Psychoeducation for siblings of people with severe mental illness.
Many people with severe mental illness (SMI) have siblings. Siblings are often both natural agents to promote service users' recovery and vulnerable to mental ill health due to the negative impact of psychosis within the family. Despite a wealth of research evidence supporting the effectiveness of psychoeducation for service users with SMI and their family members, in reducing relapse and promoting compliance with treatment, siblings remain relatively invisible in clinical service settings as well as in research studies. If psychoeducational interventions target siblings and improve siblings' knowledge, coping with caring and overall wellbeing, they could potentially provide a cost-effective option for supporting siblings with resulting benefits for service users' outcomes. To assess the effectiveness of psychoeducation compared with usual care or any other intervention in promoting wellbeing and reducing distress of siblings of people affected by SMI.The secondary objective was, if possible, to determine which type of psychoeducation is most effective. We searched the Cochrane Schizophrenia Group Trials Register and screened the reference lists of relevant reports and reviews (12th November 2013). We contacted trial authors for unpublished and specific data on siblings' outcomes. All relevant randomised controlled trials focusing on psychoeducational interventions targeting siblings of all ages (on their own or amongst other family members including service users) of individuals with SMI, using any means and formats of delivery, i.e. individual (family), groups, computer-based. Two review authors independently screened the abstracts and extracted data and two other authors independently checked the screening and extraction process. We contacted authors of trials to ascertain siblings' participation in the trials and seek sibling-specific data in those studies where siblings' data were grouped together with other participants' (most commonly other family members'/carers') outcomes. We calculated the risk difference (RD), its 95% confidence interval (CI) on an intention-to-treat basis. We presented continuous data using the mean difference statistic (MD) and 95% CIs. We assessed risk of bias for the included study and rated quality of evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE). We found 14 studies that included siblings amongst other family members in receipt of psychoeducational interventions. However, we were only able to include one small trial with relevant and available data (n = 9 siblings out of n = 84 family member/carer-participants) comparing psychoeducational intervention with standard care in a community care setting, over a duration of 21 months. There was insufficient evidence to determine the effects of psychoeducational interventions compared with standard care on 'siblings' quality of life' (n = 9, MD score 3.80 95% CI -0.26 to 7.86, low quality of evidence), coping with (family) burden (n = 9, MD -8.80 95% CI -15.22 to -2.34, low quality of evidence). No sibling left the study early by one year (n = 9, RD 0.00 CI -0.34 to 0.34, low quality of evidence). Low quality and insufficient evidence meant we were unable to determine the effects of psychoeducational interventions compared with standard care on service users' global mental state (n = 9, MD -0.60 CI -3.54 to 2.38, low quality of evidence), their frequency of re-hospitalisation (n = 9, MD -0.70 CI -2.46 to 1.06, low quality of evidence) or duration of inpatient stay (n = 9, MD -2.60 CI -6.34 to 1.14, low quality of evidence), whether their siblings received psychoeducation or not. No study data were available to address the other primary outcomes: 'siblings' psychosocial wellbeing', 'siblings' distress' and adverse effects. Most studies evaluating psychoeducational interventions recruited siblings along with other family members. However, the proportion of siblings in these studies was low and outcomes for siblings were not reported independently from those of other types of family members. Indeed, only data from one study with nine siblings were available for the review. The limited study data we obtained provides no clear good quality evidence to indicate psychoeducation is beneficial for siblings' wellbeing or for clinical outcomes of people affected by SMI. More randomised studies are justified and needed to understand the role of psychoeducation in addressing siblings' needs for information and support.


Laminin-5 inhibits human keratinocyte migration.
Laminin-5 (previously known as kalinin, epiligrin, and nicein) is an adhesive protein localized to the anchoring filaments within the lamina lucida space of the basement membrane zone lying between the epidermis and dermis of human skin. Anchoring filaments are structures within the lamina lucida and lie immediately beneath the hemidesmosomes of the overlying basal keratinocytes apposed to the basement membrane zone. Human keratinocytes synthesize and deposit laminin-5. Laminin-5 is present at the wound edge during reepithelialization. In this study, we demonstrate that laminin-5, a powerful matrix attachment factor for keratinocytes, inhibits human keratinocyte migration. We found that the inhibitory effect of laminin-5 on keratinocyte motility can be reversed by blocking the alpha3 integrin receptor. Laminin-5 inhibits keratinocyte motility driven by a collagen matrix in a concentration-dependent fashion. Using antisense oligonucleotides to the alpha3 chain of laminin-5 and an antibody that inhibits the cell binding function of secreted laminin-5, we demonstrated that the endogenous laminin-5 secreted by the keratinocyte also inhibits the keratinocyte's own migration on matrix. These findings explain the hypermotility that characterizes keratinocytes from patients who have forms of junctional epidermolysis bullosa associated with defects in one of the genes encoding for laminin-5 chains, resulting in low expression and/or functional inadequacy of laminin-5 in these patients. These studies also suggest that during reepithelialization of human skin wounds, the secreted laminin-5 stabilizes the migrating keratinocyte to establish the new basement membrane zone.


Progestin regulation of estrogen receptor messenger RNA in human breast cancer cells.
Progestin antagonism of estrogen action is thought to be due, at least in part, to progestin down-regulation of the estrogen receptor (ER). The molecular mechanisms subserving this effect, and the functional consequences in terms of target cell sensitivity to estrogens, are poorly understood. The present study was undertaken to address these issues with particular emphasis on progestin regulation of ER gene expression at the mRNA level. The T-47D human breast cancer cell line was treated with the synthetic progestin, ORG 2058, and the resultant changes in ER mRNA and ER levels determined by Northern analysis and radioligand binding, respectively. Treatment of T-47D cells with ORG 2058 resulted in rapid down-regulation of ER mRNA levels to a nadir of 35-40% of control by 6 h. This fall in ER mRNA levels was accompanied by a slower but more sustained fall in ER binding to a nadir of 20% of control at 24 h. Between 12 and 24 h ER mRNA levels recovered partially while ER ligand binding continued to fall. At 48 h both ER mRNA and ER concentrations remained depressed, although the latter to a greater extent. ER mRNA half-life was determined by [3H]uridine incorporation to be approximately 60 min and was unaffected by progestin treatment during the early rapid phase of ER mRNA down-regulation. These data demonstrate that progestins cause rapid down-regulation of the ER mRNA and suggest that during the early rapid phase of this effect, reduced transcription of the ER gene rather than altered ER mRNA half-life mediate this effect.(ABSTRACT TRUNCATED AT 250 WORDS)


Mean Expected Error in Prediction of Total Body Water: A True Accuracy Comparison between Bioimpedance Spectroscopy and Single Frequency Regression Equations.
For several decades electrical bioimpedance (EBI) has been used to assess body fluid distribution and body composition. Despite the development of several different approaches for assessing total body water (TBW), it remains uncertain whether bioimpedance spectroscopic (BIS) approaches are more accurate than single frequency regression equations. The main objective of this study was to answer this question by calculating the expected accuracy of a single measurement for different EBI methods. The results of this study showed that all methods produced similarly high correlation and concordance coefficients, indicating good accuracy as a method. Even the limits of agreement produced from the Bland-Altman analysis indicated that the performance of single frequency, Sun's prediction equations, at population level was close to the performance of both BIS methods; however, when comparing the Mean Absolute Percentage Error value between the single frequency prediction equations and the BIS methods, a significant difference was obtained, indicating slightly better accuracy for the BIS methods. Despite the higher accuracy of BIS methods over 50 kHz prediction equations at both population and individual level, the magnitude of the improvement was small. Such slight improvement in accuracy of BIS methods is suggested insufficient to warrant their clinical use where the most accurate predictions of TBW are required, for example, when assessing over-fluidic status on dialysis. To reach expected errors below 4-5%, novel and individualized approaches must be developed to improve the accuracy of bioimpedance-based methods for the advent of innovative personalized health monitoring applications.


Selective Upper-Body Perfusion Technique for Removal of Renal Cell Carcinoma Extending into the Inferior Vena Cava and Right Atrium.
Invasion of a renal cell carcinoma thrombus into the inferior vena cava and right atrium is infrequent. Reaching and completely excising a tumor from the inferior vena cava is particularly challenging because the liver covers the surgical field. We report the case of a 61-year-old man who underwent surgery for a renal cell carcinoma of the right kidney that extended into the inferior vena cava and right atrium. During dissection of the liver to expose the inferior vena cava, transesophageal echocardiograms revealed right atrial mass migration into the tricuspid valve. On emergency sternotomy, the tumor embolized into the main pulmonary artery. We used a selective upper-body perfusion technique involving moderately hypothermic cardiopulmonary bypass, cardioplegic arrest, and clamping of the descending aorta, which provided a bloodless surgical field for precise removal of the mass and resulted in minimal blood loss. Our technique might be useful in other patients with tumor thrombus extending into the right atrium because it reduces the need for transfusion and avoids the deleterious effects of deep hypothermic circulatory arrest. Our case also illustrates the importance of continuous transesophageal echocardiographic monitoring to detect thrombus embolization.


Parent- and self-reported dimensions of oppositionality in youth: construct validity, concurrent validity, and the prediction of criminal outcomes in adulthood.
Different dimensions of oppositional defiant disorder (ODD) have been found as valid predictors of further mental health problems and antisocial behaviors in youth. The present study aimed at testing the construct, concurrent, and predictive validity of ODD dimensions derived from parent- and self-report measures. Confirmatory factor analyses were performed to test a three-dimensional model (ODD-irritability, ODD-headstrong, and ODD-hurtful) and a two-dimensional model (ODD-irritability, ODD-headstrong/hurtful) based on items of the Child Behavior Checklist (CBCL) and the Youth Self Report (YSR) collected in a Swiss community study of 1,031 adolescents (519 boys, 512 girls) aged between 10.7 and 17.9 (M = 13.85, SD = 1.63) years. Logistic regression analyses were applied to predict scores in the clinical range of concurrent CBCL/YSR-anxiety/depression, CBCL/YSR-attention problems, and CBCL/YSR-delinquent behavior and depression as measured by the Center for Epidemiological Studies Depression Scale (CES-D) as well as to predict the presence of adult criminal convictions. CFA findings were in favor of a three-dimensional model rather than a two-dimensional model of ODD. The CBCL/YSR-ODD-irritability scale was related to concurrent self-reported depression, but also to attention problems and delinquent behavior. CBCL/YSR-ODD-hurtful and less strongly also the combined YSR-headstrong/hurtful scale predicted adult criminal outcomes. As proposed by the DSM-5 workgroup, different ODD-dimensions were confirmed by the present study. ODD-irritability predicts psychiatric comorbidity and ODD-hurtful symptoms should be specifically considered in youth at risk for criminal outcomes.


Metabolism of methylenedioxymethamphetamine: formation of dihydroxymethamphetamine and a quinone identified as its glutathione adduct.
The in vitro conversion of (+)-3,4-methylenedioxymethamphetamine and (-)-3,4-methylenedioxymethamphetamine to the corresponding catecholamine, 3,4-dihydroxymethamphetamine (N-methyl-alpha-methyldopamine), by rat liver microsomes was examined. Metabolite formation was monitored after short-term incubations using high-performance liquid chromatography-electrochemical detection to determine concentrations of the catecholamine. The formation of N-methyl-alpha-methyldopamine exhibited enantioselectivity and levels were significantly higher after incubation of the (+)-isomer. The reaction appears to be cytochrome P-450 dependent as it was sensitive to SKF 525A and carbon monoxide. The catecholamine was unstable and was metabolized rapidly to a compound capable of forming an adduct with glutathione (GSH) and other thiol compounds. This second oxidation did not appear to be cytochrome P-450-dependent but required NADPH and microsomal protein. Catecholamine oxidation was inhibited by superoxide dismutase and by reducing agents. The same catecholamine oxidation product, characterized as the GSH adduct, could be generated by a xanthine-xanthine oxidase mixture and by tyrosinase. Mass spectral data showed that it was a 1:1 amine GSH adduct. These results indicate that MDMA is oxidized by cytochrome P-450 to the catechol and the catecholamine oxidized by superoxide to a quinone to which GSH or other thiol functions add. The formation of this quinone and its thiol adducts may account for some of the irreversible actions of this compound on serotonergic neurons.


Timing and deciphering mitochondrial DNA macro-haplogroup R0 variability in Central Europe and Middle East.
Nearly half of the West Eurasian assemblage of human mitochondrial DNA (mtDNA) is fractioned into numerous sub-lineages of the predominant haplogroup (hg) R0. Several hypotheses have been proposed on the origin and the expansion times of some R0 sub-lineages, which were partially inconsistent with each other. Here we describe the phylogenetic structure and genetic variety of hg R0 in five European populations and one population from the Middle East. Our analysis of 1,350 mtDNA haplotypes belonging to R0, including entire control region sequences and 45 single nucleotide polymorphisms from the coding region, revealed significant differences in the distribution of different sub-hgs even between geographically closely located regions. Estimates of coalescence times that were derived using diverse algorithmic approaches consistently affirmed that the major expansions of the different R0 hgs occurred in the terminal Pleistocene and early Holocene. Given an estimated coalescence time of the distinct lineages of 10-18 kya, the differences in the distributions could hint to either limited maternal gene flow after the Last Glacial Maximum due to the alpine nature of the regions involved or to a stochastic loss of diversity due to environmental events and/or disease episodes occurred at different times and in distinctive regions. Our comparison of two different ways of obtaining the timing of the most recent common ancestor confirms that the time of a sudden expansion can be adequately recovered from control region data with valid confidence intervals. For reliable estimates, both procedures should be applied in order to cross-check the results for validity and soundness.


Long-Term Endurance Exercise in Humans Stimulates Cell Fusion of Myoblasts along with Fusogenic Endogenous Retroviral Genes In Vivo.
Myogenesis is defined as growth, differentiation and repair of muscles where cell fusion of myoblasts to multinucleated myofibers is one major characteristic. Other cell fusion events in humans are found with bone resorbing osteoclasts and placental syncytiotrophoblasts. No unifying gene regulation for natural cell fusions has been found. We analyzed skeletal muscle biopsies of competitive cyclists for muscle-specific attributes and expression of human endogenous retrovirus (ERV) envelope genes due to their involvement in cell fusion of osteoclasts and syncytiotrophoblasts. Comparing muscle biopsies from post- with the pre-competitive seasons a significant 2.25-fold increase of myonuclei/mm fiber, a 2.38-fold decrease of fiber area/nucleus and a 3.1-fold decrease of satellite cells (SCs) occurred. We propose that during the pre-competitive season SC proliferation occurred following with increased cell fusion during the competitive season. Expression of twenty-two envelope genes of muscle biopsies demonstrated a significant increase of putative muscle-cell fusogenic genes Syncytin-1 and Syncytin-3, but also for the non-fusogenic erv3. Immunohistochemistry analyses showed that Syncytin-1 mainly localized to the sarcolemma of myofibers positive for myosin heavy-chain isotypes. Cellular receptors SLC1A4 and SLC1A5 of Syncytin-1 showed significant decrease of expression in post-competitive muscles compared with the pre-competitive season, but only SLC1A4 protein expression localized throughout the myofiber. Erv3 protein was strongly expressed throughout the myofiber, whereas envK1-7 localized to SC nuclei and myonuclei. Syncytin-1 transcription factors, PPARγ and RXRα, showed no protein expression in the myofiber, whereas the pCREB-Ser133 activator of Syncytin-1 was enriched to SC nuclei and myonuclei. Syncytin-1, Syncytin-3, SLC1A4 and PAX7 gene regulations along with MyoD1 and myogenin were verified during proliferating or actively-fusing human primary myoblast cell cultures, resembling muscle biopsies of cyclists. Myoblast treatment with anti-Synycytin-1 abrogated cell fusion in vitro. Our findings support functional roles for ERV envelope proteins, especially Syncytin-1, contributing to cell fusion of myotubes.


Wideband wavelength conversion of 16 Gbaud 16-QAM and 5 Gbaud 64-QAM signals in a semiconductor optical amplifier.
We demonstrate wavelength conversion based on four-wave mixing in a semiconductor optical amplifier of signals with quadrature amplitude modulation (QAM). We first demonstrate wavelength conversion of 16 Gbaud 16-QAM signals over the entire C-band using two co-polarized pumps with low power penalty at the forward error correction threshold (FEC) for a wide range of input optical-signal-to-noise-ratio (OSNR). We also demonstrate for the first time wavelength conversion of 5 Gbaud 64-QAM signals in a semiconductor optical amplifier with bit-error rate below the FEC threshold over the entire C-band and investigate the dependence of the power penalty on input OSNR with a single pump configuration.


Gene Regulation by Redox-Sensitive Burkholderia thailandensis OhrR and Its Role in Bacterial Killing of Caenorhabditis elegans.
Fatty acid hydroperoxides are involved in host-pathogen interactions. In both plants and mammals, polyunsaturated fatty acids are liberated during infection and enzymatically oxidized to the corresponding toxic hydroperoxides during the defensive oxidative burst that is designed to thwart the infection. The bacterial transcription factor OhrR (organic hydroperoxide reductase regulator) is oxidized by organic hydroperoxides, as a result of which the ohr gene encoding organic hydroperoxide reductase is induced. This enzyme converts the hydroperoxides to less toxic alcohols. We show here that OhrR from Burkholderia thailandensis represses expression of ohr Gene expression is induced by cumene hydroperoxide and to a lesser extent by inorganic oxidants; however, Ohr contributes to degradation only of the organic hydroperoxide. B. thailandensis OhrR, which binds specific sites in both ohr and ohrR promoters, as evidenced by DNase I footprinting, belongs to the 2-Cys subfamily of OhrR proteins, and its oxidation leads to reversible disulfide bond formation between conserved N- and C-terminal cysteines in separate monomers. Oxidation of the N-terminal Cys is sufficient for attenuation of DNA binding in vitro, with complete restoration of DNA binding occurring on addition of a reducing agent. Surprisingly, both overexpression of ohr and deletion of ohr results in enhanced survival on exposure to organic hydroperoxide in vitro While Δohr cells are more virulent in a Caenorhabditis elegans model of infection, ΔohrR cells are less so. Taken together, our data suggest that B. thailandensis OhrR has several unconventional features and that both OhrR and organic hydroperoxides may contribute to virulence.


A status report on the sequencing and annotation of the P. falciparum genome.
Almost 5 years ago, an international consortium of sequencing centers and funding agencies was formed to sequence the genome of the human malaria parasite Plasmodium falciparum. A novel chromosome by chromosome shotgun strategy was devised to sequence this very AT-rich genome. Two of the 14 chromosomes have been completed and the remaining chromosomes are in the final stages of gap closure. The consortium recently developed plans for the annotation and analysis of the complete genome sequence and its publication in 2002.


Molecular docking analysis of 2009-H1N1 and 2004-H5N1 influenza virus HLA-B*4405-restricted HA epitope candidates: implications for TCR cross-recognition and vaccine development.
The pandemic 2009-H1N1 influenza virus circulated in the human population and caused thousands deaths worldwide. Studies on pandemic influenza vaccines have shown that T cell recognition to conserved epitopes and cross-reactive T cell responses are important when new strains emerge, especially in the absence of antibody cross-reactivity. In this work, using HLA-B*4405 and DM1-TCR structure model, we systematically generated high confidence conserved 2009-H1N1 T cell epitope candidates and investigated their potential cross-reactivity against H5N1 avian flu virus. Molecular docking analysis of differential DM1-TCR recognition of the 2009-H1N1 epitope candidates yielded a mosaic epitope (KEKMNTEFW) and potential H5N1 HA cross-reactive epitopes that could be applied as multivalent peptide towards influenza A vaccine development. Structural models of TCR cross-recognition between 2009-H1N1 and 2004-H5N1 revealed steric and topological effects of TCR contact residue mutations on TCR binding affinity. The results are novel with regard to HA epitopes and useful for developing possible vaccination strategies against the rapidly changing influenza viruses. Yet, the challenge of identifying epitope candidates that result in heterologous T cell immunity under natural influenza infection conditions can only be overcome if more structural data on the TCR repertoire become available.


Usefulness of the simplified cough test in evaluating cough reflex sensitivity as a screening test for silent aspiration.
To assess cough reflex sensitivity using the simplified cough test (SCT) and to evaluate the usefulness of SCT to screen for silent aspiration. THE HEALTHY CONTROL GROUP WAS DIVIDED INTO TWO SUBGROUPS: the young (n=29, 33.44±9.99 years) and the elderly (n=30, 63.66±4.37 years). The dysphagic elderly group (n=101, 72.95±9.19 years) consisted of patients with dysphagia, who suffered from a disease involving central nervous system (ischemic stroke 47, intracerebral hemorrhage 27, traumatic brain injury 11, encephalitis 5, hypoxic brain damage 3, and Parkinson disease 8). The SCT was performed using the mist of a 1% citric acid from a portable nebulizer. The time from the start of the inhalation to the first cough was measured as the cough latency. All the dysphagic patients underwent the videofluoroscopic swallowing study. The cough latency was more significantly prolonged in the healthy elderly group than in the healthy young group (p<0.001), and in the dysphagic elderly group than in the healthy elderly group (p<0.001). The sensitivity and specificity of SCT were 73.8% and 72.5% for detecting aspiration in the dysphagic patients, and 87.1% and 66.7% for detecting silent aspiration in the aspirated patients. Cough latency measured with the SCT reflects the impairment of cough reflex in healthy elderly and dysphasic subjects. The results of this study show that the SCT test can be a valuable method of screening aspiration with or without cough in dysphasic patients.


A scoping review of theories and conceptual frameworks used to analyse health financing policy processes in sub-Saharan Africa.
Health financing policies are critical policy instruments to achieve Universal Health Coverage, and they constitute a key area in policy analysis literature for the health policy and systems research (HPSR) field. Previous reviews have shown that analyses of policy change in low- and middle-income countries are under-theorised. This study aims to explore which theories and conceptual frameworks have been used in research on policy processes of health financing policy in sub-Saharan Africa and to identify challenges and lessons learned from their use. We conducted a scoping review of literature published in English and French between 2000 and 2017. We analysed 23 papers selected as studies of health financing policies in sub-Saharan African countries using policy process or health policy-related theory or conceptual framework ex ante. Theories and frameworks used alone were from political science (35%), economics (9%) and HPSR field (17%). Thirty-five per cent of authors adopted a 'do-it-yourself' (bricolage) approach combining theories and frameworks from within political science or between political science and HPSR. Kingdon's multiple streams theory (22%), Grindle and Thomas' arenas of conflict (26%) and Walt and Gilson's policy triangle (30%) were the most used. Authors select theories for their empirical relevance, methodological rational (e.g. comparison), availability of examples in literature, accessibility and consensus. Authors cite few operational and analytical challenges in using theory. The hybridisation, diversification and expansion of mid-range policy theories and conceptual frameworks used deductively in health financing policy reform research are issues for HPSR to consider. We make three recommendations for researchers in the HPSR field. Future research on health financing policy change processes in sub-Saharan Africa should include reflection on learning and challenges for using policy theories and frameworks in the context of HPSR.


An early look at changes in employer-sponsored insurance under the Affordable Care Act.
Critics frequently characterize the Affordable Care Act (ACA) as a threat to the survival of employer-sponsored insurance. The Medicaid expansion and Marketplace subsidies could adversely affect employers' incentives to offer health insurance and workers' incentives to take up such offers. This article takes advantage of timely data from the Health Reform Monitoring Survey for June 2013 through September 2014 to examine, from the perspective of workers, early changes in offer, take-up, and coverage rates for employer-sponsored insurance under the ACA. We found no evidence that any of these rates have declined under the ACA. They have, in fact, remained constant: around 82 percent, 86 percent, and 71 percent, respectively, for all workers and around 63 percent, 71 percent, and 45 percent, respectively, for low-income workers. To date, the ACA has had no effect on employer coverage. Economic incentives for workers to obtain coverage from employers remain strong.


The impact of infection after total hip arthroplasty on hospital and surgeon resource utilization.
Deep infection following total hip arthroplasty is a devastating complication for the patient and a costly one for patients, surgeons, hospitals, and payers. The purpose of this study was to compare revision total hip arthroplasty for infection, revision total hip arthroplasty for aseptic loosening, and primary total hip arthroplasty with respect to their impact on hospital and surgeon resource utilization and referral patterns to a tertiary-care hospital. Clinical, demographic, and economic data were obtained for twenty-five consecutive patients with an infection after a total hip replacement who underwent a two-stage revision arthroplasty (Group 1) performed by one of two surgeons, between March 2001 and December 2002, at a single institution. Similar data were collected during the same time-period for a cohort of twenty-five consecutive patients who underwent revision of both components because of aseptic loosening (Group 2) and twenty-five consecutive patients who underwent a primary hip arthroplasty (Group 3). Quantitative and categorical variables were compared among the groups. Referral patterns were examined by reviewing the primary diagnosis for all patients referred to our institution for a revision total hip arthroplasty during a five-year period. Revision procedures for infection were associated with longer operative time, more blood loss, and a higher number of complications compared with revisions for aseptic loosening or primary total hip arthroplasty (p < 0.02 for all). Revisions for infection were also associated with a higher total number of hospitalizations, total number of days in the hospital, total number of operations, total hospital costs, total outpatient visits, and total outpatient charges during the twelve-month period following the index procedure (p < 0.001 for all). The incidence of referrals to our institution for a diagnosis of infection following total hip arthroplasty increased significantly over a five-year period (Spearman rank correlation, 1.0; p = 0.0083), while referral rates for revision for causes other than infection remained relatively constant (Spearman rank correlation, 0.500; p = 0.3910). The treatment of patients with an infection after a total hip arthroplasty is associated with significantly greater hospital and physician resource utilization compared with the treatment of patients who have a revision because of aseptic loosening or who have a primary total hip arthroplasty. We believe that the lack of incremental reimbursement associated with these procedures results in strong financial disincentives for physicians and hospitals to provide treatment for patients with an infection after a total hip arthroplasty.


Direct radioimmunoassay and immunocytochemical localization of renin in human kidneys.
1. Highly specific antibodies to human renin were prepared in rabbits and used for the preparation of a renin-free substrate, the direct radioimmunoassay of renin in plasma and kidneys, and the localization of renin with fluoresceinated antibodies. 2. In a patient with a partially infarcted kidney, plasma renin activity was increased, and could be activated by acid. The direct measurement of plasma renin by radioimmunoassay gave identical values before and after acidification. 3. In the ischaemic part of the kidney, renin content was high, both by the enzymatic and the direct method of measurement. It was low in the non-ischaemic part of the kidney. 4. All afferent and some interlobular arteries of the obsolescent glomeruli were stained with fluoresceinated anti-renin antibodies. In the non-ischaemic area, the juxtaglomerular appratus did not stain. 5. Renin can now be measured in human plasma and kidney as an entity, by a specific radioimmunoassay. A direct investigation of this intrarenal hormone is now possible at the renal tissue level.


Diabetes and cardiovascular risk evaluation and management in primary care: progress and unresolved issues - rationale for a nationwide primary care project in Germany.
This review highlights established and more recently recognized risk factors for coronary heart disease (CHD) relevant for patients seen in primary care, emphasizing the key role of diabetes mellitus type 2. Recent trends in risk factor research as well as current methods of risk stratification, and new systemic markers are discussed. Beyond the need for more forceful public health strategies to improve early recognition and intervention, the necessity of an integrated comprehensive investigation of the overall characteristics of cardiovascular disease, especially in primary care patients as a prerequisite for future concerted actions is pointed out. Based on this, a large-scale epidemiological investigation focusing on CHD and diabetes in the primary care sector is suggested.


Respiratory symptoms and FEV1 as predictors of hospitalization and medication in the following 12 years due to respiratory disease.
The predictive value of cough, mucus hypersecretion, breathlessness, chronic bronchitis and forced expiratory volume in one second (FEV1) for hospitalization and medication were examined in a random population sample of 876 men, 46-69 yrs of age. All of the men were examined in 1974 with interview and lung function tests. Information on hospitalization in the period 1977-1986 was obtained from the Danish National Patient Register, and information on drug usage was obtained from 567 men in a questionnaire survey ultimo 1985. FEV1 was a strong predictor of both hospitalization and medication. Respiratory symptoms were good predictors of hospitalization due to either respiratory disease in general (odds ratios 2.56-3.29), or chronic obstructive pulmonary disease (COPD), (odds ratios 4.16-5.75). They contained predictive values in addition to that provided by FEV1. Respiratory symptoms were good predictors of medication for airway obstruction, relative risks 3.56-4.70, and/or airway disease in general, relative risks 2.67-4.69. After controlling for FEV1, cough was still significantly associated with treatment for airway disease in general and both cough, mucus hypersecretion and chronic bronchitis were significantly associated with treatment for airway obstruction. We conclude that apart from FEV1, respiratory symptoms are independent predictors of hospitalization and medication due to respiratory disease.


Nanocrystalline cellulose mediated seed-growth for ultra-robust colorimetric detection of hydrogen sulfide.
We describe an ultra-stable, ultra-robust, straightforward and low-cost approach for the colorimetric detection of H2S with nanocrystalline cellulose (NCC) based on the reaction of H2S with lead acetate. The presence of NCC not only mediates the seed growth of a PbS/NCC complex, but also acts as a stabilizer protecting PbS from precipitation. This stable system is so robust that it can be used to quantitatively detect H2S even after two-year storage.


Ancestral polyploidy in seed plants and angiosperms.
Whole-genome duplication (WGD), or polyploidy, followed by gene loss and diploidization has long been recognized as an important evolutionary force in animals, fungi and other organisms, especially plants. The success of angiosperms has been attributed, in part, to innovations associated with gene or whole-genome duplications, but evidence for proposed ancient genome duplications pre-dating the divergence of monocots and eudicots remains equivocal in analyses of conserved gene order. Here we use comprehensive phylogenomic analyses of sequenced plant genomes and more than 12.6 million new expressed-sequence-tag sequences from phylogenetically pivotal lineages to elucidate two groups of ancient gene duplications-one in the common ancestor of extant seed plants and the other in the common ancestor of extant angiosperms. Gene duplication events were intensely concentrated around 319 and 192 million years ago, implicating two WGDs in ancestral lineages shortly before the diversification of extant seed plants and extant angiosperms, respectively. Significantly, these ancestral WGDs resulted in the diversification of regulatory genes important to seed and flower development, suggesting that they were involved in major innovations that ultimately contributed to the rise and eventual dominance of seed plants and angiosperms.


Echocardiographic detection of coronary artery disease during dobutamine infusion.
Two-dimensional echocardiography performed during dobutamine infusion has been proposed as a potentially useful method for detecting coronary artery disease. However, the safety and diagnostic value of dobutamine stress echocardiography has not been established. In this study, echocardiograms were recorded during step-wise infusion of dobutamine to a maximum dose of 30 micrograms/kg/min in 103 patients who also underwent quantitative coronary angiography. The echocardiograms were digitally stored and displayed in a format that allowed simultaneous analysis of rest and stress images. Development of a new abnormality in regional function was used as an early end point for the dobutamine infusion. No patient had a symptomatic arrhythmia or complications from stress-induced ischemia. Significant coronary artery disease (greater than or equal to 50% diameter stenosis) was present in 35 of 55 patients who had normal echocardiograms at rest. The sensitivity and specificity of dobutamine-induced wall motion abnormalities for coronary artery disease was 89% (31 of 35) and 85% (17 of 20), respectively. The sensitivity was 81% (17 of 21) in those with one-vessel disease and 100% (14 of 14) in those with multivessel or left main disease. Forty-one of 48 patients with abnormal echocardiograms at baseline had localized rest wall motion abnormalities. Fifteen had coronary artery disease confined to regions that had abnormal rest wall motion, and 26 had disease remote from these regions. Thirteen of 15 patients (87%) without remote disease did not develop remote stress-induced abnormalities, and 21 of 26 (81%) who had remote disease developed corresponding abnormalities. Echocardiography combined with dobutamine infusion is a safe and accurate method for detecting coronary artery disease and for predicting the extent of disease in those who have localized rest wall motion abnormalities.


Perceptual-motor abilities in pre-school preterm children.
Several studies report a high percentage of premature infants presenting perceptual motor difficulties at school age. The new version of the Movement Assessment Battery for Children allows the assessment of perceptual-motor abilities in children from the age of 3years. To evaluate early perceptual-motor abilities in prematurely born children below the age of 4years. The Movement Assessment Battery for Children 2nd edition was administered to 105 low-risk prematurely born children (<32weeks gestation) and in a control group of 105 term-born children matched for age and sex. All children were assessed between the age of 3years and 3years-11months. 63 children (60%) had total scores above the 15th percentile, 15 (14.3%) had scores between the 5th and the 15th percentile, and 13 (12.4%) below the 5th percentile. The remaining 14 children (13.3%) refused to perform or to complete the test. The difference between preterm and control group was significant for total scores, Manual Dexterity and Aiming and Catching scores. In the preterm group there was a correlation between age at testing, total scores and Aiming and Catching subscores. The Movement ABC-2 subscores were significantly lower in children born below 29weeks. Perceptual-motor difficulties can already be detected on the assessment performed before the age of 4years. Prematurely born children assessed between 3years and 3years-3months appeared to have more difficulties in performing the test than the older ones or their age matched term-born peers. These findings support the possibility of a delayed maturation in the younger age group.


Snapshots of tRNA sulphuration via an adenylated intermediate.
Uridine at the first anticodon position (U34) of glutamate, lysine and glutamine transfer RNAs is universally modified by thiouridylase into 2-thiouridine (s2U34), which is crucial for precise translation by restricting codon-anticodon wobble during protein synthesis on the ribosome. However, it remains unclear how the enzyme incorporates reactive sulphur into the correct position of the uridine base. Here we present the crystal structures of the MnmA thiouridylase-tRNA complex in three discrete forms, which provide snapshots of the sequential chemical reactions during RNA sulphuration. On enzyme activation, an alpha-helix overhanging the active site is restructured into an idiosyncratic beta-hairpin-containing loop, which packs the flipped-out U34 deeply into the catalytic pocket and triggers the activation of the catalytic cysteine residues. The adenylated RNA intermediate is trapped. Thus, the active closed-conformation of the complex ensures accurate sulphur incorporation into the activated uridine carbon by forming a catalytic chamber to prevent solvent from accessing the catalytic site. The structures of the complex with glutamate tRNA further reveal how MnmA specifically recognizes its three different tRNA substrates. These findings provide the structural basis for a general mechanism whereby an enzyme incorporates a reactive atom at a precise position in a biological molecule.


A mapping of the evidence on integrated long term condition services.
Policies in long term conditions care continue to develop rapidly in England. Currently there is a focus on the integration of services and enabling patient and carer choice. Integration of care across disciplines and services is complex and community nursing services are commonly central to reorganization processes in long term condition care. This paper presents the findings of a mapping of the evidence on integration in long term condition services. Literature on horizontal integration including integrated teams will first be discussed, followed by an exploration of the evidence on vertical integration exemplified by integrated care pathways and disease management programmes. As a relatively recent service innovation, the mapping found a lack of evidence of the effectiveness of integration in long term conditions. Furthermore, the paper highlights the potential tension between vertical integration structures such as care pathways and the patient choice and empowerment agenda in long term conditions.


Long-Term Effects of Zinc Deficiency and Zinc Supplementation on Developmental Seizure-Induced Brain Damage and the Underlying GPR39/ZnT-3 and MBP Expression in the Hippocampus.
We previously illustrated that long-term upregulated expression of ZnT-3 in the hippocampus of rats that underwent neonatal seizures was restored by pretreatment with a ketogenic diet. It was recently demonstrated that upregulated expression of ZnT-3 was associated with increased concentrations of intracellular free zinc ions in an in vitro model of glutamate-induced hippocampal neuronal excitotoxic damage. However, there is still a lack of research on the effects of different concentrations of zinc in the diet on developmental convulsive brain injury. The aim of this study was to investigate the effects of different zinc concentrations in the diet on long-term neurobehavioral and seizure thresholds following lithium chloride-pilocarpine-induced developmental seizures. Sprague-Dawley rats (postnatal day 27, P27) were randomly assigned to one of six dietary groups for 4 weeks: normal zinc control group (Control group, 44 mg/kg Zn), Zn-deficient control group (ZD group, 2.7 mg/kg Zn), Zn supplemented control group (ZS group, 246 mg/kg Zn), pilocarpine-induced seizure plus regular zinc diet group (SE group, 44 mg/kg Zn), seizure plus low-zinc diet group (SE + ZD group, 2.7 mg/kg Zn), and seizure plus high-zinc diet group (SE + ZS group, 246 mg/kg Zn). Novel object recognition and passive avoidance tests were performed on rats at P42 and P56. After routine seizure threshold detection and Timm staining procedures at P57, expression of GPR39, ZnT-3, and MBP were detected in the hippocampus by Western blot analysis. The results revealed that the Zinc-deficient diet for 4 weeks aggravated the long-term adverse effects of developmental seizures, evidenced by weight, cognition, seizure threshold and serum zinc concentrations, which were paralleled by expression changes in hippocampal GPR39 and ZnT-3. In contrast, zinc supplementation for 4 weeks significantly improved damage-related changes described above and rescued the abnormal expression of GPR39, ZnT-3, and MBP in the hippocampus. Similar alterations between the expression pattern of MBP and aberrant sprouting of mossy fibers in the hippocampus may indicate that sprouting is a secondary pathological change caused by developmental brain damage rather than the cause of epileptogenesis. Up-regulation of MBP protein levels in the high zinc diet-treated seizure group as well as the corresponding improvement of cognitive impairment and reduced hippocampal mossy fiber regenerative sprouting, may represent a compensatory mechanism for neuronal membrane damage and repair.


Fracked ecology: Response of aquatic trophic structure and mercury biomagnification dynamics in the Marcellus Shale Formation.
Unconventional natural gas development and hydraulic fracturing practices (fracking) are increasing worldwide due to global energy demands. Research has only recently begun to assess fracking impacts to surrounding environments, and very little research is aimed at determining effects on aquatic biodiversity and contaminant biomagnification. Twenty-seven remotely-located streams in Pennsylvania's Marcellus Shale basin were sampled during June and July of 2012 and 2013. At each stream, stream physiochemical properties, trophic biodiversity, and structure and mercury levels were assessed. We used δ15N, δ13C, and methyl mercury to determine whether changes in methyl mercury biomagnification were related to the fracking occurring within the streams' watersheds. While we observed no difference in rates of biomagnificaion related to within-watershed fracking activities, we did observe elevated methyl mercury concentrations that were influenced by decreased stream pH, elevated dissolved stream water Hg values, decreased macroinvertebrate Index for Biotic Integrity scores, and lower Ephemeroptera, Plecoptera, and Trichoptera macroinvertebrate richness at stream sites where fracking had occurred within their watershed. We documented the loss of scrapers from streams with the highest well densities, and no fish or no fish diversity at streams with documented frackwater fluid spills. Our results suggest fracking has the potential to alter aquatic biodiversity and methyl mercury concentrations at the base of food webs.


A comparative study: do "clickers" increase student engagement in multidisciplinary clinical microbiology teaching?
Audience response devices, or "clickers", have been used in the education of future healthcare professionals for several years with varying success. They have been reported to improve the learning experience by promoting engagement and knowledge retention. In 2014, our department evaluated the use of "clickers" in a newly introduced multidisciplinary approach to teaching large groups of third year medical students clinical cases developed around a microbiology theme. Six multidisciplinary teaching sessions covering community-acquired pneumonia, tuberculosis, infective endocarditis, peritonitis, bloodstream infection with pyelonephritis and bacterial meningitis were included in the study. Three involved the use of the "clickers" and three did not. Consenting undergraduate students attended the designated classes and afterwards answered a short online quiz relating to the session. Students also answered a short questionnaire about the "clickers" to gauge their attitudes on the use of these devices. Of 310 students, 294 (94.8%) agreed to participate in the study. Interestingly, the grades of online quizzes after a session where a "clicker" was used were slightly lower. Looking only at the grades of students who engaged completely with the process (n = 19), there was no statistical difference to suggest that the devices had a positive or negative impact on knowledge retention. However, student attitudes to using the devices were positive overall. Fifty-five percent strongly agreed and 27% agreed that teaching sessions where the "clickers" were used were more engaging. Thirty-four percent strongly agreed and 36% agreed that the "clickers" made important concepts more memorable and 54% felt the device enhanced their understanding of the topic being covered. Overall, it appears that "clickers" help in improving student engagement in large classroom environments, enhance the learning experience, and are received positively by medical students but their impact on knowledge retention is variable.


Rapidly locating and characterizing pollutant releases in buildings.
Releases of airborne contaminants in or near a building can lead to significant human exposures unless prompt response measures are taken. However, possible responses can include conflicting strategies, such as shutting the ventilation system off versus running it in a purge mode or having occupants evacuate versus sheltering in place. The proper choice depends in part on knowing the source locations, the amounts released, and the likely future dispersion routes of the pollutants. We present an approach that estimates this information in real time. It applies Bayesian statistics to interpret measurements of airborne pollutant concentrations from multiple sensors placed in the building and computes best estimates and uncertainties of the release conditions. The algorithm is fast, capable of continuously updating the estimates as measurements stream in from sensors. We demonstrate the approach using a hypothetical pollutant release in a five-room building. Unknowns to the interpretation algorithm include location, duration, and strength of the source, and some building and weather conditions. Two sensor sampling plans and three levels of data quality are examined. Data interpretation in all examples is rapid; however, locating and characterizing the source with high probability depends on the amount and quality of data and the sampling plan.


Low Radiation Environment Switches the Overgrowth-Induced Cell Apoptosis Toward Autophagy.
Low radiation doses can affect and modulate cell responses to various stress stimuli, resulting in perturbations leading to resistance or sensitivity to damage. To explore possible mechanisms taking place at an environmental radiation exposure, we set-up twin biological models, one growing in a low radiation environment (LRE) laboratory at the Gran Sasso National Laboratory, and one growing in a reference radiation environment (RRE) laboratory at the Italian National Health Institute (Istituto Superiore di Sanità, ISS). Studies were performed on pKZ1 A11 mouse hybridoma cells, which are derived from the pKZ1 transgenic mouse model used to study the effects of low dose radiation, and focused on the analysis of cellular/molecular end-points, such as proliferation and expression of key proteins involved in stress response, apoptosis, and autophagy. Cells cultured up to 4 weeks in LRE showed no significant differences in proliferation rate compared to cells cultured in RRE. However, caspase-3 activation and PARP1 cleavage were observed in cells entering to an overgrowth state in RRE, indicating a triggering of apoptosis due to growth-stress conditions. Notably, in LRE conditions, cells responded to growth stress by switching toward autophagy. Interestingly, autophagic signaling induced by overgrowth in LRE correlated with activation of p53. Finally, the gamma component of environmental radiation did not significantly influence these biological responses since cells grown in LRE either in incubators with or without an iron shield did not modify their responses. Overall, in vitro data presented here suggest the hypothesis that environmental radiation contributes to the development and maintenance of balance and defense response in organisms.


Qualitative comparison of 3-T and 1.5-T MRI in the evaluation of epilepsy.
MRI at 3 T, which has a higher signal-to-noise ratio than 1.5-T MRI, is potentially more sensitive and specific at delineating epileptogenic lesions and may influence management of refractory epilepsy. The purposes of the current study were to compare image quality of 3-T MRI with that of 1.5-T MRI in the evaluation of epilepsy and, in cases of focal epilepsy, to compare the two field strengths in terms of lesion detection and characterization. Retrospective review was performed on 50 sets of MR images of 25 patients who underwent both 3-T and 1.5-T brain imaging with a dedicated epilepsy protocol, including fast spin-echo T2-weighted, coronal FLAIR, coronal fast multiplanar inversion recovery, and 3D spoiled gradient-recalled echo pulse sequences. Parameters assessed were distortion and artifact, lesion conspicuity, gray-white matter differentiation, and motion. Each pulse sequence was graded on a 4-point scale. Reviewers performed qualitative assessments of the site of abnormality and the most likely diagnosis. MRI at 3 T outperformed MRI at 1.5 T in all four parameters and was statistically superior (p < 0.05) to 1.5-T MRI in all categories except motion. On 3-T MRI, lesions were detected in 65 of 74 cases compared with 55 of 74 cases at 1.5 T (p = 0.0364), and lesions were accurately characterized in 63 of 74 cases compared with 51 of 74 cases at 1.5 T (p = 0.0194). The odds ratios showed identification of a focal epileptogenic lesion with 3-T MRI 2.57 times as likely as identification with 1.5-T MRI and accurate characterization of lesions 2.66 times as likely as characterization with 1.5-T MRI. In evaluation of epilepsy, MRI at 3 T performed better than 1.5-T MRI in image quality, detection of structural lesions, and characterization of lesions. High-field-strength imaging should be considered for patients with intractable epilepsy and normal or equivocal findings on 1.5-T MRI.


The 3'-to-5' exonuclease activity of vaccinia virus DNA polymerase is essential and plays a role in promoting virus genetic recombination.
Poxviruses are subjected to extraordinarily high levels of genetic recombination during infection, although the enzymes catalyzing these reactions have never been identified. However, it is clear that virus-encoded DNA polymerases play some unknown yet critical role in virus recombination. Using a novel, antiviral-drug-based strategy to dissect recombination and replication reactions, we now show that the 3'-to-5' proofreading exonuclease activity of the viral DNA polymerase plays a key role in promoting recombination reactions. Linear DNA substrates were prepared containing the dCMP analog cidofovir (CDV) incorporated into the 3' ends of the molecules. The drug blocked the formation of concatemeric recombinant molecules in vitro in a process that was catalyzed by the proofreading activity of vaccinia virus DNA polymerase. Recombinant formation was also blocked when CDV-containing recombination substrates were transfected into cells infected with wild-type vaccinia virus. These inhibitory effects could be overcome if CDV-containing substrates were transfected into cells infected with CDV-resistant (CDV(r)) viruses, but only when resistance was linked to an A314T substitution mutation mapping within the 3'-to-5' exonuclease domain of the viral polymerase. Viruses encoding a CDV(r) mutation in the polymerase domain still exhibited a CDV-induced recombination deficiency. The A314T substitution also enhanced the enzyme's capacity to excise CDV molecules from the 3' ends of duplex DNA and to recombine these DNAs in vitro, as judged from experiments using purified mutant DNA polymerase. The 3'-to-5' exonuclease activity appears to be an essential virus function, and our results suggest that this might be because poxviruses use it to promote genetic exchange.


circRNADb: A comprehensive database for human circular RNAs with protein-coding annotations.
It has been known that circular RNAs are widely expressed in human tissues and cells, and play important regulatory roles in physiological or pathological processes. However, there is lack of comprehensively annotated human circular RNAs database. In this study we established a circRNA database, named as circRNADb, containing 32,914 human exonic circRNAs carefully selected from diversified sources. The detailed information of the circRNA, including genomic information, exon splicing, genome sequence, internal ribosome entry site (IRES), open reading frame (ORF) and references were provided in circRNADb. In addition, circRNAs were found to be able to encode proteins, which have not been reported in any species. 16328 circRNAs were annotated to have ORF longer than 100 amino acids, of which 7170 have IRES elements. 46 circRNAs from 37 genes were found to have their corresponding proteins expressed according mass spectrometry. The database provides the function of data search, browse, download, submit and feedback for the user to study particular circular RNA of interest and update the database continually. circRNADb will be built to be a biological information platform for circRNA molecules and related biological functions in the future. The database can be freely available through the web server at http://reprod.njmu.edu.cn/circrnadb.


Chronic catastrophes: exploring the concentration and sustained nature of ambulatory prescription drug expenditures in the population of British Columbia, Canada.
Previous research has shown that a small proportion of the population accounts for a substantial proportion of spending on physician and hospital services. Much less is known about the high-cost users of ambulatory prescription medicines. We investigate the concentration and sustained nature of ambulatory prescription drug expenditures among residents of British Columbia, Canada in 2001 and 2004. Linking person-specific administrative data from several sources, we examine the demographics, socio-economic status, and health status of high-cost ambulatory pharmaceutical users and the extent that high-cost pharmaceutical use was sustained, at the individual level, from 2001 to 2004. The top 5% of users were responsible for 48% of ambulatory prescription expenditures in the province. A significant burden of morbidity, as well as sustained high expenditures, characterized these users. They were older, more likely to be female, more likely to be of low income, and more likely to be hospitalized and die within the year of study than other pharmaceutical users and non-users. Our results suggest that careful consideration should be given to the long-term financial burdens and access barriers created by pharmaceutical insurance policies that rely heavily on private payments by individuals. Our focus is on costs associated with ambulatory prescription drug use, however, had we included information on the cost of prescription drugs used in hospitals, we would likely have detected an even stronger relationship between high-cost pharmaceutical use and poor health status.


Mangiferin Ameliorates Cisplatin Induced Acute Kidney Injury by Upregulating Nrf-2 via the Activation of PI3K and Exhibits Synergistic Anticancer Activity With Cisplatin.
Occurrence of oxidative stress is the principal cause of acute kidney injury induced by cisplatin. Mangiferin, a naturally occurring antioxidant molecule, is found to ameliorate several oxidative stress mediated pathophysiological conditions including cancer. Cisplatin induced cytotoxicity was measured in NKE cells by MTT assay and microscopic analysis. Induction of oxidative stress and regulation of proapoptotic molecules were subsequently investigated by using different spectrophotometric analyses, FACS and immunocytochemistry. Induction of nephrotoxicity was determined by analyzing different serum biomarkers and histological parameters in vivo using swiss albino mice. Activation of NF-κB mediated pro-inflammatory and caspase dependent signaling cascades were investigated by semi-quantitative RT-PCR and immunoblotting. Mangiferin was found to ameliorate cisplatin induced nephrotoxicity in vitro and in vivo by attenuating the induction of oxidative stress and upregulating Nrf-2 mediated pro-survival signaling cascades via the activation of PI3K. Additionally, mangiferin showed synergistic anticancer activity with cisplatin in cancer cell lines (MCF-7 and SKRC-45) and EAC cell induced solid tumor bearing experimental mice. The ameliorative effect of mangiferin is primarily attributed to its anti-oxidant and anti-inflammatory properties. It acts differentially in normal tissue cells and tumor cells by modulating different cell survival regulatory signaling molecules. For the first time, the study reveals a mechanistic basis of mangiferin action against cisplatin induced nephrotoxicity. Since Mangiferin shows synergistic anticancer activity with cisplatin, it can be considered as a promising drug candidate, to be used in combination with cisplatin.


Natural History of Untreated Transverse/Sigmoid Sinus Thrombosis Following Posterior Fossa Surgery: Case Series and Literature Review.
Transverse or sigmoid sinus thrombosis occurs in 4% to 11% of patients following posterior fossa surgery. Anticoagulation has been the mainstay treatment, mostly based on extrapolation from the literature on spontaneous sinus thrombosis. To analyze the rate and associated complications of postoperative transverse/sigmoid sinus thrombosis for patients undergoing posterior fossa tumor resection. In this series, no antithrombotic therapy was initiated, and no postoperative treatment alterations were made following thrombosis diagnosis. Prospectively accrued cases from a single surgeon operating at a single academic center were retrospectively reviewed to determine the natural history of untreated transverse/sigmoid sinus thrombosis following posterior fossa surgery. Inclusion criteria were patients 18 yr or older undergoing resection of a posterior fossa tumor. A total of 538 patients were analyzed. In all 26 out of 538 (4.8%) patients were diagnosed with transverse/sigmoid sinus thrombosis on routine postoperative imaging. Early postoperative complication rate was 38% in the sinus thrombosis group, as compared to 15% in the no-thrombosis group (P = .02). A significantly higher rate of pseudomeningocele, dysphagia requiring gastrostomy, and cerebellar stroke signs were noted in patients with postoperative sinus thrombosis. However, only 3 of the 26 patients (12%) with postoperative sinus occlusion suffered prolonged central nervous system complications. Transverse/sigmoid sinus thrombosis following suboccipital craniectomy results in a higher rate of early complications; however, most of these complications resolve without anticoagulation. It may be reasonable, therefore, to manage these patients conservatively in order to avoid the risks associated with anticoagulation in the perioperative period.


Conformational analysis of triphenylphosphine ligands in stereogenic monometallic complexes: tools for predicting the preferred configuration of the triphenylphosphine rotor.
The extension of our simple model for predicting the propeller configuration of a triphenylphosphine ligand co-ordinated to achiral metal centres to include stereogenic metal systems is described. By considering nadir energy planes (NEP's) and a series of rigid-body calculations, a model has been developed to reliably predict the configuration of the triphenylphosphine rotor of stereogenic metal complexes. For complexes of the form [M(η(5)-C5H5)(PPh3)(L(1))(L(2))], where it is assumed that L(1) is larger than L(2), the configuration of the triphenylphosphine rotor may be predicted by viewing a Newman projection along the L(1)-M bond. In the orientation where the PPh3 unit is pointing vertically downwards and the orthogonal L(2) ligand is pointing to the right [i.e., an (RM)-configured complex, assuming that L(2) is ranked higher priority than L(1)], the conformation of L(1) can be expected to place the most sterically demanding substituent in the top-right quadrant. In cases where ligand L(1) still presents a steric incursion towards the PPh3 ligand (any part of L(1) other than H proximal to the PPh3 in the approximate zone -30° to +60° from the M-P bond) an (M)-configured rotor is expected, and when this interaction is not present a (P)-configured propeller is predicted. Without exception, these rules are consistent with all empirical data (>140 known crystal structures).


Are neuroendocrine cells of practical value as an independent prognostic parameter in prostate cancer?
To assess whether the presence of neuroendocrine (NE) cells is of value as an independent indicator of poor prognosis in patients with prostate carcinoma. A series of 160 consecutive patients with prostate carcinoma was studied retrospectively. In 120 there was sufficient tissue for review and to perform immunoperoxidase stains for neuron specific enolase (NSE) and chromogranin A (CGA). All patients had a potential follow-up of at least 5 years. Five-year survival was poorer for patients with a high tumour grade and stage at presentation compared to those with a lower grade and stage. NE cells were more common in higher grade and stage disease, but 5-year survival did not differ significantly between patients with NE cell positive and negative tumours. NE cells are of no practical value as an independent prognostic indicator in patients with prostatic adenocarcinoma.


Comparative sequencing of the serine-aspartate repeat-encoding region of the clumping factor B gene (clfB) for resolution within clonal groups of Staphylococcus aureus.
Molecular techniques such as spa typing and multilocus sequence typing use DNA sequence data for differentiating Staphylococcus aureus isolates. Although spa typing is capable of detecting both genetic micro- and macrovariation, it has less discriminatory power than the more labor-intensive pulsed-field gel electrophoresis (PFGE) and costly genomic DNA microarray analyses. This limitation hinders strain interrogation for newly emerging clones and outbreak investigations in hospital or community settings where robust clones are endemic. To overcome this constraint, we developed a typing system using DNA sequence analysis of the serine-aspartate (SD) repeat-encoding region within the gene encoding the keratin- and fibrinogen-binding clumping factor B (clfB typing) and tested whether it is capable of discriminating within clonal groups. We analyzed 116 S. aureus strains, and the repeat region was present in all isolates, varying in sequence and in length from 420 to 804 bp. In a sample of 36 well-characterized genetically diverse isolates, clfB typing subdivided identical spa and PFGE clusters which had been discriminated by whole-genome DNA microarray mapping. The combination of spa typing and clfB typing resulted in a discriminatory power (99.5%) substantially higher than that of spa typing alone and closely approached that of the whole-genome microarray (100.0%). clfB typing also successfully resolved genetic differences among isolates differentiated by PFGE that had been collected over short periods of time from single hospitals and that belonged to the most prevalent S. aureus clone in the United States. clfB typing demonstrated in vivo, in vitro, and interpatient transmission stability yet revealed that this locus may be recombinogenic in a primarily clonal population structure. Taken together, these data show that the SD repeat-encoding region of clfB is a highly stable marker of microvariation, that in conjunction with spa typing it may serve as a DNA sequence-based alternative to PFGE for investigating genetically similar strains, and that it is useful for analyzing collections of isolates in both long-term population-based and local epidemiologic studies.


Correlations between prefrontal neurons form a small-world network that optimizes the generation of multineuron sequences of activity.
Sequential patterns of prefrontal activity are believed to mediate important behaviors, e.g., working memory, but it remains unclear exactly how they are generated. In accordance with previous studies of cortical circuits, we found that prefrontal microcircuits in young adult mice spontaneously generate many more stereotyped sequences of activity than expected by chance. However, the key question of whether these sequences depend on a specific functional organization within the cortical microcircuit, or emerge simply as a by-product of random interactions between neurons, remains unanswered. We observed that correlations between prefrontal neurons do follow a specific functional organization-they have a small-world topology. However, until now it has not been possible to directly link small-world topologies to specific circuit functions, e.g., sequence generation. Therefore, we developed a novel analysis to address this issue. Specifically, we constructed surrogate data sets that have identical levels of network activity at every point in time but nevertheless represent various network topologies. We call this method shuffling activity to rearrange correlations (SHARC). We found that only surrogate data sets based on the actual small-world functional organization of prefrontal microcircuits were able to reproduce the levels of sequences observed in actual data. As expected, small-world data sets contained many more sequences than surrogate data sets with randomly arranged correlations. Surprisingly, small-world data sets also outperformed data sets in which correlations were maximally clustered. Thus the small-world functional organization of cortical microcircuits, which effectively balances the random and maximally clustered regimes, is optimal for producing stereotyped sequential patterns of activity.


The Arabidopsis AtUNC-93 Acts as a Positive Regulator of Abiotic Stress Tolerance and Plant Growth via Modulation of ABA Signaling and K+ Homeostasis.
Potassium (K+) is one of the essential macronutrients required for plant growth and development, and the maintenance of cellular K+ homeostasis is important for plants to adapt to abiotic stresses and growth. However, the mechanism involved has not been understood clearly. In this study, we demonstrated that AtUNC-93 plays a crucial role in this process under the control of abscisic acid (ABA). AtUNC-93 was localized to the plasma membrane and mainly expressed in the vascular tissues in Arabidopsis thaliana. The atunc-93 mutants showed typical K+-deficient symptoms under low-K+ conditions. The K+ contents of atunc-93 mutants were significantly reduced in shoots but not in roots under either low-K+ or normal conditions compared with wild type plants, whereas the AtUNC-93-overexpressing lines still maintained relatively higher K+ contents in shoots under low-K+ conditions, suggesting that AtUNC-93 positively regulates K+ translocation from roots to shoots. The atunc-93 plants exhibited dwarf phenotypes due to reduced cell expansion, while AtUNC-93-overexpressing plants had larger bodies because of increased cell expansion. After abiotic stress and ABA treatments, the atunc-93 mutants was more sensitive to salt, drought, osmotic, heat stress and ABA than wild type plants, while the AtUNC-93-overexpressing lines showed enhanced tolerance to these stresses and insensitive phenotype to ABA. Furthermore, alterations in the AtUNC-93 expression changed expression of many ABA-responsive and stress-related genes. Our findings reveal that AtUNC-93 functions as a positive regulator of abiotic stress tolerance and plant growth by maintaining K+ homeostasis through ABA signaling pathway in Arabidopsis.


Improved ground-state modulation characteristics in 1.3 μm InAs/GaAs quantum dot lasers by rapid thermal annealing.
We investigated the ground-state (GS) modulation characteristics of 1.3 μm InAs/GaAs quantum dot (QD) lasers that consist of either as-grown or annealed QDs. The choice of annealing conditions was determined from our recently reported results. With reference to the as-grown QD lasers, one obtains approximately 18% improvement in the modulation bandwidth from the annealed QD lasers. In addition, the modulation efficiency of the annealed QD lasers improves by approximately 45% as compared to the as-grown ones. The observed improvements are due to (1) the removal of defects which act as nonradiative recombination centers in the QD structure and (2) the reduction in the Auger-related recombination processes upon annealing.


Summary of the findings of the International Collaboration on Mild Traumatic Brain Injury Prognosis.
In 2004, the WHO Collaborating Centre for Neurotrauma, Prevention, Management and Rehabilitation Task Force published the first large systematic review and best evidence synthesis on the clinical course and prognosis for recovery after MTBI. Ten years later, the International Collaboration on Mild Traumatic Brain Injury Prognosis (ICoMP) formed to update the original WHO Task Force results. This summary review highlights important clinical findings from the full ICoMP results including the current evidence on the course and prognosis of recovery after MTBI in diverse patient populations (e.g., adults, athletes and children) and injury environments (e.g., motor vehicle collisions) as well as on the risk of long-term outcomes after MTBI, such as Parkinson's disease and dementia. Additional clinical areas of interest in MTBI are also discussed including the similarities between MTBI and other traumatic injuries and the risk of Second Impact Syndrome after sport concussion. Clinicians can use this information to help inform patients on the likely course of recovery after MTBI/concussion and guide better decision-making in the care of these patients.


Evolution driven by differential dispersal within a wild bird population.
Evolutionary theory predicts that local population divergence will depend on the balance between the diversifying effect of selection and the homogenizing effect of gene flow. However, spatial variation in the expression of genetic variation will also generate differential evolutionary responses. Furthermore, if dispersal is non-random it may actually reinforce, rather than counteract, evolutionary differentiation. Here we document the evolution of differences in body mass within a population of great tits, Parus major, inhabiting a single continuous woodland, over a 36-year period. We show that genetic variance for nestling body mass is spatially variable, that this generates different potential responses to selection, and that this diversifying effect is reinforced by non-random dispersal. Matching the patterns of variation, selection and evolution with population ecological data, we argue that the small-scale differentiation is driven by density-related differences in habitat quality affecting settlement decisions. Our data show that when gene flow is not homogeneous, evolutionary differentiation can be rapid and can occur over surprisingly small spatial scales. Our findings have important implications for questions of the scale of adaptation and speciation, and challenge the usual treatment of dispersal as a force opposing evolutionary differentiation.


Portopulmonary hypertension: a report from the US-based REVEAL Registry.
We evaluated survival and hospitalization rates in patients with group 1 portopulmonary hypertension (PoPH) in the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry). The REVEAL Registry is a multicenter, observational, US-based study evaluating demographics and management of patients with pulmonary arterial hypertension (PAH). Outcomes were examined using Kaplan-Meier time-to-event estimates and compared with patients with idiopathic PAH (IPAH) or familial PAH (FPAH). One hundred seventy-four patients with PoPH were enrolled in the REVEAL Registry (IPAH/FPAH; n = 1,478) from March 2006 to December 2009. Mean age was 53 ± 10 years, 52% were female, 32% were newly diagnosed, and 6% were New York Heart Association/World Health Organization functional class IV. Outcome parameters were worse for PoPH vs IPAH/FPAH, respectively: 2-year survival from enrollment (67% vs 85%, P < .001), 5-year survival from time of diagnosis (40% vs 64%, P < .001), and 2-year freedom from all-cause hospitalization (49% vs 59%, P = .019). However, despite worse outcomes, hemodynamic parameters at diagnosis were better for PoPH vs IPAH/FPAH, respectively: mean pulmonary artery pressure (49 mm Hg vs 53 mm Hg, P < .001), mean right atrial pressure (9 mm Hg vs 10 mm Hg, P = .005), pulmonary vascular resistance (8 Wood units vs 12 Wood units, P < .001), and cardiac output (5 L/min vs 4 L/min, P < .001). Compared with patients with IPAH/FPAH, patients with PoPH were less likely to be on a PAH-specific therapy at enrollment (P < .001), suggesting potential delays in therapy for patients with PoPH. Patients with PoPH had significantly poorer survival and all-cause hospitalization rates compared with patients with IPAH/FPAH, despite having better hemodynamics at diagnosis. Further studies should investigate such outcomes and differences in treatment patterns. ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov.


Pre-procedural pacing bias among transcatheter aortic valves with higher post-procedure pacing rates: evidence from the UK TAVI Registry.
Rates of permanent pacemaker (PPM) implantation following transcatheter aortic valve implantation (TAVI) are higher than following surgery and are dependent on patient factors and valve type. There is an increasing trend towards pre-emptive PPM insertion in patients with significant conduction disease prior to TAVI. We report results from the British Cardiovascular Intervention Society (BCIS) on pre- and post-procedural PPM implantation in the TAVI population. All centres in the United Kingdom performing TAVI are required to submit data on all TAVI procedures to the National database which are then reported annually. During 2015, there were 2373 TAVI procedures in the UK. 22.4% of TAVI patients had a PPM implanted either pre-procedure (including the distant past), or during the in-hospital procedural episode. Of these, 7.9% were pre-procedure and 14.5% post-procedure. Overall PPM rates were Edwards Sapien (13.5%), Medtronic CoreValve (28.2%) and Boston Lotus (42.1%; p < 0.01). Pre-procedure pacing rates were Edwards Sapien (6.0%), Medtronic CoreValve (9.1%) and Boston Lotus (12.3%; p < 0.01). Pre-procedural pacing rates for the Boston Lotus valve have risen year-on-year from 5.8% (2013) to 8.6% (2014) to 12.3% (2015). The UK TAVI Registry demonstrates a pre-procedural permanent pacing bias amongst patients receiving transcatheter valves with higher post-procedure pacing rates. Pre-emptive permanent pacing is likely to be responsible for this difference.


Acceleration of mammary neoplasia in transforming growth factor alpha transgenic mice by 7,12-dimethylbenzanthracene.
A mouse mammary tumor virus enhancer/promoter-transforming growth factor alpha transgenic mouse model has been described in which mammary tumors develop (Y. Matsui et al., Cell, 61: 1147-1155, 1990). In Line 29, spontaneous mammary tumors do not develop before 300 days of age in virgin females. Herein, Line 29 virgin females and their nontransgenic littermates have been treated with 7,12-dimethylbenzanthracene (DMBA) at varying dosages and times. Orogastric instillation of a single dose of DMBA (0.5 mg) dramatically accelerates mammary tumor formation when administered to 21- and 56-day-old virgin transgenic females compared to their nontransgenic littermates. The latency period for tumor formation is significantly shorter in transgenic mice treated with DMBA at 56 days compared to transgenic mice treated with DMBA at 21 days when results are analyzed by time from DMBA administration. To determine whether differences in the proliferative state of the mammary gland may contribute to these findings, bromodeoxyuridine incorporation was examined in the mammary glands of untreated 21- and 56-day-old mice. No differences in bromodeoxyuridine incorporation were detected between 21-day-old transgenic and nontransgenic mice. However, there was a marked increase in bromodeoxyuridine incorporation in the epithelial cells comprising the smaller ducts of 56-day-old transgenic mice compared to their nontransgenic littermates. These data indicate an enhancing interaction between a growth factor and a genotoxic carcinogen in mammary tumorigenesis and provide evidence that the transforming growth factor alpha transgene acts as a tumor promoter in this experimental model.


Fully automatic CAD design of the occlusal morphology of partial crowns compared to dental technicians' design.
The aim of this study was to compare the occlusal morphology of partial crown reconstructions made by dental technicians with reconstructions made by a fully automatic software process (biogeneric tooth model) in relation to the original natural tooth shape. Stone replicas of natural teeth were measured three-dimensionally before preparing inlay and onlay cavities for ceramic restorations (n = 5). For each preparation, five reconstructions (in total n = 25) were made by five dental technicians. Additionally, reconstructions were calculated automatically by a software based on the biogeneric tooth model (Cerec 3D). In order to compare the two different kinds of reconstruction, an objective metrical similarity measure (shape similarity value, SSV) based on calculated volumes between compared datasets was used. In 22 of 25 cases, the reconstructions made by the CAD software were closer to the original situation than the reconstructions made by the technicians. Mean average SSV of reconstructions made by the technicians (310.2 ± 78.8 μm) was significantly higher (p < 0.05) than mean SSV of CAD reconstructions (biogeneric model) (222.0 ± 47.7 μm). In the design of naturally shaped occlusal inlay/onlay surfaces, a fully automatic CAD system can be at least as good as conventional wax-ups by dental technicians. The adjustment of a dental restoration to fit the morphology of surrounding tooth structures, still presents challenges for the dentist.


Immunodefense of the round window.
A systematic analysis using serial sectioning of the round window membrane (RWM) in the cynomolgus monkey was performed. Light and transmission electron microscopy (LM and TEM) revealed that the RWM rim may be endowed with gland-like structures with glyco-protein material secernated into the window niche. This was detected in one third of the specimens. The secreted material displayed waste material and scavenger cells. There was also a rich network of capillaries, lymph channels, and sinusoidal veins containing leukocytes. Their abluminal surfaces displayed mature plasma cells and monocytes. These findings suggest that in certain primates the middle ear may have developed specific immunoprotective means for disposal of foreign and noxious substances before they reach the inner ear.


Interaction of -55CT polymorphism of UCP3 gene with Trp64Arg polymorphism of beta3adrenoreceptor gene on insulin resistance in obese patients.
The aim of our study was to investigate the interaction of tryptophan-to-arginine (Trp64Arg) missense mutation in the beta3 adrenoreceptor (Beta3AR) with polymorphism in the UCP3 promotor (-55C->T) on insulin resistance in obese patients. A population of 212 obese patients was analyzed. A bipolar electrical bioimpedance, a biochemical analysis and concentrations of adipocytokines were assessed. One hundred and sixty-two patients (76.4%) had the genotype Trp64/Trp64 (wild type group) and 50 patients Trp64/Arg64 (23.6%) (mutant type group). One hundred and seventy five (87.2%) had the genotype -55CC (wild type group) and 27 patients (22.8%) -55CT (mutant type group). Five patients (2.4%) had both polymorphisms Trp64/Arg64 and -55CT. Patients with one or both mutant genotypes had higher BMI, weight, fat mass, systolic blood pressure and waist circumference than wild type patients. Patients with 55CT or 55CT and Trp64Arg genotype had higher BMI, weight, fat mass, waist circumference, waist to hip ratio glucose, insulin, triglycerides and HOMA than wild type or Trp64Arg mutation. Higher concentrations of insulin, HOMA, triglycerides, glucose, BMI, weight, fat mass, waist to hip ratio and waist circumference were observed in patients with -55CT genotype alone or -55CT plus Trp64Arg genotypes than in patients without mutation or only Trp64Arg mutation.


Different types of chimera states: an interplay between spatial and dynamical chaos.
We discuss the occurrence of chimera states in networks of nonlocally coupled bistable oscillators, in which individual subsystems are characterized by the coexistence of regular (a fixed point or a limit cycle) and chaotic attractors. By analyzing the dependence of the network dynamics on the range and strength of coupling, we identify parameter regions for various chimera states, which are characterized by different types of chaotic behavior at the incoherent interval. Besides previously observed chimeras with space-temporal and spatial chaos in the incoherent intervals we observe another type of chimera state in which the incoherent interval is characterized by a central interval with standard space-temporal chaos and two narrow side intervals with spatial chaos. Our findings for the maps as well as for time-continuous van der Pol-Duffing's oscillators reveal that this type of chimera states represents characteristic spatiotemporal patterns at the transition from coherence to incoherence.


Adapting our Flood Risk Policies to Changing Conditions.
Flooding causes more damage and severely impacts more people worldwide than any other natural disaster. Flood risk in many parts of the United States is projected to increase due to both continued floodplain development and climate change. Many of our institutions and public policies are not designed to address these changing risk conditions. The practice of grandfathering insurance premiums in the National Flood Insurance Program (NFIP)-allowing an insured to keep a lower rate even when risk has increased-is one such policy. We link a flood hazard model to a flood insurance premium calculator in order to provide illustrative calculations of the possible impact of grandfathering on program revenue and policyholder premiums due to sea level rise for a New York City neighborhood. We conclude by discussing how to preserve the financial soundness of the NFIP while addressing the affordability of insurance in the face of increasing flood risk.


Hormonal therapy for menopause and ovarian cancer in a collaborative re-analysis of European studies.
The relationship between hormonal therapy for menopause (hormone replacement therapy, HRT) and the risk of epithelial ovarian cancer was evaluated in a collaborative re-analysis of 4 European case-control studies, 2 conducted in Greece and 1 each in Italy and the United Kingdom, including a total of 1,470 ovarian cancer cases and 3,271 hospital controls. Odds ratios (ORs) for HRT use were derived after allowance for study centre, age, socio-economic level, parity, menopausal status, type of menopause, age at menopause and oral contraceptive use. Overall, 109 (8.0%) ovarian cancer cases and 146 (4.7%) controls had ever used HRT, corresponding to an adjusted OR of 1.71 (95% confidence interval 1.30-2.25). The point estimates of the OR were 1.77 in the first Greek study, 1.40 in the second Greek study, 1.66 in the Italian study and 1.68 in the British study. Adjustment for possible confounders, including menopausal status, type of menopause, age at menopause and oral contraceptive use, slightly increased the OR. Limiting the analysis to women with information on relevant aspects of HRT use revealed a weak positive association with duration and some evidence that the excess relative risk for ovarian cancer declined with time since last use. These findings are compatible with a promoting effect of HRT in ovarian carcinogenesis. It is also possible, however, that the positive association reflects chance or selective administration of HRT to high-risk individuals, since until recently in Europe HRT was prescribed mainly for alleviation of peri-menopausal symptoms.


Ketamine: stimulating antidepressant treatment?
The appeal of ketamine - in promptly ameliorating depressive symptoms even in those with non-response - has led to a dramatic increase in its off-label use. Initial promising results await robust corroboration and key questions remain, particularly concerning its long-term administration. It is, therefore, timely to review the opinions of mood disorder experts worldwide pertaining to ketamine's potential as an option for treating depression and provide a synthesis of perspectives - derived from evidence and clinical experience - and to consider strategies for future investigations. G.S.M. Grant/research support: National Health Medical Research Council, NSW Health, Ramsay Health, American Foundation for Suicide Prevention, AstraZeneca, Eli Lilly & Co, Organon, Pfizer, Servier, and Wyeth; has been a speaker for Abbott, AstraZeneca, Eli Lilly & Co, Janssen Cilag, Lundbeck, Pfizer, Ranbaxy, Servier, and Wyeth; consultant: AstraZeneca, Eli Lilly & Co, Janssen Cilag, Lundbeck, and Servier. M.A.F. Grant support: AssureRx, Janssen Research & Development, Mayo Foundation, Myriad, National Institute of Alcohol Abuse and Alcoholism (NIAAA), National Institute of Mental Health (NIMH), Pfizer. Consultant (Mayo): Janssen Research & Development, LLC, Mitsubishi Tanabe Pharma Corporation, Myriad Genetics, Neuralstem Inc., Sunovion, Supernus Pharmaceuticals, Teva Pharmaceuticals. CME/travel support: American Physician Institute, CME Outfitters. Financial interest/Mayo Clinic 2016: AssureRx. S.H.K. Grant/research support: Brain Canada, Bristol Meyer Squibb, CIHR, Janssen, Johnson & Johnson, Lundbeck, Ontario Brain Institute, Pfizer, Servier, St. Jude Medical, Sunovion. T.A.K. Grant/research support (through Stanford University): Sunovion Pharmaceuticals and Merck & Co., Inc.; consultant/advisory board bember: Allergan, Inc., Janssen Pharmaceuticals, Myriad Genetic Laboratories, Inc., and Sunovion Pharmaceuticals; lecture honoraria (not Speaker's Bureau payments): GlaxoSmithKline, and Sunovion Pharmaceuticals; royalties from American Psychiatric Publishing, Inc. Also, AstraZeneca Pharmaceuticals LP provided publication support to Parexel for preparation of a manuscript. Spouse employee and stockholder of Janssen Pharmaceuticals. R.W.L. Honoraria for speaking/advising/consulting, and/or received research funds: AstraZeneca, Brain Canada, Bristol Myers Squibb, Canadian Institutes of Health Research, Canadian Depression Research and Intervention Network, Canadian Network for Mood and Anxiety Treatments, Canadian Psychiatric Association, Coast Capital Savings, Johnson and Johnson, Lundbeck, Lundbeck Institute, Pfizer, Servier, St. Jude Medical, Takeda University, Health Network Foundation, and Vancouver Coastal Health Research Institute. R.M. Investigator Janssen trials of esketamine; 'paid-for' ketamine clinic operated by Oxford Health NHS Foundation Trust - fees used to support the Trust. M.J.O. Consultant: Sunovion and Acadia Pharmaceuticals. Full-time employee of U.S. Department of Veterans Affairs. M.E.T. Advisory/Consultant: Alkermes, Allergan, AstraZeneca, Bristol-Myers Squibb Company, Cerecor inc., Eli Lilly & Co., Forest Laboratories, Gerson Lehrman Group, Fabre-Kramer Pharmaceuticals, Inc., GlaxoSmithKline, Guidepoint Global, H. Lundbeck A/S, MedAvante Inc., Merck and Co. Inc. (formerly Schering Plough and Organon), Moksha8, Naurex Inc., Neuronetics Inc., Novartis, Ortho-McNeil Pharmaceuticals (Johnson & Johnson; Janssen), Otsuka, Pamlab, L.L.C. (Nestle), Pfizer (formerly Wyeth Ayerst Pharmaceuticals), Shire US Inc., Sunovion Pharmaceuticals Inc., Trius Therapeutical Inc. and Takeda. Grant support: Agency for Healthcare Research and Quality, Alkermes, AssureRx, Avanir, Forest Pharmaceuticals, Janssen, National Institute of Mental Health, and Otsuka Pharmaceuticals. Speakers Bureau: None since June, 2010. Equity Holdings: MedAvante, Inc. Royalties: American Psychiatric Foundation, Guilford Publications, Herald House, W.W. Norton & Company, Inc. Spouse's employment: Peloton Advantage, which does business with Pfizer. M.T. Full-time employee at Lilly 1997 to 2008. Honoraria/consulted: Abbott, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Lilly, Johnson & Johnson, Allergan, Otsuka, Merck, Sunovion, Forest, Geodon Richter Plc, Roche, Elan, Alkermes, Lundbeck, Teva, Pamlab, Minerva, Wyeth and Wiley Publishing. Spouse was full time-employee at Lilly 1998-2013. © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.


Testosterone threshold levels and lean tissue mass targets needed to enhance skeletal muscle strength and function: the HORMA trial.
In the HORMA (Hormonal Regulators of Muscle and Metabolism in Aging) Trial, supplemental testosterone and recombinant human growth hormone (rhGH) enhanced lean body mass, appendicular skeletal muscle mass, muscle performance, and physical function, but there was substantial interindividual variability in outcomes. One hundred and twelve men aged 65-90 years received testosterone gel (5 g/d vs 10 g/d via Leydig cell clamp) and rhGH (0 vs 3 vs 5 μg/kg/d) in a double-masked 2 × 3 factorial design for 16 weeks. Outcomes included lean tissue mass by dual energy x-ray absorptiometry, one-repetition maximum strength, Margaria stair power, and activity questionnaires. We used pathway analysis to determine the relationship between changes in hormone levels, muscle mass, strength, and function. Increases in total testosterone of 1046 ng/dL (95% confidence interval = 1040-1051) and 898 ng/dL (95% confidence interval = 892-904) were necessary to achieve median increases in lean body mass of 1.5 kg and appendicular skeletal muscle mass of 0.8 kg, respectively, which were required to significantly enhance one-repetition maximum strength (≥ 30%). Co-treatment with rhGH lowered the testosterone levels (quantified using liquid chromatography-tandem mass spectrometry) necessary to reach these lean mass thresholds. Changes in one-repetition maximum strength were associated with increases in stair climbing power (r = .26, p = .01). Pathway analysis supported the model that changes in testosterone and insulin-like growth factor 1 levels are related to changes in lean body mass needed to enhance muscle performance and physical function. Testosterone's effects on physical activity were mediated through a different pathway because testosterone directly affected Physical Activity Score of the Elderly. To enhance muscle strength and physical function, threshold improvements in lean body mass and appendicular skeletal muscle mass are necessary and these can be achieved by targeting changes in testosterone levels. rhGH augments the effects of testosterone. To maximize functional improvements, the doses of anabolic hormones should be titrated to achieve target blood levels.


Femtosecond dispersion compensation with multilayer coatings: toward the optical octave.
Dispersive multilayer coatings have found widespread use, particularly in the compensation of material dispersion in femtosecond oscillators and amplifiers. Other than prism or grating sequences, only chirped mirrors allow for the compensation of a much more general spectral dependence of the dispersion. The current state of the art in ultrabroadband mirror design for dispersion compensation is reviewed. Approaches to expand the utility of chirped-mirror coatings toward the coverage of an even-wider bandwidth beyond the optical octave are discussed.


Efficacy of IDET for relief of leg pain associated with discogenic low back pain.
Intradiscal electrothermal annuloplasty (IDET) is an effective treatment for chronic discogenic low back pain (LBP). However, efficacy of IDET for the treatment of referred leg pain has not been examined. This study was performed to assess the long-term efficacy of IDET for the treatment of referred leg pain in chronic discogenic LBP patients. Data were retrospectively analyzed as an IDET case series from January 1999 to December 2000. The IDET procedure was performed at 1-3 symptomatic levels confirmed by pressure-controlled discography. General pain outcome was evaluated by Visual Analog Scale (VAS). LBP and leg pain were assessed separately using five-point pain scales (subsets of the North American Spine Society [NASS] LBP outcome assessment instrument: 0 = no pain, 4 = worst pain) at the 18-month follow-up. Among 129 patients who underwent IDET, 30 patients underwent subsequent back surgery and were excluded from the study, giving a total of 99 patients. Eighty-three patients (83.8%) had leg pain without sciatica. Fifty-two (52.5%), 21 (21.2%), and 8 (8.0%) patients showed LBP > leg pain, LBP = leg pain and LBP < leg pain, respectively. Fifty-three out of 83 patients (63.9%) showed post-IDET improvement in pain, with a mean VAS score of 3.28 +/- 2.31. Thirty patients (36.1%) showed no improvement. A statistically significant (P < 0.05) improvement in subjective back and referred leg pain was observed. Improvements in back and referred leg pain were well-correlated (r = 0.721, P < 0.01). A relatively large number of LBP patients who underwent IDET (84%) presented with referred leg pain without sciatica. The IDET procedure afforded improvements in leg pain that correlated well with improvements in back pain (0.75/4 and 0.88/4, respectively). These data suggest that IDET may relieve associated limb pain in chronic discogenic LBP patients.