Depressive symptomatology and mental health help-seeking patterns of U.S.- and foreign-born mothers.
This report presents the national estimates of maternal depressive symptomatology prevalence and its socio-demographic correlates among major racial/ethnic-nativity groups in the United States. We also examined the relationship of mental health-seeking patterns by race/ethnicity and nativity. Using the Early Childhood Longitudinal Survey-Birth Cohort Nine-month data, we present the distribution of Center for Epidemiological Study-Depression (CES-D) score by new mothers' nativity and race/ethnicity. The mental health-seeking pattern study was limited to mothers with moderate to severe symptoms. Weighted prevalence and 95% confidence intervals for depression score categories were presented by race/ethnic groups and nativity. Multi-variable logistic regression was used to obtain the adjusted odds ratios of help-seeking patterns by race/ethnicity and nativity in mothers with moderate to severe symptoms. Compared to foreign-born mothers, mothers born in the U.S. were more likely to have moderate to severe depressive symptoms in every racial/ethnic group except for Asian/Pacific Islanders. These US-born mothers were also more likely to be teenagers, lack a partner at home, and live in rural areas. Among Asians, Filipina mothers had the highest rate of severe depressive symptoms (9.6%), similar to those of US-born black mothers (10.2%). Racial/ethnic minorities and foreign-born mothers were less likely to consult doctors (OR: 2.2 to 2.5) or think they needed consultation (OR: 1.9 to 2.2) for their emotional problems compare to non-Hispanic White mothers. Our research suggests that previous "global estimates" on Asian American mental health underestimated sub-ethnic group differences. More efforts are needed to overcome the barriers in mental health services access and utilizations, especially in minority and foreign-born populations.


How does patient-clinician information engagement influence self-reported cancer-related problems?: findings from a longitudinal analysis.
Past research has linked patient-physician communication with improved emotional, physical, and social health. One component of communication, patient-clinician information engagement (PCIE), predicts improved short-term patient-reported outcomes, such as treatment satisfaction, through perceptions of feeling informed. However, to the authors' knowledge, the relation between PCIE and longer term cancer-related problems has not been examined previously. The authors examined the influence of PCIE on self-reported problems associated with cancer diagnosis and treatment based on a longitudinal survey among a randomly selected sample from the 2005 Pennsylvania Cancer Registry. In total, 1293 respondents were surveyed who were diagnosed with colorectal, breast, or prostate cancers during 2006 and 2007. The baseline response rate was 64%, and the retention rate was 65%. The authors predicted an index of cancer-related problems at 1-year follow-up with the baseline cancer-related problem index and PCIE, controlling for demographic and clinical factors using regression analyses. The mean age of participants was 65 years, approximately 50% were women, and 86% were white. Having more cancer-related problems and PCIE at baseline significantly predicted more cancer-related problems at follow-up. In addition, baseline cancer-related problems and PCIE interacted significantly (P = .01): PCIE was associated with more cancer-related problems at follow-up among participants who reported more symptoms rather than fewer symptoms at baseline. If respondents reported engaging more with their physicians at baseline, then they reported experiencing more cancer-related issues at follow-up; this pattern was stronger among those who reported more baseline problems. The current results indicated that increased discussion of cancer information with physicians may maintain the salience of these problems in cancer survivors' minds over time.


Reliability of serum hormones in premenopausal and postmenopausal women over a one-year period.
Serum hormones have been intensively investigated in association with several chronic diseases, but limited information exists on the reliability of a number of hormone determinations. The one-year reproducibility of dehydroepiandrosterone sulfate (DHEAS), total and free testosterone, total estradiol, insulin, C-peptide, and prolactin was studied in 60 premenopausal and 47 postmenopausal women recruited in Varese province, Italy, 1991-1992. The hormonal determinations were made in blood samples collected twice, one year apart, after 12-h fast, in the same month, day, and hour and for premenopausal women on the same day of the luteal phase of the menstrual cycle. Samples from the first drawing were stored at -80 degrees C. Samples from both drawings were assayed simultaneously and in blind fashion. Total estradiol in postmenopause was not evaluated for limitation in the sensitivity of the laboratory method. The intraclass correlation coefficient in premenopausal women was 0.85 for DHEAS, 0.60 for total testosterone, 0.66 for free testosterone, 0.81 for insulin, 0.83 for C-peptide, 0.40 for prolactin, and 0.06 for total estradiol. In postmenopausal women, the coefficient was 0.90 for DHEAS, 0.88 for total testosterone, 0.71 for free testosterone, 0.67 for insulin, 0.73 for C-peptide, and 0.18 for prolactin. These data indicate that total estradiol measured during the luteal phase has a poor intraindividual reproducibility over time, and these findings may have important implications in studies of hormones in the etiology of chronic disease.


Impact of cycling cells and cell cycle regulation on Hydra regeneration.
Hydra tissues are made from three distinct populations of stem cells that continuously cycle and pause in G2 instead of G1. To characterize the role of cell proliferation after mid-gastric bisection, we have (i) used flow cytometry and classical markers to monitor cell cycle modulations, (ii) quantified the transcriptomic regulations of 202 genes associated with cell proliferation during head and foot regeneration, and (iii) compared the impact of anti-proliferative treatments on regeneration efficiency. We confirm two previously reported events: an early mitotic wave in head-regenerating tips, when few cell cycle genes are up-regulated, and an early-late wave of proliferation on the second day, preceded by the up-regulation of 17 cell cycle genes. These regulations appear more intense after mid-gastric bisection than after decapitation, suggesting a position-dependent regulation of cell proliferation during head regeneration. Hydroxyurea, which blocks S-phase progression, delays head regeneration when applied before but not after bisection. This result is consistent with the fact that the Hydra central region is enriched in G2-paused adult stem cells, poised to divide upon injury, thus forming a necessary constitutive pro-blastema. However a prolonged exposure to hydroxyurea does not block regeneration as cells can differentiate apical structures without traversing S-phase, and also escape in few days the hydroxyurea-induced S-phase blockade. Thus Hydra head regeneration, which is a fast event, is highly plastic, relying on large stocks of adult stem cells paused in G2 at amputation time, which immediately divide to proliferate and/or differentiate apical structures even when S-phase is blocked.


Evidence for multiple signaling pathways in single squid olfactory receptor neurons.
At least two different G-protein-mediated transduction cascades, the adenylate cyclase and phospholipase C (PLC) pathway, process chemosensory stimuli for various species. In squid olfactory receptor neurons (ORNs), physiological studies indicate that both pathways may be present; however, confirmation of the transduction molecules at the protein level is absent. Here we provide evidence that the G-proteins involved in both adenylate cyclase and PLC pathways are present in squid ORNs (Lolliguncula brevis). We used immunoblotting to show that Galpha(olf), Galpha(q), and a downstream effector, enzyme PLC140, are present in the squid olfactory epithelium (OE). To localize these proteins to one or more of the five morphological cell types described for squid OE, paraformaldehyde-fixed olfactory organs were cryosectioned (10 microm), double-labeled for Galpha(olf), Galpha(q), or PLC140, and imaged. Analysis of serial sections from entire olfactory organs for epithelial area and patterns of immunofluorescence revealed a region of highest immunoreactivity at the anterior half of the organ. At the cellular level, type 1 cells could not be distinguished morphologically and were not included in the analysis. The three labeling patterns observed in type 2 cells were Galpha(q) alone, PLC140 alone, and colocalization of Galpha(q) and PLC140. Subsets of cell types 3, 4, and 5 showed colocalization of Galpha(olf) with Galpha(q) but not with PLC140. These data suggest that the PLC pathway predominates in type 2 cells; however, coexpression of Galpha(olf) with Galpha(q) in cell types 3, 4, and 5 suggests that both pathways may participate in olfactory transduction in non-type 2 squid ORNs.


Computational Study of Quasi-2D Liquid State in Free Standing Platinum, Silver, Gold, and Copper Monolayers.
Recently, freestanding atomically thick Fe metal patches up to 10 atoms wide have been fabricated experimentally in tiny pores in graphene. This concept can be extended conceptually to extended freestanding monolayers. We have therefore performed ab initio molecular dynamics simulations to evaluate the early melting stages of platinum, silver, gold, and copper freestanding metal monolayers. Our calculations show that all four freestanding monolayers will form quasi-2D liquid layers with significant out-of-plane motion and diffusion in the plane. Remarkably, we observe a 4% reduction in the Pt most likely bond length as the system enters the liquid state at 2400 K (and a lower effective spring constant), compared to the system at 1200 and 1800 K. We attribute this to the reduced average number of bonds per atom in the Pt liquid state. We used the highly accurate and reliable Density Functional Theory (DFT-D) method that includes dispersion corrections. These liquid states are found at temperatures of 2400 K, 1050 K, 1600 K, and 1400 K for platinum, silver, gold, and copper respectively. The pair correlation function drops in the liquid state, while the bond orientation order parameter is reduced to a lesser degree. Movies of the simulations can be viewed online (see Supplementary Material).


1-deoxynojirimycin inhibits glucose absorption and accelerates glucose metabolism in streptozotocin-induced diabetic mice.
We investigated the role of 1-deoxynojirimycin (DNJ) on glucose absorption and metabolism in normal and diabetic mice. Oral and intravenous glucose tolerance tests and labeled (13)C6-glucose uptake assays suggested that DNJ inhibited intestinal glucose absorption in intestine. We also showed that DNJ down-regulated intestinal SGLT1, Na(+)/K(+)-ATP and GLUT2 mRNA and protein expression. Pretreatment with DNJ (50 mg/kg) increased the activity, mRNA and protein levels of hepatic glycolysis enzymes (GK, PFK, PK, PDE1) and decreased the expression of gluconeogenesis enzymes (PEPCK, G-6-Pase). Assays of protein expression in hepatic cells and in vitro tests with purified enzymes indicated that the increased activity of glucose glycolysis enzymes was resulted from the relative increase in protein expression, rather than from direct enzyme activation. These results suggest that DNJ inhibits intestinal glucose absorption and accelerates hepatic glucose metabolism by directly regulating the expression of proteins involved in glucose transport systems, glycolysis and gluconeogenesis enzymes.


Effect of a fever control protocol-based strategy on ventilator-associated pneumonia in severely brain-injured patients.
Fever is associated with a poor outcome in severely brain-injured patients, and its control is one of the therapies used in this condition. But, fever suppression may promote infection, and severely brain-injured patients are frequently exposed to infectious diseases, particularly ventilator-associated pneumonia (VAP). Therefore, we designed a study to explore the role of a fever control protocol in VAP development during neuro-intensive care. An observational study was performed on severely brain-injured patients hospitalized in a university ICU. The primary goal was to assess whether fever control was a risk factor for VAP in a prospective cohort in which a fever control protocol was applied and in a historical control group. Moreover, the density of VAP incidence was compared between the two groups. The statistical analysis was based on a competing risk model multivariate analysis. The study included 189 brain-injured patients (intervention group, n = 98, and historical control group, n = 91). The use of a fever control protocol was an independent risk factor for VAP (hazard ratio 2.73, 95% confidence interval (1.38, 5.38; P = 0.005)). There was a significant increase in the incidence of VAP in patients treated with a fever control protocol (26.1 versus 12.5 VAP cases per 1000 days of mechanical ventilation). In cases in which a fever control protocol was applied for > 3 days, we observed a higher rate of VAP in comparison with the rate among patients treated for ≤ 3 days. Fever control in brain-injured patients was a major risk factor for VAP occurrence, particularly when applied for > 3 days.


Copayments and physicians visits: A panel data study of Swedish regions 2003-2012.
This paper analyzes how primary care physician visits are affected by the level of copayment in Sweden. We use data between the years 2003-2012 from 21 Swedish health care regions that have the mandate to set their own level of copayment. The copayment per visit varies between €10 and €20 for these years and regions. Our strategy to identify the causal effect and deal with unobserved endogeneity of price changes on physician visits is based on a panel data model using fixed effects to control for region and time and regional-variation in time trends. We cannot reject that the copayment has no statistical or economic effect of significance, and we estimate the "zero effect" with very high precision. In a setting with sub-national regions with autonomy to set co-payments the results points to that the copayment is not an important predictor for the number of health care visits. The result is in line with some previous studies on European data where the range of copayments used tends to be relatively low.


Mycolicibacterium smegmatis, Basonym Mycobacterium smegmatis, Expresses Morphological Phenotypes Much More Similar to Escherichia coli Than Mycobacterium tuberculosis in Quantitative Structome Analysis and CryoTEM Examination.
A series of structome analyses, that is, quantitative and three-dimensional structural analysis of a whole cell at the electron microscopic level, have already been achieved individually in Exophiala dermatitidis, Saccharomyces cerevisiae, Mycobacterium tuberculosis, Myojin spiral bacteria, and Escherichia coli. In these analyses, sample cells were processed through cryo-fixation and rapid freeze-substitution, resulting in the exquisite preservation of ultrastructures on the serial ultrathin sections examined by transmission electron microscopy. In this paper, structome analysis of non pathogenic Mycolicibacterium smegmatis, basonym Mycobacterium smegmatis, was performed. As M. smegmatis has often been used in molecular biological experiments and experimental tuberculosis as a substitute of highly pathogenic M. tuberculosis, it has been a task to compare two species in the same genus, Mycobacterium, by structome analysis. Seven M. smegmatis cells cut into serial ultrathin sections, and, totally, 220 serial ultrathin sections were examined by transmission electron microscopy. Cell profiles were measured, including cell length, diameter of cell and cytoplasm, surface area of outer membrane and plasma membrane, volume of whole cell, periplasm, and cytoplasm, and total ribosome number and density per 0.1 fl cytoplasm. These data are based on direct measurement and enumeration of exquisitely preserved single cell structures in the transmission electron microscopy images, and are not based on the calculation or assumptions from biochemical or molecular biological indirect data. All measurements in M. smegmatis, except cell length, are significantly higher than those of M. tuberculosis. In addition, these data may explain the more rapid growth of M. smegmatis than M. tuberculosis and contribute to the understanding of their structural properties, which are substantially different from M. tuberculosis, relating to the expression of antigenicity, acid-fastness, and the mechanism of drug resistance in relation to the ratio of the targets to the corresponding drugs. In addition, data obtained from cryo-transmission electron microscopy examination were used to support the validity of structome analysis. Finally, our data strongly support the most recent establishment of the novel genus Mycolicibacterium, into which basonym Mycobacterium smegmatis has been classified.


Does receiving an American Academy of Otolaryngology-Head and Neck Surgery Foundation Centralized Otolaryngology Research Efforts grant influence career path and scholarly impact among fellowship-trained rhinologists?
To determine whether American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNSF) Centralized Otolaryngology Research Efforts (CORE) grants influence career paths and scholarly impact of fellowship-trained rhinologists, and whether funding from the National Institutes of Health (NIH) and CORE programs is associated with increased scholarly impact among rhinologists. Another aim was to explore whether obtaining CORE grant funding is associated with NIH award acquisition. Practice setting, academic rank, and fellowship-training status were determined for individuals in the CORE grant database. The h-index and publication experience of practitioners was calculated using the Scopus database. Faculty listings were used to determine this data for a non-CORE-grants-funded "control" group of academic rhinologists. Active and past NIH funding was obtained using the NIH RePORTER database. Fifteen of 26 (57.7%) fellowship-trained rhinologists receiving CORE grants were funded for rhinologic projects. Five of 6 rhinologists receiving NIH funding had a CORE-grants-funding history. Twenty-two of 26 (84.6%) rhinologists receiving CORE funding are currently in academic practice. Academic rhinologists receiving CORE or NIH funding had higher h-indices, a result reaching significance among promoted faculty and those with greater than 10 years of publication experience. Encouraging the pursuit of CORE grants among junior faculty as well as trainees interested in rhinology may be a strategy for developing highly effective research habits that pay dividends after the first few years of one's career. Fellowship-trained rhinologists with a CORE funding history predominantly pursue careers in academic medicine, although their CORE projects are not necessarily related to rhinologic topics.


The protective effect of neighborhood composition on increasing frailty among older Mexican Americans: a barrio advantage?
Little is known about the nature of the frailty syndrome in older Hispanics who are projected to be the largest minority older population by 2050. The authors examine prospectively the relationship between medical, psychosocial, and neighborhood factors and increasing frailty in a community-dwelling sample of Mexican Americans older than 75 years. Based on a modified version of the Cardiovascular Health Study Frailty Index, the authors examine 2-year follow-up data from the Hispanic Established Populations for Epidemiologic Studies of the Elderly (H-EPESE) to ascertain the rates and determinants of increasing frailty among 2,069 Mexican American adults 75+ years of age at baseline. Respondents at risk of increasing frailty live in a less ethnically dense Mexican-American neighborhood, are older, do not have private insurance or Medicare, have higher levels of medical conditions, have lower levels of cognitive functioning, and report less positive affect. Personal as well as neighborhood characteristics confer protective effects on individual health in this representative, well-characterized sample of older Mexican Americans. Potential mechanisms that may be implicated in the protective effect of ethnically homogenous communities are discussed.


Superficial paramucosal clear cell sarcoma of the soft parts resembling melanoma in a 13-year-old boy.
Clear cell sarcoma (CCS) of tendons and aponeuroses, also known as melanoma of soft parts, represents an aggressive rare malignancy that is characterized by a nested or fascicular pattern of spindled cells and a pathognomonic reciprocal translocation, t(12;22)(q13;q12), that results in the fusion of EWSR1 and ATF1 genes. Numerous recent studies have recognized the importance of a cutaneous CCS variant that can mimic a broad spectrum of entities, including spindle cell melanoma, spindle cell squamous carcinoma, cutaneous leiomyosarcoma and atypical fibroxanthoma. We report a case of a 13-year-old boy with cutaneous CCS who presented with a few months history of an asymptomatic papule on the lower lip that was suggestive of a mucocele. Biopsy of the lesion showed a wedge shaped neoplasm arranged in nests and fascicles of epithelioid- to oval-shaped cells with pale cytoplasm, open chromatin and prominent nucleolus. The superficial component was closely opposed to the basal epithelium resembling the junctional nests of a melanocytic neoplasm. The process extended into and involved the striated muscle of the lip. The cells expressed S-100, CD99 and synaptophysin by immunohistochemistry, and there was focal HMB-45 and microphthalmia transcription factor (MiTF) positivity as well. Fluorescence in situ hybridization confirmed the presence of the t(12;22) (ESWR1-ATF1) translocation.


The role of particle physico-chemical properties in pulmonary drug delivery for tuberculosis therapy.
There is increasing interest in the use of inhaled aerosol drug therapy for the treatment of tuberculosis (TB). A number of methods of preparation of particles have been employed including spray drying, solvent evaporation, emulsion and phospholipid methods to create microparticles, macroaggregated nanoparticles, solid lipid nanoparticles and liposomes. Each of these methods involves the use of different proportions of additives to aid in the particle formation or to achieve important physico-chemical properties such as ease of dispersion. While these approaches all have merit their practical value is limited by constraints on dose and means of delivery as an aerosol in order to achieve a therapeutic effect. A review of a number of approaches is presented and placed in the context of the need for effective aerosol delivery systems for the treatment of TB as a guide to selection of appropriate excipients, processes and delivery strategies to support product development activities.


Super-resolution fusion of complementary panoramic images based on cross-selection kernel regression interpolation.
A complementary catadioptric imaging technique was proposed to solve the problem of low and nonuniform resolution in omnidirectional imaging. To enhance this research, our paper focuses on how to generate a high-resolution panoramic image from the captured omnidirectional image. To avoid the interference between the inner and outer images while fusing the two complementary views, a cross-selection kernel regression method is proposed. First, in view of the complementarity of sampling resolution in the tangential and radial directions between the inner and the outer images, respectively, the horizontal gradients in the expected panoramic image are estimated based on the scattered neighboring pixels mapped from the outer, while the vertical gradients are estimated using the inner image. Then, the size and shape of the regression kernel are adaptively steered based on the local gradients. Furthermore, the neighboring pixels in the next interpolation step of kernel regression are also selected based on the comparison between the horizontal and vertical gradients. In simulation and real-image experiments, the proposed method outperforms existing kernel regression methods and our previous wavelet-based fusion method in terms of both visual quality and objective evaluation.


Organismal traits are more important than environment for species interactions in the intertidal zone.
Species interactions come in a variety of forms, from weak to strong, and negative or positive, each with unique consequences for local community structure. However, interactions depend on several biotic, abiotic and scale-dependent variables that make their magnitude and direction difficult to predict. Here, we quantify the relative impacts of multiple factors on species interactions for a diverse array of intertidal organisms, using our own experiments across a range of environments in New Zealand and North America. Interaction strengths are related to organism body size and trophic level, but are relatively insensitive to environmental conditions associated with tidal height. Although species at higher trophic levels exert stronger per-capita effects on other taxa, their population-level impacts are equivalent to basal trophic groups. This indicates that interaction intensity is largely based on requirements for resources, such as food or space, that follow allometric scaling rules. These results demonstrate the potential to predict interactivity based on simple criteria without detailed information on particular species or communities.


Nucleotide sequences and functions of the Epstein-Barr virus latent membrane protein 1 genes isolated from salivary gland lymphoepithelial carcinomas.
Epstein-Barr virus (EBV) infection is associated with salivary gland lymphoepithelial carcinoma (SLEC) and nasopharyngeal carcinoma (NPC). EBV is a ubiquitous herpes virus world wide, but EBV-associated SLEC and NPC are prevalent in restricted regions such as south areas of China, Southeastern Asia and Greenland (Eskimos). To examine whether particular EBV variants play roles in the development of SLEC and NPC, we isolated the complete EBV LMP1 genes from 12 paraffin-embedded biopsy samples of SLECs isolated from China, Taiwan and Russia, and compared these LMP1 genes with those of NPC (CAO) and the prototype B95-8 EBV. Nucleotide sequence analysis showed that SLECs LMP1 is more similar to that of CAO than that of prototype B95-8. The analysis also identified several conserved (67-100%) variations in SLEC-LMP1 and CAO-LMP1 distinct from B95-8-LMP1. These included 10-amino acid deletion, 5-amino acid deletion and 12-single amino acid variations. A SLEC-LMP1 gene with the aforementioned conserved variations inhibited the growth of an embryonic kidney cell line (293T), highly activated the NF-kappaB pathway, and these activities were equivalent to those of B95-8 and CAO. These findings suggest that the biological functions of SLEC-LMP 1 are similar to those of B95-8-LMP1 and CAO-LMP1, and that these amino acid variations including the well-known 10-aa deletion did not affect these two prominent activities. While the present results could not uncover functional differences between SLEC-LMP1 and B95-8-LMP1, the nucleotide sequences and the molecular clone of LMP1 directly isolated from SLEC patients will be a useful tool to identify the high-pathogenic EBV strain(s), associated with SLEC and NPC.


High mobility group box-1 (HMGB-1) in osteoarthritic cartilage.
Nucleosomal high mobility group box-1 (HMGB-1) is translocated and released from necrotic and activated cells as an endogenous danger signal (alarmin) and cytokine. It was hypothesised that it plays a role in osteoarthritis (OA). characterised by cellular activation, inflammation and enchondral bone formation. Bovine knee joint samples, collected from culled animals, were scored using histologic/histochemical grading to intact looking, mild, moderate or severe and immunohistochemically stained for HMGB-1. Chondrocyte pellets, produced from human bone marrow-derived mesenchymal stem cells and stimulated with tumour necrosis factor-a (TNF-alpha), were similarly stained. In healthy looking OA cartilage chondrocyte nuclei were usually HMGB-1 negative and in mild OA staining was restricted to nuclei. In moderate OA lesions HMGB-1 was also seen in the cytoplasm and occasionally pericellular matrix and in severe OA lesions often also in intra- and inter-territorial matrix. The tidemark in healthy cartilage did not contain HMGB-1, which however was seen at this interface as linear deposits even in intact-looking and mild OA lesions, as multiple wave-like deposits in moderate and as heavy granular deposits in severe lesions. TNF-alpha stimulation of chondrocytes caused translocation of HMGB-1 from the nucleus to the cytoplasm. In resting chondrocytes tight nucleosomal HMGB-1 binding might cause steric hindrance of immunostaining. TNF-alpha- or OA-mediated activation leads to nuclear staining and cytoplasmic translocation. Advancing OA leads to increasingly intense extra-/pericellular deposition of HMGB-1 alarmin, indicating local chondrocyte activation and/or necrosis. In particular, HMGB-1 at the tidemark might play a role in the pathological thickening of subchondral bone plate/osteophyte formation.


Intra-individual effects of food upon the pharmacokinetics of rifampicin and isoniazid.
Poor response to TB therapy might be attributable to subtherapeutic levels in drug-compliant patients. Pharmacokinetic parameters can be affected by comorbidities or the interaction of drugs with food. This study aimed to determine the effect of food intake upon pharmacokinetics of rifampicin and isoniazid in a Peruvian population with TB. Rifampicin and isoniazid levels were analysed at 2, 4 and 6 h after drug intake in both fasting and non-fasting states using LC-MS methods. Sixty patients participated in the study. The median rifampicin Cmax and AUC0-6 were higher during fasting than non-fasting: 7.02 versus 6.59 mg/L (P = 0.054) and 28.64 versus 24.31 mg·h/L (P = 0.002). There was a statistically significant delay overall of non-fasting Tmax compared with the fasting state Tmax (P = 0.005). In the multivariate analysis, besides the effect of fasting, Cmax for females was 20% higher than for males (P = 0.03). Concerning isoniazid, there were significant differences in the Cmax during non-fasting (median = 3.51 mg/L) compared with fasting (4.54 mg/L). The isoniazid dose received had an effect upon the isoniazid levels (1.26, P = 0.038). In the multivariate analysis, isoniazid exposure during fasting was found to be 14% higher than during non-fasting (CI = 1.02-1.28, P < 0.001). Neither radiological extent of the disease nor consumption of food with drug intake nor pharmacokinetics of rifampicin or isoniazid was associated with a poorer treatment outcome. Rifampicin in particular and isoniazid pharmacokinetics were significantly affected by the intake of the drug with food between and within individuals.


A Comprehensive Subcellular Proteomic Survey of Salmonella Grown under Phagosome-Mimicking versus Standard Laboratory Conditions.
Towards developing a systems-level pathobiological understanding of Salmonella enterica, we performed a subcellular proteomic analysis of this pathogen grown under standard laboratory and phagosome-mimicking conditions in vitro. Analysis of proteins from cytoplasmic, inner membrane, periplasmic, and outer membrane fractions yielded coverage of 25% of the theoretical proteome. Confident subcellular location could be assigned to over 1000 proteins, with good agreement between experimentally observed location and predicted/known protein properties. Comparison of protein location under the different environmental conditions provided insight into dynamic protein localization and possible moonlighting (multiple function) activities. Notable examples of dynamic localization were the response regulators of two-component regulatory systems (e.g., ArcB and PhoQ). The DNA-binding protein Dps that is generally regarded as cytoplasmic was significantly enriched in the outer membrane for all growth conditions examined, suggestive of moonlighting activities. These observations imply the existence of unknown transport mechanisms and novel functions for a subset of Salmonella proteins. Overall, this work provides a catalog of experimentally verified subcellular protein locations for Salmonella and a framework for further investigations using computational modeling.


Effects of Diaphragmatic Breathing on the Pathophysiology and Treatment of Upright Gastroesophageal Reflux: A Randomized Controlled Trial.
Uncontrolled results suggest that diaphragmatic breathing (DB) is effective in gastroesophageal reflux disease (GERD) but the mechanism of action and rigor of proof is lacking. This study aimed to determine the effects of DB on reflux, lower esophageal sphincter (LES), and gastric pressures in patients with upright GERD and controls. Adult patients with pH proven upright GERD were studied. During a high-resolution impedance manometry, study patients received a standardized pH neutral refluxogenic meal followed by LES challenge maneuvers (Valsalva and abdominal hollowing) while randomized to DB or sham. After that, patients underwent 48 hours of pH-impedance monitoring, with 50% randomization to postprandial DB during the second day. On examining 23 patients and 10 controls, postprandial gastric pressure was found to be significantly higher in patients compared with that in controls (12 vs 7 mm Hg, P = 0.018). Valsalva maneuver produced reflux in 65.2% of patients compared with 44.4% of controls (P = 0.035). LES increased during the inspiratory portion of DB (42.2 vs 23.1 mm Hg, P < 0.001) in patients and healthy persons. Postprandial DB reduced the number of postprandial reflux events in patients (0.36 vs 2.60, P < 0.001) and healthy subjects (0.00 vs 1.75, P < 0.001) compared with observation. During 48-hour ambulatory study, DB reduced the reflux episodes on day 2 compared with observation on day 1 in both the patient and control groups (P = 0.049). In patients, comparing DB with sham, total acid exposure on day 2 was not different (10.2 ± 7.9 vs 9.4 ± 6.2, P = 0.804). In patients randomized to DB, esophageal acid exposure in a 2-hour window after the standardized meal on day 1 vs day 2 reduced from 11.8% ±6.4 to 5.2% ± 5.1, P = 0.015. In patients with upright GERD, DB reduces the number of postprandial reflux events pressure by increasing the difference between LES and gastric pressure. These data further encourage studying DB as therapy for GERD.


Studies on the antibodies in rabbit antisera responsible for sensitization of human skin. I. The role of impurities in crystalline egg albumin in stimulating the production of skin-sensitizing antibody.
The capacity of rabbit anti-egg albumin sera to sensitize human skin has been studied. It has been shown that passive transfer by these sera is completely unrelated to the egg albumin-anti-egg albumin system, as demonstrated by a failure of passive transfer by some antisera containing ample anti-egg albumin and persistence of passive transfer in other antisera from which all anti-egg albumin had been removed by precipitation with homologous antigen. Three preparations of non-precipitating anti-egg albumin have been shown to have sensitizing capacities which bear no relation to their non-precipitating anti-egg albumin contents. From a portion of one of these the non-precipitating anti-egg albumin was removed without impairing its sensitizing ability, while in another portion obliteration of the sensitizing capacity was accomplished without reducing the anti-egg albumin. Evidence is presented to show that there are at least two possible antibodies in anti-egg albumin sera which are capable of inducing skin sensitivity and that they are antibodies against egg white impurities in crystalline egg albumin other than anti-conalbumin, anti-ovomucoid, and anti-lysozyme. The usefulness of a suitable quantitative precipitin technic for the analysis for antibodies against antigen impurities and for their selective absorption from sera is illustrated. The principle governing the procedure is described. The technic allows for the determination of a given trace antibody by working with such small concentrations of its purified specific antigen that whatever other antigen-antibody compounds are formed simultaneously with that to be determined will be below their solubility levels and consequently will not contribute appreciably to the precipitate.


Personalized logical models to investigate cancer response to BRAF treatments in melanomas and colorectal cancers.
The study of response to cancer treatments has benefited greatly from the contribution of different omics data but their interpretation is sometimes difficult. Some mathematical models based on prior biological knowledge of signaling pathways facilitate this interpretation but often require fitting of their parameters using perturbation data. We propose a more qualitative mechanistic approach, based on logical formalism and on the sole mapping and interpretation of omics data, and able to recover differences in sensitivity to gene inhibition without model training. This approach is showcased by the study of BRAF inhibition in patients with melanomas and colorectal cancers who experience significant differences in sensitivity despite similar omics profiles. We first gather information from literature and build a logical model summarizing the regulatory network of the mitogen-activated protein kinase (MAPK) pathway surrounding BRAF, with factors involved in the BRAF inhibition resistance mechanisms. The relevance of this model is verified by automatically assessing that it qualitatively reproduces response or resistance behaviors identified in the literature. Data from over 100 melanoma and colorectal cancer cell lines are then used to validate the model's ability to explain differences in sensitivity. This generic model is transformed into personalized cell line-specific logical models by integrating the omics information of the cell lines as constraints of the model. The use of mutations alone allows personalized models to correlate significantly with experimental sensitivities to BRAF inhibition, both from drug and CRISPR targeting, and even better with the joint use of mutations and RNA, supporting multi-omics mechanistic models. A comparison of these untrained models with learning approaches highlights similarities in interpretation and complementarity depending on the size of the datasets. This parsimonious pipeline, which can easily be extended to other biological questions, makes it possible to explore the mechanistic causes of the response to treatment, on an individualized basis.


Behavioural responses of dogs to asymmetrical tail wagging of a robotic dog replica.
Recent evidence suggests that bilateral asymmetry in the amplitude of tail wagging of domestic dogs (Canis familiaris) is associated with approach (right wag) versus withdrawal (left wag) motivation and may be the by-product of hemispheric dominance. We consider whether such asymmetry in motion of the tail, a crucial appendage in intra-specific communication in all canids, provides visual information to a conspecific leading to differential behaviour. To evaluate this, we experimentally investigated the approach behaviour of free-ranging dogs to the asymmetric tail wagging of a life-size robotic dog replica. Our data, involving 452 separate interactions, showed a significantly greater proportion of dogs approaching the model continuously without stopping when the tail wagged to the left, compared with a right wag, which was more likely to yield stops. While the results indicate that laterality of a wagging tail provides behavioural information to conspecifics, the responses are not readily integrated into the predicted behaviour based on hemispheric dominance.


[Study of the effects of vinpocetin on cognitive functions].
Chronic cerebral hypoperfusion is a risk factor for the development of certain types of dementia. Mild cognitive impairment is a stage of predementia condition, because the symptoms are similar but not as severe as the symptoms in patients with dementia. Vinpocetine, due to its complex mechanism of action, has an important role in the improvement of chronic cerebral hypoperfusion. The aim of our study was to determine the severity of the cognitive decline and to investigate the efficacy and safety of per os 18 months vinpocetine treatment in patients with mild cognitive impairment. We used psychometrical tests (MMSE, ADAS-Cog) to assess the cognitive functions. CGIC-PGIC was used to evaluate the overall change in the disease status. ADL was used to assess the patient's daily activity and the Hamilton Depression Scale to evaluate the patient's mood. The assessments were performed at six visits during the 18 months treatment period. At the beginning of the treatment, the stage of our patients' mild cognitive impairment was moderately severe. Significant improvement was detected in the psychometrical tests after the 18 months treatment period. The overall status of the disease improved significantly according both to the patient and the investigator. Also significant improvement was detected in daily activity. The complex improvement of the clinical symptoms affected the patients' mood positively. Moreover, vinpocetine was safe and had a good tolerability during the whole study period. Vinpocetine, due its complex mechanism of action, improved significantly the cognitive functions, overall disease status and quality of life in patients with chronic cerebral hypoperfusion. As a result, vinpocetine treatment can be recommended for patients with mild cognitive impairment.


Gamma Knife radiosurgery to the surgical cavity following resection of brain metastases.
This study evaluated the efficacy of postoperative Gamma Knife surgery (GKS) to the tumor cavity following gross-total resection of a brain metastasis. A retrospective review was conducted of 700 patients who were treated for brain metastases using GKS. Forty-seven patients with pathologically confirmed metastatic disease underwent GKS to the postoperative resection cavity following gross-total resection of the tumor. Patients who underwent subtotal resection or who had visible tumor in the resection cavity on the postresection neuroimaging study (either CT or MR imaging with and without contrast administration) were excluded. Radiographic and clinical follow-up was assessed using clinic visits and MR imaging. The radiographic end point was defined as tumor growth control (no tumor growth regarding the resection cavity, and stable or decreasing tumor size for the other metastatic targets). Clinical end points were defined as functional status (assessed prospectively using the Karnofsky Performance Scale) and survival. Primary tumor pathology was consistent with lung cancer in 19 cases (40%), melanoma in 10 cases (21%), renal cell carcinoma in 7 cases (15%), breast cancer in 7 cases (15%), and gastrointestinal malignancies in 4 cases (9%). The mean duration between resection and radiosurgery was 15 days (range 2-115 days). The mean volume of the treated cavity was 10.5 cm3 (range 1.75-35.45 cm3), and the mean dose to the cavity margin was 19 Gy. In addition to the resection cavity, 34 patients (72%) underwent GKS for 116 synchronous metastases observed at the time of the initial radiosurgery. The mean radiographic follow-up duration was 14 months (median 10 months, range 4-37 months). Local tumor control at the site of the surgical cavity was achieved in 44 patients (94%), and tumor recurrence at the surgical site was statistically related to the volume of the surgical cavity (p=0.04). During follow-up, 34 patients (72%) underwent additional radiosurgery for 140 new (metachronous) metastases. At the most recent follow-up evaluation, 11 patients (23%) were alive, whereas 36 patients had died (mean duration until death 12 months, median 10 months). Patients who showed good systemic control of their primary tumor tended to have longer survival durations than those who did not (p=0.004). At the last clinical follow-up evaluation, the mean Karnofsky Performance Scale score for the overall group was 78 (median 80, range 40-100). Radiosurgery appears to be effective in terms of providing local tumor control at the resection cavity following resection of a brain metastasis, and in the treatment of synchronous and metachronous tumors. These data suggest that radiosurgery can be used to prevent recurrence following gross-total resection of a brain metastasis.


Bridging the gap between experimental and non-experimental neuroepidemiology, and ultimately - between neuroepidemiological research and practice: round table discussion at the First International Congress on Clinical Neurology and Epidemiology.
A highlight of the congress was an interactive and inclusive discussion of the existing gaps between clinical neurology and epidemiology and the ways of bridging these gaps. Some perceptions, challenges and scientific issues between experimental and non-experimental neuroepidemiology were brought to light. Recognizing that all study designs have advantages and disadvantages, panelists stressed that studies should aim to complement each other while answering important research- or practice-related questions. Advocated strategies included introducing more epidemiology into the medical school or residency curriculum, developing consistency in the reporting of epidemiological data to improving the strength and utility of the evidence, as well as nurturing collaborations that recognize the usefulness of both experimental and non-experimental epidemiological studies. These strategies will in the end benefit clinical practice. Indeed, clinical knowledge improves with experience and critical scientific evidence that can change perceptions, yet, individualized disease management will probably always remain an art rather than an exact science. Nevertheless, strong epidemiological studies and collaborations can influence government and public health policies. Bridging the gap between neuroepidemiological research and practice - whether through improved communication, education or basic science- is clearly a pressing challenge that requires our concerted and sustained effort.


Seasonality in adult asthma admissions, air pollutant levels, and climate: a population-based study.
Most studies of asthma seasonal variations have not examined associations of environmental risk factors and climatic changes associated with seasonality in asthma hospitalizations. This study used population-based data to examine seasonality in asthma admissions and the associated seasonality in levels of air pollutants and climatic factors during a 4-year period in Taiwan. A total of 126,671 asthma hospitalizations in Taiwan during 1998-2001 operationalized as monthly admissions per 100,000 population and monthly mean levels of criterion air pollutants and meteorological factors were subjected to Auto-Regressive Integrated Moving Average to test for seasonality and association between asthma admission rates and the pollutant and climatic factor levels. Owing to significant differences in seasonality between pediatric and adult age groups, this study was limited to 99,591 adult asthma cases to examine the seasonality issue as related to the criterion air pollutants and climatic factors using Spearman rank correlations. Seasonal trends showed a hospitalization peak in January through March and a sharp decline beginning in April to a trough in June for both sexes. Seasonal variations in adult asthma admissions were significantly positively correlated with levels of PM10, SO2, CO, NO2, and atmospheric pressure and negatively correlated with temperature and hours of sunshine. Adult asthma hospitalization propensity is highest in spring and is significantly correlated with air pollution and climate. Air quality control programs and early public warning systems on pollution and atmospheric factors are needed to enable predisposed individuals and their physicians to preempt attacks through primary and secondary preventive measures.


Rupture of aortic aneurysm with right-sided haemothorax.
A 62-yr-old male with a history of high blood pressure was admitted for persistent dyspnoea and a right-sided pleural effusion, complicated by a recent episode of shock. There was no history of trauma and the patient denied any thoracic pain. A chest tube was inserted which released nonclotting bloody fluid. A thoracic computed tomographic scan of the chest revealed an aneurysm of the inferior third of the descending thoracic aorta. The patient underwent a successful prosthetic graft replacement. We emphasize that rupture of aortic aneurysms should be considered in the evaluation of spontaneous haemothorax even if it is right-sided and not associated with pain.


Emergency Endovascular Interventions for Ruptured Descending Thoracic Aortic Aneurysm.
Ruptured descending thoracic aortic aneurysm (rDAA) is a rare but devastating condition. Open aortic surgery which uses cardiopulmonary bypass is associated with a high mortality. Thoracic endovascular aortic repair (TEVAR) is a less-invasive approach for which it remains unclear whether outcomes are superior or equivalent to open aortic surgery. In this study, we report our early and midterm outcomes with TEVAR for rDAA. This is an observational, retrospective, single-center study which included patients with rDAA and treated by TEVAR. The main objective was the 30-day in-hospital mortality. Secondary end points were 30-day in-hospital morbidity, 2-year mortality, and technical problems encountered during procedures. Twenty-five patients were included: 14 men and 11 women with a median age of 76 years (69-82 years). Thirty-day in-hospital mortality rate was 36% (95% confidence interval [CI], 20.6-57.9; n = 9), and the 2-year mortality rate was 44% (95% CI, 27.94-66.72; n = 11). Fifteen patients (60%) presented at least 1 major complication, and 8 of those patients had a second surgery because of it. There were 9 technical problems encountered that required additional open procedures to successfully deploy the aortic stent graft: lack of vascular access in 2 cases (8%), short proximal neck in 3 cases (12%), and short distal neck in 4 cases (16%). Mortality and morbidity remain high in patients treated for rDAA by TEVAR. Nonetheless, TEVAR remains an interesting alternative to open aortic surgery especially for older patients with a poor general health and functional status.


Moving corner-cube mirror interferometer and reflection characteristic of corner-cube mirror.
A novel moving corner-cube mirror interferometer (MCCMI) is presented. It has neither tilt nor shearing problems. It consists of one moving corner-cube mirror (MCCM), one fixed double-sided mirror (FDSM), one fixed plane mirror, and one beam splitter. The FDSM is a plane-parallel glass plate with both faces coated with high-reflectivity films. The effect of a FDSM tilt is analyzed. The optical path difference (OPD) is created by the straight reciprocating motion of the MCCM, and the OPD value is four times the displacement of the MCCM. The reflection characteristic of the corner-cube mirror (CCM) is analyzed by means of the vector expression, and the formulas of deviation angle of a CCM are derived. The effect of a MCCM deviation angle is analyzed. The new MCCMI is very suitable for high-resolution Fourier-transform infrared spectrometers used for atmospheric sounding.


Conduction aphasia, sensory-motor integration, and phonological short-term memory - an aggregate analysis of lesion and fMRI data.
Conduction aphasia is a language disorder characterized by frequent speech errors, impaired verbatim repetition, a deficit in phonological short-term memory, and naming difficulties in the presence of otherwise fluent and grammatical speech output. While traditional models of conduction aphasia have typically implicated white matter pathways, recent advances in lesions reconstruction methodology applied to groups of patients have implicated left temporoparietal zones. Parallel work using functional magnetic resonance imaging (fMRI) has pinpointed a region in the posterior most portion of the left planum temporale, area Spt, which is critical for phonological working memory. Here we show that the region of maximal lesion overlap in a sample of 14 patients with conduction aphasia perfectly circumscribes area Spt, as defined in an aggregate fMRI analysis of 105 subjects performing a phonological working memory task. We provide a review of the evidence supporting the idea that Spt is an interface site for the integration of sensory and vocal tract-related motor representations of complex sound sequences, such as speech and music and show how the symptoms of conduction aphasia can be explained by damage to this system.


An architectural understanding of natural sway frequencies in trees.
The relationship between form and function in trees is the subject of a longstanding debate in forest ecology and provides the basis for theories concerning forest ecosystem structure and metabolism. Trees interact with the wind in a dynamic manner and exhibit natural sway frequencies and damping processes that are important in understanding wind damage. Tree-wind dynamics are related to tree architecture, but this relationship is not well understood. We present a comprehensive view of natural sway frequencies in trees by compiling a dataset of field measurement spanning conifers and broadleaves, tropical and temperate forests. The field data show that a cantilever beam approximation adequately predicts the fundamental frequency of conifers, but not that of broadleaf trees. We also use structurally detailed tree dynamics simulations to test fundamental assumptions underpinning models of natural frequencies in trees. We model the dynamic properties of greater than 1000 trees using a finite-element approach based on accurate three-dimensional model trees derived from terrestrial laser scanning data. We show that (1) residual variation, the variation not explained by the cantilever beam approximation, in fundamental frequencies of broadleaf trees is driven by their architecture; (2) slender trees behave like a simple pendulum, with a single natural frequency dominating their motion, which makes them vulnerable to wind damage and (3) the presence of leaves decreases both the fundamental frequency and the damping ratio. These findings demonstrate the value of new three-dimensional measurements for understanding wind impacts on trees and suggest new directions for improving our understanding of tree dynamics from conifer plantations to natural forests.


In vivo delivery of DN:REST improves transcriptional changes of REST-regulated genes in HD mice.
Current therapeutic strategies for Huntington's disease (HD) are focused on symptom management of disease progression. Transcriptional dysregulation is one of the major characteristics in HD. REST is a transcriptional repressor that silences gene expression through binding to RE1/NRSE sites found in the regulatory regions of numerous neuronal genes. Dysregulation of REST and its targeted genes has been reported in different cell and mouse HD models, as well as in biopsies from human patients. In this work, we characterized transcriptional dysregulation associated with REST in two different HD mouse models and assessed the therapeutic effect of interfering with REST function by overexpressing a dominant-negative form (DN:REST). We show that delivery of DN:REST in the motor cortex restores brain-derived neurotrophic factor (BDNF) mRNA and protein levels by reducing endogenous REST occupancy at the Bdnf locus. Similarly, expression of other REST-regulated genes such as Synapsin I (Syn1), Proenkephalin (Penk1) and Cholinergic receptor muscarinic 4 (Chrm4) were restored to normal levels while non-REST-regulated genes were unaffected. This is the first study conducted to investigate REST's role in vivo in a neurodegenerative disease. Our data show that DN:REST in motor cortex reversed RESTs repressive effects on target genes. However, the lack of therapeutic effect on motor function suggests that a more widespread rescue of REST-regulated sites in the affected brain regions may be necessary.


PCASTt/SPCG-17-a randomised trial of active surveillance in prostate cancer: rationale and design.
Overtreatment of localised prostate cancer is substantial despite increased use of active surveillance. No randomised trials help define how to monitor patients or when to initiate treatment with curative intent. A randomised, multicentre, intervention trial designed to evaluate the safety of an MRI-based active surveillance protocol, with standardised triggers for repeated biopsies and radical treatment. The aim is to reduce overtreatment of prostate cancer. 2000 men will be randomly allocated to either surveillance according to current practice or to standardised triggers at centres in Sweden, Norway, Finland and the UK. Men diagnosed in the past 12 months with prostate cancer, ≤T2a, prostate-specific antigen (PSA) <15 ng/mL, PSA density ≤0.2 ng/mL/cc, any International Society of Urological Pathology (ISUP) grade 1 are eligible. Men with ISUP grade 2 in <30% of cores on systematic biopsy and <10 mm cancer in one core on systematic or targeted biopsy are also eligible. Men diagnosed on systematic biopsy should have an MRI and targeted biopsies against Prostate Imaging and Reporting Data System V.2 3-5 lesions before inclusion. Identical follow-up in the two study arms: biannual PSA testing, yearly clinical examination and MRI every second year. In the experimental arm, standardised triggers based on MRI and PSA density elicit repeated biopsies. MRI and histopathological progression trigger radical treatment. Primary outcome measure is progression-free survival. Secondary outcome measures are cumulative incidence of metastatic disease, treatments with curative intent, pT3-4 at radical prostatectomy, switch to watchful waiting, prostate cancer mortality and quality of life. Inclusion started in October 2016 and in October 2018; 275 patients have been enrolled. Ethical approval was obtained in each participating country. Results for the primary and secondary outcome measures will be submitted for publication in peer-reviewed journals. NCT02914873.


Abnormal intestinal permeability in primary biliary cirrhosis.
Antimitochondrial antibodies (AMAs) found in patients with primary biliary cirrhosis (PBC) cross-react with bacterial proteins and hence molecular mimicry has been proposed as a mechanism for AMA development. Alterations in gastrointestinal permeability would provide a potential route for increased exposure of gut flora to the immune system. In this study we aimed to compare the measured gastrointestinal permeability in patients with PBC to that in patients with liver disease (hepatitis C) and healthy control populations. Subjects drank a mixture of sucrose, lactulose, and mannitol dissolved in water. Eight-hour urinary excretion of the sugars was measured to assess intestinal permeability. Antiendomysial antibody testing was performed to exclude subclinical celiac disease. Eighty-six patients with PBC were evaluated and compared to 69 hepatitis C patients and 155 healthy controls. The mean urinary excretion of sucrose in the PBC patients (133.89 +/- 72.56 mg) was significantly higher than that in hepatitis C patients (101.07+/-63.35) or healthy controls (89.46+/-41.76) (P=0.0001), suggesting abnormal gastric or proximal small intestinal permeability. Sucrose excretion was not increased among patients with hepatitis C compared to healthy controls. The ratio of lactulose:mannitol excretion, reflecting small bowel permeability, was also elevated in the PBC group (0.017+/-0.012) compared to healthy controls (0.012+/-0.007) (P=0.0001) but was equal to that found among patients with hepatitis C (0.016+/-0.011) (P=NS). We conclude that the permeability of both the stomach and the small bowel is increased in patients with PBC, however, it is unclear if it is a cause, consequence, or manifestation of the disease.


Cholesterol, an essential molecule: diverse roles involving cytochrome P450 enzymes.
Cholesterol is an essential molecule for eukaryotic life and is an important precursor for a wide range of physiological processes. Biosynthesis and homoeostasis of cholesterol are complex mechanisms that are tightly regulated and interlinked with activities of a number of cytochrome P450 enzymes. These P450s play central critical roles in cholesterol metabolism. Key roles include a rate-limiting reaction in the synthesis of cholesterol itself, and in the oxidative transformations of cholesterol into steroid hormones and bile acids. However, microbial P450s also have important roles that impinge directly on human cholesterol synthesis and oxidation. Recent data reveal that Mycobacterium tuberculosis (which infects more than one-third of the world's human population) uses P450s to initiate breakdown of host cholesterol as an energy source. Microbial P450s also catalyse industrially important transformations in the synthesis of cholesterol-lowering statin drugs, with clear benefits to humans. The present article reviews the various roles of P450s in human cholesterol metabolism, from endogenous P450s through to microbial oxidases that enable catabolism of human cholesterol, or facilitate production of statins that regulate cholesterol production with positive outcomes in cardiovascular disease.


Dispelling the nice or naughty myth: retrospective observational study of Santa Claus.
To determine which factors influence whether Santa Claus will visit children in hospital on Christmas Day. Retrospective observational study. Paediatric wards in England, Northern Ireland, Scotland, and Wales. 186 members of staff who worked on the paediatric wards (n=186) during Christmas 2015. Presence or absence of Santa Claus on the paediatric ward during Christmas 2015. This was correlated with rates of absenteeism from primary school, conviction rates in young people (aged 10-17 years), distance from hospital to North Pole (closest city or town to the hospital in kilometres, as the reindeer flies), and contextual socioeconomic deprivation (index of multiple deprivation). Santa Claus visited most of the paediatric wards in all four countries: 89% in England, 100% in Northern Ireland, 93% in Scotland, and 92% in Wales. The odds of him not visiting, however, were significantly higher for paediatric wards in areas of higher socioeconomic deprivation in England (odds ratio 1.31 (95% confidence interval 1.04 to 1.71) in England, 1.23 (1.00 to 1.54) in the UK). In contrast, there was no correlation with school absenteeism, conviction rates, or distance to the North Pole. The results of this study dispel the traditional belief that Santa Claus rewards children based on how nice or naughty they have been in the previous year. Santa Claus is less likely to visit children in hospitals in the most deprived areas. Potential solutions include a review of Santa's contract or employment of local Santas in poorly represented regions.


The impact of reliance on private sector health services on the right to health.
A human rights approach is predicated on the responsibility of states to design health systems and implement health policies that are consistent with human rights requirements. However, in the contemporary health landscape, health services are increasingly delivered through private health sector institutions, and governments often lack direct control over some or many components of the health system. Private provision of health services does not change the role of the state as the ultimate guarantor of the realization of health rights obligations, but it makes implementing its responsibilities more difficult. This article explores the extent and ways in which privatization of health services potentially is and is not compatible with human rights commitments. Additionally, the article identifies factors and policies that can mitigate or exacerbate the impact of private health services on the realization of the right to health.


Childhood blindness in India: a population based perspective.
To estimate the prevalence and causes of blindness in children in the southern Indian state of Andhra Pradesh. These data were obtained as part of two population based studies in which 6935 children <or=15 years of age participated. Blindness was defined as presenting distance visual acuity <6/60 in the better eye. The prevalence of childhood blindness was 0.17% (95% confidence interval 0.09 to 0.30). Treatable refractive error caused 33.3% of the blindness, followed by 16.6% due to preventable causes (8.3% each due to vitamin A deficiency and amblyopia after cataract surgery). The major causes of the remaining blindness included congenital eye anomalies (16.7%) and retinal degeneration (16.7%). In the context of Vision 2020, the priorities for action to reduce childhood blindness in India are refractive error, cataract related amblyopia, and corneal diseases.


Superior colliculus neurons encode a visual saliency map during free viewing of natural dynamic video.
Models of visual attention postulate the existence of a saliency map whose function is to guide attention and gaze to the most conspicuous regions in a visual scene. Although cortical representations of saliency have been reported, there is mounting evidence for a subcortical saliency mechanism, which pre-dates the evolution of neocortex. Here, we conduct a strong test of the saliency hypothesis by comparing the output of a well-established computational saliency model with the activation of neurons in the primate superior colliculus (SC), a midbrain structure associated with attention and gaze, while monkeys watched video of natural scenes. We find that the activity of SC superficial visual-layer neurons (SCs), specifically, is well-predicted by the model. This saliency representation is unlikely to be inherited from fronto-parietal cortices, which do not project to SCs, but may be computed in SCs and relayed to other areas via tectothalamic pathways.


At the Intersection of Gut Microbiome and Stroke: A Systematic Review of the Literature.
Background: Ischemic and hemorrhagic stroke are associated with a high rate of long-term disability and death. Recent investigations focus efforts to better understand how alterations in gut microbiota composition influence clinical outcomes. A key metabolite, trimethylamine N-oxide (TMAO), is linked to multiple inflammatory, vascular, and oxidative pathways. The current biochemical underpinnings of microbial effects on stroke remain largely understudied. The goal of our study is to explore the current literature to explain the interactions between the human gut microbiome and stroke progression, recovery, and outcome. We also provide a descriptive review of TMAO. Methods: A systematic literature search of published articles between January 1, 1990, and March 22, 2020, was performed on the PubMed database to identify studies addressing the role of the microbiome and TMAO in the pathogenesis and recovery of acute stroke. Our initial investigation focused on human subject studies and was further expanded to include animal studies. Relevant articles were included, regardless of study design. The analysis included reviewers classifying and presenting selected articles by study design and sample size in a chart format. Results: A total of 222 titles and abstracts were screened. A review of the 68 original human subject articles resulted in the inclusion of 24 studies in this review. To provide further insight into TMAO as a key player, an additional 40 articles were also reviewed and included. Our findings highlighted that alterations in richness and abundance of gut microbes and increased plasma TMAO play an important role in vascular events and outcomes. Our analysis revealed that restoration of a healthy gut, through targeted TMAO-reducing therapies, could provide alternative secondary prevention for at-risk patients. Discussion: Biochemical interactions between the gut microbiome and inflammation, resulting in metabolic derangements, can affect stroke progression and outcomes. Clinical evidence supports the importance of TMAO in modulating underlying stroke risk factors. Lack of standardization and distinct differences in sample sizes among studies are major limitations.


Spotlighting Customers' Visual Attention at the Stock, Shelf and Store Levels with the 3S Model.
Several models of the in-store search process exist in the fields of retailing, marketing, and consumer-based research. The present article presents a new conceptualization of this search process, which captures customers' visual attention at three distinct levels of analysis: Stock, Shelf, and Store. We refer to this conceptualization as the 3S Model and illustrate its usefulness through three eye-tracking studies, one from each level of analysis. Our experimental examples, which range from manipulating certain stimuli on a single product (e.g., the placement of textual and pictorial packaging elements) to manipulating the entire shopping trip for customers during their stay in a store (e.g., through more or less specific shopping tasks), highlight the broad applicability of this alternative approach for understanding customers' in-store search behavior. Thus, our model can be seen as a helpful tool for researchers interested in how to conduct experimental eye-tracking studies that shed light on the perceptual processes preceding product choices and purchase decisions. The 3S Model is equally suitable in controlled lab conditions and under ecologically valid settings in the real retail environment. Furthermore, it can be used from the micro level, with a focus on the meaningful metrics on a particular product, through the intermediate level, with the emphasis on the area surrounding products in shelves and other in-store spaces, all the way to the macro level, examining customers' navigational paths throughout a store as a function of their shopping tasks, cognitive capacity, or ability to acquire in-store information.


Methylated arsenic species in plants originate from soil microorganisms.
• Inorganic arsenic (iAs) is a ubiquitous human carcinogen, and rice (Oryza sativa) is the main contributor to iAs in the diet. Methylated pentavalent As species are less toxic and are routinely found in plants; however, it is currently unknown whether plants are able to methylate As. • Rice, tomato (Solanum lycopersicum) and red clover (Trifolium pratense) were exposed to iAs, monomethylarsonic acid (MMA(V)), or dimethylarsinic acid (DMA(V)), under axenic conditions. Rice seedlings were also grown in two soils under nonsterile flooded conditions, and rice plants exposed to arsenite or DMA(V) were grown to maturity in nonsterile hydroponic culture. Arsenic speciation in samples was determined by HPLC-ICP-MS. • Methylated arsenicals were not found in the three plant species exposed to iAs under axenic conditions. Axenically grown rice was able to take up MMA(V) or DMA(V), and reduce MMA(V) to MMA(III) but not convert it to DMA(V). Methylated As was detected in the shoots of soil-grown rice, and in rice grain from nonsterile hydroponic culture. GeoChip analysis of microbial genes in a Bangladeshi paddy soil showed the presence of the microbial As methyltransferase gene arsM. • Our results suggest that plants are unable to methylate iAs, and instead take up methylated As produced by microorganisms.


High yield purification of full-length functional hERG K+ channels produced in Saccharomyces cerevisiae.
The hERG potassium channel is essential for repolarization of the cardiac action potential. Due to this vital function, absence of unintended and potentially life-threatening interactions with hERG is required for approval of new drugs. The structure of hERG is therefore one of the most sought-after. To provide purified hERG for structural studies and new hERG biomimetic platforms for detection of undesirable interactions, we have developed a hERG expression platform generating unprecedented amounts of purified and functional hERG channels. Full-length hERG, with or without a C-terminally fused green fluorescent protein (GFP) His 8-tag was produced from a codon-optimized hERG cDNA in Saccharomyces cerevisiae. Both constructs complemented the high potassium requirement of a knock-out Saccharomyces cerevisiae strain, indicating correct tetramer assembly in vivo. Functionality was further demonstrated by Astemizole binding to membrane embedded hERG-GFP-His 8 with a stoichiometry corresponding to tetramer assembly. The 156 kDa hERG-GFP protein accumulated to a membrane density of 1.6%. Fluorescence size exclusion chromatography of hERG-GFP-His 8 solubilized in Fos-Choline-12 supplemented with cholesteryl-hemisuccinate and Astemizole resulted in a monodisperse elution profile demonstrating a high quality of the hERG channels. hERG-GFP-His 8 purified by Ni-affinity chromatography maintained the ability to bind Astemizole with the correct stoichiometry indicating that the native, tetrameric structure was preserved. To our knowledge this is the first reported high-yield production and purification of full length, tetrameric and functional hERG. This significant breakthrough will be paramount in obtaining hERG crystal structures, and in establishment of new high-throughput hERG drug safety screening assays.


Risk of metachronous breast cancer after BRCA mutation-associated ovarian cancer.
This study sought to estimate the risk of breast cancer (BC) after a diagnosis of ovarian cancer (OC) associated with mutation of the BRCA1/2 (breast cancer, early onset) genes (BRCA-OC). The Memorial Sloan-Kettering Cancer Center and the University of Pennsylvania, clinical genetics databases were searched to identify women with BRCA-OC who participated in genetic testing and follow-up studies from 1995 to 2009. The primary objective was to determine the risk of developing BC after BRCA-OC. Overall survival (OS) and BC-free survival (BCFS) were determined by the Kaplan-Meier method; patients were censored at the time of last follow-up. A total of 164 patients had BRCA-OC (115 with BRCA1; 49 with BRCA2). Of these 164 patients, 152 developed OC prior to BRCA testing (median time to testing, 2.4 years [0.01-55 years]). Median follow-up from OC for those not developing BC was 5.8 years (0.25-55.6 years). There were 46 deaths, but none were due to BC. The 5- and 10-year OS were 85% (95% confidence interval [CI] = 0.78, 0.90) and 68% (95% CI = 0.59, 0.76), respectively. There were 18 metachronous BC diagnoses. The 5- and 10-year BCFS were 97% (95% CI = 0.92, 0.99) and 91% (95% CI = 0.82, 0.95), respectively. A subset of 64 women were tested either before or within 12 months of BRCA-OC. In this pseudo-incident subset, 5- and 10- year OS was 71% (95% CI = 0.53, 0.83) and 62% (95% CI = 0.44, 0.75), respectively, and 5- and 10-year BCFS were 100% and 87% (95% CI = 0.56, 0.96), respectively. OS was dominated by OC deaths. Metachronous BC risk was lower than reported for unaffected BRCA mutation carriers. These results support nonsurgical management of BC risk in women with BRCA-OC.


Plasma membrane proteomics of tumor spheres identify CD166 as a novel marker for cancer stem-like cells in head and neck squamous cell carcinoma.
Patients with advanced head and neck squamous cell carcinoma (HNSCC) have a poor prognosis with the currently available therapy, and tumor recurrence is frequently observed. The discovery of specific membrane-associated cancer stem cell (CSC) markers is crucial for the development of novel therapeutic strategies to target these CSCs. To address this issue, we established sphere cultures to enrich CSCs and used them for plasma membrane proteomics to identify specific membrane signatures of the HNSCC spheres. Of a dataset that included a total of 376 identified proteins, 200 were bona fide membrane proteins. Among them, 123 proteins were at least 1.5-fold up- or down-regulated in the spheres relative to the adherent cultures. These proteins included cell adhesion molecules, receptors, and transporter proteins. Some of them play key roles in wnt, integrin, and TGFβ signaling pathways. When we compared our dataset with two published hESC membrane protein signatures, we found 18 proteins common to all three of the databases. CD166 and CD44 were two such proteins. Interestingly, the expression of CD166, rather than that of the well-established HNSCC CSC marker CD44, was significantly related to the malignant behavior of HNSCC. Relative to CD166(low) HNSCC cells, CD166(high) HNSCC cells had a greater sphere-formation ability in vitro and tumor formation ability in vivo. Patients whose tumors expressed high levels of CD166 had a significantly poorer clinical outcome than those whose tumors expressed low levels of CD166 (cohort 1: 96 cases, p = 0.040), whereas the level of CD44 expression had only a marginal influence on the clinical outcome of patients with HNSCC (p = 0.078). The level of CD166 expression in HNSCC tumors was also associated with the tumor recurrence rate (cohort 2: 104 cases, p = 0.016). This study demonstrates that CD166 is a valuable cell surface marker for the enrichment of HNSCC stem cells and that plasma membrane proteomics is a promising biological tool for investigating the membrane proteins of CSCs.


An experimental bias-variance analysis of SVM ensembles based on resampling techniques.
Recently, bias-variance decomposition of error has been used as a tool to study the behavior of learning algorithms and to develop new ensemble methods well suited to the bias-variance characteristics of base learners. We propose methods and procedures, based on Domingo's unified bias-variance theory, to evaluate and quantitatively measure the bias-variance decomposition of error in ensembles of learning machines. We apply these methods to study and compare the bias-variance characteristics of single support vector machines (SVMs) and ensembles of SVMs based on resampling techniques, and their relationships with the cardinality of the training samples. In particular, we present an experimental bias-variance analysis of bagged and random aggregated ensembles of SVMs in order to verify their theoretical variance reduction properties. The experimental bias-variance analysis quantitatively characterizes the relationships between bagging and random aggregating, and explains the reasons why ensembles built on small subsamples of the data work with large databases. Our analysis also suggests new directions for research to improve on classical bagging.


Self-alignment of plasmonic gold nanorods in reconfigurable anisotropic fluids for tunable bulk metamaterial applications.
We demonstrate the bulk self-alignment of dispersed gold nanorods imposed by the intrinsic cylindrical micelle self-assembly in nematic and hexagonal liquid crystalline phases of anisotropic fluids. External magnetic field and shearing allow for alignment and realignment of the liquid crystal matrix with the ensuing long-range orientational order of well-dispersed plasmonic nanorods. This results in a switchable polarization-sensitive plasmon resonance exhibiting stark differences from that of the same nanorods in isotropic fluids. The device-scale bulk nanoparticle alignment may enable optical metamaterial mass production and control of properties arising from combining the switchable nanoscale structure of anisotropic fluids with the surface plasmon resonance properties of the plasmonic nanorods.


"Nomophobia": impact of cell phone use interfering with symptoms and emotions of individuals with panic disorder compared with a control group.
Panic disorder refers to the frequent and recurring acute attacks of anxiety. This study describes the routine use of mobiles phones (MPs) and investigates the appearance of possible emotional alterations or symptoms related to their use in patients with panic disorder (PD). We compared patients with PD and agoraphobia being treated at the Panic and Respiration Laboratory of The Institute of Psychiatry, Federal University of Rio de Janeiro, Brazil, to a control group of healthy volunteers. An MP-use questionnaire was administered to a consecutive sample of 50 patients and 70 controls. People with PD showed significant increases in anxiety, tachycardia, respiratory alterations, trembling, perspiration, panic, fear and depression related to the lack of an MP compared to the control group. Both groups exhibited dependence on and were comforted by having an MP; however, people with PD and agoraphobia showed significantly more emotional alterations as well as intense physical and psychological symptoms when they were apart from or unable to use an MP compared to healthy volunteers.


Availability of endovascular therapies for cerebrovascular disease at primary stroke centers.
Background Endovascular therapies (EVTs) are useful for treating cerebrovascular disease. There are few data about the availability of such services at primary stroke centers (PSCs). Our hypothesis was that some of these services may be available at some PSCs. Methods We conducted an internet-based survey of hospitals certified as PSCs by the Joint Commission. The survey inquired about EVTs such as intra-arterial (IA) lytics, IA mechanical clot removal, coiling of aneurysms, and cervical arterial stenting, physician training, coverage models, hospital type, and outcomes. Chi-square analyses were used to detect differences between academic and community PSCs. Results Data were available from 352 PSCs, of which 75% were community hospitals, 23% academic medical centers, and 80% were non-profit; almost half (48%) see 300 or more patients annually with ischemic stroke. A majority (60%) provided some or all EVTs on site, while 29% had none on site and no plans to add them. Among the respondents offering EVTs, 95% offered stenting of neck vessels, 86% IA lytics, 80% IA mechanical, and 74% aneurysm coiling. The majority (>55%) that did offer such services provided them 24/7/365. Most endovascular coverage was provided by interventional neuroradiologists (60%), fellowship trained endovascular neurosurgeons (42%), and interventional radiologists (41%). The majority of hospitals (81%) did not participate in an audited national registry. Conclusions A variety of EVT services are offered at many PSCs by interventionalists with diverse types of training. The availability of such services is clinically relevant now with the proven efficacy of mechanical thrombectomy for ischemic stroke.


Comparison of 18F-fluoro-L-DOPA, 18F-fluoro-deoxyglucose, and 18F-fluorodopamine PET and 123I-MIBG scintigraphy in the localization of pheochromocytoma and paraganglioma.
Besides (123)I-metaiodobenzylguanidine (MIBG), positron emission tomography (PET) agents are available for the localization of paraganglioma (PGL), including (18)F-3,4-dihydroxyphenylalanine (DOPA), (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG), and (18)F-fluorodopamine ((18)F-FDA). The objective of the study was to establish the optimal approach to the functional imaging of PGL and examine the link between genotype-specific tumor biology and imaging. This was a prospective observational study. There were no interventions. Fifty-two patients (28 males, 24 females, aged 46.8 +/- 14.2 yr): 20 with nonmetastatic PGL (11 adrenal), 28 with metastatic PGL (13 adrenal), and four in whom PGL was ruled out; 22 PGLs were of the succinate dehydrogenase subunit B (SDHB) genotype. Sensitivity of (18)F-DOPA, (18)F-FDG, and (18)F-FDA PET, (123)I-MIBG scintigraphy, computed tomography (CT), and magnetic resonance imaging (MRI) for the localization of PGL were measured. Sensitivities for localizing nonmetastatic PGL were 100% for CT and/or MRI, 81% for (18)F-DOPA PET, 88% for (18)F-FDG PET/CT, 78% for (18)F-FDA PET/CT, and 78% for (123)I-MIBG scintigraphy. For metastatic PGL, sensitivity in reference to CT/MRI was 45% for (18)F-DOPA PET, 74% for (18)F-FDG PET/CT, 76% for (18)F-FDA PET/CT, and 57% for (123)I-MIBG scintigraphy. In patients with SDHB metastatic PGL, (18)F-FDA and (18)F-FDG have a higher sensitivity (82 and 83%) than (123)I-MIBG (57%) and (18)F-DOPA (20%). (18)F-FDA PET/CT is the preferred technique for the localization of the primary PGL and to rule out metastases. Second best, equal alternatives are (18)F-DOPA PET and (123)I-MIBG scintigraphy. For patients with known metastatic PGL, we recommend (18)F-FDA PET in patients with an unknown genotype, (18)F-FDG or (18)F-FDA PET in SDHB mutation carriers, and (18)F-DOPA or (18)F-FDA PET in non-SDHB patients.


Ethnic differences in out-of-hospital fatal pulmonary embolism.
In-hospital pulmonary embolism (PE) has been extensively studied in large populations; however, out-of-hospital fatal PE studies are rare. Here, we systematically evaluated a large number of decedents who suffered fatal PE outside of hospitals and were subsequently investigated by the New York City Office of Chief Medical Examiner. A total of 578 consecutive out-of-hospital fatal PE cases were analyzed. All underwent autopsy, toxicology, microbiology, and genetic testing. Incidence rates and baseline characteristics were analyzed. Race-adjusted incidence rates of out-of-hospital fatal PE (per 100 000 people per year) were as follows: blacks, 3.73 (95% confidence interval, 3.31 to 4.11); whites, 1.15 (95% confidence interval, 0.96 to 1.33); and Hispanics, 0.93 (95% confidence interval, 0.72 to 1.10). Overall, obesity (body mass index ≥30 kg/m(2)) was 2.5- to 3-fold higher in fatal PE cases than in the New York City population as a whole. Carrier frequencies for prothrombin G20210A in fatal PE were 2- to 10-fold higher than reported frequencies in ethnically matched controls. Cumulative distribution curves showed that compared with whites, blacks and Hispanics died at significantly younger ages (P<0.001). Univariate and multiple linear regression analyses showed that in addition to nonwhite ethnicity, heterozygous carriers for factor V Leiden (P=0.001) and obesity (P=0.002) are significantly associated with younger age at death. There are unique epidemiological differences in out-of-hospital fatal PE between ethnic groups in New York City.


Intracellular distribution of phosphate in cultured Humulus lupulus cells growing at elevated exogenous phosphate concentrations.
The distribution of inorganic phosphate (Pi) between the cytoplasm and the vacuole of Humulus lupulus L. cells grown in suspension culture at different exogenous Pi levels was examined by 31-P nuclear magnetic resonance. In growing cells excess Pi accumulated in the vacuoles and the inhibitory effect of high exogenous Pi was not associated with a change in the cytoplasmic Pi level or with a change in the cytoplasmic pH.


Absolute calibration of fiber-coupled single-photon detector.
We show a setup for characterising the efficiency of a single-photon-detector absolutely and with a precision better than 1%. Since the setup does not rely on calibrated devices and can be implemented with standard-optic components, it can be realised in any laboratory. Our approach is based on an Erbium-Doped-Fiber-Amplifier (EDFA) radiometer as a primary measurement standard for optical power, and on an ultra-stable source of spontaneous emission. As a proof of principle, we characterise the efficiency of an InGaAs/InP single-photon detector. We verified the correctness of the characterisation with independent measurements. In particular, the measurement of the optical power made with the EDFA radiometer has been compared to that of the Federal Institute of Metrology using a transfer power meter. Our approach is suitable for frequent characterisations of high-efficient single-photon detectors.


Plasticity of the visual system after early brain damage.
The aim of this review is to discuss the existing evidence supporting different processes of visual brain plasticity after early damage, as opposed to damage that occurs during adulthood. There is initial evidence that some of the neuroplastic mechanisms adopted by the brain after early damage to the visual system are unavailable at a later stage. These are, for example, the ability to differentiate functional tissue within a larger dysplastic cortex during its formation, or to develop new thalamo-cortical connections able to bypass the lesion and reach their cortical destination in the occipital cortex. The young brain also uses the same mechanisms available at later stages of development but in a more efficient way. For example, in people with visual field defects of central origin, the anatomical expansion of the extrastriatal visual network is greater after an early lesion than after a later one, which results in more efficient mechanisms of visual exploration of the blind field. A similar mechanism is likely to support some of the differences found in people with blindsight, the phenomenon of unconscious visual perception in the blind field. In particular, compared with people with late lesions, those with early brain damage appear to have stronger subjective awareness of stimuli hitting the blind visual field, reported as a conscious feeling that something is present in the visual field. Expanding our knowledge of these mechanisms could help the development of early therapeutic interventions aimed at supporting and enhancing visual reorganization at a time of greatest potential brain plasticity.


Unpacking grit: Motivational correlates of perseverance and passion for long-term goals.
In two cross-sectional studies, we explored the motivational orientations correlates of the character strength of grit and its two component facets: perseverance of effort and consistency of interests over time. Specifically, we examined how individual differences in grit are explained by distinct approaches to pursuing happiness in life: pleasure in immediately hedonically positive activities, meaning in activities that serve a higher, altruistic purpose, and engagement in attention-absorbing activities. In both samples, grit demonstrated medium-sized associations with an orientation toward engagement, small-to-medium associations with an orientation toward meaning, and small-to-medium (inverse) associations with an orientation toward pleasure. These motivational orientations differentially related to the two facets of grit: pursuing engagement was more strongly associated with perseverance of effort, whereas pursuing pleasure was more strongly (inversely) associated with consistency of interests over time. Collectively, findings suggest that individual differences in grit may derive in part from differences in what makes people happy.


Duration of Brucella ovis infection in ewes.
Twenty Romney Marsh ewes, some 5 to 40 days pregnant, were inoculated with a strain of Brucella ovis onto the scarified mucous membrane of the vagina. Establish of infection was ascertained by recovery of the organisms from blood; supramammary and inguinal lymph nodes; the vagina, after initial disappearance of the organism from this organ; and the complement fixation tests. The bacteremia was transitory or intermittent, but organisms could not be recovered from blood, or any other tissue examined, after 98 days of infection. Abortions or placentitis were not observed. It is recommended that in countries where sheep breeding is aseasonal a sexual rest of infected ewes for at least 4 months must be part of any program for the control and eradication of ram epididymitis.


Phosphorylation and calcium antagonistically tune myosin-binding protein C's structure and function.
During each heartbeat, cardiac contractility results from calcium-activated sliding of actin thin filaments toward the centers of myosin thick filaments to shorten cellular length. Cardiac myosin-binding protein C (cMyBP-C) is a component of the thick filament that appears to tune these mechanochemical interactions by its N-terminal domains transiently interacting with actin and/or the myosin S2 domain, sensitizing thin filaments to calcium and governing maximal sliding velocity. Both functional mechanisms are potentially further tunable by phosphorylation of an intrinsically disordered, extensible region of cMyBP-C's N terminus, the M-domain. Using atomic force spectroscopy, electron microscopy, and mutant protein expression, we demonstrate that phosphorylation reduced the M-domain's extensibility and shifted the conformation of the N-terminal domain from an extended structure to a compact configuration. In combination with motility assay data, these structural effects of M-domain phosphorylation suggest a mechanism for diminishing the functional potency of individual cMyBP-C molecules. Interestingly, we found that calcium levels necessary to maximally activate the thin filament mitigated the structural effects of phosphorylation by increasing M-domain extensibility and shifting the phosphorylated N-terminal fragments back to the extended state, as if unphosphorylated. Functionally, the addition of calcium to the motility assays ablated the impact of phosphorylation on maximal sliding velocities, fully restoring cMyBP-C's inhibitory capacity. We conclude that M-domain phosphorylation may have its greatest effect on tuning cMyBP-C's calcium-sensitization of thin filaments at the low calcium levels between contractions. Importantly, calcium levels at the peak of contraction would allow cMyBP-C to remain a potent contractile modulator, regardless of cMyBP-C's phosphorylation state.


Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder.
The pathophysiology of bipolar disorder is still unclear, although family, twin and linkage studies implicate genetic factors. Here we identified XBP1, a pivotal gene in the endoplasmic reticulum (ER) stress response, as contributing to the genetic risk factor for bipolar disorder. Using DNA microarray analysis of lymphoblastoid cells derived from two pairs of twins discordant with respect to the illness, we found downregulated expression of genes related to ER stress response in both affected twins. A polymorphism (-116C-->G) in the promoter region of XBP1, affecting the putative binding site of XBP1, was significantly more common in Japanese patients (odds ratio = 4.6) and overtransmitted to affected offspring in trio samples of the NIMH Bipolar Disorder Genetics Initiative. XBP1-dependent transcription activity of the -116G allele was lower than that of the -116C allele, and in the cells with the G allele, induction of XBP1 expression after ER stress was markedly reduced. Valproate, one of three mood stabilizers, rescued the impaired response by inducing ATF6, the gene upstream of XBP1. These results indicate that the -116C-->G polymorphism in XBP1 causes an impairment of its positive feedback system and increases the risk of bipolar disorder.


Small-molecule AT2 receptor agonists.
The discovery of the first selective, small-molecule ATR receptor (AT2R) agonist compound 21 (C21) (8) that is now extensively studied in a large variety of in vitro and in vivo models is described. The sulfonylcarbamate derivative 8, encompassing a phenylthiofen scaffold is the drug-like agonist with the highest affinity for the AT2R reported to date (Ki = 0.4 nM). Structure-activity relationships (SAR), regarding different biaryl scaffolds and functional groups attached to these scaffolds and with a particular focus on the impact of various para substituents displacing the methylene imidazole group of 8, are discussed. Furthermore, the consequences of migration of the methylene imidazole group and presumed structural requirements for ligands that are aimed as AT2R agonists (e.g. 8) or AT2R antagonists (e.g. 9), respectively, are briefly addressed. A summary of the pharmacological actions of C21 (8) is also presented.


Associations between parental smoking restrictions and adolescent smoking.
The purpose of this study was to examine the cross-sectional relation between reported levels of parental smoking restriction and several behavioral and cognitive variables in a sample of 757 (363 males, 394 females) adolescent smokers. Experimenters administered surveys to students in the homerooms of three Florida high schools. After controlling for student age, gender, and parental smoking status, results revealed that more restrictive parental smoking policies were significantly associated with less smoking on weekdays and weekend days, greater latency to smoking the first cigarette of the day, greater motivation to quit smoking, greater confidence in ability to quit smoking, and higher estimated risk perception regarding the health consequences of smoking. Results also revealed that 44% of adolescent smokers reported that their parents or legal guardians did not know that they smoked tobacco. These findings suggest that parental smoking restrictions may have the potential to impede adolescent progression to adult smoking behavior by reducing smoking rates and nicotine dependence, and increasing motivation to quit, self-confidence to quit, and health risk perception. Parental restrictions on smoking may present obstacles and inconveniences to adolescent smoking behavior that make smoking cessation a more attractive option.


The Role of Sensation Seeking and R-rated Movie Watching in Early Substance Use Initiation.
Adolescence is a time of heightened impulsivity as well as substantial exposure to the effects of popular media. Specifically, R-rated movie content and sensation seeking have been shown to be individually and multiplicatively associated with early alcohol initiation, as well as to mutually influence one another over time. The present study attempts to replicate and extend these findings to cigarette and marijuana use, considering several peer, parental, and individual correlates, as well as substance-specific movie exposure, among 1023 youth (mean age 12.4 years, 52% female), using a combination of cross-lagged path models, latent growth models, and discrete-time survival models. Changes over time were associated between R-rated movie watching and sensation seeking, and both individually, not multiplicatively, predicted earlier alcohol initiation. R-rated movie watching (but not sensation seeking) also predicted earlier smoking and marijuana initiation. Parental R-rated movie restriction may thus potentially delay smoking and marijuana initiation as well as adolescent drinking.