell attachment significantly. Pores (where present) can also be packed with pharmaceuticals and biomolecules (e.g., bone morphogenetic proteins [BMPs], which can stimulate bone formation). Finally, the most bio-efficient - in terms of collagen formation and apatite nucleation - materials are those that are able to provide soluble mineralizing species (Si, Ca, PO(4)) at their implant sites and/or are doped or have been surface-activated with specific functional groups. This article presents the context and latest advances in the field of bone-repair materials, especially with respect to the development of bioactive glasses and micro/mesoporous and macroporous inorganic scaffolds. It deals with the possible methods of preparing porous pure/doped or functionalized silicas or their composites, the studies that have been undertaken to evaluate their abilities to act as bone repair scaffolds and also presents future directions for work in that context.


Prevalence and risk factors of obstructive sleep apnea syndrome in a Saudi Arabian population.
Obstructive sleep apnea (OSA) is a common disorder worldwide; however, epidemiological studies on its prevalence lack in Saudi Arabia. This study aimed to determine the prevalence and risk factors of OSA in Saudi Arabia. The study was performed from 2013 to 2015 in two stages. The screening stage was first; a random sample of Saudi employees (n = 2682) 30-60 years of age completed a survey that included the Wisconsin questionnaire. According to these data, the subjects were categorized as habitual, moderate, or nonsnorers (NSs). The confirmatory second stage was a case-control study conducted on 346 individuals selected from each group using polysomnography (PSG). In the first stage, the prevalence of habitual snoring was 23.5%, moderate snoring was16.6%, while 59.9% of the sample was NSs. Among the 346 individuals who underwent PSG, a total of 235 (67.9%) subjects had OSA with an apnea-hypopnea index (AHI) of ≥5; 76 (22.0%) had OSA syndrome (OSAS), defined by an AHI of ≥5 plus daytime sleepiness; and 227 (65.6%) had clinically diagnosed OSA syndrome (COSAS), as defined by the American Academy of Sleep Medicine. A conservative estimate of at least 8.8% (12.8% in men and 5.1% in women) was calculated for the overall prevalence of OSA. Similarly, the overall estimated prevalence of OSAS and COSAS was 2.8% (4.0% in men and 1.8% in women) and 8.5% (12.4% in men and 4.8% in women), respectively. A multivariate analysis revealed age, gender, obesity, and hypertension as independent risk factors of OSA. Our study demonstrated that the rate and risk factors of OSA in the Saudi population are similar to those observed in Western studies.


Influence of protein kinases on the osmosensitive release of taurine from cerebellar granule neurons.
The role of phosphorylation events on the activation and modulation of the osmosensitive (3)H-taurine release (OTR) was examined in cultured cerebellar granule neurons (CGN) stimulated with 30% hyposmotic solutions. OTR was not decreased when [Ca(2+)](i) rise evoked by hyposmolarity was prevented by EGTA-AM (50 microM) or depleted by treatment with 1 microM ionomycin in Ca(2+)-free medium. Accordingly, OTR was not inhibited by Ca(2+)-dependent signaling events. The calmodulin (CAM) blocker W-7 (50 microM) potentiated OTR while the Ca(2+)/CAM kinase blocker KN-93 (10 microM) was without effect. Blockade of PKC by H-7, H-8 (50 microM) and Gö6976 (1 microM), as well as activation by phorbol myristate acetate (PMA) (100 nM) did not influence OTR, but chronic treatment to down regulate PKC decreased it by 30%. Forskolin (20 microM) and 8-BrcAMP (10 microM) did not change OTR. Protein tyrosine phosphorylation seems to be of crucial importance in the activation and modulation of OTR, as it was markedly inhibited (90%) by tyrphostine A23 (50 microM) and potentiated by the tyrosine phosphatase inhibitor ortho-vanadate (100 microM). The PI3 kinase blocker wortmannin 100 nM essentially abolished OTR but LY294002 (10-100 microM) was without effect. This difference may be accounted for PI3K isoforms in neurons with different sensitivity to the blockers. Alternatively, the effect of wortmannin may be exerted not in PI3 kinase but instead on phospholipases, which are also sensitive to this blocker. The hyposmotic stimulus induced activation of Erk1/Erk2, but blockade of this effect by PD 98059 (50 microM) only marginally decreased OTR suggesting that the Erk1/Erk2 is an epiphenomenon, not directly involved in OTR activation.


Effects of saddle height on anaerobic power production in cycling.
In competitive cycling, setting the proper saddle height is important for both performance and injury prevention. This is also true for ergometer use in a laboratory. The cycling literature recommends using a 25 to 35 degrees knee angle to set saddle height for injury prevention and recommends using 109% of inseam length for optimal performance. Prior research has demonstrated that these 2 methods do not produce similar saddle heights. The purpose of this study was to determine if there is a difference in performance between these 2 methods. Trained cyclists (n = 9) and noncyclists (n = 18) participated in this study. Anaerobic power production was compared using a 30s Wingate protocol at a saddle height of 109% of inseam and at 25 and 35 degrees knee angles. Saddle height set using 109% of inseam fell outside the recommended 25 to 35 degrees knee angle 63% of the time. There were no significant differences (p > 0.05) for peak power and mean power in either group between saddle heights. The data when using 109% to set saddle height were then divided into those that fell within the recommended 25 to 35 degrees knee angle and those that fell outside. A 25 degrees knee angle produced a significantly higher mean power compared with 109% in those that fell outside the recommended range. An increase in power, at a 25 degrees angle, can be extrapolated to increased performance. There was no difference in performance detected in those individuals who fell within the recommended range. For this reason it is recommended that saddle height for cycles and ergometers be set using a 25 to 35 degrees knee angle for both trained and untrained cyclists for both injury prevention and increased performance.


Opacity-associated adhesin repertoire in hyperinvasive Neisseria meningitidis.
The opacity (Opa) proteins mediate a variety of interactions between the bacterium Neisseria meningitidis and its human host. These interactions are thought to be of central importance in both the asymptomatic colonization of the nasopharynx and the sporadic occurrence of meningococcal disease. The receptor specificities of a limited number of Opa protein variants have been explored, but the high level of amino acid sequence diversity among variants has complicated the assignment of specific roles to individual Opa variants or combinations of variants. In addition, the distribution of Opa protein variants among diverse meningococci, information that is potentially informative for studies of Opa function, is poorly understood. A systematic survey of the genetic diversity in the four opa gene loci in each of 77 meningococcal isolates was undertaken. These isolates were representative of the seven hyperinvasive meningococcal clonal complexes that caused the majority of meningococcal disease over the last 50 years. Consistent with previous studies, a high level of sequence diversity was observed among the opa genes and the proteins that they encoded; however, particular sets of Opa protein variants were consistently associated with each of the clonal complexes over time periods often spanning decades and during global spread. These observations were consistent with the postulate that particular combinations of Opa proteins confer fitness advantages to individual clonal complexes and have implications for studies of Opa function and the inclusion of Opa proteins in novel meningococcal vaccines.


Critical roles of αII spectrin in brain development and epileptic encephalopathy.
The nonerythrocytic α-spectrin-1 (SPTAN1) gene encodes the cytoskeletal protein αII spectrin. Mutations in SPTAN1 cause early infantile epileptic encephalopathy type 5 (EIEE5); however, the role of αII spectrin in neurodevelopment and EIEE5 pathogenesis is unknown. Prior work suggests that αII spectrin is absent in the axon initial segment (AIS) and contributes to a diffusion barrier in the distal axon. Here, we have shown that αII spectrin is expressed ubiquitously in rodent and human somatodendritic and axonal domains. CRISPR-mediated deletion of Sptan1 in embryonic rat forebrain by in utero electroporation caused altered dendritic and axonal development, loss of the AIS, and decreased inhibitory innervation. Overexpression of human EIEE5 mutant SPTAN1 in embryonic rat forebrain and mouse hippocampal neurons led to similar developmental defects that were also observed in EIEE5 patient-derived neurons. Additionally, patient-derived neurons displayed aggregation of spectrin complexes. Taken together, these findings implicate αII spectrin in critical aspects of dendritic and axonal development and synaptogenesis, and support a dominant-negative mechanism of SPTAN1 mutations in EIEE5.


Desalting large protein complexes during native electrospray mass spectrometry by addition of amino acids to the working solution.
Native mass spectrometry is a rapidly emerging field for characterising the structure of proteins and protein assemblies. The technique relies on electrospray ionisation (ESI) to efficiently ionise the protein analyte and transmit it into the gas phase with retention of protein structure, non-covalent protein-ligand and protein-protein interactions. In native ESI, both the ionisation efficiency and the resulting mass spectral signal is adversely effected by the presence of non-volatile inorganic salts, such as sodium chloride, which form extensive adducts with the protein ions. Consequently, there is great interest in finding experimental strategies that mitigate these phenomena. Here we report our findings that the addition of 10 mM l-serine to the ESI spray solution reduces the adverse effects of sodium adduction to proteins. In the analysis of bovine serum albumin (BSA; 66 kDa), 10 mM serine increased signal to noise ratio (S/N) ∼4 fold. This increase in sensitivity was accompanied by peak narrowing (∼10 fold), which allowed more precise assignment of molecular mass. Similar effects were observed when analysing protein complexes - serine palmitoyl transferase (SPT, a 92 kDa homodimer), enolase (a 93 kDa homodimer); and alcohol dehydrogenase (ADH, a 148 kDa tetramer). Reduction in sodium ion adduction occurs with no loss of the non-covalent protein-protein interactions, and with little effect on the overall observed charge state-distribution. As a consequence of increasing signal intensity, the addition of serine to the ESI spray solution greatly improved the quality of the data obtained from native top-down electron-capture dissociation (ECD) experiments. In ECD analysis of native BSA, we observed an increasing in the S/N of all ECD fragments upon addition of 10 mM l-serine. The number of ECD fragments we observed with S/N > 1.5 increased from 15 to 44 and the number of assigned c and z ions increased from 5 to 16. Finally we show that this phenomenon is not specific to l-serine, and occurs with several amino acids such as l-alanine. Our findings suggest that desalting may occur via binding of sodium ion to the amino acid in solution. This simple and inexpensive strategy has broad utility for improving the mass spectra obtained in a range of MS-based structural proteomic studies.


Olfactory deficits predict cognitive decline and Alzheimer dementia in an urban community.
To determine the predictive utility of baseline odor identification deficits for future cognitive decline and the diagnosis of Alzheimer disease (AD) dementia. In a multiethnic community cohort in North Manhattan, NY, 1,037 participants without dementia were evaluated with the 40-item University of Pennsylvania Smell Identification Test (UPSIT). In 757 participants, follow-up occurred at 2 years and 4 years. In logistic regression analyses, lower baseline UPSIT scores were associated with cognitive decline (relative risk 1.067 per point interval; 95% confidence interval [CI] 1.040, 1.095; p < 0.0001), and remained significant (relative risk 1.065 per point interval; 95% CI 1.034, 1.095; p < 0.0001) after including covariates. UPSIT, but not Selective Reminding Test-total immediate recall, predicted cognitive decline in participants without baseline cognitive impairment. During follow-up, 101 participants transitioned to AD dementia. In discrete time survival analyses, lower baseline UPSIT scores were associated with transition to AD dementia (hazard ratio 1.099 per point interval; 95% CI 1.067, 1.131; p < 0.0001), and remained highly significant (hazard ratio 1.072 per point interval; 95% CI 1.036, 1.109; p < 0.0001) after including demographic, cognitive, and functional covariates. Impairment in odor identification was superior to deficits in verbal episodic memory in predicting cognitive decline in cognitively intact participants. The findings support the cross-cultural use of a relatively inexpensive odor identification test as an early biomarker of cognitive decline and AD dementia. Such testing may have the potential to select/stratify patients in treatment trials of cognitively impaired patients or prevention trials in cognitively intact individuals.


A systematic review of cost-effectiveness analysis of screening interventions for assessing the risk of venous thromboembolism in women considering combined oral contraceptives.
Use of combined oral contraceptives (COCs) by women increases the risk of venous thromboembolism (VTE), which can have a major impact on an individuals' quality of life. VTE is also associated with an increase in healthcare costs. Our aim was to systematically review cost-effectiveness analyses (CEAs) considering any screening for risk of VTE in women using COCs. The quality of reporting in each study was assessed, a summary of results was prepared, and the key drivers of cost effectiveness in each of the eligible CEAs were identified. A search strategy using MeSH terms was performed in MEDLINE, Embase, the Centre for Review and Dissemination (CRD) database including the Economic Evaluation Database from the UK National Health Service, and Cochrane reviews. Two reviewers independently screened and determined the final articles, and a third reviewer resolved any discrepancies. Consolidated Health Economic Evaluation Reporting Standards was used to assess the quality of reporting in terms of perspective, effectiveness measures, model structure, cost, time-horizon and discounting. Four publications (three from Europe, one from the United States) were eligible for inclusion in the review. According to current criteria, relevant elements were sometimes not captured and the sources of epidemiological and effectiveness data used in the CEAs were of limited quality. The studies varied in terms of type of costs assessed, country settings, model assumptions and uncertainty around input parameters. Key drivers of CEAs were sensitivity and specificity of the test, incidence rate of VTE, relative risk of prophylaxis, and costs of the test. The reviewed studies were too dissimilar to draw a firm conclusion on cost-effectiveness analysis about universal and selective screening in high-risk groups. The new emerging diagnostic tools for identifying women at risk of developing VTE, that are more predictive and less costly, highlight the need for more studies that apply the latest evidence and utilize robust methods for cost-effectiveness analysis. This information is required to improve decision making for this pertinent issue within personalized medicine.


Long-term retention of ECM hydrogel after implantation into a sub-acute stroke cavity reduces lesion volume.
Salvaging or functional replacement of damaged tissue caused by stroke in the brain remains a major therapeutic challenge. In situ gelation and retention of a hydrogel bioscaffold composed of 8mg/mL extracellular matrix (ECM) can induce a robust invasion of cells within 24h and potentially promote a structural remodeling to replace lost tissue. Herein, we demonstrate a long-term retention of ECM hydrogel within the lesion cavity. A decrease of approximately 32% of ECM volume is observed over 12weeks. Lesion volume, as measured by magnetic resonance imaging and histology, was reduced by 28%, but a battery of behavioral tests (bilateral asymmetry test; footfault; rotameter) did not reveal a therapeutic or detrimental effect of the hydrogel. Glial scarring and peri-infarct astrocytosis were equivalent between untreated and treated animals, potentially indicating that permeation into host tissue is required to exert therapeutic effects. These results reveal a marked difference of biodegradation of ECM hydrogel in the stroke-damaged brain compared to peripheral soft tissue repair. Further exploration of these structure-function relationships is required to achieve a structural remodeling of the implanted hydrogel, as seen in peripheral tissues, to replace lost tissue and promote behavioral recovery. In situ gelation of ECM is essential for its retention within a tissue cavity. The brain is a unique environment with restricted access that necessitates image-guided delivery through a thin needle to access tissue cavities caused by stroke, as well as other conditions, such as traumatic brain injury or glioma resection. Knowledge about a brain tissue response to implanted hydrogels remains limited, especially in terms of long-term effects and potential impact on behavioral function. We here address the long-term retention of hydrogel within the brain environment, its impact on behavioral function, as well as its ability to reduce further tissue deformation caused by stroke. This study highlights considerable differences in the brain's long-term response to an ECM hydrogel compared to peripheral soft tissue. It underlines the importance of understanding the effect of the structural presence of a hydrogel within a cavity upon host brain tissue and behavioral function. As demonstrated herein, ECM hydrogel can fill a cavity long-term to reduce further progression of the cavity, while potentially serving as a reservoir for local drug or cell delivery.


Effects of maternally exposed food coloring additives on laryngeal histology in rats.
Experimental reports showed carcinogenic effects of artificial food colors and additives (AFCAs) on many organs, including the head and neck region. We aimed to investigate the effect of AFCAs on laryngeal histomorphology and immunohistochemical expression in maternally exposed rats. "No observable adverse effect levels" of commonly used AFCAs as a mixture were given to female rats before and during gestation. Histopathological and immunohistochemical findings were evaluated in their offspring. Significant decreasing in goblet cell count and cilia loss were observed with AFCAs in maternally exposed rats (p<0.05). Immunohistochemically, the Ki67 index was significantly increased and villin expression was significantly reduced in laryngeal epithelium in the study group (p<0.05), whereas expression of cyclooxygenase type 2, Muc-2, Muc-5AC, p53, and epidermal growth factor receptors did not differ between the groups. This study demonstrated that maternal exposure of AFCAs plays a role in the mucosal defense system and possibly in carcinogenesis.


CSF-1 receptor structure/function in MacCsf1r-/- macrophages: regulation of proliferation, differentiation, and morphology.
CSF-1 is the major regulator of tissue macrophage development and function. A GM-CSF-dependent, CSF-1 receptor (CSF-1R)-deficient F4/80(hi)Mac-1(+)Gr1(-)CD11c(+) bone marrow macrophage (BMM) line (MacCsf1r-/-) was developed to study the roles of the eight intracellular CSF-1R tyrosines phosphorylated upon receptor activation. Retroviral expression of the wild-type CSF-1R rescued the CSF-1-induced survival, proliferation, differentiation, and morphological characteristics of primary BMM. Mutation of all eight tyrosines failed to rescue, whereas the individual Y --> F mutants (544, 559, 697, 706, 721, 807, 921, 974) rescued these CSF-1-inducible phenotypes to varying degrees. The juxtamembrane domain Y559F and activation loop Y807F mutations severely compromised proliferation and differentiation, whereas Y706, Y721F, and Y974F mutations altered morphological responses, and Y706F increased differentiation. Despite their retention of significant in vitro tyrosine kinase activity, Y559F and Y807F mutants exhibited severely impaired in vivo receptor tyrosine phosphorylation, consistent with the existence of cellular mechanisms inhibiting CSF-1R tyrosine phosphorylation that are relieved by phosphorylation of these two sites. The MacCsf1r-/- macrophage line will facilitate genetic and proteomic approaches to CSF-1R structure/function studies in the major disease-related CSF-1R-expressing cell type.


Dendrimer as a multifunctional capping agent for metal nanoparticles for use in bioimaging, drug delivery and sensor applications.
Advances in nanoparticle research, particularly in the domain of surface-engineered, function-oriented nanoparticles, have had a profound effect in many areas of scientific research and aided in bringing unprecedented developments forward, particularly in the biomedical field. Surface modifiers/capping agents have a direct bearing on the major properties of metal nanoparticles (MNPs), ranging from their physico-chemical properties to their stability and functional applications. Among the different classes of capping agents, dendrimers have gained traction as effective multifunctional capping agents for MNPs due to their unique structural qualities, dendritic effect and polydentate nature. Dendrimer-coated metal nanoparticles (DC-MNPs) are typically produced by both (i) a one-pot strategy, where metal ions are reduced in the presence of dendrimer molecules and (ii) a multi-pot strategy, where a sequence of reactions involving the reduction of metal ions, activation, conjugation and purification steps are involved. These DC-MNPs have shown remarkable ability to stabilize MNPs by means of electrostatic interactions, coordination chemistry or covalent attachment, due to them entailing a large number of sites at which further molecular moieties can be conjugated. This review article is an attempt to consolidate the on-going work, particularly over the last five years, in the field of the synthesis of dendrimer-coated MNPs and their potential applications in bioimaging, drug delivery and biochemical sensors.


Sex Differences During an Overhead Squat Assessment.
A disparity exists between the rates of male and female lower extremity injuries. One factor that may contribute to this disparity is high-risk biomechanical patterns that are commonly displayed by females. It is unknown what biomechanical differences exist between males and females during an overhead squat. This study compared lower extremity biomechanics during an overhead squat and ranges of motion between males and females. An electromagnetic motion tracking system interfaced with a force platform was used to quantify peak lower extremity kinematics and kinetics during the descent phase of each squat. Range of motion measurements were assessed with a standard goniometer. Differences between male and female kinematics, kinetics, and ranges of motion were identified with t tests. Males displayed greater peak knee valgus angle, peak hip flexion angle, peak vertical ground reaction forces, and peak hip extension moments. Males also displayed less active ankle dorsiflexion with the knee extended and hip internal and external rotation than females. No other differences were observed. The biomechanical differences between males and females during the overhead squat may result from differences in lower extremity ranges of motion. Therefore, sex-specific injury prevention programs should be developed to improve biomechanics and ranges of motion.


A review of complementary and alternative medicine (CAM) by people with multiple sclerosis.
Multiple sclerosis (MS) is a chronic, unpredictable disease of the central nervous system without a known cure. Because of this, people with MS often seek complementary and alternative medicines (CAM) to manage their disease symptoms. The goal of this review article was to describe the use of CAM by individuals diagnosed with MS. Evidence was obtained by searching Medline (1950-2007), EBSCOhost and PubMed for studies relating CAM to MS. Results from the literature showed that people with MS reported that they used CAM from 27 to 100%. The major reasons for choosing CAM were as follows: conventional treatment was not effective, anecdotal reports of CAM's help, and doctor referral. The types of CAM reported by people with MS included exercise, vitamins, herbal and mineral supplements, relaxation techniques, acupuncture, cannabis and massage. The major symptoms treated by CAM as noted in the literature were pain, fatigue and stress. There is a need for further research to evaluate the effectiveness of CAM with MS patients and their application by occupational therapists. The limitation of this literature review was the low response rate in many of the surveys reported.


[Evaluation of statin use on LDL cholesterol levels in Turkey: A systematic review].
The aim of this study was to examine and present the effect of statin treatment on the low-density lipoprotein (LDL) cholesterol level of patients in Turkey by evaluating the data of studies conducted in the country. Manuscripts published between January 1, 2008 and December 31, 2017 with terms 'LDL' and 'TURK' in the title or abstract and reporting LDL cholesterol data of patients treated with statins were evaluated for inclusion in the study. From the initial search result a total of 1795 papers, 39 manuscripts with 63 study arms were selected for analysis and the data of 3486 patients were included. Descriptive analysis was used to assess the data. Weighted averages of the data were also calculated. The female/male ratio was 42/58. The mean age was 52.9±10.1 years. The proportion of patients with the recommended LDL cholesterol level of <70 mg/dL after treatment with statins was 15.3%;. In all, 10.2% of the patients who were prescribed a low-dose statin and 28.0% of those who were prescribed a high-dose statin had an LDL cholesterol of <70 mg/dL after treatment. Among patients who were being treated with statins for ≤2 months, 25.7% achieved an LDL cholesterol level of <70 mg/dL. Among those who were being treated with statins for 2-4 months and >4 months the proportion was 11.4% and 9.7%, respectively. The percentage of patients at the target level was 21.8%, 21.7%, 17.9%;, 8.6%, and 0.8% among those using atorvastatin, simvastatin, rosuvastatin, fluvastatin, and pravastatin, respectively. In Turkey, only 15% of the patients who had received statin therapy had a LDL cholesterol level of <70 mg/dL. Revision of the current treatment should be considered to reach the target levels recommended in the guidelines, especially for patients with high cardiovascular risk.


Relationship between thyroid peroxidase T cell epitope restriction and antibody recognition of the autoantibody immunodominant region in human leukocyte antigen DR3 transgenic mice.
We investigated the relationship between thyroid peroxidase (TPO) antibody and T lymphocyte epitopes in TPO-adenovirus (TPO-Ad) immunized BALB/c mice and mice transgenic for the human class II molecule DR3 associated with human thyroid autoimmunity. TPO autoantibodies are largely restricted to an immunodominant region (IDR). BALB/c mice immunized with fewer (10(7) vs. 10(9)) TPO-Ad particles developed TPO antibodies with lower titers that displayed greater restriction to the IDR. However, as with higher-dose TPO-Ad immunization, T cell epitopes (assessed by splenocyte interferon-gamma response to TPO in vitro) were highly diverse and variable in different animals. In contrast, DR3 mice immunized the higher TPO-Ad dose (10(9) particles) had high TPO antibody levels that showed relative focus on the IDR. Moreover, T cell epitopes recognized by splenocytes from DR3 mice showed greater restriction than BALB/c mice. Antibody affinities for TPO were higher in DR3 than in BALB/c mice. The present study indicates that weak TPO-Ad immunization of BALB/c mice (with consequent low TPO antibody titers) is required for enhanced IDR focus yet is not associated with T cell epitopic restriction. Humanized DR3 transgenic mice, despite stronger TPO-Ad immunization, develop higher titer TPO antibodies that do focus on the autoantibody IDR with T cells that recognize a more limited range of TPO peptides. These data suggest a relationship between major histocompatibility complex class II molecules and the development of antibodies to the IDR, a feature of human thyroid autoimmunity.


Manual and manipulative therapy in addition to rehabilitation for osteoarthritis of the knee: assessor-blind randomized pilot trial.
The purpose of this study was to examine the methodological integrity, sample size requirements, and short-term preliminary clinical outcomes of manual and manipulative therapy (MMT) in addition to a rehabilitation program for symptomatic knee osteoarthritis (OA). This was a pilot study of an assessor-blinded, randomized, parallel-group trial in 2 independent university-based outpatient clinics. Participants with knee OA were randomized to 3 groups: 6 MMT sessions alone, training in rehabilitation followed by a home rehabilitation program alone, or MMT plus the same rehabilitation program, respectively. Six MMT treatment sessions (provided by a chiropractic intern under supervision or by an experienced chiropractor) were provided to participants over the 4-week treatment period. The primary outcome was a description of the research methodology and sample size estimation for a confirmatory study. The secondary outcome was the short-term preliminary clinical outcomes. Data were collected at baseline and 5weeks using the Western Ontario and McMasters Osteoarthritis Index questionnaire, goniometry for knee flexion/extension, and the McMaster Overall Therapy Effectiveness inventory. Analysis of variance was used to compare differences between groups. Eighty-three patients were randomly allocated to 1 of the 3 groups (27, 28, and 28, respectively). Despite 5 dropouts, the data from 78 participants were available for analysis with 10% of scores missing. A minimum of 462 patients is required for a confirmatory 3-arm trial including the respective interventions, accounting for cluster effects and a 20% dropout rate. Statistically significant and clinically meaningful changes in scores from baseline to week 5 were found for all groups for the Western Ontario and McMasters Osteoarthritis Index (P ≤ .008), with a greater change in scores for MMT and MMT plus rehabilitation. Between-group comparison did not reveal statistically significant differences between group scores at week 5 for any of the outcome measures (P ≥ .46). This pilot trial suggests that a confirmatory trial is feasible. There were significant changes in scores from baseline to week 5 across all groups, suggesting that all 3 treatment approaches may be of benefit to patients with mild-to-moderate knee OA, justifying a confirmatory trial to compare these interventions.


Lessons Learned for the Study of Childhood Asthma from the Centers for Children's Environmental Health and Disease Prevention Research.
The National Children's Study will address, among other illnesses, the environmental causes of both incident asthma and exacerbations of asthma in children. Seven of the Centers for Children's Environmental Health and Disease Prevention Research (Children's Centers), funded by the National Institute of Environmental Health Sciences and the U.S. Environmental Protection Agency, conducted studies relating to asthma. The design of these studies was diverse and included cohorts, longitudinal studies of older children, and intervention trials involving asthmatic children. In addition to the general lessons provided regarding the conduct of clinical studies in both urban and rural populations, these studies provide important lessons regarding the successful conduct of community research addressing asthma. They demonstrate that it is necessary and feasible to conduct repeated evaluation of environmental exposures in the home to address environmental exposures relevant to asthma. The time and staff required were usually underestimated by the investigators, but through resourceful efforts, the studies were completed with a remarkably high completion rate. The definition of asthma and assessment of disease severity proved to be complex and required a combination of questionnaires, pulmonary function tests, and biologic samples for markers of immune response and disease activity. The definition of asthma was particularly problematic in younger children, who may exhibit typical asthma symptoms sporadically with respiratory infections without developing chronic asthma. Medications confounded the definition of asthma disease activity, and must be repeatedly and systematically estimated. Despite these many challenges, the Children's Centers successfully conducted long-term studies of asthma.


Isoliquiritigenin Suppresses E2-Induced Uterine Leiomyoma Growth through the Modulation of Cell Death Program and the Repression of ECM Accumulation.
Uterine leiomyomas, also known as fibroids, are common and prevalent in women of reproductive age. In this study, the effect of Isoliquiritigenin (ISL), a licorice flavonoid, on the anti-proliferation of uterine leiomyoma was investigated. We found that the survival of uterine leiomyoma ELT3 cells and primary uterine smooth muscle (UtSMC) cells was reduced by treatment with ISL alone or with ISL plus estradiol (E2). Cell cycles were arrested through the reduction of G2/M- and S-phase populations in ELT3 and UtSMC cells, respectively. Furthermore, increased sub-G1 phase and nucleus condensation were observed in ELT3 cells but not in UtSMC cells. Co-treatment of ELT3 cells with E2 and ISL inhibited ERK1/2 activation, whereas p38 and c-Jun N-terminal kinase (JNK) activation was enhanced. Moreover, ISL-induced apoptosis and autophagy cell death in ELT3 cells were observed. Serum E2 and P4 levels were reduced in a E2-enhanced uterine myometrium hyperplasia mouse model by ISL treatment, which contributed to the downregulation of the expression of extracellular matrix (ECM) associated proteins and matrix metalloproteinase (MMPs). Taken together, these results showed that ISL exerted a higher effect on the inhibition of estrogen-induced uterine leiomyoma growth for both in vitro and in vivo ECM accumulation, demonstrating its potential as a new option for treatment of uterine leiomyoma.


The centralization of robotic surgery in high-volume centers for endometrial cancer patients--a study of 6560 cases in the U.S.
To evaluate the hospital and patient factors associated with robotic surgery for endometrial cancer in the United States. Data was obtained from the Nationwide Inpatient Sample from the year 2010. Chi-squared and multivariate analyses were used for statistical analysis. Of the 6560 endometrial cancer patients who underwent surgery, the median age was 62 (range: 22 to 99). 1647 (25%) underwent robotic surgery, 820 (13%) laparoscopic, and 4093 (62%) had open surgery. The majority was White (65%). Hospitals with 76 or more hysterectomy cases for endometrial cancer patients per year (4% of hospitals in the study) performed 31% of all hysterectomies and 40% of all robotic hysterectomies (p<0.01). 29% of Whites had robotic surgery compared to 15% of Hispanics, 12% of Blacks, and 11% of Asians (p<0.01). Patients with upper-middle and high incomes underwent robotic surgery more than patients with low or middle incomes (p<0.01). 27% of Medicare patients and 26% of patients with private insurance had robotic surgery compared to only 14% of Medicaid patients and 12% of uninsured patients (p<0.01). The majority of robotic surgeries for endometrial cancer were performed at a small number of high-volume hospitals in the United States. Socioeconomic status, insurance type, and race were also important predictors for the use of RS. Further studies are warranted to better understand the barriers to receiving minimally invasive surgery.


Long-term epilation with long-pulsed neodimium:YAG laser.
Unwanted body hair can represent a severe cosmetic disturbance. The traditional methods used to epilate often have limitations, side effects, and unsatisfactory results. In recent years, various light sources (lasers and others) have been developed for long-term epilation of unwanted hair. This study evaluates, on a large number of patients, the efficiency and safety of a long-pulsed low-potency Nd-Yag laser invented specifically for long-term hair removal. Some 208 subjects needing epilation were divided into three groups and treated during an 11-month period. Group A included 79 patients with a normal distribution of unwanted hair; Group B 67 patients with constitutional hypertrichosis; and Group C 62 patients with hirsutism. Treatment sessions were performed with a fluence of 23-56 J/cm2 at 1-month intervals until obtaining desirable results. Follow-ups ranged from 1 to 6 months. In 3 patients 4-mm diameter punch biopsy specimens were obtained before the first session and again after 6 hours. A third biopsy was performed after 3 months. Every session resulted in a 20-40% hair loss, depending on the color of hair. Complete epilation was obtained in 4 to 6 sessions. Only white hair was not receptive to laser light, and its growth was not modified. No patients, including dark-complexioned patients, had blistering, hypo-or hyperpigmentation. No pain was present during treatment except for the axillary area. In the specimen obtained after 6 hours, very extensive necrosis of the hair follicular and sebaceous gland epithelium was evident. Histologic findings of the biopsies taken after three months showed complete disappearance of hair and moderate fibrosis. This study proves that the long-pulsed Nd:Yag laser treatment produces an excellent prolonged epilation with no relevant side effects. This laser light, having a 1064 nm wavelength, is minimally absorbed in superficial skin layers, and pronounced scattering up to 5 mm occurs targeting the deeper follicles.


Vegetation on mesic loamy and sandy soils along a 1700-km maritime Eurasia Arctic Transect.
How do plant communities on zonal loamy vs. sandy soils vary across the full maritime Arctic bioclimate gradient? How are plant communities of these areas related to existing vegetation units of the European Vegetation Classification? What are the main environmental factors controlling transitions of vegetation along the bioclimate gradient? 1700-km Eurasia Arctic Transect (EAT), Yamal Peninsula and Franz Josef Land (FJL), Russia. The Braun-Blanquet approach was used to sample mesic loamy and sandy plots on 14 total study sites at six locations, one in each of the five Arctic bioclimate subzones and the forest-tundra transition. Trends in soil factors, cover of plant growth forms (PGFs) and species diversity were examined along the summer warmth index (SWI) gradient and on loamy and sandy soils. Classification and ordination were used to group the plots and to test relationships between vegetation and environmental factors. Clear, mostly non-linear, trends occurred for soil factors, vegetation structure and species diversity along the climate gradient. Cluster analysis revealed seven groups with clear relationships to subzone and soil texture. Clusters at the ends of the bioclimate gradient (forest-tundra and polar desert) had many highly diagnostic taxa, whereas clusters from the Yamal Peninsula had only a few. Axis 1 of a DCA was strongly correlated with latitude and summer warmth; Axis 2 was strongly correlated with soil moisture, percentage sand and landscape age. Summer temperature and soil texture have clear effects on tundra canopy structure and species composition, with consequences for ecosystem properties. Each layer of the plant canopy has a distinct region of peak abundance along the bioclimate gradient. The major vegetation types are weakly aligned with described classes of the European Vegetation Checklist, indicating a continuous floristic gradient rather than distinct subzone regions. The study provides ground-based vegetation data for satellite-based interpretations of the western maritime Eurasian Arctic, and the first vegetation data from Hayes Island, Franz Josef Land, which is strongly separated geographically and floristically from the rest of the gradient and most susceptible to on-going climate change.


A pilot randomized, controlled trial of the effectiveness of a psychoeducational intervention on family caregivers of patients with advanced cancer.
To evaluate the effectiveness of a psychoeducational intervention, the Caring for the Caregiver Programme (CCP). A pilot randomized, controlled trial, two-group pretest, and repeated post-tests. Four home hospice organizations and an outpatient clinic in Singapore. 80 caregivers were randomized into experimental and standard care groups. Outcomes were measured at baseline, week 4, and week 8 after the intervention. The standard care group received routine home hospice care, and the intervention group received the CCP in addition to routine care. Quality of life (QOL), social support, stress and depression, self-efficacy in self-care, closeness with the patient, rewards, and knowledge. Compared to the standard care group, the intervention group reported significantly higher QOL, social support satisfaction and number of supported people, closeness with the patient, self-efficacy in self-care, rewards of caregiving, and knowledge, and lower stress and depression. The CCP had positive effects on family caregivers of patients with advanced cancer. A psychoeducational intervention potentially could help caregivers cope with the demands of caregiving.


High protein prescription in methylmalonic and propionic acidemia patients and its negative association with long-term outcome.
Methylmalonic acidemia (MMA) and propionic acidemia (PA) are inborn errors of metabolism. While survival of MMA and PA patients has improved in recent decades, long-term outcome is still unsatisfactory. A protein restricted diet is the mainstay for treatment. Additional amino acid mixtures (AAM) can be prescribed if natural protein is insufficient. It is unknown if dietary treatment can have an impact on outcome. We performed a nationwide retrospective cohort study and evaluated both longitudinal dietary treatment and clinical course of Dutch MMA and PA patients. Protein prescription was compared to the recommended daily allowances (RDA); the safe level of protein intake as provided by the World Health Organization. The association of longitudinal dietary treatment with long-term outcome was evaluated. The cohort included 76 patients with a median retrospective follow-up period of 15 years (min-max: 0-48 years) and a total of 1063 patient years on a protein restricted diet. Natural protein prescription exceeded the RDA in 37% (470/1287) of all prescriptions and due to AAM prescription, the total protein prescription exceeded RDA in 84% (1070/1277). Higher protein prescriptions were associated with adverse outcomes in severely affected patients. In PA early onset patients a higher natural protein prescription was associated with more frequent AMD. In MMA vitamin B12 unresponsive patients, both a higher total protein prescription and AAM protein prescription were associated with more mitochondrial complications. A higher AAM protein prescription was associated with an increased frequency of cognitive impairment in the entire. Protein intake in excess of recommendations is frequent and is associated with poor outcome.


Concomitant whole-abdominal radiation and intraperitoneal chemotherapy in advanced ovarian carcinoma. A pilot study.
Because the use of cisplatin-based chemotherapy for ovarian carcinoma has not significantly improved 5-year survival rates compared with either whole-abdominal radiation (WAR) or single-agent chemotherapy, a pilot study was begun to assess the feasibility of concomitant radiation and chemotherapy. Eleven previously untreated patients with Stages III and IV ovarian carcinoma were treated concomitantly with 2000 cGy of WAR and intraperitoneal (IP) cisplatin followed by additional IP cisplatin after debulking surgery. Toxicity was moderate to severe. Sixty-four percent of patients had Grades 3 to 4 hematologic toxicity, and 36% required hospitalization for sepsis during WAR/IP cisplatin. Hematologic toxicity was less pronounced during IP cisplatin alone. All patients experienced moderate gastrointestinal toxicity. The average percentage of total body weight lost was 13.5%. Fifty-five percent of all patients demonstrated a complete clinical response to therapy, and patients with minimal postoperative residual disease fared better. One patient with persistent disease had acute nonlymphocytic leukemia (ANLL) 24 months after initial diagnosis. No patients with residual disease greater than 20 mm survived, while 50% of patients with less than 20 mm are clinically free of disease. Toxicity appears to be additive with the combination of WAR and IP cisplatin. Therapeutic efficacy was comparable with standard chemotherapy regimens, but no therapeutic or survival advantages were demonstrated with the use of this treatment protocol.


Synaptic homeostasis in a zebrafish glial glycine transporter mutant.
Truncated escape responses characteristic of the zebrafish shocked mutant result from a defective glial glycine transporter (GlyT1). In homozygous GlyT1 mutants, irrigating brain ventricles with glycine-free solution rescues normal swimming. Conversely, elevating brain glycine levels restores motility defects. These experiments are consistent with previous studies that demonstrate regulation of global glycine levels in the CNS as a primary function of GlyT1. As GlyT1 mutants mature, their ability to mount an escape response naturally recovers. To understand the basis of this recovery, we assay synaptic transmission in primary spinal motor neurons by measuring stimulus-evoked postsynaptic potentials. At the peak of the motility defect, inhibitory synaptic potentials are both significantly larger and more prolonged indicating a prominent role for GlyT1 in shaping fast synaptic transmission. However, as GlyT1 mutants naturally regain their ability to swim, the amplitude of inhibitory potentials decreases to below wild-type levels. In parallel with diminishing synaptic potentials, the glycine concentration required to evoke the mutant motility defect increases 61-fold during behavioral recovery. Behavioral recovery is also mirrored by a reduction in the levels of both glycine receptor protein and transcript. These results suggest that increased CNS glycine tolerance and reduced glycine receptor expression in GlyT1 mutants reflect compensatory mechanisms for functional recovery from excess nervous system inhibition.


Therapeutic targeting of interleukin-6 for the treatment of COVID-19.
Coronavirus disease 19 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first identified in China and has spread worldwide with a significant rate of infection. Considering the elevated levels of proinflammatory cytokines in COVID-19, it is suggested that cytokine storms play a critical role in its pathogenesis, including acute respiratory distress syndrome (ARDS). However, there is no specific drug for preventing the cytokine release syndrome (CRS) caused by COVID-19. Indeed, interleukin 6 (IL-6) has been highlighted for its many biological functions, such as immune regulation, inflammatory response, and metabolism. Therapeutic blockade of the IL-6 signaling pathway is expected to reduce the excessive immune reponse observed in COVID-19. Currently, the IL-6 receptor antagonists tocilizumab and sarilumab, have been adopted for preventing CRS during the progression of COVID-19, and remarkable beneficial effects were observed by using these humanized monoclonal antibodies. Based on the pathogenesis of COVID-19, we reviewed the biological mechanism of IL-6 blockade in the treatment of SARS-CoV-2 infection and evaluated its clinical applications.


Group counseling: A silver lining in the psychological management of disaster trauma.
Management of disaster effects, physical or psychological, has been the subject of considerable research. Though physical rehabilitation of the victims of any disaster, whether natural or man-made, receives immediate attention, the management of psychological trauma often remains a challenge for the disaster management machinery, in general, and mental health professionals, in particular. The magnitude of population affected, on the one hand, and lack of sufficient mental health professionals, on the other hand, often hinders the psychological rehabilitation of a cross section of the affected population. We attempt to present an overview of the literature to bring home the understanding of correlates of psychological effects in the mass disaster affected population in this article. It dwells on the efficacy of group counseling as the most appropriate paradigm of primary prevention to check the onset of severe psychological disorders. The article also presents an overview of two case studies: tsunami disaster (Nagapatanam, Tamil Nadu, India) and victims of bomb blast (Dhimajee, Assam, India) to highlight the silver lining in the psychological management of disaster traumas. It is proposed that group counseling can prove to be a most important mental rehabilitation program to further strengthen the efficacy of individual therapeutic interventions.


Alcohol Exposure In Utero and Child Academic Achievement.
We examine the effect of alcohol exposure in utero on child academic achievement. As well as studying the effect of any alcohol exposure, we investigate the effect of the dose, pattern, and duration of exposure. We use a genetic variant in the maternal alcohol-metabolism gene ADH1B as an instrument for alcohol exposure, whilst controlling for the child's genotype on the same variant. We show that the instrument is unrelated to an extensive range of maternal and paternal characteristics and behaviours. OLS regressions suggest an ambiguous association between alcohol exposure in utero and children's academic attainment, but there is a strong social gradient in maternal drinking, with mothers in higher socio-economic groups more likely to drink. In stark contrast to the OLS, the IV estimates show negative effects of prenatal alcohol exposure on child educational attainment. These results are very robust to an extensive set of model specifications. In addition, we show that that the effects are solely driven by the maternal genotype, with no impact of the child's genotype.


HTA and its legal issues: a framework for identifying legal issues in health technology assessment.
Legal analysis can highlight important issues that are relevant when deciding whether a medical technology should be implemented or reimbursed. Literature and studies show that even though the law is an acknowledged part of health technology assessment (HTA), legal issues are rarely considered in practice. One reason for this may be the lack of knowledge about the diversity of legal issues that are relevant for HTA. Therefore, this contribution aims primarily to identify and then explain the relevant legal issues in HTA. This study offers a framework for identifying the legal issues in HTAs in different jurisdictions and provides a basis for further research. After extensive literature search, the authors review Swiss health law to identify legal issues that are relevant to HTA. The authors then categorize these legal issues using a framework with an inside and outside perspective. Finally, they explain a selection of these legal issues with several examples. This study reveals numerous legal issues that are relevant for HTA and underlines the necessity of incorporating legal analysis in HTAs. The suggested perspectival framework in this study provides a basis to structure the legal analysis. The identified legal issues are relevant in other countries and the perspectival framework is transferable to other jurisdictions. The article underlines the importance of in-depth discussion about the role of law in HTA. It provides a structured overview of the legal issues in HTA and suggests a development of more concrete instruments toward a standardized legal technology assessment.


First-Principle-Based Phonon Transport Properties of Nanoscale Graphene Grain Boundaries.
The integrity of phonon transport properties of large graphene (linear and curved) grain boundaries (GBs) is investigated under the influence of structural and dynamical disorder. To do this, density functional tight-binding (DFTB) method is combined with atomistic Green's function technique. The results show that curved GBs have lower thermal conductance than linear GBs. Its magnitude depends on the length of the curvature and out-of-plane structural distortions at the boundary, having stronger influence the latter one. Moreover, it is found that by increasing the defects at the boundary, the transport properties can strongly be reduced in comparison to the effect produced by heating up the boundary region. This is due to the large reduction of the phonon transmission for in-plane and out-of-plane vibrational modes after increasing the structural disorder in the GBs.


Health resource utilisation by patients with neuroendocrine tumours with or without carcinoid heart disease: a multinational study.
Carcinoid heart disease (CHD) is a rare and severe complication from carcinoid syndrome which may be associated with high health resource utilisation (HRU). We aimed to compare HRU between patients with and without CHD. Multicentre retrospective study of 137 consecutive patients with neuroendocrine tumours (NET) and elevated urinary 5-hydroxyindoleacetic acid treated in seven large hospitals in Latin America. We used the chi-squared test for binary variables and the Mann-Whitney test for quantitative correlations. Variables were entered into a multivariable linear regression model for higher HRU. One-third of the patients had (45) had CHD. Patients with CHD had significantly more emergency visits and echocardiograms as compared to patients without CHD. In the bivariate models, CHD (R2 = 0.61, p = 0.01), private health system (R 2 = 0.63, p = 0.02) and simultaneous cardiovascular comorbidities (R 2 = 0.61, p = 0.04) were associated with a higher HRU. The multivariate model pointed out the accumulated effect of variables on HRU (R 2 = 0.2, p < 0.01). NET patients with CHD present higher HRU independently of other clinical factors or health system. Effectively treating carcinoid syndrome, and likely delaying the onset of CHD, may potentially reduce the amount of HRU by these patients.


Reboxetine may cause amenorrhea in female patients.
Objective. Reboxetine is a selective noradrenaline reuptake inhibitor (NaRI), a study on the effects of reboxetine on amenorrhea has not been reported in the literature up to now. This report describes a patient with symptoms of amenorrhea which is thought to be caused by reboxetine. Case. A female patient with major depressive disorder was given reboxetine 8 mg/day. She had experienced secondary amenorrhea for 3 months. The patient had no periodic irregularity before reboxetine use, and after reboxetine was discontinued menstruation resumed. After another trial with reboxetine at the optimal dose (8 mg/day, increased gradually), the patient reported amenorrhea again for 2 months. On discontinuing reboxetine, her menstrual cycle became regular again. Discussion. FSH, LH, E2 and prolactin levels were normal in our patient. Because amenorrhea was temporally related with reboxetine trials, we posit that this phenomenon may be due to side effects of reboxetine. This may be due to noraderenergic effects on hormonal function.


Age effects on voluntary and automatic adjustments in anti-pointing tasks.
We examined the effects of age on automatic and voluntary motor adjustments in pointing tasks. To this end, young (20-25 years) and middle-aged adults (48-62 years) were instructed to point at a target that could unexpectedly change its location (to the left or right) or its color (to green or red) during the movement. In the location change conditions, participants were asked to either adjust their pointing movement toward the new location (i.e., normal pointing) or in the opposite direction (i.e., anti-pointing). In the color change conditions, participants were instructed to adjust their movement to the left or right depending on the change in color. The results showed that in a large proportion of the anti-pointing trials, participants made two adjustments: an early initial automatic adjustment in the direction of the target shift followed by a late voluntary adjustment toward the opposite direction. It was found that the late voluntary adjustments were delayed for the middle-aged participants relative to the young participants. There were no age differences for the fast automatic adjustment in normal pointing, but the early adjustment in anti-pointing tended to be later in the middle-aged adults. Finally, the difference in the onset of early and late adjustments in anti-pointing adjustments was greater among the middle-aged adults. Hence, this study is the first to show that aging slows down voluntary goal-directed movement control processes to greater extent than the automatic stimulus-driven processes.


Bacterial vaginosis: a synthesis of the literature on etiology, prevalence, risk factors, and relationship with chlamydia and gonorrhea infections.
Bacterial vaginosis (BV) is a common vaginal disorder in women of reproductive age. Since the initial work of Leopoldo in 1953 and Gardner and Dukes in 1955, researchers have not been able to identify the causative etiologic agent of BV. There is increasing evidence, however, that BV occurs when Lactobacillus spp., the predominant species in healthy vaginal flora, are replaced by anaerobic bacteria, such as Gardenella vaginalis, Mobiluncus curtisii, M. mulieris, other anaerobic bacteria and/or Mycoplasma hominis. Worldwide, it estimated that 20-30 % of women of reproductive age attending sexually transmitted infection (STI) clinics suffer from BV, and that its prevalence can be as high as 50-60 % in high-risk populations (e.g., those who practice commercial sex work (CSW). Epidemiological data show that women are more likely to report BV if they: 1) have had a higher number of lifetime sexual partners; 2) are unmarried; 3) have engaged in their first intercourse at a younger age; 4) have engaged in CSW, and 5) practice regular douching. In the past decade, several studies have provided evidence on the contribution of sexual activity to BV. However, it is difficult to state that BV is a STI without being able to identify the etiologic agent. BV has also emerged as a public health problem due to its association with other STIs, including: human immunodeficiency virus (HIV), herpes simplex virus type 2 (HSV-2), Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG). The most recent evidence on the association between BV and CT/NG infection comes from two secondary analyses of cohort data conducted among women attending STI clinics. Based on these studies, women with BV had a 1.8 and 1.9-fold increased risk for NG and CT infection, respectively. Taken together, BV is likely a risk factor or at least an important contributor to subsequent NG or CT infection in high-risk women. Additional research is required to determine whether this association is also present in other low-risk sexually active populations, such as among women in the US military. It is essential to conduct large scale cross-sectional or population-based case-control studies to investigate the role of BV as a risk factor for CT/NG infections. These studies could lead to the development of interventions aimed at reducing the burden associated with bacterial STIs worldwide.


Role of complementary and alternative medicine in geriatric care: A mini review.
Since time immemorial homo sapiens are subjected to both health and diseases states and seek treatment for succor and assuagement in compromised health states. Since last two decades the progressive rise in the alternative form of treatment cannot be ignored and population seems to be dissatisfied with the conventional treatment modalities and therefore, resort to other forms of treatment, mainly complementary and alternative medicine (CAM). The use of CAM is predominantly more popular in older adults and therefore, numerous research studies and clinical trials have been carried out to investigate the effectiveness of CAM in the management of both communicable and non-communicable disease. In this current mini review, we attempt to encompass the use of CAM in chronic non-communicable diseases that are most likely seen in geriatrics. The current review focuses not only on the reassurance of good health practices, emphasizing on the holistic development and strengthening the body's defense mechanisms, but also attempts to construct a pattern of self-care and patient empowerment in geriatrics. The issues of safety with CAM use cannot be sidelined and consultation with a health care professional is always advocated to the patient. Likewise, responsibility of the health care professional is to inform the patient about the safety and efficacy issues. In order to substantiate the efficacy and safety of CAMs, evidence-based studies and practices with consolidated standards should be planned and executed.


Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer's disease.
Late onset Alzheimer's disease is the most common form of dementia for which about 30 susceptibility loci have been reported. The aim of the current study is to identify novel genes associated with Alzheimer's disease using the largest up-to-date reference single nucleotide polymorphism (SNP) panel, the most accurate imputation software and a novel gene-based analysis approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 million genotypes from 17,008 Alzheimer's cases and 37,154 controls. In addition to earlier reported genes, we detected three novel gene-wide significant loci PPARGC1A (p = 2.2 × 10-6), RORA (p = 7.4 × 10-7) and ZNF423 (p = 2.1 × 10-6). PPARGC1A and RORA are involved in circadian rhythm; circadian disturbances are one of the earliest symptoms of Alzheimer's disease. PPARGC1A is additionally linked to energy metabolism and the generation of amyloid beta plaques. RORA is involved in a variety of functions apart from circadian rhythm, such as cholesterol metabolism and inflammation. The ZNF423 gene resides in an Alzheimer's disease-specific protein network and is likely involved with centrosomes and DNA damage repair.


Safety and efficacy of opicinumab in acute optic neuritis (RENEW): a randomised, placebo-controlled, phase 2 trial.
The human monoclonal antibody opicinumab (BIIB033, anti-LINGO-1) has shown remyelinating activity in preclinical studies. We therefore assessed the safety and tolerability, and efficacy of opicinumab given soon after a first acute optic neuritis episode. This randomised, double-blind, placebo-controlled, phase 2 study (RENEW) was done at 33 sites in Australia, Canada, and Europe in participants (aged 18-55 years) with a first unilateral acute optic neuritis episode within 28 days from study baseline. After treatment with high-dose methylprednisolone (1 g/day, intravenously, for 3-5 days), participants were assigned with a computer-generated sequence with permuted block randomisation (1:1) using a centralised interactive voice and web response system to receive 100 mg/kg opicinumab intravenously or placebo once every 4 weeks (six doses) and followed up to week 32. All study participants and all study staff, including the central readers, were masked to treatment assignment apart from the pharmacist responsible for preparing the study treatments and the pharmacy monitor at each site. The primary endpoint was remyelination at 24 weeks, measured as recovery of affected optic nerve conduction latency using full-field visual evoked potential (FF-VEP) versus the unaffected fellow eye at baseline. Analysis was by intention-to-treat (ITT); prespecified per-protocol (PP) analyses were also done. This study is registered with ClinicalTrials.gov, number NCT01721161. The study was done between Dec 21, 2012, and Oct 21, 2014. 82 participants were enrolled, and 41 in each group comprised the ITT population; 33 participants received opicinumab and 36 received placebo in the PP population. Adjusted mean treatment difference of opicinumab versus placebo was -3·5 ms (17·3 vs 20·8 [95% CI -10·6 to 3·7]; 17%; p=0·33) in the ITT population, and -7·6 ms in the PP population (14·7 vs 22·2 [-15·1 to 0·0]; 34%; p=0·050) at week 24 and -6·1 ms (15·1 vs 21·2 [-12·7 to 0·5]; 29%; p=0·071) in the ITT population and -9·1 ms (13·2 vs 22·4 [-16·1 to -2·1]; 41%; p=0·011) in the PP population at week 32. The overall incidence (34 [83%] of 41 in each group) and severity of adverse events (two [5%] of 41 severe adverse events with placebo vs three [7%] of 41 with opicinumab) were similar between groups and no significant effects on brain MRI measures were noted in either group (mean T2 lesion volume change, 0·05 mL [SD 0·21] for placebo vs 0·20 mL [0·52] with opicinumab; 27 [77%] of 35 participants with no change in gadolinium-enhancing [Gd+] lesion number with opicinumab vs 27 [79%] of 34 with placebo; mean 0·4 [SD 0·79 for the placebo group and 0·85 for the opicinumab group] new Gd+ lesions per participant in both groups). Treatment-related serious adverse events were reported in three (7%) of 41 participants in the opicinumab group (hypersensitivity [n=2], asymptomatic increase in transaminase concentrations [n=1]) and none of the participants in the placebo group. Remyelination did not differ significantly between the opicinumab and placebo groups in the ITT population at week 24. However, results from the prespecified PP population suggest that enhancing remyelination in the human CNS with opicinumab might be possible and warrant further clinical investigation. Biogen.


Lineage-Specific Genome Architecture Links Enhancers and Non-coding Disease Variants to Target Gene Promoters.
Long-range interactions between regulatory elements and gene promoters play key roles in transcriptional regulation. The vast majority of interactions are uncharted, constituting a major missing link in understanding genome control. Here, we use promoter capture Hi-C to identify interacting regions of 31,253 promoters in 17 human primary hematopoietic cell types. We show that promoter interactions are highly cell type specific and enriched for links between active promoters and epigenetically marked enhancers. Promoter interactomes reflect lineage relationships of the hematopoietic tree, consistent with dynamic remodeling of nuclear architecture during differentiation. Interacting regions are enriched in genetic variants linked with altered expression of genes they contact, highlighting their functional role. We exploit this rich resource to connect non-coding disease variants to putative target promoters, prioritizing thousands of disease-candidate genes and implicating disease pathways. Our results demonstrate the power of primary cell promoter interactomes to reveal insights into genomic regulatory mechanisms underlying common diseases.


Seeking Help From Everyone and No-One: Conceptualizing the Online Help-Seeking Process Among Adolescent Males.
Online help-seeking is an emerging trend within the 21st century. Yet, despite some movement toward developing online services, little is known about how young people locate, access, and receive support online. This study aims to conceptualize the process of online help-seeking among adolescent males. Modified photo-elicitation techniques were employed within eight semi-structured focus group sessions with adolescent males aged 14 to 15 years (n = 56) across seven schools in Northern Ireland. Thematic analyses were conducted within an ontological framework of critical realism and an epistemological framework of contextualism. Informal online help-seeking pathways increased opportunity for social support and reduced stigma but also included loss of control and reduced anonymity. Formal pathways offered increased anonymity but concerns were raised regarding participants' ability to locate and appraise the quality of information online. A conceptual model of online help-seeking has been developed to highlight the key help-seeking pathways taken by adolescent males.


Indications for rotator cuff repair: a systematic review.
Despite the popularity of surgical repair of rotator cuff tears, literature regarding the indications for and timing of surgery are sparse. We performed a systematic review of the literature to investigate factors influencing the decision to surgically repair symptomatic, full-thickness rotator cuff tears. Specifically, how do demographic variables, duration of symptoms, timing of surgery, physical examination findings, and size of tear affect treatment outcome and indications for surgery? We reviewed the best available evidence, which offers some guidelines for surgical decision making. Variables suggest earlier surgical intervention may be needed in the setting of weakness and substantial functional disability. With regard to demographic variables, the evidence is unclear regarding their association with treatment outcome. However, older chronological age does not seem to portend a worse outcome. Pending worker's compensation claims does seem to negatively affect treatment results. Further research is required to define the indications for surgery for full thickness rotator cuff tears. However, the design and conduct of an ethical study to obtain Level I evidence on this issue will be a major challenge.


A gene subset requires CTCF bookmarking during the fast post-mitotic reactivation of mouse ES cells.
Mitosis leads to global downregulation of transcription that then needs to be efficiently resumed. In somatic cells, this is mediated by a transient hyper-active state that first reactivates housekeeping and then cell identity genes. Here, we show that mouse embryonic stem cells, which display rapid cell cycles and spend little time in G1, also display accelerated reactivation dynamics. This uniquely fast global reactivation lacks specificity towards functional gene families, enabling the restoration of all regulatory functions before DNA replication. Genes displaying the fastest reactivation are bound by CTCF, a mitotic bookmarking transcription factor. In spite of this, the post-mitotic global burst is robust and largely insensitive to CTCF depletion. There are, however, around 350 genes that respond to CTCF depletion rapidly after mitotic exit. Remarkably, these are characterised by promoter-proximal mitotic bookmarking by CTCF. We propose that the structure of the cell cycle imposes distinct constrains to post-mitotic gene reactivation dynamics in different cell types, via mechanisms that are yet to be identified but that can be modulated by mitotic bookmarking factors.