Structural analogues of the natural products magnolol and honokiol as potent allosteric potentiators of GABA(A) receptors.

Biphenylic compounds related to the natural products magnolol and 4'-O-methylhonokiol were synthesized, evaluated and optimized as positive allosteric modulators (PAMs) of GABA(A) receptors. The most efficacious compounds were the magnolol analog 5-ethyl-5'-hexylbiphenyl-2,2'-diol (45) and the honokiol analogs 4'-methoxy-5-propylbiphenyl-2-ol (61), 5-butyl-4'-methoxybiphenyl-2-ol (62) and 5-hexyl-4'-methoxybiphenyl-2-ol (64), which showed a most powerful potentiation of GABA-induced currents (up to 20-fold at a GABA concentration of 3μM). They were found not to interfere with the allosteric sites occupied by known allosteric modulators, such as benzodiazepines and N-arachidonoylglycerol. These new PAMs will be useful as pharmacological tools and may have therapeutic potential for mono-therapy, or in combination, for example, with GABA(A) receptor agonists.

Reducing fall risk in the elderly: risk factors and fall prevention, a systematic review

Falls in the elderly are a major source of injury resulting in disability and hospitalization. They have a significant impact on individual basis (loss of quality of live, nursing home admissions) and social basis (healthcare costs). Even though falls in the elderly are common there are some well studied risk factors. Special emphasis should be put on sarcopenia/frailty, polypharmacy, multimorbidity, vitamin D status and home hazards. There are several well evaluated fall prevention approaches that either target a single fall risk factor or focus on multiple risk factors. It has to be kept in mind that not all fall prevention strategies are useful for all patients as for example dietary substitution of vitamin D is only recommended in people with increased risk for a vitamin D deficiency. Home hazard reduction strategies are more effective when combined with other fall prevention approaches such as for example exercise programs. In conclusion elderly patients should routinely be screened for relevant risk factors and if need an indiviudally targeted fall prevention program compiled.

Prognostic factors and outcomes in primary urethral cancer: results from the international collaboration on primary urethral carcinoma.

PURPOSE To evaluate risk factors for survival in a large international cohort of patients with primary urethral cancer (PUC). METHODS A series of 154 patients (109 men, 45 women) were diagnosed with PUC in ten referral centers between 1993 and 2012. Kaplan-Meier analysis with log-rank test was used to investigate various potential prognostic factors for recurrence-free (RFS) and overall survival (OS). Multivariate models were constructed to evaluate independent risk factors for recurrence and death. RESULTS Median age at definitive treatment was 66 years (IQR 58-76). Histology was urothelial carcinoma in 72 (47 %), squamous cell carcinoma in 46 (30 %), adenocarcinoma in 17 (11 %), and mixed and other histology in 11 (7 %) and nine (6 %), respectively. A high degree of concordance between clinical and pathologic nodal staging (cN+/cN0 vs. pN+/pN0; p < 0.001) was noted. For clinical nodal staging, the corresponding sensitivity, specificity, and overall accuracy for predicting pathologic nodal stage were 92.8, 92.3, and 92.4 %, respectively. In multivariable Cox-regression analysis for patients staged cM0 at initial diagnosis, RFS was significantly associated with clinical nodal stage (p < 0.001), tumor location (p < 0.001), and age (p = 0.001), whereas clinical nodal stage was the only independent predictor for OS (p = 0.026). CONCLUSIONS These data suggest that clinical nodal stage is a critical parameter for outcomes in PUC.

Circulating oxidized low-density lipoprotein (LDL) is associated with risk factors of the metabolic syndrome and LDL size in clinically healthy 58-year-old men (AIR study).

OBJECTIVES Hypothetically the atherogenic effect of the metabolic syndrome may be mediated through the increased occurrence of small LDL-particles which are easily modified to atherogenic oxidized LDL (ox-LDL). The aim of this study was to test this concept by examining the association between circulating ox-LDL, LDL-particle size, and the metabolic syndrome. DESIGN AND RESULTS A population-based sample of clinically healthy 58-year-old men (n = 391) was recruited. Ox-LDL was measured by ELISA (specific monoclonal antibody, mAb-4E6) and LDL-particle size by gradient gel electrophoresis. The results showed that ox-LDL significantly correlated to factors constituting the metabolic syndrome; triglycerides (r = 0.43), plasma insulin (r = 0.20), body mass index (r = 0.20), waist-to-hip ratio (r = 0.21) and HDL (r = -0.24); (P < 0.001). Ox-LDL correlated also to LDL-particle size (r = -0.42), Apo-B (r = 0.70), LDL (r = 0.65); (P < 0.001) and, furthermore, with Apo A-1 (r = -0.13) and heart rate (r = 0.13); (P < 0.01). CONCLUSION The metabolic syndrome was accompanied by high plasma ox-LDL concentrations compared with those without the syndrome. Ox-LDL levels were associated with most of the risk factors constituting the metabolic syndrome and was, in addition related to small LDL-particle size. To our knowledge the present study is the first one to demonstrate that circulating ox-LDL levels are associated with small LDL-particle size in a population representative sample of clinically healthy middle-aged men. The high degree of intercorrelation amongst several factors makes it difficult to clarify the independent role of any specific factor.

Differential influence of maternal and fetal pregnancy factors on the in-vitro induction of human regulatory T cells: a preliminary study.

PROBLEM Given the important role of regulatory T cells (Treg) for successful pregnancy, the ability of soluble maternal and fetal pregnancy factors to induce human Treg was investigated. METHOD OF STUDY Peripheral blood mononuclear cells (PBMCs) or isolated CD4+CD25‒ cells were cultured in the presence of pooled second or third trimester pregnancy sera, steroid hormones or supernatants from placental explants, and the numbers and function of induced CD4+CD25+FOXP3+ Treg were analysed. RESULTS Third trimester pregnancy sera and supernatants of early placental explants, but not sex steroid hormones, induced an increase of Tregs from PBMCs. Early placental supernatant containing high levels of tumour necrosis factor-α, interferon-γ, interleukins -1, -6 and -17, soluble human leucocyte antigen-G, and transforming growth factor-β1, increased the proportion of Treg most effectively and was able to induce interleukin-10-secreting-Treg from CD4+CD25‒cells. CONCLUSIONS Compared with circulating maternal factors, placental- and fetal-derived factors appear to exert a more powerful effect on numerical changes of Treg, thereby supporting fetomaternal tolerance during human pregnancy.

[Risk factors for the oral use of antibiotics and animal treatment incidence of weaners in Switzerland].

In the present study, risk factors for the use of oral antibiotics in weaned piglets were collected on 112 pig farms by a personal questionaire. The most common indication for an antibiotic group therapy was diarrhoea, and the most frequently used antibiotic was Colistin. On average, 27.33 daily doses in the control farms and 387.21 daily doses in the problem farms per 1000 weaners were administered on a given day. The significant risk factors in the multivariate model were poor hygiene in the water supply of suckling piglets, less than two doses ofprestarter feed daily, lack of an all-in-and-all-out production system in weaners, no herd book performance data analysis, and less than two of the legally prescribed veterinary visits per year. Furthermore, the treatment incidence of weaners for oral antibiotics was calculated on the basis of the drug inventory. This study provides evidence that the use of oral antibiotics in weaners can be reduced by interventions in hygiene and management.

Collective Voluntary Agreements and the Production of Less Polluting Products

Recently, some industries have collectively agreed not to produce models that do not meet an energy efficiency (and hence an environmental) standard. This paper presents a simple model that can be used to examine a voluntary collective agreement to limit or completely eliminate the low efficiency model of a given product (e.g., a low efficiency washing machine). We show that, when there is competition between firms, a collective agreement to limit or even eliminate production of the polluting model can actually increase profits for all firms in the industry. This suggests that a collective agreement of this type might actually be beneficial to firms, while at the same time improving environmental quality. However, the implicit enforcement that comes from the public nature of the commitment is necessary to ensure this outcome. This suggests that, by promoting such agreements, policymakers may be able to achieve substantial environmental gains with relatively little inducement. The impact on social welfare will then depend on whether these gains are sufficiently large to offset consumer losses from reductions in product variety and the associated price increases.

Maternal factors, fetal parameters and the risk of shoulder dystocia

Introduction. Shoulder dystocia is a serious complication of vaginal birth, with an incidence ranging from 0.15% to 2.1% of all births. There are approximately 4 million births per year in the United States and shoulder dystocia will be experienced by approximately 20,000 women each year. Although studies have been reported on shoulder dystocia, few studies have addressed both maternal and fetal risk factors. The purpose of this study was to identify maternal and fetal risk factors for shoulder dystocia while proposing factors that could be used to predict impending shoulder dystocia. ^ Material and methods. Articles were reviewed from Medline Pubmed using the search phrase "Risk factors of shoulder dystocia" and Medline Ovid using the search words "Dystocia", "Shoulder" and "Risk factors". Rigorous selection criteria were used to identify articles to be included in the study. Data collected from identified articles were transferred to STATA 10 software for trend analysis of the incidence of shoulder dystocia and the year of publication and a pair wise correlation was also determined between these two variables. ^ Results. Among a total of 343 studies identified, only 20 met our inclusion criteria and were retained for this review. The incidence of shoulder dystocia ranged from 0.07% to 2% and there was no particular trend or correlation between the incidence of shoulder dystocia and year of publication between 1985 and 2007. Pre-gestational and gestational diabetes, postdatism, obesity, birth weight > 4000g and fundal height at last visit > 40cm were identified as major risk factors in our series of studies. ^ Conclusion. Future strategies to predict shoulder dystocia should focus on pre-gestational and gestational diabetes mellitus, postdatism, obesity, birth weight > 4000g and fundal height at last visit > 40cm. ^

Analysis of prognostic factors for the development of metastases and survival in renal cell carcinoma patients

Introduction and objective. A number of prognostic factors have been reported for predicting survival in patients with renal cell carcinoma. Yet few studies have analyzed the effects of those factors at different stages of the disease process. In this study, different stages of disease progression starting from nephrectomy to metastasis, from metastasis to death, and from evaluation to death were evaluated. ^ Methods. In this retrospective follow-up study, records of 97 deceased renal cell carcinoma (RCC) patients were reviewed between September 2006 to October 2006. Patients with TNM Stage IV disease before nephrectomy or with cancer diagnoses other than RCC were excluded leaving 64 records for analysis. Patient TNM staging, Furhman Grade, age, tumor size, tumor volume, histology and patient gender were analyzed in relation to time to metastases. Time from nephrectomy to metastasis, TNM staging, Furhman Grade, age, tumor size, tumor volume, histology and patient gender were tested for significance in relation to time from metastases to death. Finally, analysis of laboratory values at time of evaluation, Eastern Cooperative Oncology Group performance status (ECOG), UCLA Integrated Staging System (UISS), time from nephrectomy to metastasis, TNM staging, Furhman Grade, age, tumor size, tumor volume, histology and patient gender were tested for significance in relation to time from evaluation to death. Linear regression and Cox Proportional Hazard (univariate and multivariate) was used for testing significance. Kaplan-Meier Log-Rank test was used to detect any significance between groups at various endpoints. ^ Results. Compared to negative lymph nodes at time of nephrectomy, a single positive lymph node had significantly shorter time to metastasis (p<0.0001). Compared to other histological types, clear cell histology had significant metastasis free survival (p=0.003). Clear cell histology compared to other types (p=0.0002 univariate, p=0.038 multivariate) and time to metastasis with log conversion (p=0.028) significantly affected time from metastasis to death. A greater than one year and greater than two year metastasis free interval, compared to patients that had metastasis before one and two years, had statistically significant survival benefit (p=0.004 and p=0.0318). Time from evaluation to death was affected by greater than one year metastasis free interval (p=0.0459), alcohol consumption (p=0.044), LDH (p=0.006), ECOG performance status (p<0.001), and hemoglobin level (p=0.0092). The UISS risk stratified the patient population in a statistically significant manner for survival (p=0.001). No other factors were found to be significant. ^ Conclusion. Clear cell histology is predictive for both time to metastasis and metastasis to death. Nodal status at time of nephrectomy may predict risk of metastasis. The time interval to metastasis significantly predicts time from metastasis to death and time from evaluation to death. ECOG performance status, and hemoglobin levels predicts survival outcome at evaluation. Finally, UISS appropriately stratifies risk in our population. ^

2005 ACIP recommendations effect on newborn hepatitis B vaccination rates and the factors affecting the successful implementation of the recommendations in the US

Background. Hepatitis B virus infection is one of major causes of acute and chronic hepatitis, cirrhosis of the liver, and primary hepatocellular carcinoma. Hepatitis B and its long term consequences are major health problems in the United States. Hepatitis B virus can be vertically transmitted from mother to infant during birth. Hepatitis B vaccination at birth is the most effective measure to prevent the newborn from HBV infection and its consequences, and is part of any robust perinatal hepatitis B prevention program following ACIP recommendations. Universal vaccination of the new born will prevent HBV infection during early childhood and, assuming that children receive the three dosages of the vaccine, it will also prevent adolescent and adult infections. Hepatitis B vaccination is now recommended as part of a comprehensive strategy to eliminate HBV transmission in the United States. ^ Objective. (1)To assess if the hepatitis B vaccination rates of newborn babies have improved after the 2005 ACIP recommendations. (2) To identify factors that affects the implementation of ACIP recommendation for hepatitis B vaccination in newborn babies. These factors will encourage ongoing improvement by identifying successful efforts and pinpointing areas that fall short and need attention. Additional focus areas may be identified to accelerate progress in eliminating perinatal HBV transmission.^ Methods. This review includes information from all pertinent articles, reviews, National immunization survey (NIS) surveys, reports, peer reviewed literature and web sources that were published after 1991.The key words to be used for selecting the articles are: "Perinatal Hepatitis B Prevention program", "Universal Hepatitis B vaccination of newborn babies", "ACIP Recommendations." The data gathered will be supplemented with an analysis of vaccination rates using the National Immunization Survey (NIS) birth dose coverage data.^ Results. The data collected in the NIS of 2009 reveals that the national coverage for birth dose of HepB increased to 60.8% from 50.1% in 2006. The largest increase observed for the birth dose in the past 5 years is from 2008 which increased from 55.3 % to 60.8% in 2009. By state, coverage ranged from 22.8% in Vermont to 80.7% in Michigan. %. Overall, in 2009 the estimated vaccination rates are in higher ranges for most states compared to the estimated vaccination rates in 2006. States vary widely in hepatitis B vaccination rates and in their compliance with the 2005 ACIP recommendation. There are many factors at various stages that might affect the successful implementation of the new ACIP recommendation as revealed in literature review. ^ Conclusions. HBV perinatal transmission can be eliminated, but it requires identifying the gaps and measures taken to increase the current vaccination coverage, ensuring timely administration of post exposure immunoprophylaxis and continued evaluations of the impact of immunization recommendations.^

What factors affect the visibility of Argentinean publications in humanities and social sciences in Scopus? Some evidence beyond the geographic realm of research

Se analizan los patrones de publicación y citación en ciencias humanas y sociales en Scopus en el período 2003-2012, según el alcance geográfico de la investigación. Los resultados muestran que los temas de alcance nacional tienen un predominio del español como lengua de publicación y una marcada preferencia por la autoría única frente a los patrones observados en el grupo de otros temas, no situados geográficamente, donde el inglés y la colaboración institucional es más fuerte y está más consolidada. La citación no parece estar determinada solo por el alcance geográfico de las investigaciones, sino también por el idioma de publicación, la coautoría y los perfiles de las revistas donde se publica. Se espera que los resultados den lugar a una reflexión constructiva sobre la cultura investigadora y editorial y que sean útiles como referencia para establecer criterios de evaluación en las comisiones evaluadoras y las políticas editoriales a nivel nacional

What factors affect the visibility of Argentinean publications in humanities and social sciences in Scopus? Some evidence beyond the geographic realm of research

Se analizan los patrones de publicación y citación en ciencias humanas y sociales en Scopus en el período 2003-2012, según el alcance geográfico de la investigación. Los resultados muestran que los temas de alcance nacional tienen un predominio del español como lengua de publicación y una marcada preferencia por la autoría única frente a los patrones observados en el grupo de otros temas, no situados geográficamente, donde el inglés y la colaboración institucional es más fuerte y está más consolidada. La citación no parece estar determinada solo por el alcance geográfico de las investigaciones, sino también por el idioma de publicación, la coautoría y los perfiles de las revistas donde se publica. Se espera que los resultados den lugar a una reflexión constructiva sobre la cultura investigadora y editorial y que sean útiles como referencia para establecer criterios de evaluación en las comisiones evaluadoras y las políticas editoriales a nivel nacional