Smith-Lemli-Opitz syndrome: Objective assessment of facial phenotype.
Smith-Lemli-Opitz syndrome (SLOS), is an autosomal recessive condition caused by cholesterol synthesis deficiency which results in a wide phenotypic spectrum which includes multiple malformations, distinctive facial appearance, and intellectual disability. This anthropometric and observational study was carried out to define the key facial characteristics of individuals with SLOS and to evaluate evolution of the facial phenotype with age. Clinical photographs were obtained on 51 subjects with SLOS and standardized facial anthropometry was performed on 42; the ages ranged from 6 months to 20 years. For each individual, 22 standardized cranial and facial measurements were obtained and compared to published age- and sex-matched controls. Craniofacial pattern profiles were compared between sexes, various age groups, plasma cholesterol concentration at the time of diagnosis, and physical severity score. Mean-Z, a measurement of overall facial size, and craniofacial variability index (CVI), a summary anthropometric measure of craniofacial deviation from the norm, were calculated and compared according to methods published previously. A characteristic craniofacial pattern profile was universally present: narrow forehead, brachycephaly, short palpebral fissures, short nasal ridge, anteverted nares, flat face, normal jaw width, and retrognathia. The facial measurements of subjects with SLOS had higher deviations from the norm with mean CVI of 2.11; SD = 0.47 (controls: Mean = 0.76, SD = 0.19; <0.0001) than age- and sex-matched controls. Their faces were also smaller than controls: 70% of subjects had mean-Z values 2 SD below the mean for controls; average Z-score was -1.64; SD = 0.85 (controls: mean = 0, SD = 0.64; <0.0001). There were no significant differences in the craniofacial pattern profile between the sexes or clinical severity as measured by either plasma cholesterol level at the time of diagnosis or the physical severity score. Patients with a lower weight at the time of assessment and patients with higher physical severity score had higher CVI measures (P < 0.001 and P < 0.002, respectively), suggesting that the degree of deviation from craniofacial norms is a function of the overall physical severity.


Evaluation of Household Bleach as an Ovicide for the Control of Aedes aegypti.
Accumulations of dormant eggs in container habitats allow Aedes aegypti populations to survive harsh environmental conditions and may frustrate control interventions directed at larval and adult life stages. While sodium hypochlorite solutions (NaOCl) have long been recognized as ovicides for use against dengue vectors, the susceptibility of eggs to spray applications has not been robustly evaluated on substrate materials representative of the most frequently utilized artificial container habitats. Experiments were performed under controlled and natural conditions by applying dilutions of household bleach (52.5 ppt NaOCl) as a spray to eggs on plastic, rubber, and concrete surfaces, with and without a smectite clay thickener. Laboratory assays identified the minimum NaOCl concentrations required to eliminate eggs on plastic (10 ppt), rubber (20 ppt) and concrete (20 ppt) surfaces. Addition of smectite clay reduced the minimum effective concentration to 10 ppt NaOCl for all 3 substrates. A minimum exposure period of 24 h was required to completely eliminate egg viability on concrete surfaces, even at the highest NaOCl concentration (52.5 ppt). Field experiments verified that spray application of a 1∶3 dilution of household bleach mixed with smectite clay can reduce egg hatching by ≥ 99% in shaded and sun-exposed plastic containers. Similarly, 4∶1 dilution of household bleach (with or without smectite clay) eliminated ≥ 98% of eggs from concrete surfaces in outdoor, water-filled drums. In this study, we propose a practical, effective and safe strategy for using household bleach to eliminate Ae. aegypti eggs in a range of artificial container habitats.


Effect of Rotation Crops on Heterodera glycines Population Density in a Greenhouse Screening Study.
Crop rotation is a common means of reducing pathogen populations in soil. Several rotation crops have been shown to reduce soybean cyst nematode (Heterodera glycines) populations, but a comprehensive study of the optimal crops is needed. A greenhouse study was conducted to determine the effect of growth and decomposition of 46 crops on population density of H. glycines. Crops were sown in soil infested with H. glycines. Plants were maintained until 75 days after planting, when the soil was mixed, a sample of the soil removed to determine egg density, and shoots and roots chopped and mixed into the soil. After 56 days, soil samples were again taken for egg counts, and a susceptible soybean ('Sturdy') was planted in the soil as a bioassay to determine egg viability. Sunn hemp (Crotalaria juncea), forage pea (Pisum sativum), lab-lab bean (Lablab purpureus), Illinois bundleflower (Desman-thus illinoensis), and alfalfa (Medicago sativa) generally resulted in smaller egg population density in soil or number of cysts formed on soybean in the bioassay than the fallow control. Sunn hemp most consistently showed the lowest numbers of eggs and cysts. As a group, legumes resulted in lower egg population densities than monocots, Brassica species, and other dicots.


Increased sympathetic and decreased parasympathetic cardiovascular modulation in normal humans with acute sleep deprivation.
Cardiovascular autonomic modulation during 36 h of total sleep deprivation (SD) was assessed in 18 normal subjects (16 men, 2 women, 26.0 +/- 4.6 yr old). ECG and continuous blood pressure (BP) from radial artery tonometry were obtained at 2100 on the first study night (baseline) and every subsequent 12 h of SD. Each measurement period included resting supine, seated, and seated performing computerized tasks and measured vigilance and executive function. Subjects were not supine in the periods between measurements. Spectral analysis of heart rate variability (HRV) and BP variability (BPV) was computed for cardiac parasympathetic modulation [high-frequency power (HF)], sympathetic modulation [low-frequency power (LF)], sympathovagal balance (LF/HF power of R-R variability), and BPV sympathetic modulation (at LF). All spectral data were expressed in normalized units [(total power of the components/total power-very LF) x 100]. Spontaneous baroreflex sensitivity (BRS), based on systolic BP and pulse interval powers, was also measured. Supine and sitting, BPV LF was significantly increased from baseline at 12, 24, and 36 h of SD. Sitting, HRV LF was increased at 12 and 24 h of SD, HRV HF was decreased at 12 h SD, and HRV LF/HF power of R-R variability was increased at 12 h of SD. BRS was decreased at 24 h of SD supine and seated. During the simple reaction time task (vigilance testing), the significantly increased sympathetic and decreased parasympathetic cardiac modulation and BRS extended through 36 h of SD. In summary, acute SD was associated with increased sympathetic and decreased parasympathetic cardiovascular modulation and decreased BRS, most consistently in the seated position and during simple reaction-time testing.


Chromoendoscopy Is More Effective Than Standard Colonoscopy in Detecting Dysplasia During Long-term Surveillance of Patients With Colitis.
Patients with colitis have an increased risk of colorectal cancer, compared with persons without colitis. Many studies have shown chromoendoscopy (CE) to be superior to standard methods of detecting dysplasia in patients with colitis at index examination. We performed a prospective, longitudinal study to compare standard colonoscopy vs CE in detecting dysplasia in patients with inflammatory bowel diseases in a surveillance program. We analyzed data from 68 patients (44 men, 24 women) diagnosed with ulcerative colitis (n = 55) or Crohn's disease (n = 13) at Mount Sinai Medical Center from September 2005 through October 2011. The patients were followed from June 2006 through October 2011 (median, 27.8 months); each patient was analyzed by random biopsy, targeted white light examination (WLE), and CE. Specimens were reviewed by a single blinded pathologist. The 3 methods were compared by using the generalized estimating equations method, and the odds ratios (ORs) for detection of dysplasia were calculated (primary outcome). Time to colectomy was analyzed by using the Cox model. In the 208 examinations conducted, 44 dysplastic lesions were identified in 24 patients; 6 were detected by random biopsy, 11 by WLE, and 27 by CE. Ten patients were referred for colectomy, and no carcinomas were found. At any time during the study period, CE (OR, 5.4; 95% confidence interval [CI], 2.9-9.9) and targeted WLE (OR, 2.3; 95% CI, 1.0-5.3) were more likely than random biopsy analysis to detect dysplasia. CE was superior to WLE (OR, 2.4; 95% CI, 1.4-4.0). Patients identified as positive for dysplasia were more likely to need colectomy (hazard ratio, 12.1; 95% CI, 3.2-46.2). In a prospective study of 68 patients with inflammatory bowel diseases, CE was superior to random biopsy or WLE analyses in detecting dysplasia in patients with colitis during an almost 28-month period. A negative result from CE examination was the best indicator of a dysplasia-free outcome, whereas a positive result was associated with earlier referral for colectomy.


[Determination of D-dimer in the blood using the Simplired method in patients with possible diagnosis of the deep veins thrombosis during urgent abdominal surgery].
The results of treatment of 78 patients, operated in the clinic in 2008-2010 yrs, are adduced. The sensitivity, specificity and the precision values were determined for diagnostic method in deep veins thrombosis (DVT). The method was based on investigation of the products of degradation content of the transversely-sutured fibrine (D-dimer) and its dynamics in the blood of patients. D-dimer was determined, using express-method of the erythrocytes agglutination identification with application of SimpliRED technology in the whole blood. In 16 (20.5%) patients DVT was revealed within vena cava inferior basin, of them in 7 (43.7%) patients the course of thrombosis was asymptomatic, and the disease presence have had become suspected after obtaining of the D-dimer test positivity and was confirmed by ultrasonographic angioscanning. In 43 (55.1%) patients of the investigated group the D-dimer test positivity was noted. In all the patients, suffering phlebothrombosis, the test was extremely positive, presented by the erythrocytes agglutination on the 5-20th second and long-term presence of D-dimer during (17 +/- 6) days, at average. In 14 (87.5%) patients the application of direct anticoagulants was stopped after the test negative results obtaining. Rethrombosis and pulmonary artery thronboembolism (according to clinical investigation) did not occur.


Development of the Cochlear Implant Quality of Life Item Bank.
Functional outcomes following cochlear implantation have traditionally been focused on word and sentence recognition, which, although important, do not capture the varied communication and other experiences of adult cochlear implant (CI) users. Although the inadequacies of speech recognition to quantify CI user benefits are widely acknowledged, rarely have adult CI user outcomes been comprehensively assessed beyond these conventional measures. An important limitation in addressing this knowledge gap is that patient-reported outcome measures have not been developed and validated in adult CI patients using rigorous scientific methods. The purpose of the present study is to build on our previous work and create an item bank that can be used to develop new patient-reported outcome measures that assess CI quality of life (QOL) in the adult CI population. An online questionnaire was made available to 500 adult CI users who represented the adult CI population and were recruited through a consortium of 20 CI centers in the United States. The questionnaire included the 101 question CIQOL item pool and additional questions related to demographics, hearing and CI history, and speech recognition scores. In accordance with the Patient-Reported Outcomes Measurement Information System, responses were psychometrically analyzed using confirmatory factor analysis and item response theory. Of the 500 questionnaires sent, 371 (74.2%) subjects completed the questionnaire. Subjects represented the full range of age, durations of CI use, speech recognition abilities, and listening modalities of the adult CI population; subjects were implanted with each of the three CI manufacturers' devices. The initial item pool consisted of the following domain constructs: communication, emotional, entertainment, environment, independence, listening effort, and social. Through psychometric analysis, after removing locally dependent and misfitting items, all of the domains were found to have sound psychometric properties, with the exception of the independence domain. This resulted in a final CIQOL item bank of 81 items in 6 domains with good psychometric properties. Our findings reveal that hypothesis-driven quantitative analyses result in a psychometrically sound CIQOL item bank, organized into unique domains comprised of independent items which measure the full ability range of the adult CI population. The final item bank will now be used to develop new instruments that evaluate and differentiate adult CIQOL across the patient ability spectrum.


Gamma aminobutyric acid (GABA) receptor agonists for acute stroke.
Gamma aminobutyric acid (GABA) receptor agonists have been shown to have a neuroprotectant effect in reducing infarct size and improving functional outcome in animal models of cerebrovascular disease. However, the sedative effects of GABA receptor agonists have limited their wider application in people with acute stroke, due to the potential risk of stupor. This is an update of a Cochrane Review first published in 2013, and previously updated in 2014 and 2016. To determine the efficacy and safety of GABA receptor agonists in the treatment of acute stroke. We searched the Cochrane Stroke Group Trials Register (accessed May 2018), the Cochrane Central Register of Controlled Trials (CENTRAL) 2018, Issue 4 (accessed May 2018), MEDLINE (from 1949 to May 2018), Embase (from 1980 to May 2018), CINAHL (from 1982 to May 2018), AMED (from 1985 to May 2018), and 11 Chinese databases (accessed May 2018). In an effort to identify further published, unpublished, and ongoing trials we searched ongoing trial registers, reference lists, and relevant conference proceedings, and contacted authors and pharmaceutical companies. We included randomized controlled trials (RCTs) investigating GABA receptor agonists versus placebo for people with acute stroke (within 12 hours after stroke onset), with the primary outcomes of efficacy and safety. Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted eligible data, cross-checked the data for accuracy, and assessed the risk of bias. We used the GRADE approach to assess the quality of the evidence. We included five trials with 3838 participants (acute ischemic or hemorrhagic stroke patients, 3758 analyzed). Most of the participants recruited had acute ischaemic stroke, with limited data available from participants with other stroke subtypes, including total anterior circulation syndrome (TACS). The methodological quality of the included trials was generally good, with an unclear risk for selection bias only. For death and dependency at three months, pooled results did not find a significant difference for chlormethiazole versus placebo (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.96 to 1.11; four trials; 2909 participants; moderate-quality evidence) and for diazepam versus placebo (RR 0.94, 95% CI 0.82 to 1.07; one trial; 849 participants; moderate-quality evidence). The most frequent adverse events related to chlormethiazole were somnolence (RR 4.56, 95% CI 3.50 to 5.95; two trials; 2527 participants; moderate-quality evidence) and rhinitis (RR 4.75, 95% CI 2.67 to 8.46; two trials; 2527 participants; moderate-quality evidence). This review provides moderate-quality evidence that fails to support the use of GABA receptor agonists (chlormethiazole or diazepam) for the treatment of people with acute stroke. More well-designed RCTs with large samples of participants with total anterior circulation syndrome are required to determine if there are benefits for this subgroup. Somnolence and rhinitis are frequent adverse events related to chlormethiazole.


Age exacerbates chronic catecholamine-induced impairments in contractile reserve in the rat.
Contractile reserve decreases with advancing age and chronic isoproterenol (ISO) administration is a well-characterized model of cardiac hypertrophy known to impair cardiovascular function. This study evaluated whether nonsenescent, mature adult rats are more susceptible to detrimental effects of chronic ISO administration than younger adult rats. Rats received daily injections of ISO (0.1 mg/kg sc) or vehicle for 3 wk. ISO induced a greater impairment in contractile reserve [maximum of left ventricular pressure development (Δ+dP/dt(max))] in mature adult ISO-treated (MA-ISO) than in young adult ISO-treated rats (YA-ISO) in response to infusions of mechanistically distinct inotropes (digoxin, milrinone; 20-200 μl·kg(-1)·min(-1)), while basal and agonist-induced changes in heart rate and systolic arterial pressure (SAP) were not different across groups. ISO decreased expression of the calcium handling protein, sarco(endo)plasmic reticulum Ca(2+)-ATPase-2a, in MA-ISO compared with YA, YA-ISO, and MA rats. Chronic ISO also induced greater increases in cardiac hypertrophy [left ventricular (LV) index: 33 ± 3 vs. 22 ± 5%] and caspase-3 activity (34 vs. 5%) in MA-ISO relative to YA-ISO rats. Moreover, β-myosin heavy chain (β-MHC) and atrial natriuretic factor (ANF) mRNA expression was significantly elevated in MA-ISO. These results demonstrate that adult rats develop greater impairments in systolic performance than younger rats when exposed to chronic catecholamine excess. Reduced contractile reserve may result from calcium dysregulation, increased caspase-3 activity, or increased β-MHC and ANF expression. Although several studies report age-related declines in systolic performance in older and senescent animals, the present study demonstrates that catecholamine excess induces reductions in systolic performance significantly earlier in life.


Freddie Mercury-acoustic analysis of speaking fundamental frequency, vibrato, and subharmonics.
Freddie Mercury was one of the twentieth century's best-known singers of commercial contemporary music. This study presents an acoustical analysis of his voice production and singing style, based on perceptual and quantitative analysis of publicly available sound recordings. Analysis of six interviews revealed a median speaking fundamental frequency of 117.3 Hz, which is typically found for a baritone voice. Analysis of voice tracks isolated from full band recordings suggested that the singing voice range was 37 semitones within the pitch range of F#2 (about 92.2 Hz) to G5 (about 784 Hz). Evidence for higher phonations up to a fundamental frequency of 1,347 Hz was not deemed reliable. Analysis of 240 sustained notes from 21 a-cappella recordings revealed a surprisingly high mean fundamental frequency modulation rate (vibrato) of 7.0 Hz, reaching the range of vocal tremor. Quantitative analysis utilizing a newly introduced parameter to assess the regularity of vocal vibrato corroborated its perceptually irregular nature, suggesting that vibrato (ir)regularity is a distinctive feature of the singing voice. Imitation of subharmonic phonation samples by a professional rock singer, documented by endoscopic high-speed video at 4,132 frames per second, revealed a 3:1 frequency locked vibratory pattern of vocal folds and ventricular folds.


Interventions for common perinatal mental disorders in women in low- and middle-income countries: a systematic review and meta-analysis.
To assess the effectiveness of interventions to improve the mental health of women in the perinatal period and to evaluate any effect on the health, growth and development of their offspring, in low- and middle-income (LAMI) countries. Seven electronic bibliographic databases were systematically searched for papers published up to May 2012 describing controlled trials of interventions designed to improve mental health outcomes in women who were pregnant or had recently given birth. The main outcomes of interest were rates of common perinatal mental disorders (CPMDs), primarily postpartum depression or anxiety; measures of the quality of the mother-infant relationship; and measures of infant or child health, growth and cognitive development. Meta-analysis was conducted to obtain a summary measure of the clinical effectiveness of the interventions. Thirteen trials representing 20 092 participants were identified. In all studies, supervised, non-specialist health and community workers delivered the interventions, which proved more beneficial than routine care for both mothers and children. The pooled effect size for maternal depression was -0.38 (95% confidence interval: -0.56 to -0.21; I (2) = 79.9%). Where assessed, benefits to the child included improved mother-infant interaction, better cognitive development and growth, reduced diarrhoeal episodes and increased immunization rates. In LAMI countries, the burden of CPMDs can be reduced through mental health interventions delivered by supervised non-specialists. Such interventions benefit both women and their children, but further studies are needed to understand how they can be scaled up in the highly diverse settings that exist in LAMI countries.


STATIN-D study: comparison of the influences of rosuvastatin and fluvastatin treatment on the levels of 25 hydroxyvitamin D.
Several studies have shown that low 25-hydroxyvitamin D levels are associated with higher risk of cardiovascular disease and an increase in 25-hydroxyvitamin D levels protects against cardiovascular disease. In this study, we aimed to compare the effects of rosuvastatin and fluvastatin on vitamin D metabolism. The study population consisted of 134 hyperlipidemic patients who had not previously been treated with lipid lowering medications. Patients were randomized in a 1:1 ratio to rosuvastatin 10 mg or fluvastatin 80 mg XL during the study. Lipid parameters, 25 hydroxyvitamin-D, and bone alkaline phosphatase (BALP) were obtained at baseline and after 8 weeks of rosuvastatin and fluvastatin treatment. Sixty-nine patients were administered rosuvastatin, and 65 patients fluvastatin. Total Cholesterol and LDL cholesterol decreased after 8 weeks of both rosuvastatin and fluvastatin treatments. Rosuvastatin was significantly more effective than fluvastatin on lowering total (P < 0.001) and LDL cholesterol (P < 0.001). There was a significant increase in 25-hydroxyvitamin D with rosuvastatin treatment (P < 0.001), whereas no significant change in 25-hydroxyvitamin D was observed with fluvastatin treatment. Mean BALP fell from 18.5 to 9.6 u/I (P < 0.001) with rosuvastatin and from 17.0 to 12.8 with fluvastatin (P= 0.004). There was no significant difference in BALP levels between rosuvastatin and fluvastatin treatment (P= 0.368). The present study demonstrated that 25-hydroxyvitamin D levels increased with rosuvastatin treatment; whereas fluvastatin treatment had no effect on 25-hydroxyvitamin D. This disparity could be related to the potency or the bioavailability of these two statins. Further studies are needed to clarify the relationship between statins and the vitamin D physiology.


De novo repeat interruptions are associated with reduced somatic instability and mild or absent clinical features in myotonic dystrophy type 1.
Myotonic dystrophy type 1 (DM1) is a multisystem disorder, caused by expansion of a CTG trinucleotide repeat in the 3'-untranslated region of the DMPK gene. The repeat expansion is somatically unstable and tends to increase in length with time, contributing to disease progression. In some individuals, the repeat array is interrupted by variant repeats such as CCG and CGG, stabilising the expansion and often leading to milder symptoms. We have characterised three families, each including one person with variant repeats that had arisen de novo on paternal transmission of the repeat expansion. Two individuals were identified for screening due to an unusual result in the laboratory diagnostic test, and the third due to exceptionally mild symptoms. The presence of variant repeats in all three expanded alleles was confirmed by restriction digestion of small pool PCR products, and allele structures were determined by PacBio sequencing. Each was different, but all contained CCG repeats close to the 3'-end of the repeat expansion. All other family members had inherited pure CTG repeats. The variant repeat-containing alleles were more stable in the blood than pure alleles of similar length, which may in part account for the mild symptoms observed in all three individuals. This emphasises the importance of somatic instability as a disease mechanism in DM1. Further, since patients with variant repeats may have unusually mild symptoms, identification of these individuals has important implications for genetic counselling and for patient stratification in DM1 clinical trials.


Phylotranscriptomics to bring the understudied into the fold: monophyletic ostracoda, fossil placement, and pancrustacean phylogeny.
An ambitious, yet fundamental goal for comparative biology is to understand the evolutionary relationships for all of life. However, many important taxonomic groups have remained recalcitrant to inclusion into broader scale studies. Here, we focus on collection of 9 new 454 transcriptome data sets from Ostracoda, an ancient and diverse group with a dense fossil record, which is often undersampled in broader studies. We combine the new transcriptomes with a new morphological matrix (including fossils) and existing expressed sequence tag, mitochondrial genome, nuclear genome, and ribosomal DNA data. Our analyses lead to new insights into ostracod and pancrustacean phylogeny. We obtained support for three epic pancrustacean clades that likely originated in the Cambrian: Oligostraca (Ostracoda, Mystacocarida, Branchiura, and Pentastomida); Multicrustacea (Copepoda, Malacostraca, and Thecostraca); and a clade we refer to as Allotriocarida (Hexapoda, Remipedia, Cephalocarida, and Branchiopoda). Within the Oligostraca clade, our results support the unresolved question of ostracod monophyly. Within Multicrustacea, we find support for Thecostraca plus Copepoda, for which we suggest the name Hexanauplia. Within Allotriocarida, some analyses support the hypothesis that Remipedia is the sister taxon to Hexapoda, but others support Branchiopoda + Cephalocarida as the sister group of hexapods. In multiple different analyses, we see better support for equivocal nodes using slow-evolving genes or when excluding distant outgroups, highlighting the increased importance of conditional data combination in this age of abundant, often anonymous data. However, when we analyze the same set of species and ignore rate of gene evolution, we find higher support when including all data, more in line with a "total evidence" philosophy. By concatenating molecular and morphological data, we place pancrustacean fossils in the phylogeny, which can be used for studies of divergence times in Pancrustacea, Arthropoda, or Metazoa. Our results and new data will allow for attributes of Ostracoda, such as its amazing fossil record and diverse biology, to be leveraged in broader scale comparative studies. Further, we illustrate how adding extensive next-generation sequence data from understudied groups can yield important new phylogenetic insights into long-standing questions, especially when carefully analyzed in combination with other data.


[The medication preparation and administration process: problem identification in order to propose improvements and prevent medication errors].
This exploratory study analyzed the medication preparation and administration process in medical-clinical units at four Brazilian hospitals located in the Southeast, Central-West and Northeast, identified problems that can contribute to the occurrence of medication errors and proposed improvement measures. Data were collected through non-participant and direct observation of nursing professionals' activities during one week. The results revealed the following main problems: the environment in Hospital B; preparation errors related to technique and anticipated medication preparation in C and D; technical, communication and patient identification mistakes in Hospital A. Suggestions to achieve greater quality and safety in patient care include the constitution of a multidisciplinary commission to evaluate the system, nursing discussion groups, environmental improvements, permanent courses and training and actual presence of a nurse during the process.


The role of CHMP2B in frontotemporal dementia.
Mutations in the CHMP2B (charged multivesicular body protein 2B) gene that lead to C-terminal truncations of the protein can cause frontotemporal dementia. CHMP2B is a member of ESCRT-III (endosomal sorting complex required for transport III), which is required for formation of the multivesicular body, a late endosomal structure that fuses with the lysosome to degrade endocytosed proteins. Overexpression of mutant C-terminally truncated CHMP2B proteins produces an enlarged endosomal phenotype in PC12 and human neuroblastoma cells, which is likely to be due to a dominant-negative effect on endosomal function. Disruption of normal endosomal trafficking is likely to affect the transport of neuronal growth factors and autophagic clearance of proteins, both of which could contribute to neurodegeneration in frontotemporal dementia.


The immunobiological and clinical role of vitamin D in obstructive lung diseases.
Vitamin D is a fat-soluble vitamin, which is obtained by conversion of 7-dehydrocholesterol in the skin by UV ray and by diet. Its role on bone mineralization has been known for over two hundred years, while its non-skeletal effects have been acknowledged only in the last few years. The discovery of important vitamin D properties on the innate and adaptive immune system created a lot of interest in a potential role of vitamin D on diseases characterized by heightened inflammation and oxidative response, and impaired antimicrobial response, such as asthma and chronic obstructive pulmonary disease (COPD). Recent studies have demonstrated that vitamin D and its deficiency have a number of biological effects which are potentially important in altering the pathogenesis and severity of both asthma and COPD. Vitamin D may improve lung function and response to steroids therapy, reduce airway remodeling and disease exacerbations. The aim of this study is to review the role of Vitamin D in asthma and COPD.


Characterization of Skin Aging-Associated Secreted Proteins (SAASP) Produced by Dermal Fibroblasts Isolated from Intrinsically Aged Human Skin.
Most molecular hallmarks of cellular senescence have been identified in studies of cells aged in vitro by driving them into replicative or stress-induced senescence. Comparatively, less is known about the characteristic features of cells that have aged in vivo. Here we provide a systematic molecular analysis of normal human dermal fibroblasts (NHDFs) that were isolated from intrinsically aged human skin of young versus middle aged versus old donors. Intrinsically aged NHDFs in culture exhibited more frequently nuclear foci positive for p53 binding protein 1 and promyelocytic leukemia protein reminiscent of 'DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS)'. Formation of such foci was neither accompanied by increased DNA double strand breaks, nor decreased cell viability, nor telomere shortening. However, it was associated with the development of a secretory phenotype, indicating incipient cell senescence. By quantitative analysis of the entire secretome present in conditioned cell culture supernatant, combined with a multiplex cytokine determination, we identified 998 proteins secreted by intrinsically aged NHDFs in culture. Seventy of these proteins exhibited an age-dependent secretion pattern and were accordingly denoted 'skin aging-associated secreted proteins (SAASP)'. Systematic comparison of SAASP with the classical senescence-associated secretory phenotype (SASP) revealed that matrix degradation as well as proinflammatory processes are common aspects of both conditions. However, secretion of 27 proteins involved in the biological processes of 'metabolism' and 'adherens junction interactions' was unique for NHDFs isolated from intrinsically aged skin. In conclusion, fibroblasts isolated from intrinsically aged skin exhibit some, but not all, molecular hallmarks of cellular senescence. Most importantly, they secrete a unique pattern of proteins that is distinct from the canonical SASP and might reflect specific processes of skin aging.


Description of Microbacterium foliorum sp. nov. and Microbacterium phyllosphaerae sp. nov., isolated from the phyllosphere of grasses and the surface litter after mulching the sward, and reclassification of Aureobacterium resistens (Funke et al. 1998) as Microbacterium resistens comb. nov..
The taxonomic position of a group of coryneform bacteria isolated from the phyllosphere of grasses and the surface litter after sward mulching was investigated. On the basis of restriction analyses of 16S rDNA, the isolates were divided into two genotypes. According to the 16S rDNA sequence analysis, representatives of both genotypes were related at a level of 99.2% similarity and clustered within the genus Microbacterium. Chemotaxonomic features (major menaquinones MK-12, MK-11 and MK-10; predominating iso- and anteiso-branched cellular fatty acids; G+C content 64-67 mol%; peptidoglycan-type B2beta with glycolyl residues) corresponded to this genus as well. DNA-DNA hybridization studies showed a reassociation value of less than 70% between representative strains of both subgroups, suggesting that two different species are represented. Although the extensive morphological and physiological analyses did not reveal any differentiating feature for the genotypes, differences in the presence of the cell-wall sugar mannose enabled the subgroups to be distinguished from one another. DNA-DNA hybridization with type strains of closely related Microbacterium spp. indicated that the isolates represent two individual species, which can also be differentiated from previously described species of Microbacterium on the basis of biochemical features. As a result of phenotypic and phylogenetic analyses, the species Microbacterium foliorum sp. nov., type strain P 333/02T (= DSM 12966T = LMG 19580T), and Microbacterium phyllosphaerae sp. nov., type strain P 369/06T (= DSM 13468T = LMG 19581T), are proposed. Furthermore, the reclassification of Aureobacterium resistens (Funke et al. 1998) as Microbacterium resistens (Funke et al. 1998) comb. nov. is proposed.


Analysis of deep tissue hypersensitivity to pressure pain in professional pianists with insidious mechanical neck pain.
The aim of this study was to investigate whether pressure pain hyperalgesia is a feature of professional pianists suffering from neck pain as their main playing-related musculoskeletal disorder. Twenty-three active expert pianists, 6 males and 17 females (age: 36 ± 12 years) with insidious neck pain and 23 pianists, 9 males and 14 females (age: 38 ± 10 years) without neck pain the previous year were recruited. A numerical pain rate scale, Neck Disability Index, hand size and pressure pain thresholds (PPT) were assessed bilaterally over the C5-C6 zygapophyseal joint, deltoid muscle, the second metacarpal and the tibialis anterior muscle in a blinded design. The results showed that PPT levels were significantly decreased bilaterally over the second metacarpal and tibialis anterior muscles (P < 0.05), but not over C5-C6 zygapophyseal joint and deltoid muscle (P > 0.10), in pianists with neck pain as compared to healthy pianists. Pianists with neck pain had a smaller (P < 0.05) hand size (mean: 181.8 ± 11.8) as compared to pianists without neck pain (mean: 188. 6 ± 13.1). PPT over the tibialis anterior muscles was negatively correlated with the intensity of neck pain. Our findings revealed pressure pain hypersensitivity over distant non-symptomatic distant points but not over the symptomatic areas in pianists suffering from neck pain. In addition, pianists with neck pain also had smaller hand size than those without neck pain. Future studies are needed to further determine the relevance of these findings in the clinical course of neck pain as playing-related musculoskeletal disorder in professional pianists.


Perampanel in patients with brain tumor-related epilepsy in real-life clinical practice: a retrospective analysis.
Epilepsy occurs in 35-70% of patients with gliomas; glutamate plays a central role via AMPA-receptor activation, which is involved both in seizure activity and tumor growth. We conducted a retrospective study on brain tumor-related epilepsy patients (BTRE) treated with perampanel in add-on (PER) for 12 months, to evaluate efficacy and tollerability, according to real-life clinical practice. Medical records of eleven patients (9 males, mean age 54 years) with glioma and epilepsy treated with PER in add-on, for inadequate seizure control or adverse events (AEs) from previous antiepileptic drugs (AEDs) therapy, were reviewed. Data collected included: tumor history, molecular factors, systemic therapy, type and number of seizures and concomitant AEDs, and AEs. After 12 months of PER therapy, five patients were seizure-free, 4 had a seizure reduction ≥50% and the seizure frequency was unchanged in 2 patients. Responder rate was 81.8%. Two patients reported AEs; PER dose was reduced only in the one case. The final median dose of PER was 7.3 mg/day. We didn't find statistically significant differences in the comparison between mean values pre, mean values post and the average of decreasing number of seizures related to: histology, presence/absence of chemotherapy, radiotherapy, progression disease, KPS, IDH1, MGMT. Despite the limitations due to small number of patients in a retrospective study, the high rate of responder and seizure-free patients suggest that PER could be a therapeutic option in BTRE. Prospective controlled studies are needed to confirm our data.


Group ICA for identifying biomarkers in schizophrenia: 'Adaptive' networks via spatially constrained ICA show more sensitivity to group differences than spatio-temporal regression.
Brain functional networks identified from fMRI data can provide potential biomarkers for brain disorders. Group independent component analysis (GICA) is popular for extracting brain functional networks from multiple subjects. In GICA, different strategies exist for reconstructing subject-specific networks from the group-level networks. However, it is unknown whether these strategies have different sensitivities to group differences and abilities in distinguishing patients. Among GICA, spatio-temporal regression (STR) and spatially constrained ICA approaches such as group information guided ICA (GIG-ICA) can be used to propagate components (indicating networks) to a new subject that is not included in the original subjects. In this study, based on the same a priori network maps, we reconstructed subject-specific networks using these two methods separately from resting-state fMRI data of 151 schizophrenia patients (SZs) and 163 healthy controls (HCs). We investigated group differences in the estimated functional networks and the functional network connectivity (FNC) obtained by each method. The networks were also used as features in a cross-validated support vector machine (SVM) for classifying SZs and HCs. We selected features using different strategies to provide a comprehensive comparison between the two methods. GIG-ICA generally showed greater sensitivity in statistical analysis and better classification performance (accuracy 76.45 ± 8.9%, sensitivity 0.74 ± 0.11, specificity 0.79 ± 0.11) than STR (accuracy 67.45 ± 8.13%, sensitivity 0.65 ± 0.11, specificity 0.71 ± 0.11). Importantly, results were also consistent when applied to an independent dataset including 82 HCs and 82 SZs. Our work suggests that the functional networks estimated by GIG-ICA are more sensitive to group differences, and GIG-ICA is promising for identifying image-derived biomarkers of brain disease.


Community-based care for chronic wound management: an evidence-based analysis.
In August 2008, the Medical Advisory Secretariat (MAS) presented a vignette to the Ontario Health Technology Advisory Committee (OHTAC) on a proposed targeted health care delivery model for chronic care. The proposed model was defined as multidisciplinary, ambulatory, community-based care that bridged the gap between primary and tertiary care, and was intended for individuals with a chronic disease who were at risk of a hospital admission or emergency department visit. The goals of this care model were thought to include: the prevention of emergency department visits, a reduction in hospital admissions and re-admissions, facilitation of earlier hospital discharge, a reduction or delay in long-term care admissions, and an improvement in mortality and other disease-specific patient outcomes.OHTAC approved the development of an evidence-based assessment to determine the effectiveness of specialized community based care for the management of heart failure, Type 2 diabetes and chronic wounds.PLEASE VISIT THE MEDICAL ADVISORY SECRETARIAT WEB SITE AT: www.health.gov.on.ca/ohtas to review the following reports associated with the Specialized Multidisciplinary Community-Based care series.Specialized multidisciplinary community-based care series: a summary of evidence-based analysesCommunity-based care for the specialized management of heart failure: an evidence-based analysisCommunity-based care for chronic wound management: an evidence-based analysisPlease note that the evidence-based analysis of specialized community-based care for the management of diabetes titled: "Community-based care for the management of type 2 diabetes: an evidence-based analysis" has been published as part of the Diabetes Strategy Evidence Platform at this URL: http://www.health.gov.on.ca/english/providers/program/mas/tech/ohtas/tech_diabetes_20091020.htmlPLEASE VISIT THE TORONTO HEALTH ECONOMICS AND TECHNOLOGY ASSESSMENT COLLABORATIVE WEB SITE AT: http://theta.utoronto.ca/papers/MAS_CHF_Clinics_Report.pdf to review the following economic project associated with this series:Community-based Care for the specialized management of heart failure: a cost-effectiveness and budget impact analysis. The objective of this evidence-based review is to determine the effectiveness of a multidisciplinary wound care team for the management of chronic wounds. CONDITION AND TARGET POPULATION Chronic wounds develop from various aetiologies including pressure, diabetes, venous pathology, and surgery. A pressure ulcer is defined as a localized injury to the skin/and or underlying tissue occurring most often over a bony prominence and caused, alone or in combination, by pressure, shear, or friction. Up to three fifths of venous leg ulcers are due to venous aetiology. Approximately 1.5 million Ontarians will sustain a pressure ulcer, 111,000 will develop a diabetic foot ulcer, and between 80,000 and 130,000 will develop a venous leg ulcer. Up to 65% of those afflicted by chronic leg ulcers report experiencing decreased quality of life, restricted mobility, anxiety, depression, and/or severe or continuous pain. MULTIDISCIPLINARY WOUND CARE TEAMS: The term 'multidisciplinary' refers to multiple disciplines on a team and 'interdisciplinary' to such a team functioning in a coordinated and collaborative manner. There is general consensus that a group of multidisciplinary professionals is necessary for optimum specialist management of chronic wounds stemming from all aetiologies. However, there is little evidence to guide the decision of which professionals might be needed form an optimal wound care team. A literature search was performed on July 7, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, Wiley Cochrane, Centre for Reviews and Dissemination/International Agency for Health Technology Assessment, and on July 13, 2009 using the Cumulative Index to Nursing & Allied Health Literature (CINAHL), and the International Agency for Health Technology Assessment (INAHTA) for studies pertaining to leg and foot ulcers. A similar literature search was conducted on July 29' 2009 for studies pertaining to pressure ulcers. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with an unknown eligibility were reviewed with a second clinical epidemiologist and then a group of epidemiologists until consensus was established. Randomized controlled trials and Controlled clinical Trials (CCT)Systematic review with meta analysisPopulation includes persons with pressure ulcers (anywhere) and/or leg and foot ulcersThe intervention includes a multidisciplinary (two or more disciplines) wound care team.The control group does not receive care by a wound care teamStudies published in the English language between 2004 and 2009 EXCLUSION CRITERIA: Single centre retrospective observational studies Proportion of persons and/or wounds completely healedTime to complete healingQuality of LifePain assessment Two studies met the inclusion and exclusion criteria, one a randomized controlled trial (RCT), the other a CCT using a before and after study design. There was variation in the setting, composition of the wound care team, outcome measures, and follow up periods between the studies. In both studies, however, the wound care team members received training in wound care management and followed a wound care management protocol. In the RCT, Vu et al. reported a non-significant difference between the proportion of wounds healed in 6 months using a univariate analysis (61.7% for treatment vs. 52.5% for control; p=0.074, RR=1.19) There was also a non-significant difference in the mean time to healing in days (82 for treatment vs. 101 for control; p=0.095). More persons in the intervention group had a Brief Pain Inventory (BPI) score equal to zero (better pain control) at 6 months when compared with the control group (38.6% for intervention vs. 24.4% for control; p=0.017, RR=1.58). By multivariate analysis a statistically significant hazard ratio was reported in the intervention group (1.73, 95% CI 1.20-1.50; p=0.003). In the CCT, Harrison et al. reported a statistically significant difference in healing rates between the pre (control) and post (intervention) phases of the study. Of patients in the pre phase, 23% had healed ulcers 3 months after study enrolment, whereas 56% were healed in the post phase (P<0.001, OR=4.17) (Figure 3). Furthermore, 27% of patients were treated daily or more often in the pre phase whereas only 6% were treated at this frequency in the post phase (P<0.001), equal to a 34% relative risk reduction in frequency of daily treatments. The authors did not report the results of pain relief assessment. The body of evidence was assessed using the GRADE methodology for 4 outcomes: proportion of wounds healed, proportion of persons with healed wounds, wound associated pain relief, and proportion of persons needing daily wound treatments. In general, the evidence was found to be low to very low quality. The evidence supports that managing chronic wounds with a multidisciplinary wound care team significantly increases wound healing and reduces the severity of wound-associated pain and the required daily wound treatments compared to persons not managed by a wound care team. The quality of evidence supporting these outcomes is low to very low meaning that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.


The degradation behaviour of nine diverse contaminants in urban surface water and wastewater prior to water treatment.
An increasing diversity of emerging contaminants are entering urban surface water and wastewater, posing unknown risks for the environment. One of the main contemporary challenges in ensuring water quality is to design efficient strategies for minimizing such risks. As a first step in such strategies, it is important to establish the fate and degradation behavior of contaminants prior to any engineered secondary water treatment. Such information is relevant for assessing treatment solutions by simple storage, or to assess the impacts of contaminant spreading in the absence of water treatment, such as during times of flooding or in areas of poor infrastructure. Therefore in this study we examined the degradation behavior of a broad array of water contaminants in actual urban surface water and wastewater, in the presence and absence of naturally occurring bacteria and at two temperatures. The chemicals included caffeine, sulfamethoxazole, carbamazepine, atrazine, 17β-estradiol, ethinylestradiol, diclofenac, desethylatrazine and norethindrone. Little information on the degradation behavior of these pollutants in actual influent wastewater exist, nor in general in water for desethylatrazine (a transformation product of atrazine) and the synthetic hormone norethindrone. Investigations were done in aerobic conditions, in the absence of sunlight. The results suggest that all chemicals except estradiol are stable in urban surface water, and in waste water neither abiotic nor biological degradation in the absence of sunlight contribute significantly to the disappearance of desethylatrazine, atrazine, carbamazepine and diclofenac. Biological degradation in wastewater was effective at transforming norethindrone, 17β-estradiol, ethinylestradiol, caffeine and sulfamethoxazole, with measured degradation rate constants k and half-lives ranging respectively from 0.0082-0.52 d(-1) and 1.3-85 days. The obtained degradation data generally followed a pseudo-first-order-kinetic model. This information can be used to model degradation prior to water treatment.


Antimicrobial peptides in 2014.
This article highlights new members, novel mechanisms of action, new functions, and interesting applications of antimicrobial peptides reported in 2014. As of December 2014, over 100 new peptides were registered into the Antimicrobial Peptide Database, increasing the total number of entries to 2493. Unique antimicrobial peptides have been identified from marine bacteria, fungi, and plants. Environmental conditions clearly influence peptide activity or function. Human α-defensin HD-6 is only antimicrobial under reduced conditions. The pH-dependent oligomerization of human cathelicidin LL-37 is linked to double-stranded RNA delivery to endosomes, where the acidic pH triggers the dissociation of the peptide aggregate to release its cargo. Proline-rich peptides, previously known to bind to heat shock proteins, are shown to inhibit protein synthesis. A model antimicrobial peptide is demonstrated to have multiple hits on bacteria, including surface protein delocalization. While cell surface modification to decrease cationic peptide binding is a recognized resistance mechanism for pathogenic bacteria, it is also used as a survival strategy for commensal bacteria. The year 2014 also witnessed continued efforts in exploiting potential applications of antimicrobial peptides. We highlight 3D structure-based design of peptide antimicrobials and vaccines, surface coating, delivery systems, and microbial detection devices involving antimicrobial peptides. The 2014 results also support that combination therapy is preferred over monotherapy in treating biofilms.


Sustainable Pharmacy: Piloting a Session on Pharmaceuticals, Climate Change, and Sustainability within a U.S. Pharmacy Curriculum.
To design and assess an innovative session for pharmacy students that addresses the role of pharmaceuticals with climate change and sustainability. One hundred and sixteen third-year students at the University of California, San Francisco School of Pharmacy participated during their required Health Policy course. This 3-hour session included guided pre-course activities, an interactive lecture, a panel of healthcare professionals discussing complex decision-making and small group case-based learning. Curricular assessment was conducted through pre-/post-test measures of knowledge acquisition, student evaluations, and course projects. One hundred and two students (response rate 88%) completed the pre-test and 115 students (response rate 99%) completed the post-test assessment. We identified a significant increase in the proportion of correct answers on post-test questions addressing drug disposal legislation (75% pre-test vs 91% post-test, p=0.002) and the predicted effects of climate change on health (55% pre-test vs 90% post-test, p < 0.001). The session was also well received; average student evaluation scores were above 4 in all areas of course evaluation (where 5=ideal). In addition, 17% of student groups (relative to 0% in 2015) proposed a sustainability-related policy as their final coursework project. The development and implementation of this brief session resulted in knowledge gain and favorable student response. This project is feasible for other Schools of Pharmacy to adapt and implement.


Foundations for literacy: An early literacy intervention for deaf and hard-of-hearing children.
The present study evaluated the efficacy of a new preschool early literacy intervention created specifically for deaf and hard-of-hearing (DHH) children with functional hearing. Teachers implemented Foundations for Literacy with 25 DHH children in 2 schools (intervention group). One school used only spoken language, and the other used sign with and without spoken language. A "business as usual" comparison group included 33 DHH children who were matched on key characteristics with the intervention children but attended schools that did not implement Foundations for Literacy. Children's hearing losses ranged from moderate to profound. Approximately half of the children had cochlear implants. All children had sufficient speech perception skills to identify referents of spoken words from closed sets of items. Teachers taught small groups of intervention children an hour a day, 4 days a week for the school year. From fall to spring, intervention children made significantly greater gains on tests of phonological awareness, letter-sound knowledge, and expressive vocabulary than did comparison children. In addition, intervention children showed significant increases in standard scores (based on hearing norms) on phonological awareness and vocabulary tests. This quasi-experimental study suggests that the intervention shows promise for improving early literacy skills of DHH children with functional hearing.


Beat-to-beat control of human optokinetic nystagmus slow phase durations.
This study provides the first clear evidence that the generation of optokinetic nystagmus fast phases (FPs) is a decision process that is influenced by performance of a concurrent disjunctive reaction time task (DRT). Ten subjects performed an auditory DRT during constant velocity optokinetic stimulation. Eye movements were measured in three dimensions with a magnetic search coil. Slow phase (SP) durations were defined as the interval between FPs. There were three main findings. Firstly, human optokinetic nystagmus SP durations are consistent with a model of a Gaussian basic interval generator (a type of biological clock), such that FPs can be triggered randomly at the end of a clock cycle (mean duration: 200-250 ms). Kolmogorov-Smirnov tests could not reject the modeled cumulative distribution for any data trials. Secondly, the FP need not be triggered at the end of a clock cycle, so that individual SP durations represent single or multiple clock cycles. Thirdly, the probability of generating a FP at the end of each interval generator cycle decreases significantly during performance of a DRT. These findings indicate that the alternation between SPs and FPs of optokinetic nystagmus is not purely reflexive. Rather, the triggering of the next FP is postponed more frequently if a recently presented DRT trial is pending action when the timing cycle expires. Hence, optokinetic nystagmus FPs show dual-task interference in a manner usually attributed to voluntary movements, including saccades. This study provides the first clear evidence that the generation of optokinetic nystagmus (OKN) fast phases is a decision process that is influenced by performance of a concurrent disjunctive reaction time task (DRT). The slow phase (SP) durations are consistent with a Gaussian basic interval generator and multiple interval SP durations occur more frequently in the presence of the DRT. Hence, OKN shows dual-task interference in a manner observed in voluntary movements, such as saccades.


Dietary Inflammatory Index and Risk of Bladder Cancer in a Large Italian Case-control Study.
To evaluate the association between diet in relation to its inflammatory property and bladder cancer (BC) risk. In this study we explored the association between the dietary inflammatory index (DII) and BC risk in an Italian case-control study conducted between 2003 and 2014. Cases were 690 patients with incident and histologically confirmed BC from 4 areas in Italy. Controls were 665 cancer-free subjects admitted to the same network of hospitals as cases for a wide spectrum of acute, non-neoplastic conditions. The DII was computed based on dietary intake assessed using a reproducible and valid 80-item food frequency questionnaire. Odds ratios (OR) were estimated through logistic regression models adjusting for age, sex, total energy intake, and other recognized confounding factors. Subjects in the highest quartile of DII scores (ie, with a more pro-inflammatory diet) had a higher risk of BC compared to subjects in the lowest quartile (ie, with an anti-inflammatory diet) (ORQuartile4vs1 = 1.97; 95% [confidence interval], 1.28, 3.03; P trend = .003). Stratified analyses produced stronger associations between DII and BC risk among females (ORQuartile4vs1 = 5.73; 95% CI = 1.46, 22.44), older ≥65 years (ORQuartile4vs1 = 2.45; 95% CI = 1.38, 4.34), subjects with higher education ≥7 years (ORQuartile4vs1 = 2.22; 95% CI = 1.27, 3.88), and never smokers (ORQuartile4vs1 = 4.04; 95% CI = 1.51, 10.80). A pro-inflammatory diet as indicated by higher DII scores is associated with increased BC risk.


Understanding heterogeneous tumor microenvironment in metastatic melanoma.
A systemic analysis of the tumor-immune interactions within the heterogeneous tumor microenvironment is of particular importance for understanding the antitumor immune response. We used multiplexed immunofluorescence to elucidate cellular spatial interactions and T-cell infiltrations in metastatic melanoma tumor microenvironment. We developed two novel computational approaches that enable infiltration clustering and single cell analysis-cell aggregate algorithm and cell neighborhood analysis algorithm-to reveal and to compare the spatial distribution of various immune cells relative to tumor cell in sub-anatomic tumor microenvironment areas. We showed that the heterogeneous tumor human leukocyte antigen-1 expressions differently affect the magnitude of cytotoxic T-cell infiltration and the distributions of CD20+ B cells and CD4+FOXP3+ regulatory T cells within and outside of T-cell infiltrated tumor areas. In a cohort of 166 stage III melanoma samples, high tumor human leukocyte antigen-1 expression is required but not sufficient for high T-cell infiltration, with significantly improved overall survival. Our results demonstrate that tumor cells with heterogeneous properties are associated with differential but predictable distributions of immune cells within heterogeneous tumor microenvironment with various biological features and impacts on clinical outcomes. It establishes tools necessary for systematic analysis of the tumor microenvironment, allowing the elucidation of the "homogeneous patterns" within the heterogeneous tumor microenvironment.


Particles with similar LET values generate DNA breaks of different complexity and reparability: a high-resolution microscopy analysis of γH2AX/53BP1 foci.
Biological effects of high-LET (linear energy transfer) radiation have received increasing attention, particularly in the context of more efficient radiotherapy and space exploration. Efficient cell killing by high-LET radiation depends on the physical ability of accelerated particles to generate complex DNA damage, which is largely mediated by LET. However, the characteristics of DNA damage and repair upon exposure to different particles with similar LET parameters remain unexplored. We employed high-resolution confocal microscopy to examine phosphorylated histone H2AX (γH2AX)/p53-binding protein 1 (53BP1) focus streaks at the microscale level, focusing on the complexity, spatiotemporal behaviour and repair of DNA double-strand breaks generated by boron and neon ions accelerated at similar LET values (∼135 keV μm-1) and low energies (8 and 47 MeV per n, respectively). Cells were irradiated using sharp-angle geometry and were spatially (3D) fixed to maximize the resolution of these analyses. Both high-LET radiation types generated highly complex γH2AX/53BP1 focus clusters with a larger size, increased irregularity and slower elimination than low-LET γ-rays. Surprisingly, neon ions produced even more complex γH2AX/53BP1 focus clusters than boron ions, consistent with DSB repair kinetics. Although the exposure of cells to γ-rays and boron ions eliminated a vast majority of foci (94% and 74%, respectively) within 24 h, 45% of the foci persisted in cells irradiated with neon. Our calculations suggest that the complexity of DSB damage critically depends on (increases with) the particle track core diameter. Thus, different particles with similar LET and energy may generate different types of DNA damage, which should be considered in future research.


Synergy between glyphosate- and cypermethrin-based pesticides during acute exposures in tadpoles of the common South American toad Rhinella arenarum.
The herbicide glyphosate and the insecticide cypermethrin are key pesticides of modern management in soy and corn cultures. Although these pesticides are likely to co-occur in ephemeral ponds or aquatic systems supporting amphibian wildlife, the toxicological interactions prevailing in mixtures of these two pesticides have been little studied. The current study evaluated the toxicity of equitoxic and non-equitoxic binary mixtures of glyphosate- and cypermethrin-based pesticides to tadpoles of the common South American toad, Rhinella arenarum. Two different combinations of commercial products were tested: glyphosate Glifosato Atanor®+cypermethrin Xiper® and glyphosate Glifoglex®+cypermethrin Glextrin®. When tested individually, the formulations presented the following 96 h-LC50s: Glifosato Atanor® 19.4 mg ae L(-1) and Glifoglex 72.8 mg ae L(-1), Xiper® 6.8 mg L(-1) and Glextrin® 30.2 mg L(-1). Equitoxic and non-equitoxic mixtures were significantly synergic in both combinations of commercial products tested. The magnitude of the synergy (factor by which toxicity differed from concentration addition) was constant at around twofold for all tested proportions of the glyphosate Glifoglex®+cypermethrin Glextrin® mixture; whereas the magnitude of the synergy varied between 4 and 9 times in the glyphosate Glifosato Atanor®+cypermethrin Xiper® mixture. These results call for more research to be promptly undertaken in order to understand the mechanisms behind the synergy observed and to identify and quantify the extent of its environmental impacts.


An Assessment of Indoor Air Quality before, during and after Unrestricted Use of E-Cigarettes in a Small Room.
Airborne chemicals in the indoor environment arise from a wide variety of sources such as burning fuels and cooking, construction materials and furniture, environmental tobacco smoke as well as outdoor sources. To understand the contribution of exhaled e-cigarette aerosol to the pre-existing chemicals in the ambient air, an indoor air quality study was conducted to measure volatile organic compounds (including nicotine and low molecular weight carbonyls), polycyclic aromatic hydrocarbons, tobacco-specific nitrosamines and trace metal levels in the air before, during and after e-cigarette use in a typical small office meeting room. Measurements were compared with human Health Criteria Values, such as indoor air quality guidelines or workplace exposure limits where established, to provide a context for potential bystander exposures. In this study, the data suggest that any additional chemicals present in indoor air from the exhaled e-cigarette aerosol, are unlikely to present an air quality issue to bystanders at the levels measured when compared to the regulatory standards that are used for workplaces or general indoor air quality.


Experimental-numerical method for calculating bending moments in swimming fish shows that fish larvae control undulatory swimming with simple actuation.
Most fish swim with body undulations that result from fluid-structure interactions between the fish's internal tissues and the surrounding water. Gaining insight into these complex fluid-structure interactions is essential to understand how fish swim. To this end, we developed a dedicated experimental-numerical inverse dynamics approach to calculate the lateral bending moment distributions for a large-amplitude undulatory swimmer that moves freely in three-dimensional space. We combined automated motion tracking from multiple synchronised high-speed video sequences, computation of fluid dynamic stresses on the swimmer's body from computational fluid dynamics, and bending moment calculations using these stresses as input for a novel beam model of the body. The bending moment, which represent the system's net actuation, varies over time and along the fish's central axis due to muscle actions, passive tissues, inertia, and fluid dynamics. Our three-dimensional analysis of 113 swimming events of zebrafish larvae ranging in age from 3 to 12 days after fertilisation shows that these bending moment patterns are not only relatively simple but also strikingly similar throughout early development and from fast starts to periodic swimming. This suggests that fish larvae may produce and adjust swimming movements relatively simply, yet effectively, while restructuring their neuromuscular control system throughout their rapid development.


A family study of the association between insulin dependent diabetes mellitus, autoantibodies and the HLA system.
A family study of the patients attending a paediatric diabetic clinic was undertaken. Seventy-three percent of the index patients and their families provided samples for HLA typing and autoantibody analysis. The HLA types were analysed and correlated with the auto-antibody data. Ways of predicting which siblings are at risk of developing insulin dependent diabetes mellitus (IDDM) were sought. The antigen DR4 carries a higher relative risk and delta value (viz. 27 and 0.93) than any other antigen. The data did not support the notion of heterogeneity of IDDM on the basis of HLA types or autoantibody status. However, the majority of patients with a younger age of onset were DR4/DR4 homozygotes. The presence of ICA was a good marker for siblings at risk of developing IDDM. Some siblings who developed IDDM had ICA and CF-ICA for long periods of time before developing diabetes. The data supported an intermediate model of inheritance for IDDM.


Corneal Fibroblast Migration Patterns During Intrastromal Wound Healing Correlate With ECM Structure and Alignment.
To assess keratocyte backscattering, alignment, morphology, and connectivity in vivo following a full-thickness corneal injury using the Heidelberg Retina Tomograph Rostock Cornea Module (HRT-RCM), and to correlate these findings with en bloc three-dimensional (3-D) confocal fluorescence and second harmonic generation (SHG) imaging. Rabbit corneas were scanned in vivo both before and 3, 7, 14, and 28 days after transcorneal freeze injury (FI), which damages all corneal cell layers. Corneal tissue was also fixed and labeled for f-actin and nuclei en bloc, and imaged using 3-D confocal fluorescence microscopy and SHG imaging. Using the modified HRT-RCM, full-thickness scans of all cell layers were consistently obtained. Following FI, stromal cells repopulating the damaged tissue assumed an elongated fibroblastic morphology, and a significant increase in cellular light scattering was measured. This stromal haze gradually decreased as wound healing progressed. Parallel, interconnected streams of aligned corneal fibroblasts were observed both in vivo (from HRT-RCM reflection images) and ex vivo (from f-actin and nuclear labeling) during wound healing, particularly in the posterior cornea. Second harmonic generation imaging demonstrated that these cells were aligned parallel to the collagen lamellae. The modified HRT-RCM allows in vivo measurements of sublayer thickness, assessment of cell morphology, alignment and connectivity, and estimation of stromal backscatter during wound healing. In this study, these in vivo observations led to the novel finding that the pattern of corneal fibroblast alignment is highly correlated with lamellar organization, suggesting contact guidance of intrastromal migration that may facilitate more rapid wound repopulation.


Awareness of asthma and its management in primary school teachers in Eastern Province.
Asthma is one of the most common chronic respiratory disease affecting young children. It is estimated that 14% of the world's children have had asthmatic symptoms, according to the International Study of Asthma and Allergies in Childhood (ISAAC). Schools represent "home" for most children as they spend about a third of their waking hours in school each weekday. Also, schools are significant sources of exposure to asthma-triggering allergens. Therefore, school personnel, including teachers, face all the issues of asthma management that the family meets at home. The aim of this study is to assess the levels of knowledge about asthma and its management among primary school teachers in Eastern Province; Saudi Arabia. 396 primary school teachers answered an electronic questionnaire about asthma. This questionnaire contained different questions which assessed teacher's knowledge about symptoms of asthma, and its management. Also, the survey can determine the teacher's attitude and practice regarding asthmatic students. Overall, 59.6% of teachers had a high level of asthma knowledge as they were able to answer ≥75% of the knowledge questions correctly. Teachers' level of asthma knowledge was not significantly associated with age, but significantly associated with years of teaching experience, educational level and contact with an asthmatic individual. Most of the respondents were at a high level of awareness concerning asthma symptoms, triggering and treatment (73.2%, 60.9%, 60.7%), respectively, while only 19.4% had high knowledge level about sport and asthma. The primary school teachers are not well informed about asthma and its management. Future educational efforts should seek to provide teachers with accurate information about asthma with particular concern for sport and asthma. This will have a significant impact on the management of this chronic respiratory disorder.


The Community Diabetes Education (CoDE) program: cost-effectiveness and health outcomes.
Limited evidence exists regarding the long-term effects of community health worker-led diabetes management programs on health outcomes and cost-effectiveness, particularly in low-income, ethnic minority populations. To examine the long-term cost-effectiveness and improvements in diabetes-related complications of a diabetes education and management intervention led by community health workers among uninsured Mexican Americans. Clinical data, changes in hemoglobin A1c over 12 months, and costs from an RCT of 180 uninsured Mexican Americans with type 2 diabetes conducted in 2006 were utilized for secondary analyses in 2012. Simulation modeling was used to estimate long-term cost and health outcomes using the validated Archimedes Model. The absolute differences for the incremental cost-effectiveness ratios and cumulative incidence of diabetes-related complications were derived by comparing intervention and control groups. During a 20-year time horizon, participants who received the intervention would be expected to have significantly lower hemoglobin A1c levels (p<0.001), fewer foot ulcers (p<0.001), and a reduced number of foot amputations (p=0.005) in comparison with a control group receiving usual medical care. An incremental cost-effectiveness ratio of $355 per quality-adjusted life year gained was estimated for intervention participants during the same time period. A simulated clinical trial suggests that a community health worker-led diabetes intervention is a cost-effective way to reduce diabetes-related complications for uninsured Mexican Americans during a 20-year horizon in comparison to usual medical care.


Rewarding psychiatric aides for the behavioral improvement of assigned patients.
Different ways of modifying the aide-patient relationship to promote improvement in psychiatric patients were investigated. Psychiatric aides were given information about the behavior of assigned patients, cash awards based on the improvement of assigned patients, and different kinds of supervision by the psychology staff; the effects of these variables on a large number of psychiatrically relevant behaviors were measured. Appropriate behavior of patients increased when the aides were given quantitative information about the improvement of assigned patients. Cash awards for aides, which were not contingent on the behavior of patients had little effect, while cash awards contingent on the behavior of assigned patients were associated with more appropriate behavior. Direct supervision of aide-patient interactions was associated with an increase in appropriate behavior, while required consultation for the aides about assigned patients was not. Behavior of patients deteriorated when the program was terminated.


Expansins abundant in secondary xylem belong to subgroup A of the alpha-expansin gene family.
Differentiation of xylem cells in dicotyledonous plants involves expansion of the radial primary cell walls and intrusive tip growth of cambial derivative cells prior to the deposition of a thick secondary wall essential for xylem function. Expansins are cell wall-residing proteins that have an ability to plasticize the cellulose-hemicellulose network of primary walls. We found expansin activity in proteins extracted from the cambial region of mature stems in a model tree species hybrid aspen (Populus tremula x Populus tremuloides Michx). We identified three alpha-expansin genes (PttEXP1, PttEXP2, and PttEXP8) and one beta-expansin gene (PttEXPB1) in a cambial region expressed sequence tag library, among which PttEXP1 was most abundantly represented. Northern-blot analyses in aspen vegetative organs and tissues showed that PttEXP1 was specifically expressed in mature stems exhibiting secondary growth, where it was present in the cambium and in the radial expansion zone. By contrast, PttEXP2 was mostly expressed in developing leaves. In situ reverse transcription-PCR provided evidence for accumulation of mRNA of PttEXP1 along with ribosomal rRNA at the tips of intrusively growing xylem fibers, suggesting that PttEXP1 protein has a role in intrusive tip growth. An examination of tension wood and leaf cDNA libraries identified another expansin, PttEXP5, very similar to PttEXP1, as the major expansin in developing tension wood, while PttEXP3 was the major expansin expressed in developing leaves. Comparative analysis of expansins expressed in woody stems in aspen, Arabidopsis, and pine showed that the most abundantly expressed expansins share sequence similarities, belonging to the subfamily A of alpha-expansins and having two conserved motifs at the beginning and end of the mature protein, RIPVG and KNFRV, respectively. This conservation suggests that these genes may share a specialized, not yet identified function.


Focus on health, motivation, and pride: A discussion of three theoretical perspectives on the rehabilitation of sick-listed people.
During the last decades sickness absence from work has become a great societal problem. Questions of how rehabilitation processes should become successful and how peoples' ability to work can be improved have become of great public interest. In this paper we discuss three well-known theoretical perspectives regarding their usefulness when it comes to research on rehabilitation for return to work. The three perspectives are: Antonovsky's salutogenic model of health, Kielhofner's model of human occupation and Scheff's sociological theory of "shame and pride". Each of these can be applied to increase understanding and knowledge concerning sickness absence and return to work. We discuss points of affinity among the three perspectives, as well as significant differences, and we propose that a very essential common denominator is the importance of self-experience.


Explaining continued high HIV prevalence in South Africa: socioeconomic factors, HIV incidence and sexual behaviour change among a rural cohort, 2001-2004.
To estimate HIV incidence and explore evidence for changing sexual behaviour over time among men and women belonging to different socioeconomic groups in rural South Africa. A cohort study conducted between 2001 and 2004; 3881 individuals aged 14-35 years enumerated in eight villages were eligible. At least three household visits were made to contact each eligible respondent at both timepoints. Sexual behaviour data were collected in structured, respondent-focused interviews. HIV serostatus was assessed using an oral fluid enzyme-linked immunosorbent assay at each timepoint. Data on sexual behaviour were available from 1967 individuals at both timepoints. A total of 1286 HIV-negative individuals at baseline contributed to the analysis of incidence. HIV incidence was 2.2/100 person-years among men and 4.9/100 person-years in women, among whom it was highest in the least educated group. Median age at first sex was lower among later birth cohorts. A higher number of previously sexually active individuals reported having multiple partners in the past year in 2004 than 2001. Condom use with non-spousal partners increased from 2001 to 2004. Migrant men more often reported multiple partners. Migrant and more educated individuals of both sexes and women from wealthier households reported higher levels of condom use. HIV incidence is high in rural South Africa, particularly among women of low education. Some risky sexual behaviours (early sexual debut, having multiple sexual partners) are becoming more common over time. Condom use is increasing. Existing HIV prevention strategies have only been partly effective in generating population-level behavioural change.


Feasibility of cisplatin/pemetrexed with 15 mg/kg bevacizumab for the treatment of patients with advanced non-squamous non-small cell lung cancer.
The aim of the present study was to retrospectively evaluate the feasibility of cisplatin/pemetrexed/bevacizumab (CPB) therapy at a bevacizumab (BEV) dose of 15 mg/kg as a first-line chemotherapeutic strategy for patients with advanced non-squamous non-small cell lung cancer (NSCLC). A total of 31 consecutive patients with non-squamous NSCLC were treated with first-line chemotherapy of CPB at a BEV dose of 15 mg/kg at the National Kyushu Cancer Center (Fukuoka, Japan) between November 2009 and December 2011. Clinical characteristics, response rate (RR), progression-free survival (PFS) time, overall survival (OS) time and adverse events were retrospectively analyzed. The 31 patients exhibited a male:female ratio of 21:10 and a median age of 60 years (range, 38-76 years). In total, 5 patients were of clinical stage III and 26 patients were of stage IV, 15 had a performance status of 0 and 16 had a performance status of 1, and 29 patients were diagnosed with adenocarcinoma and 2 were diagnosed with adenosquamous carcinoma. The EGFR mutation status was positive (exon 19 deletion), wild-type and unknown in 3, 21 and 7 patients, respectively. A total of 28 patients (90.3%) received a minimum of four courses of CPB therapy. Hematological toxicities classified as grade III or higher included neutropenia (29.0%), anemia (3.2%) and thrombocytopenia (3.2%), however, no severe non-hematological toxicities were observed. Additionally, 22 patients (71.0%) exhibited a partial response and 9 (29.0%) exhibited stable disease, resulting in a RR of 71.0% [95% confidence interval (CI), 41-74]. The median PFS and OS times were 8.4 months (95% CI, 7.9-9.0) and 28.5 months (95% CI, 26.4-30.6), respectively. Therefore, CPB therapy at a BEV dose of 15 mg/kg appears to be a feasible treatment strategy for patients with advanced non-squamous NSCLC.


Effects of oxidative stress on endothelial function after a high-fat meal.
Postprandial lipaemia is known to cause endothelial dysfunction, but its underlying mechanism is still under debate. The present study was undertaken to investigate the effects of postprandial lipaemia on endothelial dysfunction and oxidative stress. We measured plasma glutathione peroxidase (GSH-Px), an antioxidant enzyme, and the urinary excretion of 8-epi-prostaglandin F2alpha (8-PGF2alpha), a free radical-catalysed product from the oxidative modification of arachidonic acid, in 16 healthy subjects (mean age, 30 +/- 5 years) without major coronary risk factors. Plasma high-sensitive C-reactive protein, soluble intercellular cell-adhesion molecule-1 and vascular cell-adhesion molecule-1 were also measured. High-resolution ultrasound was used to assess the flow-mediated vasodilatation (FMD) of the brachial artery. Blood and urine samples were collected before and 2, 4 and 6 h after a standard high-fat meal (3677 J, containing 50 g of fat). Serum triacylglycerol (triglyceride) increased and FMD decreased significantly after a high-fat meal. Plasma GSH-Px significantly decreased from 27.2 +/- 12.3 microg/ml to 25.7 +/- 11.8 microg/ml (P=0.022) 2 h after the meal, and urinary excretion of 8-PGF2alpha significantly increased from 1286 +/- 1401 pg/mg of creatinine to 2197 +/- 1343 pg/mg of creatinine (P=0.014) at 4 h after the meal. However, there were no significant changes in the levels of high-sensitive C-reactive protein and adhesion molecules after a high-fat meal. In conclusion, endothelial dysfunction was observed after consuming a high-fat meal and is associated with augmented oxidative stress manifested by the depletion of serum antioxidant enzymes and increased excretion of oxidative modification products.


Low plasma neurofilament light levels associated with raised cortical microglial activation suggest inflammation acts to protect prodromal Alzheimer's disease.
Plasma and cerebrospinal fluid levels of neurofilament light (NfL), a marker of axonal degeneration, have previously been reported to be raised in patients with clinically diagnosed Alzheimer's disease (AD). Activated microglia, an intrinsic inflammatory response to brain lesions, are also known to be present in a majority of Alzheimer or mild cognitive impaired (MCI) subjects with raised β-amyloid load on their positron emission tomography (PET) imaging. It is now considered that the earliest phase of inflammation may be protective to the brain, removing amyloid plaques and remodelling synapses. Our aim was to determine whether the cortical inflammation/microglial activation load, measured with the translocator protein marker 11C-PK11195 PET, was correlated with plasma NfL levels in prodromal and early Alzheimer subjects. Twenty-seven MCI or early AD cases with raised cortical β-amyloid load had 11C-(R)-PK11195 PET, structural and diffusion magnetic resonance imaging, and levels of their plasma NfL measured. Correlation analyses were performed using surface-based cortical statistics. Statistical maps localised areas in MCI cases where levels of brain inflammation correlated inversely with plasma NfL levels. These areas were localised in the frontal, parietal, precuneus, occipital, and sensorimotor cortices. Brain inflammation correlated negatively with mean diffusivity (MD) of water with regions overlapping. We conclude that an inverse correlation between levels of inflammation in cortical areas and plasma NfL levels indicates that microglial activation may initially be protective to axons in AD. This is supported by the finding of an inverse association between cortical water diffusivity and microglial activation in the same regions. Our findings suggest a rationale for stimulating microglial activity in early and prodromal Alzheimer cases-possibly using immunotherapy. Plasma NfL levels could be used as a measure of the protective efficacy of immune stimulation and for monitoring efficacy of putative neuroprotective agents.


Recombination in enteroviruses is a biphasic replicative process involving the generation of greater-than genome length 'imprecise' intermediates.
Recombination in enteroviruses provides an evolutionary mechanism for acquiring extensive regions of novel sequence, is suggested to have a role in genotype diversity and is known to have been key to the emergence of novel neuropathogenic variants of poliovirus. Despite the importance of this evolutionary mechanism, the recombination process remains relatively poorly understood. We investigated heterologous recombination using a novel reverse genetic approach that resulted in the isolation of intermediate chimeric intertypic polioviruses bearing genomes with extensive duplicated sequences at the recombination junction. Serial passage of viruses exhibiting such imprecise junctions yielded progeny with increased fitness which had lost the duplicated sequences. Mutations or inhibitors that changed polymerase fidelity or the coalescence of replication complexes markedly altered the yield of recombinants (but did not influence non-replicative recombination) indicating both that the process is replicative and that it may be possible to enhance or reduce recombination-mediated viral evolution if required. We propose that extant recombinants result from a biphasic process in which an initial recombination event is followed by a process of resolution, deleting extraneous sequences and optimizing viral fitness. This process has implications for our wider understanding of 'evolution by duplication' in the positive-strand RNA viruses.


Neuropathy in a human without the PMP22 gene.
Haploinsufficiency of PMP22 causes hereditary neuropathy with liability to pressure palsies. However, the biological functions of the PMP22 protein in humans have largely been unexplored owing to the absence of patients with PMP22-null mutations. To investigate the function of PMP22 in the peripheral nervous system by studying a boy without the PMP22 gene and mice without the Pmp22 gene. The clinical and pathological features of a patient with a PMP22 homozygous deletion are compared with those of Pmp22-null mice. Clinical evaluation was performed at tertiary hospitals in the United Kingdom. Molecular diagnosis was performed at the West Midlands Regional Genetics Laboratory. Immunohistochemistry and electron microscopy analyses were conducted at Wayne State University, Detroit, Michigan. Analysis of the Pmp22 +/- and null mice was performed at Vanderbilt University, Nashville, Tennessee. A 7-year-old boy without the PMP22 gene. Motor and sensory deficits in the proband were nonlength-dependent. Weakness was found in cranial muscles but not in the limbs. Large fiber sensory modalities were profoundly abnormal, which started prior to the maturation of myelin. This is in line with the temporal pattern of PMP22 expression predominantly in cranial motor neurons and dorsal root ganglia during embryonic development, becoming undetectable in adulthood. Moreover, there were conspicuous maturation defects of myelinating Schwann cells; these defects were more significant in motor nerve fibers than in sensory nerve fibers. Taken together, the data suggest that PMP22 is important for the normal function of neurons that express PMP22 during early development, such as cranial motor neurons and spinal sensory neurons. Moreover, PMP22 deficiency differentially affects myelination between motor and sensory nerves, which may have contributed to the unique clinical phenotype in the patient with an absence of PMP22.


Cabergoline monotherapy in the long-term treatment of Cushing's disease.
Cabergoline is a long-acting dopamine receptor agonist used to treat prolactinomas. Identification of D(2) receptors in corticotroph tumors led to clinical trials of cabergoline therapy in limited cases of Nelson's syndrome, ectopic ACTH-secreting tumors, and recently Cushing's disease (CD). To evaluate the long-term efficacy of cabergoline monotherapy in patients with CD. Retrospective analysis of non-randomized clinical therapy with cabergoline in 30 patients with CD treated in academic centers of Buenos Aires and Montreal. Cabergoline was initiated at 0.5-1.0 mg/week and adjusted up to a maximal dose of 6 mg/week based on urinary free cortisol (UFC) levels. Complete response to cabergoline was defined as a sustained normalization of UFC with at least two normal values measured at 1-3 months interval; partial response was defined as a decrease of UFC to <125% of the upper limit of normal, and treatment failure as UFC ≥ 125% of it. Within 3-6 months, complete response was achieved in 11 patients (36.6%) and partial response in 4 patients (13.3%). After long-term therapy, nine patients (30%) remain with a complete response after a mean of 37 months (range from 12 to 60 months) with a mean dose of 2.1 mg/week of cabergoline. Two patients escaped after 2 and 5 years of complete response, but one patient transiently renormalized UFC after an increase in cabergoline dosage. No long-term response was maintained in four initial partial responders. Cabergoline monotherapy can provide an effective long-term medical therapy for selected patients with CD, but requires close follow-up for dose adjustments.


Influence of a desensitizing agent on efficacy of a paint-on bleaching agent.
To evaluate the influence of a desensitizing agent (VivaSens) on efficacy of a paint-on bleaching agent (VivaStyle Paint On Plus). Bleaching was performed for 7 days with VivaStyle Paint On Plus. The varnish was applied twice a day for 10 minutes each. 80 subjects were included in the study and randomly distributed in two groups (n = 40) according to exposed cervical dentin and perceived hypersensitivities. Group A used VivaStyle without VivaSens while Group B used VivaStyle Paint On Plus after a single application of VivaSens. Tooth color was assessed on facial surfaces of first upper incisors with Vita shade guide at baseline and 10 days after bleaching therapy. Sensitivity, with intensity graded from 0 (no sensitivity) to 10 (high sensitivity), was assessed chair-side using a blow of air at baseline, at the end of therapy (7 days) and 10 days after bleaching therapy. Statistical evaluation was performed with non parametric ANOVA. Thirteen subjects dropped out of the study; six due to gingival burning sensation (A: 3; B: 3) related to the bleaching regimen and seven due to lack of compliance. Directly after completion of bleaching therapy, tooth color had changed significantly compared to baseline in both treatment groups without difference among the groups. Color changes (Delta) according to Vita shade guide were as follows (mean +/- standard deviation): Group A: Delta 2.7 +/- 1.0, Group B: Delta 2.8 +/- 0.9. After bleaching (7 days) the intensity of tooth hypersensitivity (mean +/- standard deviation) was increased significantly compared to baseline in both groups (P < 0.05): Group A: 1.58 +/- 1.91 (baseline: 0.4 +/- 0.5); Group B: 1.3 +/- 1.8 (baseline: 0.5 +/- 0.7). The number of subjects reporting tooth hypersensitivity increased in Group A by 5 (n = 13) and in Group B by 1 (n = 10) subject. Although degree of hypersensitivities and number of subjects with hypersensitivities were lower in Group B, there was no significant difference between the groups.


Novel, host-restricted genotypes of Bordetella bronchiseptica associated with phocine respiratory tract isolates.
During a succession of phocine morbillivirus outbreaks spanning the past 25 years, Bordetella bronchiseptica was identified as a frequent secondary invader and cause of death. The goal of this study was to evaluate genetic diversity and the molecular basis for host specificity among seal isolates from these outbreaks. MLST and PvuII ribotyping of 54 isolates from Scottish, English or Danish coasts of the Atlantic or North Sea revealed a single, host-restricted genotype. A single, novel genotype, unique from that of the Atlantic and North Sea isolates, was found in isolates from an outbreak in the Caspian Sea. Phylogenetic analysis based either on MLST sequence, ribotype patterns or genome-wide SNPs consistently placed both seal-specific genotypes within the same major clade but indicates a distinct evolutionary history for each. An additional isolate from the intestinal tract of a seal on the south-west coast of England has a genotype otherwise found in rabbit, guinea pig and pig isolates. To investigate the molecular basis for host specificity, DNA and predicted protein sequences of virulence genes that mediate host interactions were used in comparisons between a North Sea isolate, a Caspian Sea isolate and each of their closest relatives as inferred from genome-wide SNP analysis. Despite their phylogenetic divergence, fewer nucleotide and amino acid substitutions were found in comparisons of the two seal isolates than in comparisons with closely related strains. These data indicate isolates of B. bronchiseptica associated with respiratory disease in seals comprise unique, host-adapted and highly clonal populations.


Sero-positive African Americans' beliefs about alcohol and their impact on anti-retroviral adherence.
Alcohol consumption has been associated with HIV disease progression; yet, the nature of this association is poorly understood. This study sought to determine the influence of patient beliefs about alcohol on ART adherence, and elucidate clinician beliefs about drinking and taking ART. Most patients (85%) believed alcohol and ART do not mix. The three alcohol consumption groups, light, moderate, and heavy, differed in their beliefs about drinking and ART with 64% of light and 55% of moderate drinkers skipping ART when drinking compared to 29% of heavy drinkers. Beliefs were derived from folk models of alcohol-ART interaction. Patients 50 and older were less likely to skip ART when drinking. Alcohol appears to affect adherence through decisions to forgo ART when drinking not through drunken forgetfulness. Furthermore, over one-half of clinicians believed alcohol and ART should not be taken together. These findings have implications for patient care and physician training.


Evaluating the utility of trefoil factor 1 as a mammary-specific immunostain compared and in conjunction with GATA-3 and mammaglobin in the distinction between carcinoma of breast and lung.
The distinction between metastatic breast carcinomas (BCs) and primary lung carcinomas (PLCs) can be difficult. This study tested the utility of trefoil factor 1 (TFF1) for this purpose and compared it with mammaglobin and GATA protein binding 3 (GATA-3). Tissue microarrays containing 365 BCs and 338 PLCs were stained with TFF1, mammaglobin, and GATA-3, and an H-score was calculated. Sensitivity, specificity, and accuracy were calculated, and logistical regression analysis was performed. Accuracy of correctly classifying the tumor type was 81.9%, 71.3%, and 64.0% for GATA-3, mammaglobin, and TFF1, respectively. Odds ratios for selecting BCs were 25.69, 93.15, and 4.17, respectively, with P values less than .001. With a single exception, the best immunopanel included GATA-3 and mammaglobin in all comparisons. TFF1 demonstrated breast specificity but was inferior to mammaglobin and GATA-3. Therefore, its routine clinical use may not be justified. TFF1 showed little benefit when added to an immunopanel.


Optical negative refraction in bulk metamaterials of nanowires.
Negative refraction in metamaterials has generated great excitement in the scientific community. Although negative refraction has been realized in microwave and infrared by using metamaterials and by using two-dimensional waveguide structures, creation of a bulk metamaterial showing negative refraction at visible frequency has not been successful, mainly because of the significant resonance losses and fabrication difficulties. We report bulk metamaterials made of nanowires that show such negative refraction for all incident angles in the visible region. Moreover, the negative refraction occurs far from any resonance, resulting in a low-loss and a broad-band propagation at visible frequencies. These remarkable properties can substantially affect applications such as imaging, three-dimensional light manipulation, and optical communication.