Regional leukoaraiosis and cognition in non-demented older adults.
Frontal lobe-executive functions are heavily dependent on distal white matter connectivity. Even with healthy aging there is an increase in leukoaraiosis that might interrupt this connectivity. The goal of this study is to learn 1) the location, depth, and percentage of leukoaraiosis in white matter among a sample of non-demented older adults and 2) associations between these leukoarioasis metrics and composites of cognitive efficiency (processing speed, working memory, and inhibitory function), and episodic memory. Participants were 154 non-demented older adults (age range 60-85) who completed a brain MRI and neuropsychological testing on the same day. Brain MRIs were segmented via Freesurfer and white matter leukoaraiosis depth segmentations was based on published criteria. On average, leukoaraiosis occupied 1 % of total white matter. There was no difference in LA distribution in the frontal (1.12%), parietal (1.10%), and occipital (0.95%) lobes; there was less LA load within the temporal lobe (0.23%). For cortical depth, leukoaraiosis was predominantly in the periventricular region (3.39%; deep 1.46%, infracortical 0.15%). Only increasing frontal lobe and periventricular leukoaraiosis were associated with a reduction in processing speed, working memory, and inhibitory function. Despite the general presence of LA throughout the brain, only frontal and periventricular LA contributed to the speeded and mental manipulation of executive functioning. This study provides a normative description of LA for non-demented adults to use as a comparison to more disease samples.


Educational and organizational interventions to improve the management of depression in primary care: a systematic review.
Depression is commonly encountered in primary care settings yet is often missed or suboptimally managed. A number of organizational and educational strategies to improve management of depression have been proposed. The clinical effectiveness and cost-effectiveness of these strategies have not yet been subjected to systematic review. To systematically evaluate the effectiveness of organizational and educational interventions to improve the management of depression in primary care settings. We searched electronic medical and psychological databases from inception to March 2003 (MEDLINE, PsycLIT, EMBASE, CINAHL, Cochrane Controlled Trials Register, United Kingdom National Health Service Economic Evaluations Database, Cochrane Depression Anxiety and Neurosis Group register, and Cochrane Effective Professional and Organisational Change Group specialist register); conducted correspondence with authors; and used reference lists. Search terms were related to depression, primary care, and all guidelines and organizational and educational interventions. We selected 36 studies, including 29 randomized controlled trials and nonrandomized controlled clinical trials, 5 controlled before-and-after studies, and 2 interrupted time-series studies. Outcomes relating to management and outcome of depression were sought. Methodological details and outcomes were extracted and checked by 2 reviewers. Summary relative risks were, where possible, calculated from original data and attempts were made to correct for unit of analysis error. A narrative synthesis was conducted. Twenty-one studies with positive results were found. Strategies effective in improving patient outcome generally were those with complex interventions that incorporated clinician education, an enhanced role of the nurse (nurse case management), and a greater degree of integration between primary and secondary care (consultation-liaison). Telephone medication counseling delivered by practice nurses or trained counselors was also effective. Simple guideline implementation and educational strategies were generally ineffective. There is substantial potential to improve the management of depression in primary care. Commonly used guidelines and educational strategies are likely to be ineffective. The implementation of the findings from this research will require substantial investment in primary care services and a major shift in the organization and provision of care.


Predictive role of authenticity on psychological vulnerability in Turkish university students.
Authenticity is associated with adaptive psychological characteristics and may be predictive of psychological vulnerability. The study was conducted with Turkish university students (N = 303; 158 women, 145 men; M age = 20.1 yr.). Participants completed the Turkish version of Authenticity Scale and the Psychological Vulnerability Scale. Psychological vulnerability was correlated positively with two subfactors of authenticity, accepting external influence and self-alienation, and negatively with the authentic living factor of authenticity. Self-alienation, accepting external influence, and authentic living were related to psychological vulnerability, accounting for 33% of the variance collectively. Authenticity is an important predictor of psychological vulnerability.


Synergistic haemolysis test for presumptive identification and differentiation of Clostridium perfringens, C. bifermentans, C. sordellii, and C. paraperfringens.
A new test for the presumptive identification of Clostridium perfringens, C. bifermentans, C. sordellii, and C. paraperfringens is described. The test is based on the synergistic haemolysis shown by the clostridia and group B streptococci on sheep and human and CaCl2-supplemented human blood agar. C. perfringens gave crescent-shaped synergistic lytic zones (7 to over 20 mm in length), and C. paraperfringens usually small-sized (3 mm), bullet-shaped reactions on all three types of media. C. bifermentans showed a horseshoe-shaped synergistic reaction only on human blood containing media, and C. sordellii only on CaCl2-supplemented human blood agar. C. perfringens type A antiserum inhibited synergistic lytic activities of the four species. The test provided a reliable method for presumptive identification and differentiation of the four clostridial species and may obviate the need for the Nagler test.


Impact of anemia on platelet response to clopidogrel in patients undergoing percutaneous coronary stenting.
High residual platelet reactivity (HRPR) on clopidogrel is a predictor of recurrent ischemic events in patients undergoing percutaneous coronary interventions (PCI). Significant intraindividual variability in platelet aggregation on repeat testing has been reported. To understand factors contributing to the variability in platelet aggregation testing, we examined clinical and laboratory elements linked to HRPR in 255 consecutive patients tested ≥12 hours after PCI using light transmission aggregometry (LTA) in response to adenosine diphosphate 5 μmol/L and VerifyNow P2Y12 assay (VNP2Y12; Accumetrics). HRPR was defined as >46% residual aggregation for LTA and >236 P2Y12 response units (PRUs) for VNP2Y12. On multivariate analysis the only variable independently associated with HRPR with both LTA and VNP2Y12 was laboratory-defined anemia. Prevalences of HRPR by LTA were 34.3% in anemic patients, 15.6% in patients with normal hemoglobin levels, and 59.8% versus 25.9% by VNP2Y12 (p <0.005 for the 2 comparisons). In a subgroup of 50 patients, testing was done before and after the clopidogrel loading dose. At baseline there were no differences in platelet aggregation with either assay; however, absolute decrease in reactivity after the clopidogrel load was significantly less in anemic patients compared to patients with normal hemoglobin (change in residual aggregation by LTA 15.8 ± 5.8% vs 28.8 ± 3.2%, p <0.05; change in PRU by VNP2Y12 56.5 ± 35.5 vs 145.0 ± 14.2 PRUs, p <0.05, respectively). In conclusion, anemia is an important contributor to apparent HRPR on clopidogrel and may explain some of the intraindividual variability of platelet aggregation testing.


MASTR directs MyoD-dependent satellite cell differentiation during skeletal muscle regeneration.
In response to skeletal muscle injury, satellite cells, which function as a myogenic stem cell population, become activated, expand through proliferation, and ultimately fuse with each other and with damaged myofibers to promote muscle regeneration. Here, we show that members of the Myocardin family of transcriptional coactivators, MASTR and MRTF-A, are up-regulated in satellite cells in response to skeletal muscle injury and muscular dystrophy. Global and satellite cell-specific deletion of MASTR in mice impairs skeletal muscle regeneration. This impairment is substantially greater when MRTF-A is also deleted and is due to aberrant differentiation and excessive proliferation of satellite cells. These abnormalities mimic those associated with genetic deletion of MyoD, a master regulator of myogenesis, which is down-regulated in the absence of MASTR and MRTF-A. Consistent with an essential role of MASTR in transcriptional regulation of MyoD expression, MASTR activates a muscle-specific postnatal MyoD enhancer through associations with MEF2 and members of the Myocardin family. Our results provide new insights into the genetic circuitry of muscle regeneration and identify MASTR as a central regulator of this process.


Comparison of beak and feather disease virus prevalence and immunity-associated genetic diversity over time in an island population of red-crowned parakeets.
Pathogen outbreaks in the wild can contribute to a population's extinction risk. Concern over the effects of pathogen outbreaks in wildlife is amplified in small, threatened populations, where degradation of genetic diversity may hinder natural selection for enhanced immunocompetence. Beak and feather disease virus (BFDV) was detected for the first time in an island population of red-crowned parakeets (Cyanoramphus novaezelandiae) in 2008 on Little Barrier Island (Hauturu-o-Toi) of New Zealand. By 2013, the prevalence of the viral infection had significantly decreased within the population. We tested whether the population of red-crowned parakeets showed a selective response to BFDV, using neutral microsatellite and two immunity-associated genetic markers, the major histocompatibility complex (MHC) and Toll-like receptors (TLRs). We found evidence for selection at viral-associated TLR3; however, the ability of TLR3 to elicit an immune response in the presence of BFDV warrants confirmation. Alternatively, because red-crowned parakeet populations are prone to fluctuations in size, the decrease in BFDV prevalence over time may be attributed to the Little Barrier Island population dropping below the density threshold for viral maintenance. Our results highlight that natural processes such as adaptation for enhanced immunocompetence and/or density fluctuations are efficient mechanisms for reducing pathogen prevalence in a threatened, isolated population.


Autoantibodies against the amino-terminal cadherin-like binding domain of pemphigus vulgaris antigen are pathogenic.
Complementary DNA cloning of the 130-kD pemphigus vulgaris (PV) autoantigen (PVA) has indicated that it is a member of the cadherin family of Ca(2+)-dependent cell adhesion molecules. By homology with typical cadherins, PVA has five extracellular domains (EC1 through EC5). To localize immunogenic domains and to determine whether antibodies against them might be pathogenic, we produced beta-galactosidase fusion proteins with cDNA encoding different portions of the extracellular domains of PVA (EC1-2, EC3-5, and each individual domain). Immunoblot analysis of these fusion proteins with 23 PV patients' sera demonstrated that major immunogenic regions of PVA are located on the EC1, EC2, and EC4 domains. IgG was affinity-purified from PV sera on fusion proteins representing the amino (EC1-2) and carboxy (EC3-5) terminus of the extracellular PVA, and injected into neonatal mice. PV IgG affinity-purified on the EC1-2 fusion protein caused suprabasilar acantholysis, the typical histological finding of PV, but IgG affinity-purified on the EC3-5 fusion protein or beta-galactosidase alone did not. These results indicate that at least one pathogenic epitope, which is sufficient to cause suprabasilar acantholysis in neonatal mice, is located on the amino-terminal region of PVA, an area thought to be important in cadherin homophilic adhesion.


A multi-centre investigation of delivering national guidelines on exercise training for men with advanced prostate cancer undergoing androgen deprivation therapy in the UK NHS.
National guidelines (NICE-CG175) recommended 12 weeks of supervised exercise training for men treated with androgen deprivation therapy (ADT) for prostate cancer to counter debilitating adverse effects of castration. As with other chronic conditions where exercise is indicated, it is uncertain if these services are being delivered in the health services. The aim of this multi-centre investigation was to examine what exercise referral is currently available for men on ADT as provided by the NHS and if a supervised, individually-tailored exercise training package (as per the national NICE guidelines CG175) is embedded within prostate cancer care. A multi-centre investigation of current National Health Service (NHS) care involving a web-based survey of NHS prostate cancer care, five focus groups involving 26 men on ADT and 37 semi-structured interviews with healthcare professionals (HCPs) involved in the management of prostate cancer. Descriptive statistics and thematic analysis evaluated quantitative and qualitative data, respectively. Qualitative methods followed COREQ standards. HCPs and men on ADT asserted that medical castration has a serious and debilitating impact on many features of men's quality of life. There is support for exercise training programmes as part of cancer care and patients would support their initiation soon after diagnosis. Involving the Multidisciplinary Team (MDT) is proposed as key to this. Critically, traditional values in oncology would need to be overcome for widespread acceptance. Specialist further training for HCPs around behaviour change support could encourage this. Given that these schemes are seen as a fundamental part of cancer care, it is felt the NHS should commission and support provision. 79 representatives of 154 NHS trusts (51%) provided survey data on current delivery: only 17% could provide supervised exercise as per CG175. Evidence-based national exercise guidelines are not being delivered to men on ADT as intended. Traditional values in oncology and the need for NHS financial support are seen as major barriers to provision of current best practice guidelines. Despite this both HCPs and men on ADT are in favour of such programmes being a fundamental part of their cancer care.


A Comparison of the Visual Field Parameters of SITA Faster and SITA Standard Strategies in Glaucoma.
To compare the visual field (VF) parameters of the new Swedish Interactive Thresholding Algorithm (SITA), SITA Faster (SFR) with that of SITA Standard (SS) on the Humphrey Field Analyzer. Ninety-seven eyes of 97 subjects (63 glaucoma, 26 glaucoma suspects, and 8 normal eyes) underwent VF examination with SFR and SS strategies on the same day in random order. Agreement in VF parameters between SFR and SS strategies was assessed by Bland and Altman plots. In addition, some subjects underwent a second VF examination with SFR strategy to evaluate its test-retest variability. The median test duration of SS strategy was 6 minutes 14 seconds, whereas SFR was 2 minutes 49 seconds (55% shorter, P<0.001). Median mean deviation (-7.3 vs. -7.6 dB, P=0.73) and VF index (88 vs. 88%, P=0.32) were similar between the 2 strategies, whereas pattern standard deviation was significantly higher (4.8 vs. 4.7 dB, P=0.01) with SS strategy. Overall average threshold sensitivity and Garway-Heath sector-wise threshold sensitivities were similar between the 2 strategies except for the nasal sector where SFR strategy had higher sensitivity (26 vs. 25 dB, P=0.02). Bland-Altman plots showed the mean difference in all VF parameters between the SS and SFR strategies were small (ranging from -1.0 dB for the nasal sector to -0.01 dB for superotemporal sector sensitivity). The test-retest variability of VF parameters with SFR strategy was low. VF parameters with SFR showed good agreement with that of SS strategy. This, combined with low test-retest variability, suggests that SFR can be considered for diagnosis and monitoring of glaucoma.


Community outcome in cognitively normal schizophrenia patients.
Recent reports suggest that cognition is relatively preserved in some schizophrenia patients. However, little is known about the functional advantage these patients may demonstrate. The purpose of this study was to identify cognitively normal patients with a recently developed test battery and to determine the functional benefit of this normality relative to cognitively impaired patients. Average-range cognitive ability was defined by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) composite score (T≥40) and applied to 100 patients with schizophrenia or schizoaffective disorder and to 81 non-psychiatric research participants. With group assignment adjusted for demographic variables, this procedure yielded 14 cognitively normal patients, 21 cognitively impaired patients, and 21 healthy adults with normal-range MCCB scores. Cognitively normal patients were indistinguishable from controls across all MCCB scales. Furthermore, their performance was superior to impaired patients on all scales except Social Cognition. Cognitively normal patients were also superior to impaired patients on a summary index of simulated life skills and functional competence. Nevertheless, both patient groups were equally disadvantaged relative to controls in independent community living. These findings suggest that normal-range cognition exists in schizophrenia, but fails to translate into enhanced community outcome.


Nicotine receptor partial agonists for smoking cessation.
Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist) and reducing smoking satisfaction (acting as an antagonist). Varenicline was developed as a nicotine receptor partial agonist from cytisine, a drug widely used in central and eastern Europe for smoking cessation. The first trial reports of varenicline were released in 2006, and further trials have now been published or are currently are underway. The primary objective of this review is to assess the efficacy and tolerability of nicotine receptor partial agonists, including varenicline and cytisine, for smoking cessation. We searched the Cochrane Tobacco Addiction Group's specialised register for trials, using the terms ('varenicline' or 'cytisine' or 'Tabex' or 'nicotine receptor partial agonist') and 'smoking' in the title or abstract, or as keywords. We also searched MEDLINE, EMBASE, PsycINFO and CINAHL using MeSH terms and free text, and we contacted authors of trial reports for additional information where necessary. The latest search was in March 2008. We included randomized controlled trials which compared the treatment drug with placebo. We also included comparisons with bupropion and nicotine patches where available. We excluded trials which did not report a minimum follow-up period of six months from start of treatment. We extracted data in duplicate on the type of participants, the dose and duration of treatment, the outcome measures, the randomization procedure, concealment of allocation, and completeness of follow up. The main outcome measured was abstinence from smoking after at least six months from the beginning of treatment. We used the most rigorous definition of abstinence, and preferred biochemically validated rates where they were reported. Where appropriate we performed meta-analysis to produce a risk ratio, using the Mantel-Haenszel fixed-effect model. We found seven trials of varenicline compared with placebo for smoking cessation; three of these also included a bupropion experimental arm. We found one relapse prevention trial, comparing varenicline with placebo. We also found one open-label trial comparing varenicline with nicotine replacement therapy. The nine trials covered 7267 participants, 4744 of whom used varenicline. We identified one trial of cytisine (Tabex) for inclusion. The pooled risk ratio (RR) for continuous abstinence at six months or longer for varenicline versus placebo was 2.33 (95% confidence interval [CI] 1.95 to 2.80). The pooled RR for varenicline versus bupropion at one year was 1.52 (95% CI 1.22 to 1.88). The RR for varenicline versus NRT at one year was 1.31 (95% CI 1.01 to 1.71). The two trials which tested the use of varenicline beyond the 12-week standard regimen found the drug to be well-tolerated during long-term use. The main adverse effect of varenicline was nausea, which was mostly at mild to moderate levels and usually subsided over time. Post-marketing safety data suggest that varenicline may be associated with depressed mood, agitation, and suicidal behaviour or ideation. The labelling of varenicline has been amended, and the FDA is conducting a safety review. The one cytisine trial included in this review found that more participants taking cytisine stopped smoking compared with placebo at two-year follow up, with an RR of 1.61 (95% CI 1.24 to 2.08). Varenicline increased the chances of successful long-term smoking cessation between two- and threefold compared with pharmacologically unassisted quit attempts. More participants quit successfully with varenicline than with bupropion. One open-label trial of varenicline versus nicotine replacement therapy demonstrated a modest benefit of varenicline. The effectiveness of varenicline as an aid to relapse prevention has not been clearly established. The main adverse effect of varenicline is nausea, but mostly at mild to moderate levels and tending to subside over time. Possible links with serious adverse events, including depressed mood, agitation and suicidal thoughts, are currently under review. There is a need for independent community-based trials of varenicline, to test its efficacy and safety in smokers with varying co-morbidities and risk patterns. There is a need for further trials of the efficacy of treatment extended beyond 12 weeks. Cytisine may also increase the chances of quitting, but the evidence at present is inconclusive.


Host cell factor-1 and E2F4 interact via multiple determinants in each protein.
Host Cell Factor (HCF-1) is a conserved, essential protein initially identified as a co-regulator for the Herpes Simplex Virus transactivator VP16. HCF-1 is variously involved in regulating transcription, splicing, cell proliferation and cytokinesis; however, its mechanisms of action remain unknown. HCF-1 function is manifested through an increasing assortment of cellular factors that target different regions of the protein. Several HCF-1 partners target the amino-terminal kelch domain of HCF-1 (residues 1-380) via a consensus HCF-binding motif (HBM) comprising the tetrapeptide (D/E)HXY. Searches of sequence databases indicated that this motif is present in E2F1 and E2F4, two members of the E2F family of cell cycle regulators. We show here that E2F4 specifically and directly interacts with HCF-1. Mutational analysis showed E2F4 independently targets the kelch domain and the basic domain (residues 450-902) of HCF-1, both of which are required for normal cell-cycle progression via separate determinants. The HBM-containing domain of E2F4 was necessary for interaction with the kelch domain of HCF-1 but not for interaction with the basic domain. Mutations in the HCF-1 kelch domain known to block cell growth abrogated E2F4 binding to the kelch domain in the absence but not in the presence of the juxtaposed basic region. Functionally, HCF-1 co-activated E2F4/DP-1 in transient transfection assays, while E2F4 blocked HCF-1-dependent rescue of a cell line that harbors a temperature sensitive mutant of HCF-1 that causes growth arrest. Our findings show that HCF-1 and E2F4 interact via multiple determinants and suggest a linkage between E2F4 and HCF-1 cell growth pathways.


Handedness Matters for Motor Control But Not for Prediction.
Skilled motor behavior relies on the ability to control the body and to predict the sensory consequences of this control. Although there is ample evidence that manual dexterity depends on handedness, it remains unclear whether control and prediction are similarly impacted. To address this issue, right-handed human participants performed two tasks with either the right or the left hand. In the first task, participants had to move a cursor with their hand so as to track a target that followed a quasi-random trajectory. This hand-tracking task allowed testing the ability to control the hand along an imposed trajectory. In the second task, participants had to track with their eyes a target that was self-moved through voluntary hand motion. This eye-tracking task allowed testing the ability to predict the visual consequences of hand movements. As expected, results showed that hand tracking was more accurate with the right hand than with the left hand. In contrast, eye tracking was similar in terms of spatial and temporal gaze attributes whether the target was moved by the right or the left hand. Although these results extend previous evidence for different levels of control by the two hands, they show that the ability to predict the visual consequences of self-generated actions does not depend on handedness. We propose that the greater dexterity exhibited by the dominant hand in many motor tasks stems from advantages in control, not in prediction. Finally, these findings support the notion that prediction and control are distinct processes.


The history of the patient history since 1850.
For the ordinary doctor the taking of a medical patient history is and has been one of the fundamental procedures. This article looks at instructions on the taking of a history in medical texts, to delineate what happened to the position of the patient history in clinical assessment with the increased emphasis on physical examination that began around the middle of the nineteenth century. The analysis reveals that the taking of a history remained important, with a consistent approach from 1850 to the end of the twentieth century. The patient history became incorporated into the physician's examination as another set of observations and signs, thus producing two histories: a superficial, chaotic story presented by the patient, and a deep, "true" history revealed by the skill of the physician. Within pediatrics, the primacy of the physical examination appears to have been asserted well before the introduction of history-taking.


Risk factors for anal HPV infection and anal precancer in HIV-infected men who have sex with men.
Carcinogenic human papillomaviruses (HPVs) cause a large proportion of anal cancers. Human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) are at increased risk of HPV infection and anal cancer compared with HIV-negative men. We evaluated risk factors for HPV infection and anal precancer in a population of HIV-infected MSM. Our study included 305 MSM at an HIV/AIDS clinic in the Kaiser Permanente Northern California Health Maintenance Organization. Logistic regression was used to estimate associations of risk factors comparing men without anal HPV infection; men with anal HPV infection, but no precancer; and men with anal precancer. Low CD4 count (<350 cells/mm(3)) and previous chlamydia infection were associated with an increased risk of carcinogenic HPV infection (odds ratio [OR], 3.65; 95% confidence interval [CI], 1.28-10.40 and OR, 4.24; 95% CI, 1.16-15.51, respectively). History of smoking (OR, 2.71 95% CI, 1.43-5.14), duration, recency, and dose of smoking increased the risk of anal precancer among carcinogenic HPV-positive men but had no association with HPV infection. We found distinct risk factors for anal HPV infection and anal precancer. Risk factors for HPV infection and anal precancer are similar to established risk factors for cervical cancer progression.


A small field for fertile science: the low visibility of reproductive science in high impact journals.
Our success as a field and as individuals in reproductive science and medicine relies on our ability to produce high quality work that has broad visibility and impact. A common metric for assessing such success is the quantity of publications that are published in journals with high impact factors. It is unclear, however, how frequently work related to reproductive science and medicine actually appears in what are considered the highest impact journals. To address this gap in knowledge, we first determined how the field of reproductive biology in general compared to other research areas in terms of composite journal impact factor. Second, using a targeted search approach in the PubMed database, we examined the relationship between a journal's impact factor and the number of reproductive research articles published per journal issue. We found that compared to other major scientific disciplines, our field lacks journals with impact factors above 4. In addition, primary original research articles on reproduction-irrespective of male or female search terms-do not appear often in high impact journals. Instead, there is an increased percentage of secondary reproductive literature in high impact journals compared to topic-specific journals of lower impact. There are likely several explanations for why reproductive science and medicine has low visibility, including the field's small relative size, its lack of a specific disease and associated strong advocacy, and its surrounding social, ethical, and political unease. Nevertheless, there are concrete actions we can take to minimize the role of impact factor in our evaluation while simultaneously increasing influence through global awareness of the importance and need for reproductive research.


Population genomics of the wild yeast Saccharomyces paradoxus: Quantifying the life cycle.
Most microbes have complex life cycles with multiple modes of reproduction that differ in their effects on DNA sequence variation. Population genomic analyses can therefore be used to estimate the relative frequencies of these different modes in nature. The life cycle of the wild yeast Saccharomyces paradoxus is complex, including clonal reproduction, outcrossing, and two different modes of inbreeding. To quantify these different aspects we analyzed DNA sequence variation in the third chromosome among 20 isolates from two populations. Measures of mutational and recombinational diversity were used to make two independent estimates of the population size. In an obligately sexual population these values should be approximately equal. Instead there is a discrepancy of about three orders of magnitude between our two estimates of population size, indicating that S. paradoxus goes through a sexual cycle approximately once in every 1,000 asexual generations. Chromosome III also contains the mating type locus (MAT), which is the most outbred part in the entire genome, and by comparing recombinational diversity as a function of distance from MAT we estimate the frequency of matings to be approximately 94% from within the same tetrad, 5% with a clonemate after switching the mating type, and 1% outcrossed. Our study illustrates the utility of population genomic data in quantifying life cycles.


Early objective response to avelumab treatment is associated with improved overall survival in patients with metastatic Merkel cell carcinoma.
Response rates are primary endpoints in many oncology trials; however, correlation with overall survival (OS) is not uniform across cancer types, treatments, or lines of therapy. This study explored the association between objective response (OR) and OS in patients with chemotherapy-refractory metastatic Merkel cell carcinoma who received avelumab (anti-PD-L1). Eighty-eight patients enrolled in JAVELIN Merkel 200 (part A; NCT02155647) received i.v. avelumab 10 mg/kg every 2 weeks until confirmed progression, unacceptable toxicity, or withdrawal. Using conditional landmark analyses, we compared OS in patients with and without confirmed OR (RECIST v1.1). We applied a Cox model that included OR as a time-varying covariate and adjusted for age, visceral disease, and number of previous therapies. Twenty-nine patients had confirmed OR; 20 by study week 7 and 7 more between study weeks 7 and 13. Survival probabilities 18 months after treatment initiation were 90% [95% confidence interval (CI) 65.6-97.4] in patients with OR at week 7 and 26.2% (95% CI 15.7-37.8) in patients without OR but who were alive at week 7. Median OS was not reached in patients with OR and was 8.8 months (95% CI 6.4-12.9) in patients without. Similar results were observed for the week 13 landmark. The adjusted Cox model showed OR was associated with a 95% risk reduction of death [hazard ratio 0.052 (95% CI 0.018-0.152)] compared with a nonresponse. Patients with OR by 7 or 13 weeks had significantly longer OS than patients without, confirming that early OR is an endpoint of major importance.


Traumatic experiences, posttraumatic stress symptoms, depression, and health-risk behavior in relation to injury among University of Nairobi students in Kenya.
To describe the prevalence and types of injuries in relation to traumatic experiences, posttraumatic stress symptoms, depression, and health-risk behaviors among university students in Kenya. A cross-sectional study collected data on a random sample of university students using a questionnaire to record sociodemographic variables while injuries experiences recorded using the Centers for Disease control criteria and Breslau's seven-item screener was used to identify post-traumatic stress disorder (PTSD) symptoms. Depressive symptoms were measured using Center for Epidemiological Studies Short Depression Scale. Nine hundred and twenty-three students (525 male and 365 female) were included in the study, mean age 23 years (SD 4.0). Serious injury in the previous 12 months was reported by 29.00% of the students. PTSD was present in 15.67% (men 15.39% and women 16.1%). Out of the total, 41.33% of the students had depressive symptoms (35.71% mild-moderate symptoms and 5.62% severe). In the multivariable logistic regression being poor, binge drinking, tobacco use, ever been diagnosed with HIV, physically abused as a child, high PTSD score, and depression (adjusted odds ratio 5.49, 95% confidence interval 4.32-13.21) were significantly (p value<5%) associated with injury in the last 12 months. Unintentional injuries and PTSD symptoms are common in this student population and are positively linked to depression and other risky behaviors. Measures aimed at improving the mental health, such as early identification and treatment of depression, may be useful in reducing the prevalence of such injuries among the youth.


Chemical composition, in vitro antitumor and pro-oxidant activities of Glandora rosmarinifolia (Boraginaceae) essential oil.
The biological properties of essential oils have been demonstrated in the treatment of several diseases and to enhance the bioavailability of other drugs. In natural habitats the essential oils compounds may play important roles in the protection of the plants as antibacterials, antivirals, antifungals, insecticides and also against herbivores by reducing their appetite for such plants or by repelling undesirable others. We analyzed by gas-chromatography mass spectrometry the chemical composition of the essential oil of aerial parts of Glandora rosmarinifolia (Ten.) D.C. Thomas obtained by hydrodistillation and verified some biological activities on a panel of hepatocellular carcinoma cell lines (HA22T/VGH, HepG2, Hep3B) and triple negative breast cancer cell lines (SUM 149, MDA-MB-231). In the essential oil we detected 35 compounds. The results of the biological assays indicate that essential oil of G. rosmarinifolia induces cell growth inhibition at concentration-dependent way in all cell line models. This oil does not seem to possess antioxidant activity, while the cytotoxicity of G. rosmarinifolia essential oil appeared to involve, at least in part, a pro-oxidant mechanism. Our results show for the first time the antitumoral and pro-oxidant activities of G. rosmarinifolia essential oil and suggest that it may represent a resource of pharmacologically active compounds.


Benzothiazole-pyrimidine-based BODIPY analogues: promising luminophores with fluorescence sensing and imaging ability and asymmetrization-induced solid-state emission.
A new family of BODIPY analogues (BDB1-8) derived from benzothiazole-pyrimidine-based bidentate ligands was synthesized and fully characterized. The photophysical properties of these boron complexes were measured both in solution and solid-state. These new luminophores exhibited intense fluorescence with high quantum yields ranging from 0.27 to 0.79, and moderate Stokes shifts ranging from 660 to 2120 cm-1 in solution. Due to the existence of strong intermolecular interactions, BDB1-8 showed quenched fluorescence with low quantum yields ranging from 0.03 to 0.20 in solid-state. In addition, BDB1 and BDB2 were capable of sensing cysteine in aqueous solution with high selectivity and sensitivity, which means that these complexes hold great potential in serving as fluorogenic cysteine sensors for biological application.


Interleukin-4 Receptor α Signaling in Myeloid Cells Controls Collagen Fibril Assembly in Skin Repair.
Activation of the immune response during injury is a critical early event that determines whether the outcome of tissue restoration is regeneration or replacement of the damaged tissue with a scar. The mechanisms by which immune signals control these fundamentally different regenerative pathways are largely unknown. We have demonstrated that, during skin repair in mice, interleukin-4 receptor α (IL-4Rα)-dependent macrophage activation controlled collagen fibril assembly and that this process was important for effective repair while having adverse pro-fibrotic effects. We identified Relm-α as one important player in the pathway from IL-4Rα signaling in macrophages to the induction of lysyl hydroxylase 2 (LH2), an enzyme that directs persistent pro-fibrotic collagen cross-links, in fibroblasts. Notably, Relm-β induced LH2 in human fibroblasts, and expression of both factors was increased in lipodermatosclerosis, a condition of excessive human skin fibrosis. Collectively, our findings provide mechanistic insights into the link between type 2 immunity and initiation of pro-fibrotic pathways.


Translating genomic research into clinical practice: promise and pitfalls.
Breast cancer is a heterogeneous disease associated with variable clinical outcomes despite standard local therapy for the primary tumor and systemic adjuvant therapy to prevent distant recurrence. Management decisions are typically made using classical prognostic and predictive clinicopathologic factors, and more recently gene expression profiling assays are commonly used in practice. Recent advances in genomic sequencing-often referred to collectively as next-generation sequencing (NGS)-have facilitated more in-depth evaluation of the cancer genome than could be afforded by the initial generation of gene expression studies, including DNA single nucleotide variants, small insertions and deletions, structural alterations, and copy number alterations (CNAs). In addition, this information has been integrated with other molecular profiling methods of processes that affect gene transcription (e.g., epigenetic, microRNA) and protein expression-the ultimate readout of the genetic code. Although NGS has provided new insights on the classification of breast cancer and identified potential predictive biomarkers and novel targets, there are formidable logistical and scientific obstacles that must be addressed before the promise of this technology is fully realized.


O-pH: Optical pH Monitor to Measure Dental Biofilm Acidity and Assist in Enamel Health Monitoring.
Bacteria in the dental biofilm produceacid after consumption of carbohydrates which if left unmonitored leads to caries formation. We present O-pH, a device that can measure dental biofilm acidity and provide quantitative feedback to assist in oral health monitoring. O-pH utilizes a ratiometric pH sensing method by capturing fluorescence of Sodium Fluorescein, an FDA approved chemical dye. The device was calibrated to a lab pH meter using buffered fluorescein solution with a correlation coefficient of 0.97. The calibration was further verified in vitro on additional buffered solution, artificial, and extracted teeth. An in vivo study on 30 pediatric subjects was performed to measure pH before (rest pH) and after (drop pH) a sugar rinse, and the resultant difference in pH (diff pH) was calculated. The study enrolled subjects with low (Post-Cleaning) and heavy (Pre-Cleaning) biofilm load, having both unhealthy/healthy surfaces. Further, we modified point-based O-pH to an image-based device using a multimode-scanning fiber endoscope (mm-SFE) and tested in vivo on one subject. We found significant difference between Post-Cleaning and Pre-Cleaning group using drop pH and diff pH. Additionally, in Pre-Cleaning group, the rest and drop pH is lower at the caries surfaces compared to healthy surfaces. Similar trend was not noticed in the Post-Cleaning group. mm-SFE pH scope recorded image-based pH heatmap of a subject with an average diff pH of 1.5. This work builds an optical pH prototype and presents a pioneering study for non-invasively measuring pH of dental biofilm clinically.


Outcome of Patients Receiving Thrombolytic Therapy While on Rivaroxaban for Nonvalvular Atrial Fibrillation (from Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation).
The safety of intravenous thrombolysis in patients taking rivaroxaban has not been well established. We retrospectively analyzed the outcomes of all patients who received thrombolytic therapy in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). A review of medical and adverse event records for patients receiving thrombolytic therapy while enrolled in ROCKET AF was performed to determine their baseline characteristics, indications for thrombolysis, and type of agent used. Safety end points were 30-day post-thrombolytic rates of stroke, bleeding, and mortality. A total of 28 patients in ROCKET AF received thrombolytic therapy, with 19 patients on rivaroxaban and 9 patients on warfarin. Ischemic stroke was the most common indication for thrombolysis (n = 10), and alteplase was the most commonly used fibrinolytic agent (n = 14). Of the 19 patients in the rivaroxaban group, there were 2 nonfatal bleeding events and 2 deaths, mostly occurring when thrombolytic therapy was administered within 48 hours of the last rivaroxaban dose. Of the 9 patients in the warfarin group, there was 1 nonfatal bleeding event and 3 deaths, most occurring when thrombolytic therapy was administered outside of 48 hours from the last warfarin dose. In conclusion, these observations suggest that careful assessment of the time since the last dose may be of clinical significance in patients on novel oral anticoagulants who require emergent thrombolysis.


Characterisation of tetraspanins from Schistosoma haematobium and evaluation of their potential as novel diagnostic markers.
Schistosoma haematobium is the leading cause of urogenital schistosomiasis and it is recognised as a class 1 carcinogen due to the robust association of infection with bladder cancer. In schistosomes, tetraspanins (TSPs) are abundantly present in different parasite proteomes and could be potential diagnostic candidates due to their accessibility to the host immune system. The large extracellular loops of six TSPs from the secretome (including the soluble excretory/secretory products, tegument and extracellular vesicles) of S. haematobium (Sh-TSP-2, Sh-TSP-4, Sh-TSP-5, Sh-TSP-6, Sh-TSP-18 and Sh-TSP-23) were expressed in a bacterial expression system and polyclonal antibodies were raised to the recombinant proteins to confirm the anatomical sites of expression within the parasite. Sh-TSP-2, and Sh-TSP-18 were identified on the tegument, whereas Sh-TSP-4, Sh-TSP-5, Sh-TSP-6 and Sh-TSP-23 were identified both on the tegument and internal tissues of adult parasites. The mRNAs encoding these TSPs were differentially expressed throughout all schistosome developmental stages tested. The potential diagnostic value of three of these Sh-TSPs was assessed using the urine of individuals (stratified by infection intensity) from an endemic area of Zimbabwe. The three Sh-TSPs were the targets of urine IgG responses in all cohorts, including individuals with very low levels of infection (those positive for circulating anodic antigen but negative for eggs by microscopy). This study provides new antigen candidates to immunologically diagnose S. haematobium infection, and the work presented here provides compelling evidence for the use of a biomarker signature to enhance the diagnostic capability of these tetraspanins.


Individual clearance and therapeutic drug monitoring of quetiapine in clinical practice.
Quetiapine is one of the most frequent prescribed antipsychotics. Based on the consensus guidelines of therapeutic drug monitoring (TDM) in clinical practice, TDM of Quetiapine is "useful". In this pilot study, using a natural sample, we investigated the influence of co-medication, age and gender on the serum concentrations and clearance of Quetiapine. Also we compared the individual clearance in our sample with the expected clearance for healthy subjects, obtained in controlled studies. 150 blood samples were collected anonymously under clinical conditions, Quetiapine trough serum levels were determined using HPLC. Additional information about gender, age, co-medication and dosage was obtained. There was a significant, positive, but weak correlation between daily dose and serum levels of Quetiapine (r=0.44; p=0.01). When Carbamazepine was co-administered, the clearance was significantly higher (p=0.01). 83% of the serum levels were outside the therapeutic range, only 28% were within the expected clearance. In addition to the therapeutic range the individual clearance related to the expected clearance may help to optimize individual pharmacotherapy, especially for combination therapy or in case of incompliance or abnormal metabolism.


Labeling Maize (Zea mays L.) Leaves with 15 NH4+ and Monitoring Nitrogen Incorporation into Amino Acids by GC/MS Analysis.
The human body contains approximately 3.2% nitrogen (N), mainly present as protein and amino acids. Although N exists at a high concentration (78%) in the air, it is not readily available to animals and most plants. Plants are however able to take up both nitrate (NO3- ) and ammonium (NH4+ ) ions from the soil and convert them to amino acids and proteins, which are excellent sources for all animals. Most N is available as the stable isotope 14 N, but a second form, 15 N, is present in very low concentrations. 15 N can be detected in extracts of plants by gas chromatography followed by mass spectrometry (GC/MS). In this protocol, the methods are described for tracing the pathway by which plants are able to take up 15 N-labeled nitrate and ammonium and convert them into amino acids and proteins. A protocol for extracting and quantifying amino acids and 15 N enrichment in maize (Zea mays L.) leaves labeled with 15 NH4+ is described. Following amino acid extraction, purification, and separation by GC/MS, a calculation of the 15 N enrichment of each amino acid is carried out on a relative basis to identify any differences in the dynamics of amino acid accumulation. This will allow a study of the impact of genetic modifications or mutations on key reactions involved in primary nitrogen and carbon metabolism. © 2018 by John Wiley & Sons, Inc.


Technical review on the management of eosinophilic esophagitis: a report from the AGA institute and the joint task force on allergy-immunology practice parameters.
Eosinophilic esophagitis (EoE) is a chronic inflammatory condition of the esophagus. Many new studies have been reported recently that describe EoE management. An expert panel was convened by the American Gastroenterological Association Institute and the Joint Task Force on Allergy-Immunology Practice Parameters to provide a technical review to be used as the basis for an updated clinical guideline. This technical review was developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Eighteen focused EoE management questions were considered, with 15 answered using the GRADE framework and 3 with a narrative summary. There is moderate certainty in the evidence that topical glucocorticosteroids effectively reduce esophageal eosinophil counts to <15 per high-power field over a short-term treatment period of 4-12 weeks, but very low certainty about the effects of using topical glucocorticosteroids as maintenance therapy. Multiple dietary strategies may be effective in reducing esophageal eosinophil counts to <15 per high-power field over a short-term treatment period, with moderate certainty for elemental diets, low certainty for empiric 2-, 4-, and 6-food elimination diets, and very low certainty that allergy-based testing dietary eliminations have a higher failure rate compared to empiric diet elimination. There is very low certainty for the effect of proton pump inhibitors in patients with esophageal eosinophilia. Although esophageal dilation appears to be relatively safe, there is no evidence that it reduces esophageal eosinophil counts. There is very low certainty in the effects of multiple other medical treatments for EoE: anti-interleukin-5 therapy, anti-interleukin-13 therapy, anti-IgE therapy, montelukast, cromolyn, and anti-TNF therapy.


The distribution of the alpha7 nicotinic acetylcholine receptor in healthy aging: An in vivo positron emission tomography study with [18F]ASEM.
Altered function of the alpha7 nicotinic acetylcholine receptor (α7-nAChR) is implicated in several neuropsychiatric diseases. Nevertheless, studies of the human cerebral α7-nAChR even in healthy aging are limited in number and to postmortem tissue. The distribution of the cerebral α7-nAChR was estimated in nine brain regions in 25 healthy volunteers (ages 21-86 years; median 57 years, interquartile range 52 years) using [18F]ASEM with positron emission tomography (PET) imaging. Regional total distribution volume (VT) measurements were calculated using the Logan method from each subject's 90 min dynamic PET data and their metabolite-corrected plasma input function. Spearman's rank or Pearson's correlation analysis was used depending on the normality of the data. Correlation between age and regional 1) volume relative to intracranial volume (volume ratio) and 2) [18F]ASEM VT was tested. Correlation between regional volume ratio and [18F]ASEM VT was also evaluated. Finally, the relationship between [18F]ASEM VT and neuropsychological measures was investigated in a subpopulation of 15 elderly healthy participants (those 50 years of age and older). Bonferroni correction for multiple comparisons was applied to statistical analyses. A negative correlation between tissue volume ratio and age was observed in six of the nine brain regions including striatum and five cortical (temporal, occipital, cingulate, frontal, or parietal) regions. A positive correlation between [18F]ASEM VT and age was observed in all nine brain regions of interest (ROIs). There was no correlation between [18F]ASEM VT and volume ratio in any ROI after controlling for age. Regional [18F]ASEM VT and neuropsychological performance on each of eight representative subtests were not correlated among the well-performing subpopulation of elderly healthy participants. Our results suggest an increase in cerebral α7-nAChR distribution over the course of healthy aging that should be tested in future longitudinal studies. The preservation of the α7-nAChR in the aging human brain supports the development of therapeutic agents that target this receptor for use in the elderly. Further study of the relationship between α7-nAChR availability and cognitive impairment over aging is needed.


Quality of life of mothers whose children work on the streets of São Paulo, Brazil.
The present study evaluated the perceived quality of life of the mothers of street children and investigated the association with their history of childhood violence, the occurrence of current domestic violence, their current mental states and that of their children, and family functioning. The applied instruments were as follows: Strengths and Difficulties Questionnaire, WorldSAFECore Questionnaire, Instrument for the Assessment of Quality of Life of the WHO, Global Assessment of Relational Functioning Scale, Childhood Trauma Questionnaire and a socio-demographic questionnaire. The sample of convenience consisted of 79 low-income mothers who raised their children alone, and most of whom had a positive screening for mental illness. The multiple regression analysis showed that the perception of quality of life of these women was associated with the presence of psychopathology either in themselves or their children and family dysfunction. Thus any program aimed at improving the quality of life of such mothers should consider addressing their mental problems as well as those of their children, besides offering educational and psychotherapeutic approaches to these families to improve the social environment.


Network theory to understand microarray studies of complex diseases.
Complex diseases, such as allergy, diabetes and obesity depend on altered interactions between multiple genes, rather than changes in a single causal gene. DNA microarray studies of a complex disease often implicate hundreds of genes in the pathogenesis. This indicates that many different mechanisms and pathways are involved. How can we understand such complexity? How can hypotheses be formulated and tested? One approach is to organize the data in network models and to analyze these in a top-down manner. Globally, networks in nature are often characterized by a small number of highly connected nodes, while the majority of nodes have few connections. The highly connected nodes serve as hubs that affect many other nodes. Such hubs have key roles in the network. In yeast cells, for example, deletion of highly connected proteins is associated with increased lethality, compared to deletion of less connected proteins. This suggests the biological relevance of networks. Moving down in the network structure, there may be sub-networks or modules with specific functions. These modules may be further dissected to analyze individual nodes. In the context of DNA microarray studies of complex diseases, gene-interaction networks may contain modules of co-regulated or interacting genes that have distinct biological functions. Such modules may be linked to specific gene polymorphisms, transcription factors, cellular functions and disease mechanisms. Genes that are reliably active only in the context of their modules can be considered markers for the activity of the modules and may thus be promising candidates for biomarkers or therapeutic targets. This review aims to give an introduction to network theory and how it can be applied to microarray studies of complex diseases.


Sexual Violence Perpetration by Adolescents in Dating versus Same-Sex Peer Relationships: Differences in Associated Risk and Protective Factors.
Little is known about the risk and protective factors for youth sexual violence (SV) perpetration across different types of relationships. This study examined factors associated with perpetrating SV against a dating partner and a same-sex peer. Analyses were based on data from a survey conducted in 2004 with public school boys and girls in grades 7, 9, 11, and 12 (N = 4,131) in a high-risk, urban school district in the United States. SV perpetration was defined broadly to include forcing someone, about the same age and of the same or opposite sex as the respondent, to have sex or to do something sexual that they did not want to do. Analyses examined the associations between risk and protective factors and SV perpetration, adjusting for SV victimization and demographic characteristics. Findings revealed that 2.1% of respondents reported perpetration against a same-sex peer and 3.2% reported perpetration against a date during the past 12 months. Victims of SV for each relationship type were more likely than non-victims to perpetrate SV. A combination of factors across the individual, relationship, and community level were significantly associated with SV perpetration and there were both shared and unique factors across the relationship types. Data suggest that programs to prevent SV perpetration for both relationship types should start when students are young, with particular focus on middle school boys. Prevention efforts should have slightly different foci to address these 2 types of SV perpetration.


Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis.
Mechanotransduction is a key determinant of tissue homeostasis and tumor progression. It is driven by intercellular adhesions, cell contractility, and forces generated within the microenvironment and is dependent on extracellular matrix composition, organization, and compliance. We show that caveolin-1 (Cav1) favors cell elongation in three-dimensional cultures and promotes Rho- and force-dependent contraction, matrix alignment, and microenvironment stiffening through regulation of p190RhoGAP. In turn, microenvironment remodeling by Cav1 fibroblasts forces cell elongation. Cav1-deficient mice have disorganized stromal tissue architecture. Stroma associated with human carcinomas and melanoma metastases is enriched in Cav1-expressing carcinoma-associated fibroblasts (CAFs). Cav1 expression in breast CAFs correlates with low survival, and Cav1 depletion in CAFs decreases CAF contractility. Consistently, fibroblast expression of Cav1, through p190RhoGAP regulation, favors directional migration and invasiveness of carcinoma cells in vitro. In vivo, stromal Cav1 remodels peri- and intratumoral microenvironments to facilitate tumor invasion, correlating with increased metastatic potency. Thus, Cav1 modulates tissue responses through force-dependent architectural regulation of the microenvironment.


Optical coherence tomography segmentation reveals ganglion cell layer pathology after optic neuritis.
Post-mortem ganglion cell dropout has been observed in multiple sclerosis; however, longitudinal in vivo assessment of retinal neuronal layers following acute optic neuritis remains largely unexplored. Peripapillary retinal nerve fibre layer thickness, measured by optical coherence tomography, has been proposed as an outcome measure in studies of neuroprotective agents in multiple sclerosis, yet potential swelling during the acute stages of optic neuritis may confound baseline measurements. The objective of this study was to ascertain whether patients with multiple sclerosis or neuromyelitis optica develop retinal neuronal layer pathology following acute optic neuritis, and to systematically characterize such changes in vivo over time. Spectral domain optical coherence tomography imaging, including automated retinal layer segmentation, was performed serially in 20 participants during the acute phase of optic neuritis, and again 3 and 6 months later. Imaging was performed cross-sectionally in 98 multiple sclerosis participants, 22 neuromyelitis optica participants and 72 healthy controls. Neuronal thinning was observed in the ganglion cell layer of eyes affected by acute optic neuritis 3 and 6 months after onset (P < 0.001). Baseline ganglion cell layer thicknesses did not demonstrate swelling when compared with contralateral unaffected eyes, whereas peripapillary retinal nerve fibre layer oedema was observed in affected eyes (P = 0.008) and subsequently thinned over the course of this study. Ganglion cell layer thickness was lower in both participants with multiple sclerosis and participants with neuromyelitis optica, with and without a history of optic neuritis, when compared with healthy controls (P < 0.001) and correlated with visual function. Of all patient groups investigated, those with neuromyelitis optica and a history of optic neuritis exhibited the greatest reduction in ganglion cell layer thickness. Results from our in vivo longitudinal study demonstrate retinal neuronal layer thinning following acute optic neuritis, corroborating the hypothesis that axonal injury may cause neuronal pathology in multiple sclerosis. Further, these data provide evidence of subclinical disease activity, in both participants with multiple sclerosis and with neuromyelitis optica without a history of optic neuritis, a disease in which subclinical disease activity has not been widely appreciated. No pathology was seen in the inner or outer nuclear layers of eyes with optic neuritis, suggesting that retrograde degeneration after optic neuritis may not extend into the deeper retinal layers. The subsequent thinning of the ganglion cell layer following acute optic neuritis, in the absence of evidence of baseline swelling, suggests the potential utility of quantitative optical coherence tomography retinal layer segmentation to monitor neuroprotective effects of novel agents in therapeutic trials.


EMT, the cytoskeleton, and cancer cell invasion.
The metastatic process, i.e. the dissemination of cancer cells throughout the body to seed secondary tumors at distant sites, requires cancer cells to leave the primary tumor and to acquire migratory and invasive capabilities. In a process of epithelial-mesenchymal transition (EMT), besides changing their adhesive repertoire, cancer cells employ developmental processes to gain migratory and invasive properties that involve a dramatic reorganization of the actin cytoskeleton and the concomitant formation of membrane protrusions required for invasive growth. The molecular processes underlying such cellular changes are still only poorly understood, and the various migratory organelles, including lamellipodia, filopodia, invadopodia and podosomes, still require a better functional and molecular characterization. Notably, direct experimental evidence linking the formation of migratory membrane protrusions and the process of EMT and tumor metastasis is still lacking. In this review, we have summarized recent novel insights into the molecular processes and players underlying EMT on one side and the formation of invasive membrane protrusions on the other side.


MicroRNA expression in rat brain exposed to repeated inescapable shock: differential alterations in learned helplessness vs. non-learned helplessness.
MicroRNA (miRNA) expression was measured within frontal cortex of male Holtzman rats subjected to repeated inescapable shocks at days 1 and 7, tested for learned helplessness (LH) at days 2 and 8, and sacrificed at day 15. We compared rats that did vs. did not exhibit LH, as well as rats that were placed in the apparatus and tested for avoidance but not given shocks (tested controls, TC). Non-learned helpless (NLH) rats showed a robust adaptive miRNA response to inescapable shock whereas LH rats showed a markedly blunted response. One set of 12 miRNAs showed particularly large, significant down-regulation in NLH rats relative to tested controls (mir-96, 141, 182, 183, 183*, 298, 200a, 200a*, 200b, 200b*, 200c, 429). These were encoded at a few shared polycistronic loci, suggesting that the down-regulation was coordinately controlled at the level of transcription. Most of these miRNAs are enriched in synaptic fractions. Moreover, almost all of these share 5'-seed motifs with other members of the same set, suggesting that they will hit similar or overlapping sets of target mRNAs. Finally, half of this set is predicted to hit Creb1 as a target. We also identified a core miRNA co-expression module consisting of 36 miRNAs that are highly correlated with each other across individuals of the LH group (but not in the NLH or TC groups). Thus, miRNAs participate in the alterations of gene expression networks that underlie the normal (NLH) as well as aberrant (LH) response to repeated shocks.


Microelements and Heavy Metals Content in Frequently Utilized Medicinal Plants Collected from the Power Plant Area.
The effectiveness of medicinal plants is mainly associated with their active constituents, but one of the major quality problems frequently encountered is their high trace metals content that can be associated to extensive pollution of the environment where medicinal plants grow. Therefore the aim of this research was to evaluate the content of Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, Zn and As in selected and frequently used medicinal plants, including chicory, broadleaf, common comfrey and dandelion. The plant material was collected from their wild habitats in the area of highly developed power plant activity during the summer of 2015. Plant analyses were done according to ICP methodology, using ICAP 6300 ICP optical emission spectrometer. The obtained results showed that the content of As, Cd, Co, Mn, Ni and Zn in the investigated medicinal plant species was below the maximum permissible concentration, while in all parts of all studied plants the concentration of Cr was toxic. The toxic concentrations of Cu were determined in root and aerial parts of chicory and common comfrey, and the toxic concentrations of Fe in root and aerial parts of dandelion and broadleaf plantain, and in aerial parts of common comfrey. However, high but not toxic content of Pb was found in aerial parts of chicory. It can be concluded that medicinal plants from the studied growing site are not appropriate for use in alternative medicine and that a determination of trace metals content in these plants must become a standard criterion for evaluation of their quality.


Uniqueness of Human Running Coordination: The Integration of Modern and Ancient Evolutionary Innovations.
Running is a pervasive activity across human cultures and a cornerstone of contemporary health, fitness, and sporting activities. Yet for the overwhelming predominance of human existence running was an essential prerequisite for survival. A means to hunt, and a means to escape when hunted. In a very real sense humans have evolved to run. Yet curiously, perhaps due to running's cultural ubiquity and the natural ease with which we learn to run, we rarely consider the uniqueness of human bipedal running within the animal kingdom. Our unique upright, single stance, bouncing running gait imposes a unique set of coordinative difficulties. Challenges demanding we precariously balance our fragile brains in the very position where they are most vulnerable to falling injury while simultaneously retaining stability, steering direction of travel, and powering the upcoming stride: all within the abbreviated time-frames afforded by short, violent ground contacts separated by long flight times. These running coordination challenges are solved through the tightly-integrated blending of primitive evolutionary legacies, conserved from reptilian and vertebrate lineages, and comparatively modern, more exclusively human, innovations. The integrated unification of these top-down and bottom-up control processes bestows humans with an agile control system, enabling us to readily modulate speeds, change direction, negotiate varied terrains and to instantaneously adapt to changing surface conditions. The seamless integration of these evolutionary processes is facilitated by pervasive, neural and biological, activity-dependent adaptive plasticity. Over time, and with progressive exposure, this adaptive plasticity shapes neural and biological structures to best cope with regularly imposed movement challenges. This pervasive plasticity enables the gradual construction of a robust system of distributed coordinated control, comprised of processes that are so deeply collectively entwined that describing their functionality in isolation obscures their true irrevocably entangled nature. Although other species rely on a similar set of coordinated processes to run, the bouncing bipedal nature of human running presents a specific set of coordination challenges, solved using a customized blend of evolved solutions. A deeper appreciation of the foundations of the running coordination phenomenon promotes conceptual clarity, potentially informing future advances in running training and running-injury rehabilitation interventions.


Evaluation of the TSI aerosol impactor 3306/3321 system using a redesigned impactor stage with solution and suspension metered-dose inhalers.
The purpose of this research was to evaluate a redesigned impactor stage for the TSI Model 3306 Impactor Inlet with nozzles adjusted to obtain a target cut-point of 4.7 microm. It has been determined that the previous cut-point used in the Model 3306 was nominally closer to 4.14 microm, thus potentially impacting the characterization of aerosol mass. The reassessment of the Model 3306 was performed on 4 solution and 2 suspension metered-dose inhaler (MDI) formulations. The redesigned impactor stage resulted in a 5% to 6% increase in aerosol mass when compared with the previous impactor stage for the products Ventolin-HFA, Proventil-HFA, and 2 cyclosporin solution formulations with high ethanol concentrations (15% wt/wt). For the formulations with low ethanol concentrations (3% wt/wt), minimal differences were observed between the 2 cut-points. In addition, this study reevaluated the requirement of a vertical inlet extension length when using the TSI 3306/3321 system with the redesigned cut-point. It was shown that the use of a 20-cm extension provides mass and aerosol size distributions that are comparable to the Andersen 8-stage Cascade Impactor, for both solution and suspension MDIs. This work indicates that the TSI 3306/3321 system is suitable for preformulation studies of both suspension and solution MDI systems.


Simulated learning environments in anatomy and surgery delivered via the next generation internet.
The Next Generation Internet (NGI) will provide high bandwidth, guaranteed Quality of Service, collaboration and security, features that are not available in today's Internet. Applications that take advantage of these features will need to build them into their pedagogic requirements. We present the Anatomy Workbench and the Surgery Workbench, two applications that require most of these features of the NGI. We used pedagogic need and NGI features to define a set of applications that would be difficult to operate on the current Internet, and that would require the features of the NGI. These applications require rich graphics and visualization, and extensive haptic interaction with biomechanical models that represent bony and soft tissue. We are in the process of implementing these applications, and some examples are presented here. An additional feature that we required was that the applications be scalable such that they could run on either on a low-end desktop device with minimal manipulation tools or on a fully outfitted high-end graphic computer with a realistic set of surgical tools. The Anatomy and Surgery Workbenches will be used to test the features of the NGI, and to show the importance of these new features for innovative educational applications.


Synergism in aluminum and mercury neurotoxicity.
Aluminum and mercury are common neurotoxic contaminants in our environment - from the air we breathe to the water that we drink to the foods that we eat. It is remarkable that to date neither of these two well-established environmental neurotoxins (i.e. those having a general toxicity towards brain cells) and genotoxins (those agents which exhibit directed toxicity toward the genetic apparatus) have been critically studied, nor have their neurotoxicities been evaluated in human neurobiology or in cells of the human central nervous system (CNS). In this paper we report the effects of added aluminum [sulfate; Al₂(SO₄)₃] and/or mercury [sulfate; HgSO4] to human neuronal-glial (HNG) cells in primary co-culture using the evolution of the pro-inflammatory transcription factor NF-kB (p50/p65) complex as a critical indicator for the onset of inflammatory neurodegeneration and pathogenic inflammatory signaling. As indexed by significant induction of the NF-kB (p50/p65) complex the results indicate: (i) a notable increase in pro-inflammatory signaling imparted by each of these two environmental neurotoxins toward HNG cells in the ambient 20-200 nM range; and (ii) a significant synergism in the neurotoxicity when aluminum (sulfate) and mercury (sulfate) were added together. This is the first report on the neurotoxic effects of aluminum sulfate and/or mercury sulfate on the initiation of inflammatory signaling in human brain cells in primary culture. The effects aluminum+mercury together on other neurologically important signaling molecules or the effects of other combinations of common environmental metallic neurotoxins to human neurobiology currently remain not well understood but certainly warrant additional investigation and further study in laboratory animals, in human primary tissue cultures of CNS cells, and in other neurobiologically realistic experimental test systems.


The disulphide bond structure of thyroid-stimulating hormone beta-subunit.
Previously only one of the six disulphide bonds within the beta-subunit of bovine thyrotropin (bTSH beta) has been unequivocally assigned. In the present investigation, the fluorescent alkylating reagent 5-N-[(iodoacetamidoethyl)amino]naphthalene-1-sulphonic acid has been employed as part of a double-alkylation strategy to allow the relative reactivities and the location of the six disulphide bonds of bTSH beta, after selective reduction, to be assigned by using reversed-phase HPLC peptide mapping techniques and associated methods of structural analysis. The most reactive disulphide bond was Cys88-Cys95; the second most reactive group of disulphide bonds involved the half-cystine residues Cys16, Cys19, Cys67 and Cys105 with the experimental results consistent with the assignment of disulphide bonds to Cys16-Cys67 and Cys19-Cys105. The least reactive group of half-cystine residues consisted of Cys2, Cys27, Cys31, Cys52, Cys83 and Cys85. The isolation, by high-performance ion-exchange chromatography, of a partly reduced bTSH beta derivative in which only the half-cystine residues Cys31, Cys85, Cys88 and Cys95 were labelled enabled the assignment of a previously uncharacterized disulphide bond to Cys31-Cys85. The remaining two assignments, Cys2-Cys52 and Cys27-Cys83, were made by comparison with the recently published human chorionic gonadotropin crystal structure. The flexibility of the double-labelling approach used in these studies demonstrates that only very small quantities are required for proteins containing an extensive number of half-cystine residues such as TSH beta, owing to the combination of the high resolution of the reversed-phase HPLC peptide mapping procedures and the sensitivity of the fluorimetric detection method.


Lumbopelvic kinematics and trunk muscle activity during sitting on stable and unstable surfaces.
A single-group comparative study. To compare lumbopelvic kinematics and muscle activation patterns while sitting on stable and unstable surfaces. Unstable surfaces are commonly used during the rehabilitation of certain low back pain disorders. The benefits postulated are increased muscle activity and facilitation of sustainable midrange positions via neuromuscular control. The use of unstable sitting devices in the workplace is controversial, as the postulated increase in muscle activity is thought to lead to a muscle fatigue/pain response. However, little evidence exists for or against the ability of these devices to alleviate or prevent spinal pain. This study included 26 healthy adults (14 male, 12 female). Fastrak 3-dimensional motion analysis detected lumbar curvature, pelvic tilt, and postural sway during sitting on a stable and unstable surface over 5-minute periods. Surface electromyography was used to measure activity in the superficial lumbar multifidus, transverse fibers of internal oblique, and iliocostalis lumborum pars thoracis. Spinal postures were similar for sitting on a stable and unstable surface. Significant increases in postural sway were detected (P = .013) in 3 dimensions of movement during sitting on an unstable surface. Gender differences were noted. No EMG amplitude or variance differences were detected between seating conditions. Preliminary data show that sitting on unstable surfaces induces greater spinal motion, but does not significantly alter the lumbosacral posture nor the amount of activity in the superficial trunk muscles under investigation.


The subchondral bone in articular cartilage repair: current problems in the surgical management.
As the understanding of interactions between articular cartilage and subchondral bone continues to evolve, increased attention is being directed at treatment options for the entire osteochondral unit, rather than focusing on the articular surface only. It is becoming apparent that without support from an intact subchondral bed, any treatment of the surface chondral lesion is likely to fail. This article reviews issues affecting the entire osteochondral unit, such as subchondral changes after marrow-stimulation techniques and meniscectomy or large osteochondral defects created by prosthetic resurfacing techniques. Also discussed are surgical techniques designed to address these issues, including the use of osteochondral allografts, autologous bone grafting, next generation cell-based implants, as well as strategies after failed subchondral repair and problems specific to the ankle joint. Lastly, since this area remains in constant evolution, the requirements for prospective studies needed to evaluate these emerging technologies will be reviewed.


Split-signal FISH for detection of chromosome aberrations in acute lymphoblastic leukemia.
Chromosome aberrations are frequently observed in precursor-B-acute lymphoblastic leukemias (ALL) and T-cell acute lymphoblastic leukemias (T-ALL). These translocations can form leukemia-specific chimeric fusion proteins or they can deregulate expression of an (onco)gene, resulting in aberrant expression or overexpression. Detection of chromosome aberrations is an important tool for risk classification. We developed rapid and sensitive split-signal fluorescent in situ hybridization (FISH) assays for six of the most frequent chromosome aberrations in precursor-B-ALL and T-ALL. The split-signal FISH approach uses two differentially labeled probes, located in one gene at opposite sites of the breakpoint region. Probe sets were developed for the genes TCF3 (E2A) at 19p13, MLL at 11q23, ETV6 at 12p13, BCR at 22q11, SIL-TAL1 at 1q32 and TLX3 (HOX11L2) at 5q35. In normal karyotypes, two colocalized green/red signals are visible, but a translocation results in a split of one of the colocalized signals. Split-signal FISH has three main advantages over the classical fusion-signal FISH approach, which uses two labeled probes located in two genes. First, the detection of a chromosome aberration is independent of the involved partner gene. Second, split-signal FISH allows the identification of the partner gene or chromosome region if metaphase spreads are present, and finally it reduces false-positivity.


Feasibility of computed tomography colonography as a diagnostic procedure in colon cancer screening in India.
Computed Tomography Colonography (CTC) is a medical imaging technology used in identifying polyps and colon cancer masses in the large intestine. The technique has evolved a great deal since its invention and has become a routine diagnostic procedure in Western countries due to its non invasiveness and ease of use. The objective of our study was to explore the possibility of CTC application in Indian hospitals. This paper gives an overview of the procedure and its commercial viability. The explanation begins with the domain aspects from gastroenterologist perspective, the new way of thinking in polyp classification, the technical components of CTC procedure, and how engineering solutions have helped clinicians in solving the complexities involved in colon diagnosis. The colon cancer statistics in India and the results of single institution study we carried out with retrospective data is explained. By considering the increasing number of patients developing colon malignancies, the practicality of CTC in Indian hospitals is discussed. This paper does not reveal any technical aspects (algorithms) of engineering solutions implemented in CTC.


Bacterial Transformation of Aromatic Monomers in Softwood Black Liquor.
The valorization of lignin, a major component of plant-derived biomass, is essential to sustainable biorefining. We identified the major monoaromatic compounds present in black liquor, a lignin-rich stream generated in the kraft pulping process, and investigated their bacterial transformation. Among tested solvents, acetone extracted the greatest amount of monoaromatic compounds from softwood black liquor, with guaiacol, vanillin, and acetovanillone, in an approximately 4:3:2 ratio, constituting ~90% of the total extracted monoaromatic content. 4-Ethanol guaiacol, vanillate, and 4-propanol guaiacol were also present. Bacterial strains that grew on minimal media supplemented with the BL extracts at 1mM total aromatic compounds included Pseudomonas putida KT2442, Sphingobium sp. SYK-6, and Rhodococcus rhodochrous EP4. By contrast, the extracts inhibited the growth of Rhodococcus jostii RHA1 and Rhodococcus opacus PD630, strains extensively studied for lignin valorization. Of the strains that grew on the extracts, only R. rhodochrous GD01 and GD02, isolated for their ability to grow on acetovanillone, depleted the major extracted monoaromatics. Genomic analyses revealed that EP4, GD01, and GD02 share an average nucleotide identity (ANI) of 98% and that GD01 and GD02 harbor a predicted three-component carboxylase not present in EP4. A representative carboxylase gene was upregulated ~100-fold during growth of GD02 on a mixture of the BL monoaromatics, consistent with the involvement of the enzyme in acetovanillone catabolism. More generally, quantitative RT-PCR indicated that GD02 catabolizes the BL compounds in a convergent manner via the β-ketoadipate pathway. Overall, these studies help define the catabolic capabilities of potential biocatalytic strains, describe new isolates able to catabolize the major monoaromatic components of BL, including acetovanillone, and facilitate the design of biocatalysts to valorize under-utilized components of industrial lignin streams.


Thermal surface free energy and stress of iron.
Absolute values of surface energy and surface stress of solids are hardly accessible by experiment. Here, we investigate the temperature dependence of both parameters for the (001) and (110) surface facets of body-centered cubic Fe from first-principles modeling taking into account vibrational, electronic, and magnetic degrees of freedom. The monotonic decrease of the surface energies of both facets with increasing temperature is mostly due to lattice vibrations and magnetic disorder. The surface stresses exhibit nonmonotonic behaviors resulting in a strongly temperature dependent excess surface stress and surface stress anisotropy.


Allosuppressor- and allohelper-T cells in acute and chronic graft-vs.-host (GVH) disease. III. Different Lyt subsets of donor T cells induce different pathological syndromes.
Previous work from this laboratory has led to the hypothesis that the stimulatory pathological symptoms of chronic graft-vs.-host disease (GVHD) are caused by alloreactive donor T helper (TH) cells, whereas the suppressive pathological symptoms of acute GVHD are caused by alloreactive T suppressor (TS) cells of the donor. In the present paper we analyzed the Lyt phenotypes of B10 donor T cells required for the induction of either acute or chronic GVHD in H-2-different (B10 X DBA/2)F1 recipients. First, nonirradiated F1 mice were used as the recipients. We found that unseparated B10 T cells induced only a moderate formation of systemic lupus erythematosus (SLE)-like autoantibodies, but a high percentage of lethal GVHD (LGVHD). In contrast, Lyt-1+2- donor T cells were unable to induce LGVHD in these recipients; these cells were capable, however, of inducing a vigorous formation of SLE-like autoantibodies and the formation of severe immune-complex glomerulonephritis. Lyt-1-2+ T cells were incapable of inducing either acute or chronic GVHD. In another experiment, the sensitivity and accuracy of the GVH system were increased by using irradiated F1 mice as recipients and by comparing donor-cell inocula that contained similar numbers of T lymphocytes. In addition, donor-cell inocula were used that had been tested for their allohelper and allosuppressor effects on F1 B cells in vitro. In the irradiated F1 recipients, too, unseparated donor T cells were superior to T cell subsets in inducing LGVHD; Lyt-1-2+ donor cells were completely and Lyt-1+2- donor cells were almost incapable of doing so. In contrast, Lyt-1+2- T cells, but neither unseparated T cells nor Lyt-1-2+ T cells, were capable of inducing a vigorous formation of SLE-like auto-antibodies. We conclude that the stimulatory pathological symptoms of chronic GVHD are caused by Lyt-1+2- allohelper T cells. In contrast, the development of the suppressive pathological symptoms of acute GVHD appears to involve alloreactive Lyt-1+2+ T suppressor cells.


Tumor expressed PTHrP facilitates prostate cancer-induced osteoblastic lesions.
Expression of parathyroid hormone-related protein (PTHrP) correlates with prostate cancer skeletal progression; however, the impact of prostate cancer-derived PTHrP on the microenvironment and osteoblastic lesions in skeletal metastasis has not been completely elucidated. In this study, PTHrP overexpressing prostate cancer clones were stably established by transfection of full length rat PTHrP cDNA. Expression and secretion of PTHrP were verified by western blotting and IRMA assay. PTHrP overexpressing prostate cancer cells had higher growth rates in vitro, and generated larger tumors when inoculated subcutaneously into athymic mice. The impact of tumor-derived PTHrP on bone was investigated using a vossicle co-implant model. Histology revealed increased bone mass adjacent to PTHrP overexpressing tumor foci, with increased osteoblastogenesis, osteoclastogenesis and angiogenesis. In vitro analysis demonstrated pro-osteoclastic and pro-osteoblastic effects of PTHrP. PTHrP enhanced proliferation of bone marrow stromal cells and early osteoblast differentiation. PTHrP exerted a pro-angiogenic effect indirectly, as it increased angiogenesis but only in the presence of bone marrow stromal cells. These data suggest PTHrP plays a role in tumorigenesis in prostate cancer, and that PTHrP is a key mediator for communication and interactions between prostate cancer and the bone microenvironment. Prostate cancer-derived PTHrP is actively involved in osteoblastic skeletal progression.


Factors associated with late-life psychosis in primary care older adults without a diagnosis of dementia.
The epidemiology of late-life psychosis (LLP) remains unclear comparatively to early-onset psychosis. The study aims to estimate the prevalence and incidence of LLP over a 3-year period and examine the correlates of LLP in community-living older adults aged ≥ 65 years recruited in primary care. Study sample included N = 1481 primary care older adults participating in the Étude sur la Santé des Aînés (ESA)-Services study. Diagnoses were obtained from health administrative and self-reported data in the 3 years prior and following baseline interview. The prevalence and incidence of LLP (number of cases) were identified in the 3-year period following interview. Participants with dementia or psychosis related to dementia were excluded. Logistic regressions were used to ascertain the correlates of LLP as function of various individual and health system factors. The 3-year prevalence and incidence of LLP was 4.7% (95% CI = 3.64-5.81) and 2.8% (95% CI = 1.99-3.68), respectively. Factors associated with both prevalent and incident LLP included functional status, number of physical diseases, hospitalizations, continuity of care and physical activity. Older age and the presence of suicidal ideation were associated with incident LLP, while higher education, a depressive disorder and a history of sexual assault were associated with persistent cases. Results highlight the importance of LLP in primary care older adult patients without dementia. Health system factors were consistent determinants of prevalent and incident LLP, suggesting the need for better continuity of care in at-risk primary care older adults.


Clinical manifestations of orbital mass lesions at the Jules Stein Eye Institute, 1999-2003.
To describe the clinical manifestations, diagnoses, treatments, and outcomes of orbital mass lesions at a tertiary care referral center. All cases of newly diagnosed or referred orbital tumors at the Jules Stein Eye Institute from 1999 to 2003 were reviewed retrospectively. Demographic and clinical data were extracted from the electronic oculoplastics registry of the Division of Orbital and Ophthalmic Plastic Surgery. Three hundred sixty-nine cases of orbital mass lesions were evaluated (167 males and 202 females; mean age = 48 years). The most common presenting symptoms were mass/proptosis, pain, swelling, inflammation, and diplopia. The most common categories of diagnosis were cystic or structural lesions, benign tumors, inflammatory processes, neuronal processes, and fibrous processes. Increasing age was associated with an increased incidence of primary and metastatic malignant tumors. Half of all cases required surgical intervention consisting of excision, debulking, or exenteration; 20% to 30% of cases were managed conservatively. The differential diagnosis of orbital mass lesions differs across age groups. No clinical sign or symptom is specific for the underlying diagnosis and the biological behavior of the abnormal process may be misleading. Therefore, a careful diagnostic approach that considers the benefit of imaging studies must be undertaken. Almost 50% of these mass lesions can be managed with nonsurgical intervention.


Tardive dyskinesia and diabetes mellitus.
Two studies examine the prevalence of tardive dyskinesia (TD) in neuroleptic-treated diabetic patients. Study 1 compared 38 diabetic patients with 38 nondiabetic patients treated for psychotic disorders with low to moderate doses of neuroleptics (mean chlorpromazine equivalents = 300 mg/day) for an average of 18 years. Study 2 compared 24 diabetic and 27 nondiabetic patients treated for an average of 2.6 years with a mean 31 mg/day of metoclopramide for gastrointestinal disease. Patients were examined for TD using standardized scales by raters blind to all treatment and illness variables. In both studies, there were no differences between the diabetic and nondiabetic groups in age, sex, type of psychiatric illness, and dose and duration of neuroleptic treatment or severity of parkinsonism. In both studies, the diabetic patients had significantly greater prevalence and severity of TD. No measures of diabetes severity were associated with TD in either study. Possible pathophysiologic mechanisms for the increased prevalence of TD in neuroleptic-treated patients with diabetes will be discussed.


Phosphorylation by casein kinase 2 regulates Nap1 localization and function.
In Saccharomyces cerevisiae, the evolutionarily conserved nucleocytoplasmic shuttling protein Nap1 is a cofactor for the import of histones H2A and H2B, a chromatin assembly factor and a mitotic factor involved in regulation of bud formation. To understand the mechanism by which Nap1 function is regulated, Nap1-interacting factors were isolated and identified by mass spectrometry. We identified several kinases among these proteins, including casein kinase 2 (CK2), and a new bud neck-associated protein, Nba1. Consistent with our identification of the Nap1-interacting kinases, we showed that Nap1 is phosphorylated in vivo at 11 sites and that Nap1 is phosphorylated by CK2 at three substrate serines. Phosphorylation of these serines was not necessary for normal bud formation, but mutation of these serines to either alanine or aspartic acid resulted in cell cycle changes, including a prolonged S phase, suggesting that reversible phosphorylation by CK2 is important for cell cycle regulation. Nap1 can shuttle between the nucleus and cytoplasm, and we also showed that CK2 phosphorylation promotes the import of Nap1 into the nucleus. In conclusion, our data show that Nap1 phosphorylation by CK2 appears to regulate Nap1 localization and is required for normal progression through S phase.


Dynamical fluxionality, multiplicity of structural forms, and electronic properties of the B3Si11 cluster: anion photoelectron spectroscopy and theoretical calculations.
The geometrical structures and electronic properties of anionic, neutral, and cationic B3Si11 clusters were investigated by performing ab initio calculations combined with size-selected anion photoelectron spectroscopy. The experimental photoelectron spectrum of the B3Si11- anion is reasonably reproduced by theoretical simulations of two competing isomers. The global minimum of the B3Si11- anion is formed by the fusion of a B3Si7 bicapped tetragonal antiprism to a B3Si4 pentagonal bipyramid by sharing a B3 triangle, while that of neutral B3Si11 has a B3-endohedral sandwich structure composed of a Si5 five-membered ring and a Si6 six-membered ring, and that of the B3Si11+ cation adopts a Si11 tricapped tetragonal antiprism with three face-capping B atoms. It is interesting that a Si5 five-membered ring and a Si6 six-membered ring are stabilized by three B atoms in B3Si11. The three B atoms tend to bond with each other to form a B3 triangle with stronger B-B bonds than B-Si bonds. Moreover, neutral B3Si11 exhibits σ + π double delocalized bonding patterns. Anionic, neutral, and cationic B3Si11 clusters have multiplicity of structural forms and their low-lying isomers show dynamical fluxionality. The bond lengths, bond orders, MO, constant electronic charge density surfaces, and PDOS analyses showed that the three B atoms in B3Si11 have strong bonding interactions.


Differential determinants for coupling of distinct G proteins with the class B secretin receptor.
The secretin receptor is a prototypic class B G protein-coupled receptor that is activated by binding of its natural peptide ligand. The signaling effects of this receptor are mediated by coupling with Gs, which activates cAMP production, and Gq, which activates intracellular calcium mobilization. We have explored the molecular basis for the coupling of each of these G proteins to this receptor using systematic site-directed mutagenesis of key residues within each of the intracellular loop regions, and studying ligand binding and secretin-stimulated cAMP and calcium responses. Mutation of a conserved histidine in the first intracellular loop (H157A and H157R) markedly reduced cell surface expression, resulting in marked reduction in cAMP and elimination of measurable calcium responses. Mutation of an arginine (R153A) in the first intracellular loop reduced calcium, but not cAMP responses. Mutation of a dibasic motif in the second intracellular loop (R231A/K232A) had no significant effects on any measured responses. Mutations in the third intracellular loop involving adjacent lysine and leucine residues (K302A/L303A) or two arginine residues separated by a leucine and an alanine (R318A/R321A) significantly reduced cAMP responses, while the latter also reduced calcium responses. Additive effects were elicited by combining the effective mutations, while combining all the effective mutations resulted in a construct that continued to bind secretin normally, but that elicited no significant cAMP or calcium responses. These data suggest that, while some receptor determinants are clearly shared, there are also distinct determinants for coupling with each of these G proteins.


Primary versus early secondary referral to a specialized neurotrauma center in patients with moderate/severe traumatic brain injury: a CENTER TBI study.
Prehospital care for patients with traumatic brain injury (TBI) varies with some emergency medical systems recommending direct transport of patients with moderate to severe TBI to hospitals with specialist neurotrauma care (SNCs). The aim of this study is to assess variation in levels of early secondary referral within European SNCs and to compare the outcomes of directly admitted and secondarily transferred patients. Patients with moderate and severe TBI (Glasgow Coma Scale < 13) from the prospective European CENTER-TBI study were included in this study. All participating hospitals were specialist neuroscience centers. First, adjusted between-country differences were analysed using random effects logistic regression where early secondary referral was the dependent variable, and a random intercept for country was included. Second, the adjusted effect of early secondary referral on survival to hospital discharge and functional outcome [6 months Glasgow Outcome Scale Extended (GOSE)] was estimated using logistic and ordinal mixed effects models, respectively. A total of 1347 moderate/severe TBI patients from 53 SNCs in 18 European countries were included. Of these 1347 patients, 195 (14.5%) were admitted after early secondary referral. Secondarily referred moderate/severe TBI patients presented more often with a CT abnormality: mass lesion (52% vs. 34%), midline shift (54% vs. 36%) and acute subdural hematoma (77% vs. 65%). After adjusting for case-mix, there was a large European variation in early secondary referral, with a median OR of 1.69 between countries. Early secondary referral was not associated with functional outcome (adjusted OR 1.07, 95% CI 0.78-1.69), nor with survival at discharge (1.05, 0.58-1.90). Across Europe, substantial practice variation exists in the proportion of secondarily referred TBI patients at SNCs that is not explained by case mix. Within SNCs early secondary referral does not seem to impact functional outcome and survival after stabilisation in a non-specialised hospital. Future research should identify which patients with TBI truly benefit from direct transportation.