Somatic mutation in single human neurons tracks developmental and transcriptional history.
Neurons live for decades in a postmitotic state, their genomes susceptible to DNA damage. Here we survey the landscape of somatic single-nucleotide variants (SNVs) in the human brain. We identified thousands of somatic SNVs by single-cell sequencing of 36 neurons from the cerebral cortex of three normal individuals. Unlike germline and cancer SNVs, which are often caused by errors in DNA replication, neuronal mutations appear to reflect damage during active transcription. Somatic mutations create nested lineage trees, allowing them to be dated relative to developmental landmarks and revealing a polyclonal architecture of the human cerebral cortex. Thus, somatic mutations in the brain represent a durable and ongoing record of neuronal life history, from development through postmitotic function.


Factors Discriminating High From Low Score Performance in Biathlon Shooting.
To identify biomechanical predictors that distinguish between high- and low-score athletes in biathlon shooting and to determine the relationships among these variables in field testing. Twenty-two biathletes (8 female, 14 male) from the World Cup, the European Cup, and a federal youth squad each fired 3 clips of 5 shots in prone and standing shooting positions without physical load, followed by 2 respective series in both disciplines during a simulated 12.5-km pursuit race on roller skis. Biomechanical variables describing triggering, rifle force in the back shoulder, and body and rifle sway were calculated over the last 0.5 second before firing. For computed linear discriminant analyses, subjects were divided into high- and low-level performers based on mean scores for each condition separately. In addition, correlations among all biomechanical factors were calculated. Regarding prone shooting, shoulder force in the rest condition and vertical rifle sway in the race simulation were shown to be main discriminators. Several body- and rifle-sway variables were found to be predictors in standing rest shooting. Body sway across the shooting line discriminated the groups in the standing race situation tendentially. Thus, the main performance predictors changed due to fatigue. Correlations between triggering and rifle sway, shoulder force and rifle sway, and body sway and rifle sway were discovered. Referring to the current results, athletes are recommended to focus on vertical rifle sway in prone position and on body sway across the shooting line during standing shooting when fatigued.


Redefining outcomes in immune TTP: an international working group consensus report.
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal thrombotic microangiopathy caused by autoantibody-mediated severe deficiency of ADAMTS13. Standardized definitions of response, exacerbation, remission, and relapse were initially proposed in 2003 and modified by the International Working Group for TTP in 2017. These definitions, which have been widely used in clinical practice and research, are based primarily on the platelet count and are benchmarked against the timing of discontinuation of therapeutic plasma exchange (TPE). They do not incorporate ADAMTS13 activity or the temporizing effects on the platelet count of caplacizumab, a novel anti-von Willebrand factor (VWF) nanobody. In light of these limitations, the IWG aimed to develop revised consensus outcome definitions that incorporate ADAMTS13 activity and the effects of anti-VWF therapy, by using an estimate-talk-estimate approach. The updated definitions distinguish clinical remission and clinical relapse (defined primarily by platelet count) from ADAMTS13 remission and ADAMTS13 relapse (defined by ADAMTS13 activity). The revised definitions of exacerbation and remission are benchmarked against not only the timing of discontinuation of TPE but also that of anti-VWF therapy. Retrospective validation of the revised definitions is described, although they have yet to be prospectively validated. Clinical implications of the updated outcome definitions are also discussed and an example of their application to clinical practice is provided to highlight their clinical relevance.


MRI-Based Upper Abdominal Organs-at-Risk Atlas for Radiation Oncology.
The purpose of our study was to provide a guide for identification and contouring of upper abdominal organs-at-risk (OARs) in the setting of online magnetic resonance imaging (MRI)-guided radiation treatment planning and delivery. After a needs assessment survey, it was determined that an upper abdominal MRI-based atlas of normal OARs would be of benefit to radiation oncologists and radiation therapists. An anonymized diagnostic 1.5T MRI from a patient with typical upper abdominal anatomy was used for atlas development. Two MRI sequences were selected for contouring, a T1-weighted gadoxetic acid contrast-enhanced MRI acquired in the hepatobiliary phase and axial fast imaging with balanced steady-state precession. Two additional clinical MRI sequences from commercial online MRI-guided radiation therapy systems were selected for contouring and were included in the final atlas. Contours from each data set were completed and reviewed by radiation oncologists, along with a radiologist who specializes in upper abdominal imaging, to generate a consensus upper abdominal MRI-based OAR atlas. A normal OAR atlas was developed, including recommendations for contouring. The atlas and contouring guidance are described, and high-resolution MRI images and contours are displayed. OARs, such as the bile duct and biliary tree, which may be better seen on MRI than on computed tomography, are highlighted. The full DICOM/DICOM-RT MRI images from both the diagnostic and clinical online MRI-guided radiation therapy systems data sets have been made freely available, for educational purposes, at econtour.org. This MRI contouring atlas for upper abdominal OARs should provide a useful reference for contouring and education. Its routine use may help to improve uniformity in contouring in radiation oncology planning and OAR dose calculation. Full DICOM/DICOM-RT images are available online and provide a valuable educational resource for upper abdominal MRI-based radiation therapy planning and delivery.


Amino acids as metabolic substrates during cardiac ischemia.
The heart is well known as a metabolic omnivore in that it is capable of consuming fatty acids, glucose, ketone bodies, pyruvate, lactate, amino acids and even its own constituent proteins, in order of decreasing preference. The energy from these substrates supports not only mechanical contraction, but also the various transmembrane pumps and transporters required for ionic homeostasis, electrical activity, metabolism and catabolism. Cardiac ischemia - for example, due to compromise of the coronary vasculature or end-stage heart failure - will alter both electrical and metabolic activity. While the effects of myocardial ischemia on electrical propagation and stability have been studied in depth, the effects of ischemia on metabolic substrate preference has not been fully appreciated: oxygen deprivation during ischemia will significantly alter the relative ability of the heart to utilize each of these substrates. Although changes in cardiac metabolism are understood to be an underlying component in almost all cardiac myopathies, the potential contribution of amino acids in maintaining cardiac electrical conductance and stability during ischemia is underappreciated. Despite clear evidence that amino acids exert cardioprotective effects in ischemia and other cardiac disorders, their role in the metabolism of the ischemic heart has yet to be fully elucidated. This review synthesizes the current literature of the metabolic contribution of amino acids during ischemia by analyzing relevant historical and recent research.


Mogamulizumab (Anti-CCR4) in HTLV-1-Associated Myelopathy.
Human T-lymphotropic virus type 1 (HTLV-1) causes the debilitating neuroinflammatory disease HTLV-1-associated myelopathy-tropical spastic paraparesis (HAM-TSP) as well as adult T-cell leukemia-lymphoma (ATLL). In patients with HAM-TSP, HTLV-1 infects mainly CCR4+ T cells and induces functional changes, ultimately causing chronic spinal cord inflammation. We evaluated mogamulizumab, a humanized anti-CCR4 monoclonal antibody that targets infected cells, in patients with HAM-TSP. In this uncontrolled, phase 1-2a study, we assessed the safety, pharmacokinetics, and efficacy of mogamulizumab in patients with glucocorticoid-refractory HAM-TSP. In the phase 1 dose-escalation study, 21 patients received a single infusion of mogamulizumab (at doses of 0.003 mg per kilogram of body weight, 0.01 mg per kilogram, 0.03 mg per kilogram, 0.1 mg per kilogram, or 0.3 mg per kilogram) and were observed for 85 days. Of those patients, 19 continued on to the phase 2a study and received infusions, over a period of 24 weeks, of 0.003 mg per kilogram, 0.01 mg per kilogram, or 0.03 mg per kilogram at 8-week intervals or infusions of 0.1 mg per kilogram or 0.3 mg per kilogram at 12-week intervals. The side effects of mogamulizumab did not limit administration up to the maximum dose (0.3 mg per kilogram). The most frequent side effects were grade 1 or 2 rash (in 48% of the patients) and lymphopenia and leukopenia (each in 33%). The dose-dependent reduction in the proviral load in peripheral-blood mononuclear cells (decrease by day 15 of 64.9%; 95% confidence interval [CI], 51.7 to 78.1) and inflammatory markers in cerebrospinal fluid (decrease by day 29 of 37.3% [95% CI, 24.8 to 49.8] in the CXCL10 level and of 21.0% [95% CI, 10.7 to 31.4] in the neopterin level) was maintained with additional infusions throughout the phase 2a study. A reduction in spasticity was noted in 79% of the patients and a decrease in motor disability in 32%. Mogamulizumab decreased the number of HTLV-1-infected cells and the levels of inflammatory markers. Rash was the chief side effect. The effect of mogamulizumab on clinical HAM-TSP needs to be clarified in future studies. (Funded by the Japan Agency for Medical Research and Development and the Ministry of Health, Labor, and Welfare; UMIN trial number, UMIN000012655 .).


Sorting live stem cells based on Sox2 mRNA expression.
While cell sorting usually relies on cell-surface protein markers, molecular beacons (MBs) offer the potential to sort cells based on the presence of any expressed mRNA and in principle could be extremely useful to sort rare cell populations from primary isolates. We show here how stem cells can be purified from mixed cell populations by sorting based on MBs. Specifically, we designed molecular beacons targeting Sox2, a well-known stem cell marker for murine embryonic (mES) and neural stem cells (NSC). One of our designed molecular beacons displayed an increase in fluorescence compared to a nonspecific molecular beacon both in vitro and in vivo when tested in mES and NSCs. We sorted Sox2-MB(+)SSEA1(+) cells from a mixed population of 4-day retinoic acid-treated mES cells and effectively isolated live undifferentiated stem cells. Additionally, Sox2-MB(+) cells isolated from primary mouse brains were sorted and generated neurospheres with higher efficiency than Sox2-MB(-) cells. These results demonstrate the utility of MBs for stem cell sorting in an mRNA-specific manner.


The influence of vascular risk factors on cognitive function in early Parkinson's disease.
Hypertension, dyslipidemia, diabetes, and obesity are well-established risk factors for cognitive impairment and dementia in older adults. In contrast, previous studies that have assessed the impact of vascular risk factors (VRFs) on cognition in Parkinson's disease (PD) have had methodological limitations and reported conflicting findings. We address this question in a large well-characterized cohort of de novo PD patients. A total of 367 untreated and non-demented patients aged 50 years and older with early PD (H&Y = 1.0-2.0) underwent a comprehensive clinical and neuropsychological assessment at baseline and 24 months later. A series of linear mixed models were used to determine the effects of VRFs on cognition while controlling for patient and disease characteristics. The outcomes included norm-referenced Z-scores of global cognition, visuospatial skills, verbal episodic memory, semantic verbal fluency, attention, and working memory tests. A longer history of hypertension and a higher pulse pressure were significant predictors of lower Z-scores on immediate and delayed free recall, recognition, and verbal fluency tests. On average, every 10 mmHg increase in pulse pressure was associated with a 0.08 reduction on the cognitive Z-scores. The effects were independent of age, education, disease duration, motor impairment, medication, and depressive symptoms. Other VRFs were not associated with cognitive outcomes. Our results are consistent with previous studies suggesting that hypertension exerts a detrimental effect on memory and verbal fluency in early PD. Management of blood pressure and cardiovascular health may be important to reduce risk of cognitive decline in PD. Copyright © 2017 John Wiley & Sons, Ltd.


Using group model building to understand factors that influence childhood obesity in an urban environment.
Despite increased attention, conventional views of obesity are based upon individual behaviors, and children and parents living with obesity are assumed to be the primary problem solvers. Instead of focusing exclusively on individual reduction behaviors for childhood obesity, greater focus should be placed on better understanding existing community systems and their effects on obesity. The Milwaukee Childhood Obesity Prevention Project is a community-based coalition established to develop policy and environmental change strategies to impact childhood obesity in Milwaukee, Wisconsin. The coalition conducted a Group Model Building exercise to better understand root causes of childhood obesity in its community. Group Model Building is a process by which a group systematically engages in model construction to better understand the systems that are in place. It helps participants make their mental models explicit through a careful and consistent process to test assumptions. This process has 3 main components: (1) assembling a team of participants; (2) conducting a behavior-over-time graphs exercise; and (3) drawing the causal loop diagram exercise. The behavior-over-time graph portion produced 61 graphs in 10 categories. The causal loop diagram yielded 5 major themes and 7 subthemes. Factors that influence childhood obesity are varied, and it is important to recognize that no single solution exists. The perspectives from this exercise provided a means to create a process for dialogue and commitment by stakeholders and partnerships to build capacity for change within the community.


Modelling Dominance Hierarchies Under Winner and Loser Effects.
Animals that live in groups commonly form themselves into dominance hierarchies which are used to allocate important resources such as access to mating opportunities and food. In this paper, we develop a model of dominance hierarchy formation based upon the concept of winner and loser effects using a simulation-based model and consider the linearity of our hierarchy using existing and new statistical measures. Two models are analysed: when each individual in a group does not know the real ability of their opponents to win a fight and when they can estimate their opponents' ability every time they fight. This estimation may be accurate or fall within an error bound. For both models, we investigate if we can achieve hierarchy linearity, and if so, when it is established. We are particularly interested in the question of how many fights are necessary to establish a dominance hierarchy.


A plasma membrane Ca(2+)-ATPase (PMCA) from the liver fluke, Fasciola hepatica.
Fasciolosis is a parasitic infection by the liver fluke Fasciola hepatica, which costs the global agricultural community over US $2 billion per year. Its prevalence is rising due to factors such as climate change and drug resistance. ATP-dependent membrane transporters are considered good potential drug targets as they are essential for cellular processes and are in an exposed, accessible position in the cell. Immunolocalisation studies demonstrated that a plasma membrane calcium ATPase (PMCA) was localised to the parenchymal tissue in F. hepatica. The coding sequence for a F. hepatica PMCA (FhPMCA) has been obtained. This sequence encodes a 1,163 amino acid protein which contains motifs which are commonly conserved in PMCAs. Molecular modelling predicted that the protein has 10 transmembrane segments which include a potential calcium ion binding site and phosphorylation motif. FhPMCA interacts with the calmodulin-like protein FhCaM1, but not the related proteins FhCaM2 or FhCaM3, in a calcium-ion dependent manner. This interaction occurs through a region in the C-terminal region of FhPMCA which most likely adopts an α-helical conformation. When FhPMCA was heterologously expressed in a budding yeast strain deleted for its PMCA (Pmc1p), it restored viability. Microsomes prepared from these yeast cells had calcium ion stimulated ATPase activity which was inhibited by the known PMCA inhibitors, bisphenol and eosin. The potential of FhPMCA as a new drug target is discussed.


Quantitative determination of sst2 gene expression in neuroblastoma tumor predicts patient outcome.
Neuroblastoma (NB) is the most common pediatric neuroendocrine tumor, and it is characterized by a quite variable clinical course. We previously found a great variability in the expression of somatostatin receptor type 2 (sst2) in several human NB cell lines and primary tumors. In this report we investigated whether expression of sst2 is somehow related to clinical outcome. We performed a retrospective study on 54 patients with a maximum follow-up of 100 months. The concentration of specific messenger ribonucleic acid (mRNA) for sst2 was measured by competitive RT-PCR and validated, in a small subset of samples, by quantitative imaging of gene (in situ hybridization) and protein (immunohistochemistry) expression. We found that sst2 mRNA was variably expressed in all NB tumors (range, 2.5 x 10(5) to 8 x 10(9) molecules/microg RNA) with a relevant reduction in the more advanced stage (P < 0.01). Analysis of Kaplan-Meier curves indicated that sst2 expression is positively related to the overall (P < 0.0001) and event-free (P < 0.0001) survival. Expression of sst2 was negatively related to tumor stage (P < 0.02) and MYCN amplification (P < 0.001), a poor prognostic factor. However, the prognostic information derived from sst2 is apparently independent from MYCN amplification, as assessed by stratifying sst2 values according to MYCN. In addition, the expression of sst2 was the only significant prognostic factor (P < 0.02) when it was included in a multivariate model containing other well known prognostic factors such as age, stage, and MYCN amplification. Hence, we propose that sst2 expression represents a new prognostic marker for NB. The main clinical value of a quantitative measure of sst2 lies in its ability to detect patients at low risk, independently from other prognostic factor, including MYCN amplification.


Simvastatin improves olanzapine-induced dyslipidemia in rats through inhibiting hepatic mTOR signaling pathway.
Second-generation antipsychotic drug (SGA)-induced metabolic abnormalities, such as dyslipidemia, are a major clinical problem for antipsychotic therapy. Accumulated evidences have shown the efficacy of statins in reducing SGA-induced dyslipidemia, but the underlying mechanisms are unclear. In this study, we explored whether mTOR signaling was involved in olanzapine (OLZ)-induced dyslipidemia as well as the lipid-lowering effects of cotreatment of simvastatin (Sim) in rats. Model rats received OLZ (1.0 mg/kg, t.i.d.) for 7 weeks; from the third week a group of model rats were cotreatment of Sim (3.0 mg/kg, t.i.d.) for 5 weeks. We found that OLZ treatment significantly increased the plasma triglyceride (TG) and total cholesterol (TC) levels, and promoted lipid accumulation in the liver, whereas cotreatment of Sim reversed OLZ-induced dyslipidemia. Hepatic mTORC1 and p-mTORC1 expression was accelerated in the OLZ treatment group, with upregulation of mRNA expression of sterol regulatory element-binding protein 1c (SREBP1c) and its target genes, whereas these alterations were ameliorated by Sim cotreatment. In HepG2 cells, rapamycin (a mTOR inhibitor) significantly reduced the OLZ-stimulated hepatocellular lipid contents and weakened the ability of Sim to lower lipids via a mechanism associated with the upregulation of SREBP1c-mediated de novo lipogenesis. Our data suggest that OLZ induces lipid accumulation in both plasma and liver, and Sim ameliorates OLZ-induced lipid metabolic dysfunction through its effects on mTOR signaling via reducing SREBP1c activation and the downregulation of gene expression involved in lipogenesis. These data provide a new insight into the prevention of metabolic side effects induced by antipsychotic drugs.


Ten-year course of borderline personality disorder: psychopathology and function from the Collaborative Longitudinal Personality Disorders study.
Borderline personality disorder (BPD) is traditionally considered chronic and intractable. To compare the course of BPD's psychopathology and social function with that of other personality disorders and with major depressive disorder (MDD) over 10 years. A collaborative study of treatment-seeking, 18- to 45-year-old patients followed up with standardized, reliable, and repeated measures of diagnostic remission and relapse and of both global social functioning and subtypes of social functioning. Nineteen clinical settings (hospital and outpatient) in 4 northeastern US cities. Three study groups, including 175 patients with BPD, 312 with cluster C personality disorders, and 95 with MDD but no personality disorder. The Diagnostic Interview for DSM-IV Personality Disorders and its follow-along version (the Diagnostic Interview for DSM-IV Personality Disorders-Follow-Along Version) were used to diagnose personality disorders and assess changes in them. The Structured Clinical Interview for DSM-IV Axis I Disorders and the Longitudinal Interval Follow-up Evaluation were used to diagnose MDD and assess changes in MDD and in social function. Eighty-five percent of patients with BPD remitted. Remission of BPD was slower than for MDD (P < .001) and minimally slower than for other personality disorders (P < .03). Twelve percent of patients with BPD relapsed, a rate less frequent and slower than for patients with MDD (P < .001) and other personality disorders (P = .008). All BPD criteria declined at similar rates. Social function scores showed severe impairment with only modest albeit statistically significant improvement; patients with BPD remained persistently more dysfunctional than the other 2 groups (P < .001). Reductions in criteria predicted subsequent improvements in DSM-IV Axis V Global Assessment of Functioning scores (P < .001). The 10-year course of BPD is characterized by high rates of remission, low rates of relapse, and severe and persistent impairment in social functioning. These results inform expectations of patients, families, and clinicians and document the severe public health burden of this disorder.


Factors affecting heterologous gene expression in Saccharomyces cerevisiae.
The 'promoter' fragment from the yeast phosphoglycerate kinase (PGK) gene has been used to direct the expression of human interferon-alpha-2 (IFN alpha 2) on a high-copy-number plasmid in yeast. The yields of IFN alpha 2 are only 1-3% of yeast total protein, whereas the maximum yield of PGK produced by the PGK gene on a high-copy-number plasmid is at least 50%. IFN alpha 2 is turned over more rapidly than PGK but in addition a major reason for the relatively low level of IFN alpha 2 is that IFN-specific RNA levels are much lower. This does not reflect differences in plasmid copy number or integrity, or differences in the 5' and 3' untranslated regions of the transcripts or DNA flanking regions. It appears that the presence of heterologous coding sequences, or the absence of specific yeast sequences causes a reduction in heterologous RNA levels in yeast.


Paraganglioma-like dermal melanocytic tumor: a unique entity distinct from cellular blue nevus, clear cell sarcoma, and cutaneous melanoma.
We are reporting a previously undescribed primary dermal melanocytic tumor identified by reviewing all dermal melanocytic tumors referred in consultation that did not qualify histologically as a previously described entity. From these cases, 8 were remarkably similar. We termed them "paraganglioma-like dermal melanocytic tumor" (PDMT) based on their nested growth pattern. This term is used descriptively and does not imply any histogenetic or biologic similarity to true paraganglioma. PDMT is primarily a tumor of the extremities of adult females (18-53 years, mean 35 years; males 2; females 6) which present as a dermal nodule (range, 0.5-4.2 cm; mean, 1.4 cm) composed of nests of clear to amphophilic oval cells separated by delicate fibrous strands. Nuclear atypia was mild and mitotic activity low (1-4 mitoses/10 HPF). Melanin was not obvious on light microscopy. Tumors expressed S-100 protein (8 of 8), Melan-A (4 of 8), HMB-45 (8 of 8), and microphthalmia transcription factor (8 of 8) and lacked pancytokeratin (8 of 8) and smooth muscle actin (8 of 8). FISH analysis of 5 cases revealed an intact EWS gene locus, supporting absence of the clear cell sarcoma 12;22 translocation. Follow-up information in 8 patients (range, 35-92 months; mean, 54 months) indicated that all were alive without disease. PDMT comprises a clinically and pathologically unique subtype of dermal melanocytic tumors. Our study suggests a benign course, although a lesion of low malignant potential cannot be excluded.


Modified signed-digit optical processors using computer-generated holograms.
Modified signed-digit (MSD) numbers offer convenient parallel addition and subtraction of bits. The parallel addition of any two MSD numbers, no matter what the values of their bits may be, requires only three bit-pattern transformations. To perform such transformations optically, however, MSD data must be represented in a form suitable for cascade connection. Proposed here is a new cascade-connective MSD optical processor. Adding principles are successfully demonstrated by using an optical threshold device array in addition to new computer-generated holograms that are adjusted to equalize the intensity of their diffracted light beams.


An event-specific analysis of condom breakage among African American men at risk of HIV acquisition.
African American men are at high risk of human immunodeficiency virus acquisition. Condom breakage is an understudied aspect of their sexual protective behavior. This study identified user errors leading to condom breakage using an event-specific analysis among young African American men newly diagnosed with a sexually transmitted disease (STD). Recruitment occurred in a publicly funded STD clinic located in a metropolitan area of the Southern United States. Of 296 African American men screened as eligible, 271 (91.5%) agreed to participate. Men completed a self-administered questionnaire. Men reporting condom use with men were excluded from the analysis, leaving an analytic sample of 264 men. The recall period was for the last time men used condoms for penile-vaginal sex (within the past 3 months). More than one-fifth (21.2%) reported condom breakage. Each year of advancing age decreased the odds of breakage by 10% [adjusted odds ratio (AOR) = 0.90, 95% confidence interval (CI) = 0.81-0.99, P = 0.028]. Men who had used an oil-based lubricant were more than 3 times as likely to report breakage (AOR = 3.21, 95% CI = 1.48-7.00, P = 0.003) and those who completely unrolled the condom before putting it on were also about 3 times more likely to report breakage (AOR = 3.34, 95% CI = 1.76-6.50, P = 0.0001). The breakage rate for men indicating both errors, i.e., use of an oil-based lubricant and unrolling the condom before application, was 54.5% compared with 33.3% among those indicated either error, and 12.8% among those indicating neither error. Attributable risk for the 2 errors combined was 39%. Condom breakage among this sample of men at high risk for human immunodeficiency virus infection was common. This problem could be mitigated by counseling men to avoid the use of oil-based lubricants and by teaching them basic condom application skills.


Falciparum malaria in children.
Recent reports have substantiated claims that the clinical spectrum of falciparum malaria is different in African children as compared with nonimmune adults. The SPf66 vaccine has been tried in African children with varying success, but only insecticide-treated bed nets have reduced the mortality. Developments in ancillary treatment may reduce the morbidity and mortality of severe falciparum malaria.


Validating the psychiatric nurses methods of coping questionnaire: Arabic version.
The aim of the study was to undertake a psychometric analysis of the Psychiatric Nurses Methods of Coping Questionnaire (PNMCQ) - Arabic version when used to measure coping skills in psychiatric nurses in Jordan. A descriptive, cross-sectional design was adopted in this study. A demographic questionnaire and the 35-item PNMCQ -Arabic were the measures used to collect data. The PNMCQ demonstrated valid and reliable values when administered to psychiatric nurses in Jordan after it had been submitted to factor analysis. The development of PNMCQ: Arabic Version adequately measures coping skills in psychiatric nurses from a culturally appropriate context. Use of the tool can determine coping skills in psychiatric nurses with the view to positive staff development. Strategies identified based on results of the PNMCQ could ultimately result in better nurse retention and patient outcomes.


THE CYCLIC CHANGES IN THE MAMMARY GLAND UNDER NORMAL AND PATHOLOGICAL CONDITIONS : II. THE CHANGES IN THE PREGNANT GUINEA PIG, THE EFFECT OF LUTEIN INJECTIONS, AND THE CORRELATION BETWEEN THE CYCLE OF THE UTERUS AND OVARIES AND THE CYCLE OF THE MAMMARY GLAND.
1. In the pregnant guinea pig proliferation of the mammary gland becomes regular only at a later stage of pregnancy; namely, during the period following the 24th day of pregnancy. Previous to this period proliferation was absent in the majority of cases. Proliferation of the mammary gland during pregnancy becomes regular only at a period of time which exceeds the duration of the normal sexual cycle unaccompanied by pregnancy. It is probable that pregnancy as well as the presence of living deciduornata and corpora lutea increases the proliferative activity of the mammary gland as compared with the ordinary cycle in non-pregnant animals or in animals lacking corpora lutea and deciduornata. 2. After the completion of pregnancy and in the beginning of secretion some mitotic proliferation may still be present, but it soon ceases, probably as the result of those processes that lead to secretion. While during the period of secretion, notwithstanding the presence of a new pregnancy, mitotic proliferation soon ceases, some proliferative stimulus seems still to be active, which, however, under existing conditions apparently leads only to a mitotic multiplication of nuclei. The latter conclusion is only suggested at the present time and needs confirmation through further studies. 3. In cases in which abortion took place in the first half of pregnancy secretion in the gland was not established; secretion occurred in two animals aborting toward the latter part of pregnancy. In one of these cases, mitotic proliferation of some gland cells was associated with the microscopic appearances of secretion. 4. In guinea pigs castrated during an early period of pregnancy in which pregnancy continued for some time, proliferative changes were absent in the mammary gland. In conjunction with a partial similar effect observed after extirpation of the corpora lutea during pregnancy, we may perhaps attribute the lack of proliferation in some of these cases to the absence of the ovaries. 5. Extirpation of the corpora lutea during pregnancy induces a new ovulation and with it the primary proliferation in the mammary gland; abortion does not necessarily prevent these proliferative changes. Extirpation of the corpora lutea during pregnancy perhaps prevents the secondary proliferative changes in the mammary gland. 6. Five injections of cow's lutein given in relatively large quantities intraperitoneally do not produce proliferation of the mammary gland in the guinea pig.


Mixed methods evaluation of well-being benefits derived from a heritage-in-health intervention with hospital patients.
This study sought to determine the effects of a heritage-in-health intervention on well-being. Benefits of arts-in-health interventions are relatively well-documented yet little robust research has been conducted using heritage-in-health interventions, such as those involving museum objects. Hospital patients (n = 57) participated in semi-structured, 30-40 minute facilitated interview sessions, discussing and handling museum objects comprising selections of six artefacts and specimens loaned from archaeology, art, geology and natural history collections. Well-being measures (Positive Affect Negative Affect Scale, Visual Analogue Scales) evaluated the sessions while inductive and deductive thematic analysis investigated psycho-educational features accounting for changes. Comparison of pre- and post-session quantitative measures showed significant increases in well-being and happiness. Qualitative investigation revealed thinking and meaning-making opportunities for participants engaged with objects. Heritage-in-health sessions enhanced positive mood and social interaction, endorsing the need for provision of well-being-related museum and gallery activities for socially excluded or vulnerable healthcare audiences.


Eye Movement Reinstatement and Neural Reactivation During Mental Imagery.
Half a century ago, Donald Hebb posited that mental imagery is a constructive process that emulates perception. Specifically, Hebb claimed that visual imagery results from the reactivation of neural activity associated with viewing images. He also argued that neural reactivation and imagery benefit from the re-enactment of eye movement patterns that first occurred at viewing (fixation reinstatement). To investigate these claims, we applied multivariate pattern analyses to functional MRI (fMRI) and eye tracking data collected while healthy human participants repeatedly viewed and visualized complex images. We observed that the specificity of neural reactivation correlated positively with vivid imagery and with memory for stimulus image details. Moreover, neural reactivation correlated positively with fixation reinstatement, meaning that image-specific eye movements accompanied image-specific patterns of brain activity during visualization. These findings support the conception of mental imagery as a simulation of perception, and provide evidence consistent with the supportive role of eye movement in neural reactivation.


Airway obstruction and bronchodilator responsiveness in adults with acute cough.
We sought to determine the prevalence of airway obstruction and bronchodilator responsiveness in adults consulting for acute cough in primary care. Family physicians recruited 3,105 adult patients with acute cough (28 days or shorter) attending primary care practices in 12 European countries. After exclusion of patients with preexisting physician-diagnosed asthma or chronic obstructive pulmonary disease (COPD), we undertook complete case analysis of spirometry results (n = 1,947) 28 to 35 days after inclusion. Bronchodilator responsiveness was diagnosed if there were recurrent complaints of wheezing, cough, or dyspnea and an increase of the forced expiratory volume in 1 second (FEV(1)) of 12% or more after bronchodilation. Airway obstruction was diagnosed according to 2 thresholds for the (postbronchodilator) ratio of FEV(1) to forced vital capacity (FEV(1):FVC): less than 0.7 and less than the lower limit of normal. There were 240 participants who showed bronchodilator responsiveness (12%), 193 (10%) had a FEV(1)/FVC ratio of less than 0.7, and 126 (6%) had a ratio of less than the lower limit of normal. Spearman's correlation between the 2 definitions of obstruction was 0.71 (P <.001), with discordance most pronounced among those younger than 30 years and in older participants. Both bronchodilator responsiveness and persistent airway obstruction are common in adults without established asthma or COPD who consult for acute cough in primary care, which suggests a high risk of undiagnosed asthma and COPD. Different accepted methods to define airway obstruction detected different numbers of patients, especially at the extremes of age. As both conditions benefit from appropriate and timely interventions, clinicians should be aware and responsive to potential underdiagnosis.


Key characteristics including sex, sexual orientation and internet use associated with worse mental health among university students in Brazil and implications.
The symptoms of anxiety and depression disorders are multifactorial and can trigger a series of problems especially among university students. The aim of this study was to assess the prevalence and associated factors with anxiety and depression symptoms among first-semester university students at a Federal University in Brazil given the paucity of such data and the first semester is the most stressfultime. Cross-sectional study with first-semester university students. The questionnaire included socio-demographic variables, lifestyles, health conditions and the Depression Anxiety Stress Scales. Descriptive analysis was performed, followed by bivariate analysis and Poisson regression analysis. Three hundred and fifty-six students (65.2%) across a range of courses in their first semester participated. The prevalence of anxiety was 42.5% and depression 33.2%. Regarding symptoms of anxiety and depression disorders, a positive association was observed among females, non-heterosexual, non-white skin color, excessive internet use, lack of physical activity, not attending university parties, having psychological counseling, history of anxiety in first- or second-degree relatives, poor self-rated health and use of psychotropic medicines. Due to the high prevalence of anxiety and depression symptoms, the importance of developing programs to promote mental and physical health of university students is highlighted.


A two-dimensional analog VLSI circuit for detecting discontinuities in early vision.
A large number of computer vision algorithms for finding intensity edges, computing motion, depth, and color, and recovering the three-dimensional shape of objects have been developed within the framework of minimizing an associated "energy" or "cost" functional. Particularly successful has been the introduction of binary variables coding for discontinuities in intensity, optical flow field, depth, and other variables, allowing image segmentation to occur in these modalities. The associated nonconvex variational functionals can be mapped onto analog, resistive networks, such that the stationary voltage distribution in the network corresponds to a minimum of the functional. The performance of an experimental analog very-large-scale integration (VLSI) circuit implementing the nonlinear resistive network for the problem of two-dimensional surface interpolation in the presence of discontinuities is demonstrated; this circuit is implemented in complementary metal oxide semiconductor technology.


Developmental exposure to paracetamol causes biochemical alterations in medulla oblongata.
The effect and safety of prenatal and early life administration of paracetamol - routinely used over-the-counter antipyretic and analgesic medication on monoamines content and balance of amino acids in the medulla oblongata is still unknown. In this study we have determined the level of neurotransmitters in this structure in two-month old Wistar male rats exposed to paracetamol in the dose of 5 (P5, n=10) or 15mg/kg b.w. (P15, n=10) during prenatal period, lactation and till the end of the second month of life. Control group received drinking water (Con, n=10). Monoamines, their metabolites and amino acids concentration in medulla oblongata of rats were determined using high performance liquid chromatography (HPLC) in 60 postnatal day (PND60). This experiment shows that prenatal and early life paracetamol exposure modulates neurotransmission associated with serotonergic, noradrenergic and dopaminergic system in medulla oblongata. Reduction of alanine and taurine levels has also been established.


A comparison of mixture toxicity assessment: examining the chronic toxicity of atrazine, permethrin and chlorothalonil in mixtures to Ceriodaphnia cf. dubia.
Pesticides predominantly occur in aquatic ecosystems as mixtures of varying complexity, yet relatively few studies have examined the toxicity of pesticide mixtures. Atrazine, chlorothalonil and permethrin are widely used pesticides that have different modes of action. This study examined the chronic toxicities (7-d reproductive impairment) of these pesticides in binary and ternary mixtures to the freshwater cladoceran Ceriodaphnia cf. dubia. The toxicity of the mixtures was compared to that predicted by the independent action (IA) model for mixtures, as this is the most appropriate model for chemicals with different modes of action. Following this they were compared to the toxicity predicted by the concentration addition (CA) model for mixtures. According to the IA model, the toxicity of the chlorothalonil plus atrazine mixture conformed to antagonism, while that of chlorothalonil and permethrin conformed to synergism. The toxicity of the atrazine and permethrin mixture as well as the ternary mixture conformed to IA implying there was either no interaction between the components of these mixtures and/or in the case of the ternary mixture the interactions cancelled each other out to result in IA. The synergistic and antagonistic mixtures deviated from IA by factors greater than 3 and less than 2.5, respectively. When the toxicity of the mixtures was compared to the predictions of the CA model, the binary mixture of chlorothalonil plus atrazine, permethrin plus atrazine and the ternary mixture all conformed to antagonism, while the binary mixture of chlorothalonil plus permethrin conformed to CA. Using the CA model provided estimates of mixture toxicity that did not markedly underestimate the measured toxicity, unlike the IA model, and therefore the CA model is the most suitable to use in ecological risk assessments of these pesticides.


Systematic representation of sound locations in the primary auditory cortex.
The primary auditory cortex (A1) is involved in sound localization. A consistent observation in A1 is a clustered representation of binaural properties, but how spatial tuning varies within binaural clusters is unknown. Here, this issue was addressed in A1 of the pallid bat, a species that relies on passive hearing (as opposed to echolocation) to localize prey. Evidence is presented for systematic representations of sound azimuth within two binaural clusters in the pallid bat A1: the binaural inhibition (EI) and peaked (P) binaural interaction clusters. The representation is not a "point-to-point" space map as seen in the superior colliculus, but is in the form of a systematic increase in the area of activated cortex as azimuth changes from ipsilateral to contralateral locations. The underlying substrate in the EI cluster is a systematic representation of the medial boundary of azimuth receptive fields. The P cluster is activated mostly for sounds near the midline, providing a spatial acoustic fovea. Activity in the P cluster falls off systematically as the sound is moved to more lateral locations. Sensitivity to interaural intensity differences predicts azimuth tuning in the vast majority of neurons. Azimuth receptive field properties are relatively stable across intensity over a moderate range (20-40 dB above threshold) of intensities. This suggests that the maps will be similar across the intensities tested. These results challenge the current view that no systematic representation of azimuth is present in A1 and show that such representations are present locally within individual binaural clusters.


Direct Visualization and Manipulation of Stacking Orders in Few-Layer Graphene by Dynamic Atomic Force Microscopy.
Stacking order plays a central role in governing a wide range of properties in layered two-dimensional materials. In the case of few-layer graphene, there are two common stacking configurations: ABA and ABC stacking, which have been proven to exhibit dramatically different electronic properties. However, the controllable characterization and manipulation between them remain a great challenge. Here, we report that ABA- and ABC-stacked domains can be directly visualized in phase imaging by tapping-mode atomic force microscopy with much higher spatial resolution than conventional optical spectroscopy. The contrasting phase is caused by the different energy dissipation by the tip-sample interaction. We further demonstrate controllable manipulation on the ABA/ABC domain walls by means of propagating stress transverse waves generated by the tapping of tip. Our results offer a reliable strategy for direct imaging and precise control of the atomic structures in few-layer graphene, which can be extended to other two-dimensional materials.


The flip side of synapse elimination.
The fine tuning of synaptic circuits often requires an activity-dependent phase in which appropriate connections are strengthened and inappropriate connections are eliminated. In this issue of Neuron, Walsh and Lichtman propose a novel "synaptic takeover" mechanism for synapse elimination at the vertebrate NMJ, where withdrawal of one axon is accompanied by expansion of a competing axon into the newly vacated territory.


Vesicular stomatitis virus infection of the central nervous system activates both innate and acquired immunity.
Vesicular stomatitis virus (VSV) causes acute infection of the central nervous system (CNS) when intranasally applied. We have examined cellular inflammatory changes in the CNS following VSV infection. As early as 1 day postinfection (p.i.), astrocytes were activated in the olfactory bulb (OB). This was followed by activation of microglia, first observed in the OB at day 3 p.i. Expression of inducible nitric oxide synthase was observed in activated microglia in the OB at day 3 p.i., and increased inducible nitric oxide synthase expression coincided with decreased virus titers in tissue homogenates. Expression of major histocompatibility complex (MHC) class I molecules on astrocytes and microglial, endothelial, and ependymal cells was also rapidly induced and followed by induced expression of MHC class II molecules on astrocytes and microglial and endothelial cells. Consistent with the pattern of viral dissemination, MHC molecules were expressed temporally from the rostral-to-caudal direction. Infiltration of CD8+ cells was observed as early as 1 day p.i. in the OB. CD4+ cells were detected in the OB at day 4 p.i. Increasing T-cell infiltration coincided with decreased virus titers. In contrast, B-cell infiltration of the CNS was not detected until day 14 p.i., after the virus was cleared and mice were showing behavioral signs of recovery. Breakdown of the blood-brain barrier was detected beginning at day 6 p.i., was most severe at day 8 p.i., and was followed by full recovery. Collectively, these data show that both innate immunity (production of nitric oxide) and acquired immunity (expression of MHC molecules and T-cell infiltration) are activated following VSV infection in the CNS.


Delayed detection of cleft palate: an audit of newborn examination.
To identify prevalence of delayed detection of cleft palate, and associated factors that could lead to improved identification at neonatal clinical examination. Audit of hospital notes, parental questionnaire incorporating open ended questions, and telephone questionnaire of junior doctors in the referring hospitals incorporating fixed choice questions. Of 344 cleft palate patients without cleft lip or submucous cleft palate, the day the cleft was detected was recorded in 92%. Delayed detection, after the first day, was 28% overall, distributed as 37% with isolated cleft palate and 23% with syndromic cleft palate. Narrow V shaped clefts were more likely to be delayed in detection compared with broad U shaped clefts, as were soft palate clefts compared with hard palate clefts. Five with isolated cleft palates were not detected until after the first year. Babies born at home were unlikely to be detected on day 1. Symptoms were significantly increased in the delayed detection group for feeding problems and nasal regurgitation. A telephone questionnaire of trainee paediatricians in referring units revealed that digital examination was more commonly practised than visual inspection, and few recalled receiving specific instruction on examination of the palate. Delayed detection of cleft palate was not uncommon, and the features of those more likely to be missed suggested digital examination was related. Trainee doctors and midwives should be instructed to inspect visually using a light and tongue depressor, then digitally if submucous cleft palate is suspected.


Ru(bpy)(3) covalently doped silica nanoparticles as multicenter tunable structures for electrochemiluminescence amplification.
The electrochemiluminescence (ECL) of doped silica nanoparticles (DSNPs), prepared by a reverse microemulsion method that leads to covalent incorporation of the Ru(bpy)(3)(2+), was investigated in acetonitrile and aqueous buffers. The emission was produced for the first time by cation-anion direct annihilation, and the position of ECL maxima indirectly allowed estimation of the E(1/2,IOx) and E(1/2,IRed) potentials for Ru(bpy)(3) inside DSNPs. The weak ECL emission is most likely generated by an intrananoparticle ruthenium unit annihilation rather than by the electron transfer between a reduced and oxidized DSNP due to the very low diffusivities of the nanoparticles. Thiol-terminated DSNPs were self-assembled on gold substrates, forming compact and stable monolayers which mimic probe-target assays with DSNPs as labels. The ECL intensity obtained by such functionalized substrates in aqueous media, using tripropylamine (TPrA) as coreactant, was surprisingly increased with respect to direct electrochemical oxidation because of the ability of oxidized TPrA to diffuse within the DSNPs structure and reach a higher number of emitting units with respect to direct electron tunneling. The experimental results have been explained by proposing a basic physical-chemical model which supports evaluation of the number of redox-active centers per nanoparticle. In the model the contrasting effects of increased luminescence quantum yield and decreased diffusion coefficient with respect to free (i.e., not bound within the silica structure) emitting molecules were taken into account. This allows, in principle, optimizing the ECL emission intensity as a function of DSNP size, doping material, charge, doping level, supporting electrolyte, electrode material, and solvent. Finally, it is worth noting that this study has provided a more than 1000-fold increase of the ECL signal of a chemically and electrochemically stable DSNP compared to that of a single dye, suggesting that use of this kind of nanostructures as luminescent labels represents a very promising system for ultrasensitive bioanalysis.


Pilot study: effect of 3,3'-diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer.
Dietary indoles, present in Brassica plants such as cabbage, broccoli, and Brussels sprouts, have been shown to provide potential protection against hormone-dependent cancers. 3,3'-Diindolylmethane (DIM) is under study as one of the main protective indole metabolites. Postmenopausal women aged 50-70 yr from Marin County, California, with a history of early-stage breast cancer, were screened for interest and eligibility in this pilot study on the effect of absorbable DIM (BioResponse-DIM) supplements on urinary hormone metabolites. The treatment group received daily DIM (108 mg DIM/day) supplements for 30 days, and the control group received a placebo capsule daily for 30 days. Urinary metabolite analysis included 2-hydroxyestrone (2-OHE1), 16-alpha hydroxyestrone (16alpha-OHE1), DIM, estrone (El), estradiol(E2), estriol (E3), 6beta-hydroxycortisol (6beta-OHC), and cortisol in the first morning urine sample before intervention and 31 days after intervention. Nineteen women completed the study,for a total of 10 in the treatment group and 9 in the placebo group. DIM-treated subjects, relative to placebo, showed a significant increase in levels of2-OHE1 (P=0. 020), DIM (P =0. 045), and cortisol (P = 0.039), and a nonsignificant increase of 47% in the 2-OHE1/16alpha-OHE1 ratio from 1.46 to 2.14 (P=0.059). In this pilot study, DIM increased the 2-hydroxylation of estrogen urinary metabolites.


Strategies for effective physics plan and chart review in radiation therapy: Report of AAPM Task Group 275.
While the review of radiotherapy treatment plans and charts by a medical physicist is a key component of safe, high-quality care, very few specific recommendations currently exist for this task. The goal of TG-275 is to provide practical, evidence-based recommendations on physics plan and chart review for radiation therapy. While this report is aimed mainly at medical physicists, others may benefit including dosimetrists, radiation therapists, physicians and other professionals interested in quality management. The scope of the report includes photon/electron external beam radiotherapy (EBRT), proton radiotherapy, as well as high-dose rate (HDR) brachytherapy for gynecological applications (currently the highest volume brachytherapy service in most practices). The following review time points are considered: initial review prior to treatment, weekly review, and end-of-treatment review. The Task Group takes a risk-informed approach to developing recommendations. A failure mode and effects analysis was performed to determine the highest-risk aspects of each process. In the case of photon/electron EBRT, a survey of all American Association of Physicists in Medicine (AAPM) members was also conducted to determine current practices. A draft of this report was provided to the full AAPM membership for comment through a 3-week open-comment period, and the report was revised in response to these comments. The highest-risk failure modes included 112 failure modes in photon/electron EBRT initial review, 55 in weekly and end-of-treatment review, 24 for initial review specific to proton therapy, and 48 in HDR brachytherapy. A 103-question survey on current practices was released to all AAPM members who self-reported as working in the radiation oncology field. The response rate was 33%. The survey data and risk data were used to inform recommendations. Tables of recommended checks are presented and recommendations for best practice are discussed. Suggestions to software vendors are also provided. TG-275 provides specific recommendations for physics plan and chart review which should enhance the safety and quality of care for patients receiving radiation treatments.


De novo assembly of a young Drosophila Y chromosome using single-molecule sequencing and chromatin conformation capture.
While short-read sequencing technology has resulted in a sharp increase in the number of species with genome assemblies, these assemblies are typically highly fragmented. Repeats pose the largest challenge for reference genome assembly, and pericentromeric regions and the repeat-rich Y chromosome are typically ignored from sequencing projects. Here, we assemble the genome of Drosophila miranda using long reads for contig formation, chromatin interaction maps for scaffolding and short reads, and optical mapping and bacterial artificial chromosome (BAC) clone sequencing for consensus validation. Our assembly recovers entire chromosomes and contains large fractions of repetitive DNA, including about 41.5 Mb of pericentromeric and telomeric regions, and >100 Mb of the recently formed highly repetitive neo-Y chromosome. While Y chromosome evolution is typically characterized by global sequence loss and shrinkage, the neo-Y increased in size by almost 3-fold because of the accumulation of repetitive sequences. Our high-quality assembly allows us to reconstruct the chromosomal events that have led to the unusual sex chromosome karyotype in D. miranda, including the independent de novo formation of a pair of sex chromosomes at two distinct time points, or the reversion of a former Y chromosome to an autosome.


Multi-modal characterization of rapid anterior hippocampal volume increase associated with aerobic exercise.
The hippocampus has been shown to demonstrate a remarkable degree of plasticity in response to a variety of tasks and experiences. For example, the size of the human hippocampus has been shown to increase in response to aerobic exercise. However, it is currently unknown what underlies these changes. Here we scanned sedentary, young to middle-aged human adults before and after a six-week exercise intervention using nine different neuroimaging measures of brain structure, vasculature, and diffusion. We then tested two different hypotheses regarding the nature of the underlying changes in the tissue. Surprisingly, we found no evidence of a vascular change as has been previously reported. Rather, the pattern of changes is better explained by an increase in myelination. Finally, we show that hippocampal volume increase is temporary, returning to baseline after an additional six weeks without aerobic exercise. This is the first demonstration of a change in hippocampal volume in early to middle adulthood suggesting that hippocampal volume is modulated by aerobic exercise throughout the lifespan rather than only in the presence of age related atrophy. It is also the first demonstration of hippocampal volume change over a period of only six weeks, suggesting that gross morphometric hippocampal plasticity occurs faster than previously thought.


Widespread underrecognition and undertreatment of anxiety and mood disorders: results from 3 European studies.
Data from the World Health Organization (WHO) Collaborative Study on Psychological Problems in General Health Care, which was conducted in 26,422 primary care attendees in 14 countries worldwide, and from the Institut National de la Santé et de la Recherche Médicale (INSERM) study, which was conducted in over 2400 consecutive primary care patients in France, demonstrate the high prevalence of major depression in general practice (13.7% and 14.0% in each study, respectively). These 2 studies are supported by the more recent European Study of the Epidemiology of Mental Disorders (ESEMeD), which was conducted in over 21,400 adults from the general populations of 6 European countries and which revealed a lifetime prevalence rate for major depression of 13.4%. Despite this high prevalence, both the WHO and INSERM studies revealed that only 54% to 58% of depressed patients were recognized as "psychiatric cases" by their general practitioner and only 15% to 26% were given a specific diagnosis of depression. Even when cases were recognized, treatment was frequently inappropriate. In the WHO study, only 43% of patients correctly diagnosed with depression by their general practitioner were prescribed an antidepressant, and only 31% of patients recognized as "anxious" received an anxiolytic agent (14% were prescribed an antidepressant). In the ESEMeD study, only 4.6% of adults diagnosed with depression were using antidepressants exclusively, and 18.4% had used anxiolytic medications exclusively. The willingness to prescribe antidepressants and anxiolytic agents is influenced, in part, by diagnosis, patient age and gender, comorbidity (and severity), and the number of spontaneous psychological complaints.


Thioredoxin reductase is the major selenoprotein expressed in human umbilical-vein endothelial cells and is regulated by protein kinase C.
Damage to the endothelium by reactive oxygen species favours atherogenesis. Such damage can be prevented by selenium, which is thought to exert its actions through the expression of selenoproteins. The family of glutathione peroxidases (GPXs) may have antioxidant roles in the endothelium but other intracellular and extracellular selenoproteins with antioxidant actions may also be important. The selenoproteins expressed by cultured human umbilical-vein endothelial cells (HUVECs) were labelled with [(75)Se]selenite and separated using SDS/PAGE. HUVECs secreted no extracellular selenoproteins. There were distinct differences between the intracellular selenoprotein profile of (75)Se-labelled HUVECs and those of other tissues. A single selenoprotein with a molecular mass of 58 kDa accounted for approx. 43% of the intracellular (75)Se-labelled proteins in HUVECs. This protein was identified by Western blotting as the redox-active lipid-hydroperoxide-detoxifying selenoprotein, thioredoxin reductase (TR). TR expression in HUVECs was down-regulated by transiently exposing cells to the phorbol ester PMA for periods as short as 1 min. However, there was a delay of 48 h after PMA exposure before maximal down-regulation of TR was observed. The protein kinase C (PKC) inhibitor bisindolylmaleimide I hydrochloride had no effect on TR expression when added alone, but the agent prevented the down-regulation of TR expression seen with PMA. The calcium ionophore A23187 increased TR expression in HUVECs after a 12-h exposure, but the maximal effect was only observed after a 35-h exposure. These findings suggest that TR may be an important factor in the known ability of Se to protect HUVECs from peroxidative damage. Furthermore, the results also suggest that TR expression can be negatively regulated through PKC. It is possible that TR expression may be positively regulated by the calcium-signalling cascade, although TR induction by A23187 may be due to toxicity.


The recognition heuristic: a review of theory and tests.
The recognition heuristic is a prime example of how, by exploiting a match between mind and environment, a simple mental strategy can lead to efficient decision making. The proposal of the heuristic initiated a debate about the processes underlying the use of recognition in decision making. We review research addressing four key aspects of the recognition heuristic: (a) that recognition is often an ecologically valid cue; (b) that people often follow recognition when making inferences; (c) that recognition supersedes further cue knowledge; (d) that its use can produce the less-is-more effect - the phenomenon that lesser states of recognition knowledge can lead to more accurate inferences than more complete states. After we contrast the recognition heuristic to other related concepts, including availability and fluency, we carve out, from the existing findings, some boundary conditions of the use of the recognition heuristic as well as key questions for future research. Moreover, we summarize developments concerning the connection of the recognition heuristic with memory models. We suggest that the recognition heuristic is used adaptively and that, compared to other cues, recognition seems to have a special status in decision making. Finally, we discuss how systematic ignorance is exploited in other cognitive mechanisms (e.g., estimation and preference).


Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer.
Nuclear factor erythroid-2 related factor 2 (NRF2) is a redox-sensitive transcription factor that positively regulates the expression of genes encoding antioxidants, xenobiotic detoxification enzymes, and drug efflux pumps, and confers cytoprotection against oxidative stress and xenobiotics in normal cells. Kelch-like ECH-associated protein 1 (KEAP1) negatively regulates NRF2 activity by targeting it to proteasomal degradation. Increased expression of cellular antioxidants and xenobiotic detoxification enzymes has been implicated in resistance of tumor cells against chemotherapeutic drugs. Here we report a systematic analysis of the KEAP1 genomic locus in lung cancer patients and cell lines that revealed deletion, insertion, and missense mutations in functionally important domains of KEAP1 and a very high percentage of loss of heterozygosity at 19p13.2, suggesting that biallelic inactivation of KEAP1 in lung cancer is a common event. Sequencing of KEAP1 in 12 cell lines and 54 non-small-cell lung cancer (NSCLC) samples revealed somatic mutations in KEAP1 in a total of six cell lines and ten tumors at a frequency of 50% and 19%, respectively. All the mutations were within highly conserved amino acid residues located in the Kelch or intervening region domain of the KEAP1 protein, suggesting that these mutations would likely abolish KEAP1 repressor activity. Evaluation of loss of heterozygosity at 19p13.2 revealed allelic losses in 61% of the NSCLC cell lines and 41% of the tumor samples. Decreased KEAP1 activity in cancer cells induced greater nuclear accumulation of NRF2, causing enhanced transcriptional induction of antioxidants, xenobiotic metabolism enzymes, and drug efflux pumps. This is the first study to our knowledge to demonstrate that biallelic inactivation of KEAP1 is a frequent genetic alteration in NSCLC. Loss of KEAP1 function leading to constitutive activation of NRF2-mediated gene expression in cancer suggests that tumor cells manipulate the NRF2 pathway for their survival against chemotherapeutic agents.


Seamless Staircase Electrical Contact to Semiconducting Graphene Nanoribbons.
Electrical contact to low-dimensional (low-D) materials is a key to their electronic applications. Traditional metal contacts to low-D semiconductors typically create gap states that can pin the Fermi level (EF). However, low-D metals possessing a limited density of states at EF can enable gate-tunable work functions and contact barriers. Moreover, a seamless contact with native bonds at the interface, without localized interfacial states, can serve as an optimal electrode. To realize such a seamless contact, one needs to develop atomically precise heterojunctions from the atom up. Here, we demonstrate an all-carbon staircase contact to ultranarrow armchair graphene nanoribbons (aGNRs). The coherent heterostructures of width-variable aGNRs, consisting of 7, 14, 21, and up to 56 carbon atoms across the width, are synthesized by a surface-assisted self-assembly process with a single molecular precursor. The aGNRs exhibit characteristic vibrational modes in Raman spectroscopy. A combined scanning tunneling microscopy and density functional theory study reveals the native covalent-bond nature and quasi-metallic contact characteristics of the interfaces. Our electronic measurements of such seamless GNR staircase constitute a promising first step toward making low resistance contacts.


Toxicity of laundry detergent components to a freshwater cladoceran and their contribution to detergent toxicity.
The toxicity of 39 laundry detergent components including surfactants, enzymes, builders, fabric brighteners, fillers, and coloring agents to the cladoceran Ceriodaphnia cf. dubia was determined. The difference between the most and the least toxic components was approximately 17,000-fold and 1,000,000-fold for the mg/L and mmol/L EC50 data, respectively. Two of the components had high toxicity (EC50 values < 1 mg/L), 11 moderate toxicity (EC50 values between 1 and 10 mg/L), and the remaining 26 components had low toxicity (EC50 values > 10 mg/L). Analysis revealed that mixtures of the components interacted antagonistically, additively, and synergistically. On a molarity basis the most toxic group of compounds was the surfactants followed by the brighteners. The most toxic individual components included sodium carboxymethyl cellulose, sodium silicate solution, four brighteners, sodium perborate tetrahydrate, and the surfactants. Many of the most toxic components, however, contributed very little to the toxicity of the detergents due to being present in the detergents at low concentrations. The main contributors to the toxicity of detergents were the sodium silicate solution and the surfactants-with the remainder of the components contributing very little to detergent toxicity. The potential for acute aquatic toxic effects due to the release of secondary or tertiary sewage effluents containing the breakdown products of laundry detergents may frequently be low. However, untreated or primary treated effluents containing detergents may pose a problem. Chronic and/or other sublethal effects that were not examined in this study may also pose a problem.


Lack of CYP3A4 inhibition by grapefruit juice and ketoconazole upon clozapine administration in vivo.
The drug-food and drug-drug interaction between grapefruit juice (GFJ) and ketoconazole (KETO) was evaluated in schizophrenic patients given a single dose of clozapine (CLZ). CLZ is metabolized primarily by CYP isozymes 3A4 and 1A2 to two principal metabolites, desmethylclozapine (DCLZ) and clozapine N-oxide (CNO). GFJ and KETO are well known potent CYP 3A4 inhibitors in the gastrointestinal tract and hepatic isozymes, respectively. Twenty-one schizophrenic patients participated in the co-administration of CLZ 50 mg and GFJ. After a one-week washout, five patients were given double the GFJ (HGFJ) dose for 7 consecutive days. In another group of five patients, ketoconazole (KETO) 400 mg was given for 7 consecutive days. At the end of the 7-day period for both groups, CLZ was coadministered with the HGFJ and KETO groups. CLZ, DCLZ and CNO were assayed by HPLC. GFJ, HGJF and ketoconazole failed to significantly change CLZ disposition. Metabolites DCLZ and CNO concentrations remained unchanged during the study. The only exception was decreased Cmax in DCLZ and CNO concentrations. These results indicate that CYP 3A4 inhibition may not be clinically significant compared to CYP 1A2, as previous studies show a dramatic increase in CLZ plasma concentrations with fluvoxamine (CYP 1A2 inhibitor). The reasons for the lack of drug-food and drug-drug interactions with CLZ and CYP 3A4 inhibitors can be explained by the higher Ki values for gastrointestinal and hepatic CYP 3A4 isozymes.


Oncologic emergencies.
To provide an up-to-date review of current literature on the pathophysiology, diagnosis, and management of five key malignancy-related complications: superior vena cava syndrome, malignant pericardial effusion, malignant spinal cord compression, hypercalcemia, and acute tumor lysis syndrome. Database searches and review of relevant medical literature. Malignancy-related complications demand increased attention from intensivists due to their frequency and increasing cancer prevalence. Although such complications portend a poor prognosis, proper acute management can improve short-term outcomes by facilitating either definitive care of the underlying malignancy or the institution of appropriate palliative measures. Knowledge of malignancy-induced complications in critically ill patients expedites the ability of the intensivist to properly manage them. Five complications commonly requiring emergency management are addressed in this review. Specifically, superior vena cava syndrome may warrant radiation, chemotherapy, vascular stenting, or surgical resection. Malignant pericardial effusion may require emergency pericardiocentesis if cardiac tamponade develops. Malignant spinal cord compression demands immediate spinal imaging, glucocorticoids, and either surgery or radiation. Hypercalcemia requires aggressive intravenous hydration and a bisphosphonate. Acute tumor lysis syndrome necessitates intravenous hydration, rasburicase, and management of associated electrolyte abnormalities.


Late quaternary extinction of a tree species in eastern North America.
Widespread species- and genus-level extinctions of mammals in North America and Europe occurred during the last deglaciation [16,000-9,000 yr B.P. (by (14)C)], a period of rapid and often abrupt climatic and vegetational change. These extinctions are variously ascribed to environmental change and overkill by human hunters. By contrast, plant extinctions since the Middle Pleistocene are undocumented, suggesting that plant species have been able to respond to environmental changes of the past several glacial/interglacial cycles by migration. We provide evidence from morphological studies of fossil cones and anatomical studies of fossil needles that a now-extinct species of spruce (Picea critchfieldii sp. nov.) was widespread in eastern North America during the Last Glacial Maximum. P. critchfieldii was dominant in vegetation of the Lower Mississippi Valley, and extended at least as far east as western Georgia. P. critchfieldii disappeared during the last deglaciation, and its extinction is not directly attributable to human activities. Similarly widespread plant species may be at risk of extinction in the face of future climate change.


Information content of bistatic lidar observations of aerosols from space.
We present, for the first time, a quantitative retrieval error-propagation study for a bistatic high spectral resolution lidar (HSRL) system intended for detailed quasi-global monitoring of aerosol properties from space. Our results demonstrate that supplementing a conventional monostatic HSRL with an additional receiver flown in formation at a scattering angle close to 165° dramatically increases the information content of the measurements and allows for a sufficiently accurate characterization of tropospheric aerosols. We conclude that a bistatic HSRL system would far exceed the capabilities of currently flown or planned orbital instruments in monitoring global aerosol effects on the environment and on the Earth's climate. We also demonstrate how the commonly used a priori "regularization" methodology can artificially reduce the propagated uncertainties and can thereby be misleading as to the real retrieval capabilities of a measurement system.


Antimicrobial potential of Halophilic actinomycetes against multi drug resistant (MDR) ventilator associated pneumonia causing bacterial pathogens.
A collection of forty halophilic actinomycetes isolated from water and mud samples of the saline lake at Kalar Kahar, salt range, Pakistan, was screened to investigate their antimicrobial potential against multi drug resistant (MDR) ventilator associated pneumonia causing bacterial pathogens. The isolates exhibited significant tolerance to alkaline conditions and grew well at pH 9-11. The taxonomic status of the isolated strains was determined by morphological, biochemical and physiological characterization and by 16s rRNA gene sequencing. The results revealed that majority of the isolates (90%) belong to the genus Streptomyces. Most of the isolates exhibited remarkable antimicrobial activity up to 20mm zone of inhibition against MDR ventilator associated pneumonia causing bacteria including Staphylococcus aureus, Pseudomonas aeruginosa, Proteus vulgaris, Klebsiella pneumoniae, Escherichia coli, Enterobacter and Acinetobacter spp. Additionally the isolates showed moderate to high cytotoxicity in the range of 40 to 80% larval mortality against Artemia salina in a micro well cytotoxicity assay. The chemical screening or the so called metabolic fingerprinting of the methanolic extracts of each isolate, by thin layer chromatography (TLC) using various staining reagents and by high performance liquid chromatography (HPLC-UV), indicated an impressive diversity of the compounds produced by these strains. The study reveals that these halophilic actinomycetes are a promising source of bioactive compounds. The preparative scale fermentation, isolation, purification and structure elucidation of the compounds produced by them may yield novel antimicrobial or chemotherapeutic agents.


Surgical treatment of Parkinson's disease.
At present, there are three major surgical approaches to Parkinson's disease (PD): (1) Ablative surgery (i.e. pallidotomy, thalamotomy); (2) deep brain stimulation (DBS) of the thalamus, internal globus pallidus (GPi) and subthalamic nucleus (STN); and (3) grafting fetal mesencephalic cells into the striatum. As a result of increasing understanding of the pathophysiology of the basal ganglia and the demonstration of surgical alleviation of experimental parkinsonism, surgery has regained a paramount importance in the management of PD. The aim of pallidotomy and DBS is to reduce the excessive inhibitory output from the GPi and substantia nigra reticulata (SNr). Pallidotomy and DBS of the STN or GPi aim to reverse the pathophysiological consequences of dopamine deficiency in PD, and should be considered entirely symptomatic treatments. The ideal candidates for pallidotomy are young patients in good general health in whom dyskinesias are the main reasons for disability. Patients with severe bilateral problems uncontrollable with present pharmacological tools are candidates for DBS. As yet, there are no formal data to help decide how to choose between GPi and STN stimulation. In our practice, patients are allocated to GPi stimulation when 'on' dyskinesias are extremely severe. In most other instances, we prefer to perform STN stimulation. At present there is almost no reason to decide for the thalamic stimulation since tremor is equally arrested by STN stimulation, which in addition improves all other features of PD. Equally the only indication for thalamotomy would be a patient with long-standing tremor as the main clinical manifestation, which can not be controlled with drugs. The proportion of patients in whom the thalamus will be the preferable target for either DBS or thalamotomy is small (less than 5%). Grafting aims to repair the nigrostriatal pathway and restore dopaminergic function in the striatum. In the future implants containing not only dopaminergic cells but also growth factors and a variety of other substances could become a method to not only functionally compensate the biochemical abnormalities of PD but also to arrest its progression. This technique is limited to a few centres around the world owing to the technical, logistical and ethical problems of obtaining and handling embryonic cells. At present, grafting of dopaminergic cells is perhaps best suited for patients with young-onset PD (less than 45 years old) who are at high risk of developing complications within a short time of beginning pharmacological treatment and in whom the idea of making lesions or implanting electrodes into the brain for decades seems less appealing. Consideration of surgery in any given patient should be weighed against the risks (about 1% mortality and 2-6% of severe morbidity-hemiplegia, cognitive deficit, speech problems, etc.) associated with these techniques. The development of better imaging methods and the growing expertise of multidisciplinary teams will undoubtedly make surgery for PD safer and more effective in the future.


Aberrant upregulation of MUC4 mucin expression in cutaneous condyloma acuminatum and squamous cell carcinoma suggests a potential role in the diagnosis and therapy of skin diseases.
Mucins comprise a family of high-molecular-weight glycoproteins. MUC4, a large transmembrane mucin, has recently emerged as a novel marker for diagnosis, prognosis and therapy in several malignancies. However, its role in skin pathologies remains unknown. The aim of this study was to analyse the expression of MUC4 in cutaneous pathologies by immunohistochemistry for potential diagnostic, prognostic and therapeutic applications. A total of 330 tissue spots representing the normal skin, and benign and malignant cutaneous diseases, were analysed after staining with the monoclonal antibody to human MUC4 (clone 8G7). While the normal epidermis showed a negative to weak-positive expression of MUC4, its expression was significantly upregulated in squamous cell carcinomas (SCCs) where the intensity of staining correlated negatively with tumour grade and positively with age. A moderately strong MUC4 expression was also noted in 2/20 cancer adjacent normal skin and 2/21 chronically inflamed skin tissues, while 10/19 cases of vulval condyloma acuminate, 3/12 of vulval hyperplasia and 2 cases of verruca vulgaris also showed strong MUC4 positivity. Malignant melanoma, basal cell carcinoma and cutaneous cysts were negative. The results indicate that MUC4 expression is aberrantly upregulated in cutaneous SCCs, vulval condylomas and verruca vulgaris. Further, it appears that MUC4 expression in the skin may be modulated by chronic inflammation and the presence of an adjacent cutaneous malignancy in certain cases. These observations suggest a novel role for MUC4 mucin in the pathogenesis of cutaneous SCC and a possible application as a diagnostic and/or prognostic marker in cutaneous pathologies.


Olsalazine in patients intolerant of sulphasalazine.
Fifty patients with ulcerative colitis, intolerant of sulphasalazine, were treated with 500 mg olsalazine twice daily for a 3-month trial period. Thirty-eight of the patients (76%) tolerated the drug well, and all continued to take it beyond the 3-month period. Twelve (24%) were withdrawn because of side effects, the commonest being diarrhoea. There were no haematologic or biochemical abnormalities. Thus, olsalazine is a useful drug for patients who are intolerant of sulphasalazine.


Identifying brain tumors by differential mobility spectrometry analysis of diathermy smoke.
There is a need for real-time, intraoperative tissue identification technology in neurosurgery. Several solutions are under development for that purpose, but their adaptability for standard clinical use has been hindered by high cost and impracticality issues. The authors tested and preliminarily validated a method for brain tumor identification that is based on the analysis of diathermy smoke using differential mobility spectrometry (DMS). A DMS connected to a special smoke sampling system was used to discriminate brain tumors and control samples ex vivo in samples from 28 patients who had undergone neurosurgical operations. They included meningiomas (WHO grade I), pilocytic astrocytomas (grade I), other low-grade gliomas (grade II), glioblastomas (grade IV), CNS metastases, and hemorrhagic or traumatically damaged brain tissue as control samples. Original samples were cut into 694 smaller specimens in total. An overall classification accuracy (CA) of 50% (vs 14% by chance) was achieved in 7-class classification. The CA improved significantly (up to 83%) when the samples originally preserved in Tissue-Tek conservation medium were excluded from the analysis. The CA further improved when fewer classes were used. The highest binary classification accuracy, 94%, was obtained in low-grade glioma (grade II) versus control. The authors' results show that surgical smoke from various brain tumors has distinct DMS profiles and the DMS analyzer connected to a special sampling system can differentiate between tumorous and nontumorous tissue and also between different tumor types ex vivo.


The efficacy of acupoint stimulation for the management of therapy-related adverse events in patients with breast cancer: a systematic review.
The aim of the present study was to scrutinize the evidence on the use of acupoint stimulation for managing therapy-related adverse events in breast cancer. A comprehensive search was conducted on eight English and Chinese databases to identify clinical trials designed to examine the efficacy of acupressure, acupuncture, or acupoint stimulation (APS) for the management of adverse events due to treatments of breast cancer. Methodological quality of the trials was assessed using a modified Jadad scale. Using pre-determined keywords, 843 possibly relevant titles were identified. Eventually 26 papers, 18 in English and eight in Chinese, satisfied the inclusion criteria and entered the quality assessment stage. The 26 articles were published between 1999 and 2008. They assessed the application of acupoint stimulation on six disparate conditions related to anticancer therapies including vasomotor syndrome, chemotherapy-induced nausea and vomiting, lymphedema, post-operation pain, aromatase inhibitors-related joint pain and leukopenia. Modalities of acupoint stimulation used included traditional acupuncture, acupressure, electroacupuncture, and the use of magnetic device on acupuncture points. Overall, 23 trials (88%) reported positive outcomes on at least one of the conditions examined. However, only nine trials (35%) were of high quality; they had a modified Jadad score of 3 or above. Three high quality trials revealed that acupoint stimulation on P6 (NeiGuang) was beneficial to chemotherapy-induced nausea and vomiting. For other adverse events, the quality of many of the trials identified was poor; no conclusive remarks can be made. Very few minor adverse events were observed, and only in five trials. APS, in particular acupressure on the P6 acupoint, appears beneficial in the management of chemotherapy-induced nausea and vomiting, especially in the acute phase. More well-designed trials using rigorous methodology are required to evaluate the effectiveness of acupoint stimulation interventions on managing other distress symptoms.


Possible Triggering Effect of Influenza Vaccination on Psoriasis.
Psoriasis is a chronic, recurrent, immune-mediated inflammatory disease and it can be provoked or exacerbated by a variety of different environmental factors, particularly infections and drugs. In addition, a possible association between vaccination and the new onset and/or exacerbation of psoriasis has been reported by a number of different authors. The aim of this study is to investigate the effects of influenza vaccination on patients with psoriasis. Here, we report the findings from 43 patients suffering from psoriasis (clinical phenotypes as mixed guttate/plaque lesions, palmoplantar or scalp psoriasis) whose diseases had been triggered after influenza vaccination applied in the 2009-2010 season. The short time intervals between vaccination and psoriasis flares in our patients and the lack of other possible triggers suggest that influenza vaccinations may have provocative effects on psoriasis. However, further large and controlled studies need to be carried out to confirm this relationship.


Design of antimicrobial peptides from a cuttlefish database.
No antimicrobial peptide has been identified in cephalopods to date. Annotation of transcriptomes or genomes using basic local alignment Search Tool failed to yield any from sequence identities. Therefore, we searched for antimicrobial sequences in the cuttlefish (Sepia officinalis) database by in silico analysis of a transcriptomic database. Using an original approach based on the analysis of cysteine-free antimicrobial peptides selected from our Antimicrobial Peptide Database (APD3), the online prediction tool of the Collection of Anti-Microbial Peptides (CAMPR3), and a homemade software program, we identified potential antibacterial sequences. Nine peptides less than 25 amino acids long were synthesized. The hydrophobic content of all nine of them ranged from 30 to 70%, and they could form alpha-helices. Three peptides possessed similarities with piscidins, one with BMAP-27, and five were totally new. Their antibacterial activity was evaluated on eight bacteria including the aquatic pathogens Vibrio alginolyticus, Aeromonas salmonicida, or human pathogens such as Salmonella typhimurium, Listeria monocytogenes, or Staphylococcus aureus. Despite the prediction of an antimicrobial potential for eight of the peptides, only two-GR21 and KT19-inhibited more than one bacterial strain with minimal inhibitory concentrations below 25 µM. Some sequences like VA20 and FK19 were hemolytic, while GR21 induced less than 10% of hemolysis on human blood cells at a concentration of 200 µM. GR21 was the only peptide derived from a precursor with a signal peptide, suggesting a real role in cuttlefish immune defense.


Symptoms management at the end of life.
Numerous, well-defined symptoms are associated with end of life when death is caused by a chronic or debilitating illness (or both) such as cancer, HIV/AIDS, Alzheimer's dementia, and congestive heart failure. These symptoms, if unrelieved, are distressing to both the patients and their families and preclude any possibility of relieving psychological, social, and spiritual suffering, improving quality of life, or completing life closure. Therefore, the objective of this article is to identify some common symptoms at end of life and various management strategies for each.


Alcohol use and clinical manifestations of tuberculosis.
Excess alcohol use represents a significant challenge in tuberculosis control. Whether alcohol use enhances transmission of Mycobacterium tuberculosis is not known. We analyzed North Carolina, USA surveillance data for all adult (> 14 years) tuberculosis cases reported 1994-2006 (N = 5556). The prevalence of excess alcohol use among tuberculosis cases declined from 27.3% in 1994 to 17.9% in 2006. Cases with excess alcohol use were more likely to have pulmonary tuberculosis compared with cases without excess alcohol use (92.5% vs. 77.2%, p < 0.0001). Among pulmonary cases, excess alcohol use was associated with cavities on chest radiograph (36.8% vs. 28.2%, p < 0.0001) and positive acid-fast sputum smears (65.9% vs. 45.8%, p < 0.0001). Although excess alcohol use is becoming less prevalent among tuberculosis cases in North Carolina, cases who use excess alcohol had clinical features associated with greater infectiousness, and represent a significant public health problem.


The influence of behaviors and relationships on the vaginal microbiota of women and their female partners: the WOW Health Study.
A community-based study of women who have sex with women (WSW) was performed to determine the burden of bacterial vaginosis (BV), and behavioral factors influencing the vaginal microbiota of women and their female sexual partners (FSPs), as measured by Nugent score (NS). In a cross-sectional study of 18-55-year-old WSW recruited nationally, participants completed questionnaires and self-collected vaginal swab samples weekly on 3 occasions. BV was defined as an NS of 7-10. Factors associated with BV, stability of NS category, and concordance of these categories in co-enrolled couples were examined with multivariable logistic regression analysis. A total of 458 participants were recruited; 192 were co-enrolled with their FSP (96 couples). BV was detected in 125 women (27%; 95% confidence interval [CI], 23%-32%). BV was associated with ≥4 lifetime FSPs (adjusted odds ratio [AOR], 1.9; 95% CI, 1.2-3.1), an FSP with BV symptoms (AOR, 2.9; 1.0-8.2) and smoking, with ≥30 cigarettes per week showing greatest odds (AOR, 2.7; 1.5-5.0). Of 428 women returning ≥2 swab samples, 375 (88%) had a stable NS category across all samples, predominantly reflecting normal flora. Co-enrolled WSW were less likely to have BV (31% vs 23%; P = .07), and the majority (70%) were concordant for NS category (κ = 0.47; P ≤ .01), with most concordant for normal flora. Concordant NS category was associated with a relationship of >6 months (AOR, 4.7; 95% CI, 1.4-16.4) and frequent sexual contact (more than once per month; AOR, 2.7; 1.0-7.1). BV is associated with key behaviors and smoking practices in WSW, but longer-duration, sexually active WSW partnerships support a stable favorable vaginal microbiota.


Use of confocal and multiphoton microscopy for the evaluation of micro-optical components and emitters.
We report on the application of confocal and multiphoton microscopic techniques for the evaluation of the latest generation of micro optical components. The optical emitting characteristics of arrays of matrix addressable GaN micrometer-sized light emitting diodes (micro-LEDs) have been measured using a commercial confocal microscope utilising the LEDs' own emission along with reflection confocal microscopy to determine the surface structure. Multiphoton induced luminescence from the 10-20-micron diameter emitters has also been used to examine the structure of the device and we compare this with electrically induced emission. In related work, the optical properties of micro lens arrays (10-100-micron diameter) fabricated in SiC, Sapphire, and Diamond have been determined using transmission confocal microscopy. Such optical microscopy techniques offer a simple, non-destructive method to determine the structure and performance of such novel devices.


A three-single-nucleotide polymorphism haplotype in intron 1 of OCA2 explains most human eye-color variation.
We have previously shown that a quantitative-trait locus linked to the OCA2 region of 15q accounts for 74% of variation in human eye color. We conducted additional genotyping to clarify the role of the OCA2 locus in the inheritance of eye color and other pigmentary traits associated with skin-cancer risk in white populations. Fifty-eight synonymous and nonsynonymous exonic single-nucleotide polymorphisms (SNPs) and tagging SNPs were typed in a collection of 3,839 adolescent twins, their siblings, and their parents. The highest association for blue/nonblue eye color was found with three OCA2 SNPs: rs7495174 T/C, rs6497268 G/T, and rs11855019 T/C (P values of 1.02x10(-61), 1.57x10(-96), and 4.45x10(-54), respectively) in intron 1. These three SNPs are in one major haplotype block, with TGT representing 78.4% of alleles. The TGT/TGT diplotype found in 62.2% of samples was the major genotype seen to modify eye color, with a frequency of 0.905 in blue or green compared with only 0.095 in brown eye color. This genotype was also at highest frequency in subjects with light brown hair and was more frequent in fair and medium skin types, consistent with the TGT haplotype acting as a recessive modifier of lighter pigmentary phenotypes. Homozygotes for rs11855019 C/C were predominantly without freckles and had lower mole counts. The minor population impact of the nonsynonymous coding-region polymorphisms Arg305Trp and Arg419Gln associated with nonblue eyes and the tight linkage of the major TGT haplotype within the intron 1 of OCA2 with blue eye color and lighter hair and skin tones suggest that differences within the 5' proximal regulatory control region of the OCA2 gene alter expression or messenger RNA-transcript levels and may be responsible for these associations.


A TIN2 dyskeratosis congenita mutation causes telomerase-independent telomere shortening in mice.
The progressive bone marrow failure syndrome dyskeratosis congenita (DC) is often caused by mutations in telomerase or the factors involved in telomerase biogenesis and trafficking. However, a subset of DC patients is heterozygous for mutations in the shelterin component TIN2. To determine how the TIN2-DC mutations affect telomere function, we generated mice with the equivalent of the TIN2 K280E DC allele (TIN2(DC)) by gene targeting. Whereas homozygous TIN2(DC/DC) mice were not viable, first-generation TIN2(+/DC) mice were healthy and fertile. In the second and third generations, the TIN2(+/DC) mice developed mild pancytopenia, consistent with hematopoietic dysfunction in DC, as well as diminished fecundity. Bone marrow telomeres of TIN2(+/DC) mice shortened over the generations, and immortalized TIN2(+/DC) mouse embryonic fibroblasts (MEFs) showed telomere shortening with proliferation. Unexpectedly, telomere shortening was accelerated in TIN2(+/DC) mTR(-/-) mice and MEFs compared with TIN2(+/+) mTR(-/-) controls, establishing that the TIN2(DC) telomere maintenance defect was not solely due to diminished telomerase action. The TIN2(DC) allele induced mild ATR kinase signaling at telomeres and a fragile telomere phenotype, suggestive of telomere replication problems. These data suggest that this TIN2-DC mutation could induce telomeric dysfunction phenotypes in telomerase-negative somatic cells and tissues that further exacerbate the telomere maintenance problems in telomerase-positive stem cell compartments.


The health and psychosocial functioning of caregivers of children with neurodevelopmental disorders.
Children with neurodevelopmental disorders (Neuro) pose complex parenting challenges, particularly if the condition co-occurs with behaviour problems. Such challenges are likely to impact caregiver health and well-being. This study explores the extent to which caregivers of children with both Neuro and behaviour problems differ in their physical and psychosocial outcomes from caregivers of children with either condition or neither condition. The first wave of data collected in the National Longitudinal Survey of Children and Youth in Canada (1994) was used to identify four groups of caregivers of 4- to 11-year-old children: caregivers of children with a Neuro disorder and externalizing behaviour problems (Both; n = 414), caregivers of children with a Neuro disorder only (Neuro Only; n = 750), caregivers of children with an externalizing behaviour problem only (Ext Only; n = 1067), and caregivers of children with neither health condition (Neither; n = 7236). Caregivers in the Both group were least likely to report excellent or very good health, and more frequently reported chronic conditions such as asthma, arthritis, back problems, migraine headaches, and limitations in activities as compared to the Neither group. This group also exhibited higher depression scores, experienced more problematic family functioning and reported lower social support than the Neither group. Scores for caregivers in the Ext Only and Neuro Only groups tended to lie between the Both and Neither group scores and often did not differ from one another. Caregivers of children with both neurodevelopmental disorders and behaviour problems exhibited a greater number of health and psychosocial problems. While addressing children's behaviour problems, health care professionals should also consider caregiver physical and psychosocial health, as this may also have an impact on children's well-being.