Physical activity in early childhood education and care settings in a low-income, rural South African community: an observational study.
Research has not been conducted on physical activity in early child education and care (ECEC) settings in low-income, rural communities in South Africa. This study aimed to describe the physical activity environment of these settings and identify child and contextual factors associated with physical activity in these settings. By understanding physical activity in this environment, it will be possible to identify context-specific opportunities, including with teachers, to overcome potential challenges and maximise physical activity in a low- and middle-income country setting. The study was conducted in rural Bushbuckridge, Mpumalanga in 2014. Preschool-aged children (n=55) were recruited from five ECEC settings, including three preschools and two primary schools, where preschool-aged children are in their reception year, grade R. Preschool environment characteristics were assessed using an observational tool adapted from existing tools. Children's physical activity was assessed using the Observational System for Recording Physical Activity in Children - Preschool Version. Differences between preschool and grade R settings were assessed using χ2 analyses, and multinomial logistic regression analysis was used to determine factors associated with physical activity in the ECEC settings. The physical activity environment differed between preschool and grade R ECEC settings in terms of space (preschoolpgrade R, p<0.001). On average, children spent 28.7% of their day in the ECEC settings engaged in physical activity, of which 22.3% was moderate- to vigorous-intensity physical activity (MVPA). Children spent the greatest proportion of the day in sedentary activities (69.9%) and this differed significantly between preschool (63.2%) and grade R children (81.3%, p<0.001). Preschool children were significantly more active than grade R children, and spent greater proportions of time in light-intensity physical activity (8.6% v 2.7%, p<0.001) and MVPA (25.4% v 15.3%, p<0.001). Irrespective of ECEC setting, children were significantly more likely to participate in MVPA if they were outdoors (p=0.001), and significantly less likely to do MVPA if they were overweight/obese (p=0.006). These findings provide insight into child-level and contextual factors associated with preschool-aged children's physical activity within ECEC settings in a low-income, rural community in South Africa. Particularly, the physical and social features of ECEC settings are important in the promotion of physical activity. Findings from this study suggest that it is necessary to upskill and encourage teachers in ECEC settings to maximise opportunities for physical activity in rural low-income communities in South Africa.


Comparison of stimulus rivalry to binocular rivalry with functional magnetic resonance imaging.
When incompatible images are presented to each eye, a phenomenon known as binocular rivalry occurs in which the viewer's conscious visual perception alternates between the two images. In stimulus rivalry, similar perceptual alternations between rival images can occur even in the midst of fast image swapping between the eyes. Here, we used functional magnetic resonance imaging to directly compare brain activity underlying the two types of perceptual rivalry. Overall, we found that activity for binocular rivalry was always stronger and more widespread than that for stimulus rivalry-even more so during passive viewing conditions. In particular, the right superior parietal cortex and the right temporoparietal junction were prominently engaged for passive binocular rivalry. While both types of rivalry engaged higher tier visual regions such as the ventral temporal cortex during an active task, activity for stimulus rivalry was comparatively weak in early visual areas V1 to V3, presumably due to a weaker feed-forward signal due to both intraocular and interocular inhibition that may reduce effective contrast. In sum, only binocular rivalry produced perceptually vivid alternations, increased activation of the early visual cortex, and the coordinated engagement of dorsal stream regions, even when a task was not performed. These findings help characterize how stimulus rivalry fits within hierarchical models of binocular rivalry.


High-Tc SQUID magnetocardiography imaging system.
We set up a high-Tc SQUID system for magnetocardiography (MCG) in a moderately magnetically shielded room. The electronically balanced gradiometer consists of superconducting quantum interference device (SQUID) magnetometer. One reference SQUID was mounted above the sensing SQUID while the sensing SQUID is seated at the bottom of the cryostat. The baseline of the gradiometer is varied from 5 cm to 7 cm. The output of the MCG signal was filtered with the band pass filter (0.5 - 40 Hz) and the power-line filter. The MCG system was used to detect the magnetic signal of the human heart. Equivalent current sources were used to study the inverse problem.


A comparison between the oscillometric and the auscultatory method for ambulatory 24 h blood pressure monitoring.
OBJECTIVES: To investigate the compatibility between oscillometric and auscultatory methods, and to determine whether one is preferable over the other for ambulatory 24 h blood pressure monitoring. METHODS: For the blood pressure monitoring system we used an A&D TM 2421 device (Takeda), which enabled us to measure the blood pressure simultaneously with the two methods on the same arm. Our investigation included 281 patients (122 women and 159 men, aged 18-85 years) with suspected hypertension or undergoing treatment for hypertension. RESULTS: We obtained 23 531 measurements by the oscillometric method, which was 98% of the maximal possible number, and 81% of the maximal possible number were obtained by the auscultatory methjod. We were able to compare 98% of the paired measurements. The auscultatory method showed a uniform distribution of errors throughout the 24 h. Compared to the auscultatory method, the oscillometry method had fewer errors in the evenings, but more when the subjects were at work. There was a difference in paired single readings between the two methods amounting to 1.4+/-19 mmHg (mean+/-SD) for systolic and -2.4+/-18 mmHg for diastolic readings (auscultatory - oscillometric). The differences in mean values for the 281 cases of 24 h monitoring amounted to 0.7+/- 4 mmHg for systolic and -2.2+/-6 mmHg for diastolic measurements. For the mean systolic blood pressure, we found a difference of 0.3+/-4 mmHg in the daytime and 0.3+/-8 mmHg during the night. The mean diastolic pressures differed by -2.0+/-6 mmHg in the daytime and -1.6+/-8 mmHg during the night. We found only a weak correlation between the differences in the readings by the two methods and systolic blood pressure levels, age, pulse pressure and body mass index, and no correlations between these differences and the diastolic blood pressure levels. CONCLUSION: Although we found a considerable SD on single readings by the two methods, there was a good agreement between the mean values of the 24 h monitoring for the two methods. We obtained a significantly higher success rate by the oscillometric method. The findings suggest that, for this equipment, the oscillometric method is preferable for 24 h ambulatory blood pressure monitoring because it provides a much higher rate of successful readings.


Corpus callosum atrophy is associated with mental slowing and executive deficits in subjects with age-related white matter hyperintensities: the LADIS Study.
Previous research has indicated that corpus callosum atrophy is associated with global cognitive decline in neurodegenerative diseases, but few studies have investigated specific cognitive functions. To investigate the role of regional corpus callosum atrophy in mental speed, attention and executive functions in subjects with age-related white matter hyperintensities (WMH). In the Leukoaraiosis and Disability Study, 567 subjects with age-related WMH were examined with a detailed neuropsychological assessment and quantitative magnetic resonance imaging. The relationships of the total corpus callosum area and its subregions with cognitive performance were analysed using multiple linear regression, controlling for volume of WMH and other confounding factors. Atrophy of the total corpus callosum area was associated with poor performance in tests assessing speed of mental processing--namely, trail making A and Stroop test parts I and II. Anterior, but not posterior, corpus callosum atrophy was associated with deficits of attention and executive functions as reflected by the symbol digit modalities and digit cancellation tests, as well as by the subtraction scores in the trail making and Stroop tests. Furthermore, semantic verbal fluency was related to the total corpus callosum area and the isthmus subregion. Corpus callosum atrophy seems to contribute to cognitive decline independently of age, education, coexisting WMH and stroke. Anterior corpus callosum atrophy is related to the frontal-lobe-mediated executive functions and attention, whereas overall corpus callosum atrophy is associated with the slowing of processing speed.


Proteomics in bone research.
Osteoporosis is prevalent among the elderly and is a major cause of bone fracture in this population. Bone integrity is maintained by the dynamic processes of bone resorption and bone formation (bone remodeling). Osteoporosis results when there is an imbalance of the two counteracting processes. Bone mineral density, measured by dual-energy x-ray absorptiometry has been the primary method to assess fracture risk for decades. Recent studies demonstrated that measurement of bone turnover markers allows for a dynamic assessment of bone remodeling, while imaging techniques, such as dual-energy x-ray absorptiometry, do not. The application of proteomics has permitted discoveries of new, sensitive, bone turnover markers, which provide unique information for clinical diagnosis and treatment of patients with bone diseases. This review summarizes the recent findings of proteomic studies on bone diseases, properties of mesenchymal stem cells with high expansion rates and osteoblast and osteoclast differentiation, with emphasis on the role of quantitative proteomics in the study of signaling dynamics, biomarkers and discovery of therapeutic targets.


Impact of MHC class I alleles on the M. tuberculosis antigen-specific CD8+ T-cell response in patients with pulmonary tuberculosis.
Challenged by scattered understanding of protective immunity to Mycobacterium tuberculosis (MTB), we have mapped peptide epitopes to human leukocyte antigen (HLA)-A*0101, A*0201, A*1101, A*2402, B*0702, B*0801 and B*1501 of the secreted mycobacterial antigen Ag85B, a vaccine candidate that may be associated with immune protection. Affinity (ED(50)) and half-life (t(1/2), off-rate) analysis for individual peptide species on HLA-A and HLA-B molecules revealed binding ranges between 10(-3) and 10(-7) M. After selection of the best matches, major histocompatibility complex class I/peptide tetramer complexes were constructed to measure the CD8+ T-cell responses directly ex vivo in peripheral blood mononuclear cells (PBMC) derived from 57 patients with acute pulmonary tuberculosis. Three patterns of (allele-) specific CD8+ recognition were identified: (a). Focus on one dominant epitope with additional recognition of several subdominant T-cell epitopes (HLA-A*0301, A*2402, B*0801 and B*1501); (b). Co-dominant recognition of two distinct groups of peptides presented by HLA-B*0702; and (c). Diverse and broad recognition of peptides presented by HLA-A*0201. Peptides that bound with slow off-rates to class I alleles, that is HLA-A*0201, were associated with low frequency of CD8+ T cells in PBMCs from patients with tuberculosis. HLA-B alleles showed fast off-rates in peptide binding and restricted high numbers (up to 6%) of antigen-specific CD8+ T cells in patients with pulmonary tuberculosis.


Detection of spotted fever group Rickettsia spp. from bird ticks in the U.K.
Migratory birds are known to play a role in the long-distance transportation of microorganisms. To investigate whether this is true for rickettsial agents, we undertook a study to characterize tick infestation in populations of the migratory passerine bird Riparia riparia (Passeriformes: Hirundinidae), the sand martin. A total of 194 birds were sampled and ticks removed from infested birds. The ticks were identified as female Ixodes lividus (Acari: Ixodidae) using standard morphological and molecular techniques. Tick DNA was assayed to detect Rickettsia spp. using polymerase chain reaction and DNA was sequenced for species identification. A single Rickettsia spp. was detected in 100% of the ticks and was designated Rickettsia sp. IXLI1. Partial sequences of 17-kDa and ompA genes showed greatest similarity to Rickettsia sp. TCM1, an aetiological agent of Japanese spotted fever-like illness, previously described in Thailand. Phylogenetic analysis showed that Rickettsia sp. IXLI1 fitted neatly into a group containing strains Rickettsia japonica, Rickettsia sp. strain Davousti and Rickettsia heilongjiangensis. In conclusion, this research shows that U.K. migratory passerine birds host ticks infected with Rickettsia species and contribute to the geographic distribution of spotted fever rickettsial agents.


Low-temperature threshold for egg survival of a post-diapause and non-diapause European aedine strain, Aedes albopictus (Diptera: Culicidae).
The interplay between global warming and invasive arthropods in temperate zones is of utmost interest in terms of the potential expansions of vector-borne diseases. Up to now, investigations on the recent establishment of mosquito vectors have focused on temperatures during their phases of activity. However, cold temperatures may also act as a strong ecological constraint. Projected changes in winter climate indicate an increase of mean minimum temperatures of the coldest quarter, less frequent days with frost and a shorter frost-season in Europe at the end of the century. Nevertheless, single cold extremes are also expected to persist under warming scenarios, which have a strong impact on reproduction success. Here, the temperature constraints of European Aedes albopictus eggs, which had passed through a diapause, compared to non-diapausing eggs were examined systematically under controlled laboratory conditions. Additionally, one tropical strain of Ae. albopictus and of Ae. aegypti was used in the comparison. The lower temperature threshold tolerated by the European eggs of Ae. albopictus which have undergone a diapause, was -10°C for long term exposures (12 and 24h) and -12°C for 1h exposure. Non-diapausing eggs of European Ae. albopictus were found to hatch after a -7°C cold treatment (8, 12 and 24h exposure). Both tropical aedine species only tolerated the long term treatment at -2°C. Neither Ae. albopictus nor Ae. aegypti eggs hatched after being exposed to -15°C. Survival was mainly influenced by temperature (F = 329.2, df = 1, p < 0.001), whereas the duration of the cold treatment only significantly influenced the hatching response at the thermal limits of survival (F = 5.6, df = 1, p = 0.031) but not at 0°C (F = 0.1, df = 1, p = 0.730). Hatching success after the cold treatment was significantly increased in European eggs, which have undergone a diapause compared to non-diapausing eggs (F = 14.7, df = 3, p < 0.001). These results illustrate rapid adaptation. Here, low temperature thresholds for aedine mosquito egg survival were detected. The compilation of risk maps for temperate regions can substantially be improved by considering areas where an establishment of a vector population is unlikely due to winter conditions.


Outcome of Minnesota's gambling treatment programs.
This study measured the outcome of four state-supported outpatient gambling treatment programs in Minnesota. The programs were developed specifically for the treatment of pathological gamblers and offered multiple modalities of treatment including individual, group, education, twelve-step work, family groups, and financial counseling. The therapeutic orientation was eclectic with an emphasis on the twelve steps of Gamblers Anonymous (GA) and a treatment goal of abstinence. The sample included 348 men and 220 women treated between January 1992 and January 1995. A pretest-posttest design was utilized with multidimensional assessments obtained at intake, discharge, six-months, and twelve-months post-discharge. Variables assessed included a range of clinical and outcome variables. At six month follow-up, 28% reported that they had abstained from gambling during the six months following discharge and an additional 20% had gambled less than once per month. Almost half of the sample (48%) showed clinically significant improvement in gambling frequency at six month follow-up. Outcome variables of gambling frequency, SOGS scores, amount of money gambled, number of friends who gamble, psychosocial problems, and number of financial problems, all showed statistically significant improvements from pretreatment to follow-up. The treatment programs yielded outcome results similar to those reported for alcohol and drug abuse treatment programs.


Effects of "vitex agnus castus" extract and magnesium supplementation, alone and in combination, on osteogenic and angiogenic factors and fracture healing in women with long bone fracture.
The purpose of this study was to investigate the effects of the combination of vitex agnus castus extract, as a source of phytoestrogens, plus magnesium supplementation on osteogenic and angiogenic factors and callus formation in women with long bone fracture. In a double-blind randomized placebo controlled trial, 64 women with long bone fracture, 20-45 years old, were randomly allocated to receive 1) one Agnugol tablet (4 mg dried fruit extract of vitex agnus castus) plus 250 mg magnesium oxide (VAC + Mg group (n = 10)), 2) one Agnugol tablet plus placebo (VAC group (n = 15)), 3) placebo plus 250 mg magnesium oxide (Mg group (n = 12)), or 4) placebo plus placebo (placebo group (n = 14)) per day for 8 weeks. At baseline and endpoint of the trial, serum alkaline phosphatase, osteocalcin, and vascular endothelial growth factor (VEGF) were measured together with radiological bone assessment. There were no significant differences in the characteristic aspects of concern between the four groups at baseline. Despite the increased level of alkaline phosphatase in the VAC group (188.33 ± 16.27 to 240.40 ± 21.49, P = 0.05), administration of VAC + Mg could not increase alkaline phosphatase activity. However, treatment with VAC + Mg significantly enhanced the osteocalcin level. The serum concentration of VEGF was increased in the VAC group (269.04 ± 116.63 to 640.03 ± 240.16, P < 0.05). Callus formation in the VAC + Mg group was higher than the other groups but the differences between the four groups were not significant (P = 0.39). No relevant side effect was observed in patients in each group. Our results suggest that administration of vitex agnus castus plus magnesium may promote fracture healing. However, more studies need to further explore the roles of vitex agnus castus in fracture repair processes.


Nutrition care for renal transplant recipients: an evaluation of service delivery and outcomes.
Weight gain post-renal transplantation is common. Recommendations from recent guidelines include providing structured nutrition care to target risk factors for chronic disease in the early post-transplant period. This study aimed to evaluate the nutrition care provided to renal transplant recipients following implementation of a dietetic model of care and to identify predictors of weight change up to one year post-transplant. A retrospective and observational study of one hundred and fifty-six patients that received a renal transplant from a state-wide transplant service in Australia between October 2009 and December 2010. Nutrition care provided compared with guideline recommendations within the first three months post-transplant and weight change at 12 months post-transplant, significant weight gain equating to >5% pre-transplant weight. Only 35% of patients were provided with nutrition care according to guideline recommendations, were older, and had a higher BMI and diabetes. Significant weight gain was evident for half of the patients evaluated. Thirty-eight percent of healthy weight patients at transplant became overweight or obese and 23% of overweight patients at baseline became obese at 12 months. After multivariate analysis, time on dialysis was independently associated with weight change at 12 months. Nutrition care provided did not meet guideline recommendations, highlighting difficulty in implementing evidence to practice. Significant weight gain was evident particularly in patients classified as 'healthy weight' at the time of transplant. Long-term, prospective studies are needed to determine the effectiveness of implementing nutrition care to attenuate weight gain and improve clinical outcomes.


Increased expression of Toll-like receptors 2 and 4 is associated with poor outcome in intracerebral hemorrhage.
Inflammatory response in intracerebral hemorrhage (ICH) is associated with poor outcome and could be a consequence of Toll-like receptor (TLR) activation. We investigated the influence of TLR2 and TLR4 expression on the outcome of ICH patients. Expression levels of TLR2 and TLR4 in monocytes at admission were independently associated with poor functional outcome. On the other hand, TLR2 and TLR4 expression at admission in both monocytes and neutrophils was independently associated with residual lesion volume. In conclusion, increased expression of TLR2 and TLR4 is associated with poor functional outcome and greater residual volume in ICH patients.


Defining putative T cell epitopes from PE and PPE families of proteins of Mycobacterium tuberculosis with vaccine potential.
The identification of T cell epitopes from immune relevant antigens of Mycobacterium tuberculosis is a critical step in the development of a vaccine covering diverse populations. Two multigene families, PE-PGRS and PPE make up about 10% of the M. tuberculosis genome. However, the functions of the proteins coded by these large numbers of genes are unknown. All possible nonameric peptide sequences from PE and PPE proteins were analysed in silico for their ability to bind to 33 alleles of class I HLA. These results reveal that of all PE and PPE proteins, a significant number of these peptides are predicted to be high-affinity HLA binders, irrespective of the length of the protein. The pathogen peptides that could behave as self or partially self-peptides in the host were eliminated using a comparative study with human proteome, thus reducing the number of peptides for analysis. The structural basis for recognition of the nonamers by the respective HLA molecules thus predicted was analyzed by molecular modeling. The structural analysis showed good correlation with the binding prediction. The analysis also led to an understanding of the binding profile of the peptides with respect to different alleles of class I HLA. The predicted epitopes can be tested experimentally for their inclusion in a potential vaccine against tuberculosis that is HLA haplotype-specific.


Tissue infiltration in a CD8 lymphocytosis syndrome associated with human immunodeficiency virus-1 infection has the phenotypic appearance of an antigenically driven response.
HIV-1 infection may initiate to an HLA-associated response designated diffuse infiltrative lymphocytosis syndrome, characterized by increased numbers of circulating CD8 T cells that infiltrate salivary glands, lungs, gastrointestinal tract, and kidneys. Since this response could either be an antigenically driven process induced by HIV-1 or a lymphoproliferation of cells with neoplastic or unusual features, we sought to define the phenotype of the cellular populations, the nature of tissue derangement, and the tissue localization of virus in diffuse infiltrative lymphocytosis syndrome. Circulating CD8 T cells were greatly increased while CD4 T cell numbers remained in the range found in asymptomatic seropositive persons. The majority of CD8 and CD4 T cells in both blood and tissues had the memory phenotype of CD29+ (beta 1 integrin) and CD11a+/CD18 (beta 2 integrin) expression, but lacked markers of recent activation. A proportion of the circulating CD8 T cells also expressed CD57 (Leu 7) but not other markers of natural killer cells. HIV-encoded proteins were identified in tissue macrophages located in periacinar areas of the salivary glands. CD54 (intercellular adhesion molecule-1), a ligand for the CD11a integrin, was strongly expressed on postcapillary venule endothelium within lymphoid foci, and HLA-DR molecules were found on limited regions of ductular epithelium adjacent to lymphoid aggregates. These findings suggest that (a) the visceral lymphocytic infiltration in diffuse infiltrative lymphocytosis syndrome is an antigen-driven, and MHC-determined, host immune response to an element associated with HIV-1 infection, and (b) that the specific adhesive molecule interactions mediating the cellular influx, as well as the subsequent tissue damage, reflect altered patterns of gene expression in tissues undergoing an immune response.


Augmented quantal release of acetylcholine at the vertebrate neuromuscular junction following tdp-43 depletion.
TAR DNA binding protein (TDP-43) is a 43 kD, predominately nuclear, protein involved in RNA metabolism. Of clinical significance is that the majority of amyotrophic lateral sclerosis (ALS) patients display abnormal accumulation of misfolded TDP-43 in the cytoplasm, which is coincident with a loss of nuclear localization in the afflicted regions of the central nervous system. Little is known about defects that arise in loss-of-function models, in particular synaptic defects that arise at the neuromuscular junction (NMJ). In this report, we examined abnormalities arising at the NMJ following depletion of tdp-43 using a previously characterized mutant tardbp (encoding tdp-43) zebrafish line containing a premature stop codon (Y220X) that results in an unstable and degraded protein. Homozygous tardbpY220X/Y220X zebrafish do not produce tdp-43 but develop normally due to expression of an alternative splice variant of tardbpl (tardbp paralog). Using an antisense morpholino oligonucleotide to knockdown expression of the tardbpl in tardbpY220X/Y220X embryos, we examined locomotor defects, NMJ structural abnormalities and release of quantal synaptic vesicles at the NMJ. As in previous reports, larvae depleted of tdp-43 display reduced survival, gross morphological defects and severely impaired locomotor activity. These larvae also displayed an increased number of orphaned pre- and postsynaptic NMJ markers but surprisingly, we observed a significant increase (3.5 times) in the frequency of quantal acetylcholine release at the NMJ in larvae depleted of tdp-43. These results indicate that reduced TDP-43 levels alter quantal vesicle release at the NMJ during vertebrate development and may be relevant for understanding synaptic dysfunction in ALS.


Loss of Raf-1 kinase inhibitory protein in pancreatic ductal adenocarcinoma.
Raf-1 kinase inhibitor protein (RKIP) has emerged as a significant metastatic suppressor in a variety of human cancers. The aim of this study was to evaluate RKIP expression and to determine its association with metastasis and prognostic significance in pancreatic cancer patients. Immunohistochemical staining for RKIP was performed on 63 cases of pancreatic ductal adenocarcinoma (PDAC). We investigated whether RKIP expression correlated with clinicopathological parameters and patient outcomes. The islet cells, acinar cells and ductal epithelial cells of normal pancreas consistently showed strong RKIP immunoreactivity. In contrast, in PDAC, RKIP was lost in 57.1% (37/63) of cases. Loss of RKIP expression was significantly associated with the presence of nodal (p=0.001) and distant (p=0.010) metastases and a higher stage group (p=0.012). Univariate analysis for distant metastasis-free survival (DMFS) showed that the median DMFS of RKIP negative PDAC patients (10 months) was significantly shorter than that of RKIP positive PDAC patients (17 months; p=0.009). Multivariate analysis also revealed that loss of RKIP expression was an independent predictor of worse DMFS in PDAC patients (p=0.015). Our results strongly suggest that RKIP is a metastasis suppressor in PDAC.


Vignettes: Diverse library staff offering diverse bioinformatics services.
The paper gives examples of the bioinformatics services provided in a variety of different libraries by librarians with a broad range of educational background and training. Two investigators sent an email inquiry to attendees of the "National Center for Biotechnology Information's (NCBI) Introduction to Molecular Biology Information Resources" or "NCBI Advanced Workshop for Bioinformatics Information Specialists (NAWBIS)" courses. The thirty-five-item questionnaire addressed areas such as educational background, library setting, types and numbers of users served, and bioinformatics training and support services provided. Answers were compiled into program vignettes. The bioinformatics support services addressed in the paper are based in libraries with academic and clinical settings. Services have been established through different means: in collaboration with biology faculty as part of formal courses, through teaching workshops in the library, through one-on-one consultations, and by other methods. Librarians with backgrounds from art history to doctoral degrees in genetics have worked to establish these programs. Successful bioinformatics support programs can be established in libraries in a variety of different settings and by staff with a variety of different backgrounds and approaches.


Modeling the Pancreatic Cancer Microenvironment in Search of Control Targets.
Pancreatic ductal adenocarcinoma is among the leading causes of cancer-related deaths globally due to its extreme difficulty to detect and treat. Recently, research focus has shifted to analyzing the microenvironment of pancreatic cancer to better understand its key molecular mechanisms. This microenvironment can be represented with a multi-scale model consisting of pancreatic cancer cells (PCCs) and pancreatic stellate cells (PSCs), as well as cytokines and growth factors which are responsible for intercellular communication between the PCCs and PSCs. We have built a stochastic Boolean network (BN) model, validated by literature and clinical data, in which we probed for intervention strategies that force this gene regulatory network (GRN) from a diseased state to a healthy state. To do so, we implemented methods from phenotype control theory to determine a procedure for regulating specific genes within the microenvironment. We identified target genes and molecules, such that the application of their control drives the GRN to the desired state by suppression (or expression) and disruption of specific signaling pathways that may eventually lead to the eradication of the cancer cells. After applying well-studied control methods such as stable motifs, feedback vertex sets, and computational algebra, we discovered that each produces a different set of control targets that are not necessarily minimal nor unique. Yet, we were able to gain more insight about the performance of each process and the overlap of targets discovered. Nearly every control set contains cytokines, KRas, and HER2/neu, which suggests they are key players in the system's dynamics. To that end, this model can be used to produce further insight into the complex biological system of pancreatic cancer with hopes of finding new potential targets.


Effects of a brief intervention for reducing violence and alcohol misuse among adolescents: a randomized controlled trial.
Emergency department (ED) visits present an opportunity to deliver brief interventions to reduce violence and alcohol misuse among urban adolescents at risk of future injury. To determine the efficacy of brief interventions addressing violence and alcohol use among adolescents presenting to an urban ED. Between September 2006 and September 2009, 3338 patients aged 14 to 18 years presenting to a level I ED in Flint, Michigan, between 12 pm and 11 pm 7 days a week completed a computerized survey (43.5% male; 55.9% African American). Adolescents reporting past-year alcohol use and aggression were enrolled in a randomized controlled trial (SafERteens). All patients underwent a computerized baseline assessment and were randomized to a control group that received a brochure (n = 235) or a 35-minute brief intervention delivered by either a computer (n = 237) or therapist (n = 254) in the ED, with follow-up assessments at 3 and 6 months. Combining motivational interviewing with skills training, the brief intervention for violence and alcohol included review of goals, tailored feedback, decisional balance exercise, role plays, and referrals. Self-report measures included peer aggression and violence, violence consequences, alcohol use, binge drinking, and alcohol consequences. About 25% (n = 829) of screened patients had positive results for both alcohol and violence; 726 were randomized. Compared with controls, participants in the therapist intervention showed self-reported reductions in the occurrence of peer aggression (therapist, -34.3%; control, -16.4%; relative risk [RR], 0.74; 95% confidence interval [CI], 0.61-0.90), experience of peer violence (therapist, -10.4%; control, +4.7%; RR, 0.70; 95% CI, 0.52-0.95), and violence consequences (therapist, -30.4%; control, -13.0%; RR, 0.76; 95% CI, 0.64-0.90) at 3 months. At 6 months, participants in the therapist intervention showed self-reported reductions in alcohol consequences (therapist, -32.2%; control, -17.7%; odds ratio, 0.56; 95% CI, 0.34-0.91) compared with controls; participants in the computer intervention also showed self-reported reductions in alcohol consequences (computer, -29.1%; control, -17.7%; odds ratio, 0.57; 95% CI, 0.34-0.95). Among adolescents identified in the ED with self-reported alcohol use and aggression, a brief intervention resulted in a decrease in the prevalence of self-reported aggression and alcohol consequences. clinicaltrials.gov Identifier: NCT00251212.


Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants.
In preterm newborns, the ductus arteriosus frequently fails to close and the infants require medical or surgical closure of the patent ductus arteriosus (PDA). A PDA can be treated surgically or medically with one of two prostaglandin inhibitors, indomethacin or ibuprofen. Case reports suggest that paracetamol may be an alternative for the closure of a PDA. Concerns have been raised that in neonatal mice paracetamol may cause adverse effects on the developing brain, and an association between prenatal exposure to paracetamol and later development of autism or autism spectrum disorder has been reported. To determine the efficacy and safety of intravenous or oral paracetamol compared with placebo or no intervention, intravenous indomethacin, intravenous or oral ibuprofen, or with other cyclo-oxygenase inhibitors for closure of a PDA in preterm or low-birth-weight infants. We used the standard search strategy of the Cochrane Neonatal Review Group. This included electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL, Cochrane Library), MEDLINE, EMBASE and CINAHL. We searched abstracts from the meetings of the Pediatric Academic Societies and the Perinatal Society of Australia and New Zealand. We searched clinicaltrials.gov; controlled-trials.com; anzctr.org.au; World Health Organization International Clinical Trials Registry Platform at who.int/ictrp for ongoing trials and the Web of Science for articles quoting identified randomised controlled trials. We searched the first 200 hits on Google Scholar(TM) to identify grey literature. All searches were conducted in December 2013. A repeat search of MEDLINE in August 2014 did not identify any new trials. We identified two randomised controlled trials (RCTs) that compared oral paracetamol to oral ibuprofen for the treatment of an echocardiographically diagnosed PDA in infants born preterm (≤ 34 weeks postmenstrual age (PMA)). We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group. Two unmasked studies of treatment of PDA that enrolled 250 infants were included. The sequence of randomisation and the allocation to treatment groups were concealed in both studies. In one study the cardiologist assessing PDA closure was blinded to group allocation of the infant. In the other study it was not stated if that was the case or not. The quality of the trials, using GRADE, was low for the primary outcome of PDA closure and moderate for all other important outcomes. There was no significant difference between treatment with oral paracetamol versus oral ibuprofen for failure of ductal closure after the first course of drug administration (typical relative risk (RR) 0.90, 95% confidence interval (CI) 0.67 to 1.22; typical risk difference (RD) -0.04, 95% CI -0.16 to 0.08; I(2) = 0 % for RR and 23% for RD).There were no significant differences between the paracetamol and the ibuprofen groups in the secondary outcomes except for 'duration for need of supplemental oxygen' (mean difference -12 days, 95% CI -23 days to -2 days; 1 study, n = 90) and for hyperbilirubinaemia (RR 0.57, 95% CI 0.34 to 0.97; RD -0.15, 95% CI -0.29 to -0.01; number needed to treat to benefit (NNTB) 7, 95% CI 3 to 100 in favour of paracetamol; 1 study, n = 160). Although a limited number of infants with a PDA have been studied in randomised trials of low to moderate quality according to GRADE, oral paracetamol appears to be as effective in closing a PDA as oral ibuprofen. In view of a recent report in mice of adverse effects on the developing brain from paracetamol, and another report of an association between prenatal paracetamol and the development of autism or autism spectrum disorder in childhood, long-term follow-up to at least 18 to 24 months postnatal age must be incorporated in any studies of paracetamol in the newborn population. Such trials are required before any recommendations for the use of paracetamol in the newborn population can be made.


ABRF Proteome Informatics Research Group (iPRG) 2016 Study: Inferring Proteoforms from Bottom-up Proteomics Data.
This report presents the results from the 2016 Association of Biomolecular Resource Facilities Proteome Informatics Research Group (iPRG) study on proteoform inference and false discovery rate (FDR) estimation from bottom-up proteomics data. For this study, 3 replicate Q Exactive Orbitrap liquid chromatography-tandom mass spectrometry datasets were generated from each of 4 Escherichia coli samples spiked with different equimolar mixtures of small recombinant proteins selected to mimic pairs of homologous proteins. Participants were given raw data and a sequence file and asked to identify the proteins and provide estimates on the FDR at the proteoform level. As part of this study, we tested a new submission system with a format validator running on a virtual private server (VPS) and allowed methods to be provided as executable R Markdown or IPython Notebooks. The task was perceived as difficult, and only eight unique submissions were received, although those who participated did well with no one method performing best on all samples. However, none of the submissions included a complete Markdown or Notebook, even though examples were provided. Future iPRG studies need to be more successful in promoting and encouraging participation. The VPS and submission validator easily scale to much larger numbers of participants in these types of studies. The unique "ground-truth" dataset for proteoform identification generated for this study is now available to the research community, as are the server-side scripts for validating and managing submissions.


Reduction of morbidity and mortality from biliary complications after liver transplantation.
Over a 4-yr period that began October 1, 1986, 103 orthotopic liver transplants were performed on 91 patients at the Johns Hopkins Hospital. Biliary reconstruction at the time of transplantation was performed in standard fashion by an appropriately trained member of the surgical team. Six (7%) patients developed biliary complications, which included three cases of common bile duct stricture and one case each of bile duct obstruction caused by biopsy-related hemobilia, biloma and a retained fragment of a T tube after removal. Five of the six patients were treated successfully by nonoperative interventional radiological procedures performed under local anesthesia with light intravenous sedation. Reoperative surgery (to remove the T-tube fragment from subcutaneous tissue) was required for only one patient, and no deaths (0 of 91) were attributable to biliary complications. All six patients are alive and well 6 to 33 mo after the operation with excellent liver function. Our findings would suggest that most biliary complications of orthotopic liver transplants are avoidable and that the few that do appear can usually be managed both safely and effectively by an interventional radiological approach.


Enterovirus and parechovirus meningitis in infants younger than 90 days old in the UK and Republic of Ireland: a British Paediatric Surveillance Unit study.
This study aimed to prospectively collect detailed clinical information for all enterovirus (EV) and human parechovirus (HPeV) meningitis cases in infants aged <90 days in the UK and Ireland. Prospective, active national surveillance during July 2014 to July 2015 through the British Paediatric Surveillance Unit. Reporting paediatricians completed questionnaires requesting information on clinical presentation, investigations, management and outcomes at hospital discharge and after 12 months. To describe the clinical burden of EV and HPeV meningitis in infants aged <90 days. During the 13-month surveillance period, 703 cases (668 EV, incidence0.79/1,000 live- births; 35 HPeV, 0.04/1,000 live-births) were identified. The most common clinical presentations were fever (EV: 570/668(85%); HPeV: 28/35(80%)), irritability (EV: 441/668(66%); HPeV: 23/35(66%)) and reduced feeding (EV: 363/668(54%); HPeV 23/35(66%)). Features of circulatory shock were present in 27% (182/668) of EV and 43% (15/35) of HPeV cases. Overall, 11% (76/668) of EV and 23% (8/35) of HPeV cases required intensive care support. Nearly all cases (678/703, 96%) were confirmed by cerebrospinal fluid (CSF) PCR, with 52% (309/600) having normal CSF white cell count for age. Two infants with EV meningitis died (2/668, 0.3%) and four survivors (4/666, 0.6%) had long-term complications at 12 months' follow-up. Infants with HPeV meningitis survived without sequelae. Overall 189 infants had a formal hearing test and none had sensorineural hearing loss. The incidence of laboratory-confirmed EV/HPeV meningitis in young infants is more than twice that for bacterial meningitis. Less than 1% will develop severe neurological complications or die of their infection. Further studies are required to formally assess long-term neurodevelopmental sequelae.


Cannabinoid hyperemesis: cyclical hyperemesis in association with chronic cannabis abuse.
To explore the association between chronic cannabis abuse and a cyclical vomiting illness that presented in a series of cases in South Australia. Nineteen patients were identified with chronic cannabis abuse and a cyclical vomiting illness. For legal and ethical reasons, all patients were counselled to cease all cannabis abuse. Follow up was provided with serial urine drug screen analysis and regular clinical consultation to chart the clinical course. Of the 19 patients, five refused consent and were lost to follow up and five were excluded on the basis of confounders. The remaining nine cases are presented here and compared with a published case of psychogenic vomiting. In all cases, including the published case, chronic cannabis abuse predated the onset of the cyclical vomiting illness. Cessation of cannabis abuse led to cessation of the cyclical vomiting illness in seven cases. Three cases, including the published case, did not abstain and continued to have recurrent episodes of vomiting. Three cases rechallenged themselves after a period of abstinence and suffered a return to illness. Two of these cases abstained again, and became and remain well. The third case did not and remains ill. A novel finding was that nine of the 10 patients, including the previously published case, displayed an abnormal washing behaviour during episodes of active illness. We conclude that chronic cannabis abuse was the cause of the cyclical vomiting illness in all cases, including the previously described case of psychogenic vomiting.


Variants at the secretory phospholipase A2 (PLA2G2A) locus: analysis of associations with familial adenomatous polyposis and sporadic colorectal tumours.
The Min mouse is a model for human familial adenomatous polyposis (FAP), an autosomal dominant disease characterised by multiple adenomatous gastrointestinal polyps. The severity of the Min phenotype is modified by a locus (Mom1) on mouse chromosome 4, at a position syntenic with human chromosome 1p35-p36. The secretory phospholipase A2 (Pla2s) gene is a candidate for this modifier locus and there is evidence that a locus on human chromosome 1p35-p36 acts to modify the severity of human duodenal FAP. We have analysed the human secretory phospholipase A2 locus (PLA2G2A) for variants that could directly influence the FAP phenotype. We found no PLA2G2A variants predicted to result in functional variation in the phospholipase A2 protein. Two PLA2G2A polymorphisms were, however, discovered, one a 'silent' base change in exon 3 and another in a noncoding region. Three other variants (possible mutations) were found in non-coding regions. In 70 FAP patients from 20 families, no associations were found between the severity of duodenal polyposis and any PLA2G2A variant. One allele at the exon 3 polymorphic site did, however, occur more often then expected in patients with relatively severe colonic FAP. Although of borderline statistical significance, this association, if genuine, is likely to result from linkage disequilibrium between the PLA2G2A alleles studied and undetected genetic variation at a closely linked locus. The frequency of the alleles at both polymorphic sites has also been determined in the germ line of patients with sporadic colorectal adenomas and carcinomas and in random controls, but no differences were found among these groups. Our results suggest that PLA2G2A variants do not influence inherited or sporadic colonic tumours. A linked locus may be a modifier of human FAP, but does not influence the risk of colorectal tumours in the general population.


CRITICAL CARE ECHO ROUNDS: Extracorporeal membrane oxygenation.
Extracorporeal membrane oxygenation (ECMO) is an advanced form of organ support indicated in selected cases of severe cardiovascular and respiratory failure. Echocardiography is an invaluable diagnostic and monitoring tool in all aspects of ECMO support. The unique nature of ECMO, and its distinct effects upon cardio-respiratory physiology, requires the echocardiographer to have a sound understanding of the technology and its interaction with the patient. In this article, we introduce the key concepts underpinning commonly used modes of ECMO and discuss the role of echocardiography. A 38-year-old lady, with no significant past medical history, was admitted to her local hospital with group A Streptococcal pneumonia. Rapidly progressive respiratory failure ensued and, despite intubation and maximal ventilatory support, adequate oxygenation proved impossible. She was attended by the regional severe respiratory failure service who established her on veno-venous (VV)-ECMO for respiratory support. Systemic oxygenation improved; however, significant cardiovascular compromise was encountered and echocardiography demonstrated a severe septic cardiomyopathy (ejection fraction <15%, aortic velocity time integral 5.9 cm and mitral regurgitation dP/dt 672 mmHg/s). Her ECMO support was consequently converted to a veno-veno-arterial configuration, thus providing additional haemodynamic support. As the sepsis resolved, arterial ECMO support was weaned under echocardiographic guidance; subsequent resolution of intrinsic respiratory function allowed the weaning of VV-ECMO support. The patient was liberated from ECMO 7 days after hospital admission.


Hair matrix germinative epidermal cells confer follicle-inducing capabilities on dermal sheath and high passage papilla cells.
Low passage cultured dermal papilla cells from adult rats stimulate complete hair follicle neogenesis when re-implanted into heterotypic skin. In contrast, cultured sheath cells are non-inductive despite sharing other behavioural characteristics (a common lineage and in situ proximity) with papilla cells. However, since sheath cells can behave inductively in amputated follicles after regenerating the papilla, this poses the question of what influences the sheath to papilla cell transition? During reciprocal tissue interactions specific epidermal cues are crucial to skin appendage development, and while in vivo assays to date have focussed on dermal interactive influence, our aim was to investigate epidermal potential. We have previously observed that hair follicle epidermal cells display exceptional interactive behaviour when combined with follicle dermal cells in vitro. Thus in the present study, hair follicle germinative, outer root sheath or skin basal epidermal cells were separately combined with each of three non-inductive dermal cell types (high passage papilla, low passage sheath or fibroblast) and then implanted into small ear skin wounds. The sheath/germinative and papilla/germinative cell implants repeatedly induced giant vibrissa-type follicles and fibres. In complete contrast, any single cell type and all other forms of recombination were consistently non-inductive. Hence, the adult germinative epidermal cells enable non-inductive adult dermal cells to stimulate hair follicle neogenesis, effectively, by altering their 'status', causing the sheath cells to 'specialise' and the 'aged' papilla cells to 'rejuvenate'.


Sex-Specific Difference in the Association Between Poor Sleep Quality and Abdominal Obesity in Rural Chinese: A Large Population-Based Study.
Existing studies on sleep quality and associated obesity are inconsistent, and few studies have prospectively evaluated the association between sleep quality and abdominal obesity among Chinese individuals. To fill this void, the current study aimed to assess the association between sleep quality and abdominal obesity in a rural Chinese population. A representative sample of 9,404 adults aged 20-93 years in northeastern China was selected between 2012 and 2013 by a multistage cluster and random sampling method. Sleep quality was evaluated by the Pittsburgh Sleep Quality Index (PSQI), where a score of 6 or higher indicated sleep disorder. Abdominal obesity was measured by waist circumference (WC), with abdominal obesity defined as WC > 90 cm for men and WC > 80 cm for women. Male participants with abdominal obesity had higher global PSQI scores in addition to higher subscores in almost all of the elements compared to normal values. The odds ratios of abdominal obesity among participants with sleep disorders were 1.64 (95% confidence interval [CI]: 1.39-1.95) and 1.14 (95% CI: 0.98-1.32) for males and females compared to the reference group. The risk in all sleep elements was significantly increased, with odds ratios ranging from 1.28 (95% CI: 1.08-1.51) to 5.81 (95% CI: 3.54-9.53) for males. The risk only in four elements was significantly increased, from 1.28 (95% CI: 1.12-1.47) to 2.27 (95% CI: 1.36-3.80) for females. Poor sleep quality was associated with abdominal obesity in Chinese. Furthermore, effects in males were larger than those in females.


Epidemiology and disposition of burn injuries among infants presenting to a tertiary-care pediatric emergency department.
The objective of the study was to study the etiology of and factors determining the emergency department disposition of infants sustaining burn injuries. A retrospective chart review was performed on all patients 12 months or younger with a burn injury presenting to our emergency department over a 5-year period. We collected the chief complaint and diagnosis, patient demographics, and circumstances surrounding the burn injury from the emergency department charts. Univariable statistics, multiple imputation, and multivariable regression were performed to determine differences between races and factors leading to admission. During the study period, 344 patients meeting inclusion criteria were treated in our emergency department. Scalds (53.2%) and contact burns (39.8%) were the most common causes of burns among the study group. Significant differences were observed between races for mechanism of burn, interhospital transport, and total body surface area affected (P < 0.05). White patients were more likely to have higher body surface affected and to be transferred from another facility (P < 0.05). Increased severity of burn, burns located on the hand, and concern for abuse resulted in higher likelihood of admission (P < 0.01). No significant differences in disposition or mechanism of burn were present between English-speaking and non-English-speaking patients. Although most infant burns in our emergency department are due to scalds, burn injuries due to contact with household objects are common. Race plays a significant role in mechanism and severity of burn sustained. Increased severity of burn, concern for abuse, and burn to the hand were all associated with increased odds of admission.


Biosynthesis of branched-chain amino acids in yeast: regulation of synthesis of the enzymes of isoleucine and valine biosynthesis.
Regulation of the levels of the five enzymes required for the biosynthesis of isoleucine and valine was studied in a Saccharomyces sp. When a mixture of isoleucine, valine, and leucine was added to the medium, the enzymes in the wild-type strain were repressed from about 30% (transaminase B) to about 90% (acetohydroxy acid synthetase) relative to the level in minimal medium-grown cells. Repression was also observed when threonine replaced isoleucine in the mixture but not when it replaced the other two amino acids. Significant derepression relative to the level in minimal-grown cells was not obtained by growing suitably blocked auxotrophs on medium containing limiting amounts of valine, isoleucine, or leucine.


Both pre- and postsynaptic activity of Nsf prevents degeneration of hair-cell synapses.
Vesicle fusion contributes to the maintenance of synapses in the nervous system by mediating synaptic transmission, release of neurotrophic factors, and trafficking of membrane receptors. N-ethylmaleimide-sensitive factor (NSF) is indispensible for dissociation of the SNARE-complex following vesicle fusion. Although NSF function has been characterized extensively in vitro, the in vivo role of NSF in vertebrate synaptogenesis is relatively unexplored. Zebrafish possess two nsf genes, nsf and nsfb. Here, we examine the function of either Nsf or Nsfb in the pre- and postsynaptic cells of the zebrafish lateral line organ and demonstrate that Nsf, but not Nsfb, is required for maintenance of afferent synapses in hair cells. In addition to peripheral defects in nsf mutants, neurodegeneration of glutamatergic synapses in the central nervous system also occurs in the absence of Nsf function. Expression of an nsf transgene in a null background indicates that stabilization of synapses requires Nsf function in both hair cells and afferent neurons. To identify potential targets of Nsf-mediated fusion, we examined the expression of genes implicated in stabilizing synapses and found that transcripts for multiple genes including brain-derived neurotrophic factor (bdnf) were significantly reduced in nsf mutants. With regard to trafficking of BDNF, we observed a striking accumulation of BDNF in the neurites of nsf mutant afferent neurons. In addition, injection of recombinant BDNF protein partially rescued the degeneration of afferent synapses in nsf mutants. These results establish a role for Nsf in the maintenance of synaptic contacts between hair cells and afferent neurons, mediated in part via the secretion of trophic signaling factors.


Genetic variant Arg57His in human H+/peptide cotransporter 2 causes a complete loss of transport function.
We evaluated the functional consequences of genetic variations in human H(+)/peptide cotransporter 2 (hPEPT2, SLC15A2) resulting in the amino acid changes Arg57His (R57H) and Pro409Ser (P409S). The transport activity of variant R57H was completely abolished, whereas that of variant P409S was comparable with that of wild-type hPEPT2 at pH 5.0-8.0. R57H variant protein was detected in the crude membranes of transiently expressed HEK293 cells by Western blot analysis. The expression of the R57H variant at the plasma membrane was confirmed by indirect immunofluorescence in Xenopus oocytes, suggesting that the loss of transport function of hPEPT2 R57H was not due to a change in membrane protein expression. This is the first demonstration of a functional impairment of the SLC15A family induced by a single nucleotide polymorphism.


On the nature of human interlimb coordination.
Movement time varies as a function of amplitude and requirements for precision, according to Fitts' law, but when subjects perform two-handed movements to targets of widely disparate difficulty they do so simultaneously. The hand moving to an "easy" target moves more slowly to accommodate its "difficult" counterpart, yet both hands reach peak velocity and acceleration synchronously. This result suggests that the brain produces simultaneity of action not by controlling each limb independently, but by organizing functional groupings of muscles that are constrained to act as a single unit.


Domain specifications of the construct tactile defensiveness.
A comprehensive list of descriptors of behaviors associated with tactile defensiveness in elementary schoolchildren was compiled as a preliminary to subsequent psychometric measurement of tactile defensiveness. This, the first phase of scale development, was accomplished in the following manner. The construct tactile defensiveness was defined, and a variety of behaviors related to the domain of the construct were collected. The list of behaviors was submitted to an expert for review. Descriptors of statements a child might make based on the behaviors were generated. Then, the list of descriptors was edited, and the remaining descriptors were rated by a panel of experts according to the degree to which the descriptor was associated with tactile defensiveness. Logical and computer analyses of the descriptors' ratings were performed. Of the 73 descriptors specified, two were dropped because of cultural bias and 24 were dropped because they were not rated by the experts as being associated with tactile defensiveness. This paper discusses the importance of the remaining list of 47 descriptors for subsequent research and delineates appropriate clinical use of those descriptors.


Characteristics of children with hip displacement in cerebral palsy.
Hip dislocation in children with cerebral palsy (CP) is a common and severe problem. The dislocation can be avoided, by screening and preventive treatment of children with hips at risk. The aim of this study was to analyse the characteristics of children with CP who develop hip displacement, in order to optimise a hip surveillance programme. In a total population of children with CP a standardised clinical and radiological follow-up of the hips was carried out as a part of a hip prevention programme. The present study is based on 212 children followed until 9-16 years of age. Of the 212 children, 38 (18%) developed displacement with Migration Percentage (MP) >40% and further 19 (9%) MP between 33 and 39%. Mean age at first registration of hip displacement was 4 years, but some hips showed MP > 40% already at two years of age. The passive range of hip motion at the time of first registration of hip displacement did not differ significantly from the findings in hips without displacement. The risk of hip displacement varied according to CP-subtype, from 0% in children with pure ataxia to 79% in children with spastic tetraplegia. The risk of displacement (MP > 40%) was directly related to the level of gross motor function, classified according to the gross motor function classification system, GMFCS, from 0% in children in GMFCS level I to 64% in GMFCS level V. Hip displacement in CP often occurs already at 2-3 years of age. Range of motion is a poor indicator of hips at risk. Thus early identification and early radiographic examination of children at risk is of great importance. The risk of hip displacement varies according to both CP-subtype and GMFCS. It is sometimes not possible to determine subtype before 4 years of age, and at present several definitions and classification systems are used. GMFCS is valid and reliable from 2 years of age, and it is internationally accepted. We recommend a hip surveillance programme for children with CP with radiographic examinations based on the child's age and GMFCS level.


Accurate annotation of protein-coding genes in mitochondrial genomes.
Mitochondrial genome sequences are available in large number and new sequences become published nowadays with increasing pace. Fast, automatic, consistent, and high quality annotations are a prerequisite for downstream analyses. Therefore, we present an automated pipeline for fast de novo annotation of mitochondrial protein-coding genes. The annotation is based on enhanced phylogeny-aware hidden Markov models (HMMs). The pipeline builds taxon-specific enhanced multiple sequence alignments (MSA) of already annotated sequences and corresponding HMMs using an approximation of the phylogeny. The MSAs are enhanced by fixing unannotated frameshifts, purging of wrong sequences, and removal of non-conserved columns from both ends. A comparison with reference annotations highlights the high quality of the results. The frameshift correction method predicts a large number of frameshifts, many of which are unknown. A detailed analysis of the frameshifts in nad3 of the Archosauria-Testudines group has been conducted.


Thrombolytic therapy for acute pulmonary embolism: a critical appraisal.
Pulmonary embolism (PE) is a prevalent condition that may account for > 300,000 deaths annually in the United States alone. Although thrombolytics have been studied as a treatment for acute PE since the 1960s, to date there have been only 11 randomized controlled trials comparing thrombolytic therapy to conventional anticoagulation, and the numbers of patients included in these trials has been small. Many studies confirm that thrombolytic therapy leads to rapid improvement in hemodynamic aberrations associated with PE, and this approach to massive PE with cardiogenic shock is a guideline-based practice. It is widely accepted that acute PE without associated right ventricular (RV) dysfunction or hemodynamic instability can be readily managed with standard anticoagulation. The appropriate therapy for submassive PE (PE associated with RV dysfunction but preserved systemic arterial BP) remains an area of contention, and definitive data proving mortality benefit in this setting are lacking. Further efforts at risk stratification may better determine who is in need of aggressive therapy. This article reviews historical aspects of and current evidence for thrombolytic therapy in acute PE with specific attention to bleeding risk, and data regarding hemodynamic parameters and mortality. We also discuss risk stratification techniques and propose a clinical algorithm for the incorporation of thrombolytic therapy.


RNA nucleotide methylation.
Methylation of RNA occurs at a variety of atoms, nucleotides, sequences and tertiary structures. Strongly related to other posttranscriptional modifications, methylation of different RNA species includes tRNA, rRNA, mRNA, tmRNA, snRNA, snoRNA, miRNA, and viral RNA. Different catalytic strategies are employed for RNA methylation by a variety of RNA-methyltransferases which fall into four superfamilies. This review outlines the different functions of methyl groups in RNA, including biophysical, biochemical and metabolic stabilization of RNA, quality control, resistance to antibiotics, mRNA reading frame maintenance, deciphering of normal and altered genetic code, selenocysteine incorporation, tRNA aminoacylation, ribotoxins, splicing, intracellular trafficking, immune response, and others. Connections to other fields including gene regulation, DNA repair, stress response, and possibly histone acetylation and exocytosis are pointed out. WIREs RNA 2011 2 611-631 DOI: 10.1002/wrna.79 For further resources related to this article, please visit the WIREs website.


Animal models of copper-associated liver disease.
Recent advances in molecular biology have made possible the identification of genetic defects responsible for Wilson's disease, Indian childhood cirrhosis and copper toxicosis in Long Evans Cinnamon rats, toxic milk mice, and Bedlington terriers. The Wilson's disease gene is localized on human chromosome 13 and codes for ATP7B, a copper transporting P-type ATPase. A genetic defect similar to that of Wilson's disease occurs in Long Evans Cinnamon rats and toxic milk mice. Familial copper storage disorders in Bedlington and West Highland white terriers are associated with early subclinical disease, and copper accumulation with subsequent liver injury culminating in cirrhosis. The canine copper toxicosis locus in Bedlington terriers has been mapped to canine chromosome region CFA 10q26. Recently, a mutated MURR1 gene was discovered in Bedlington terriers affected with the disease. Idiopathic childhood cirrhosis is biochemically similar to copper toxicosis in Bedlington terriers, but clinically much more severe. Both conditions are characterized by the absence of neurologic damage and Kayser-Fleisher rings, and normal ceruloplasmin levels. A recent study added North Ronaldsay sheep to the list of promising animal models to study Indian childhood cirrhosis. Morphologic similarities between the two conditions include periportal to panlobular copper retention and liver changes varying from active hepatitis to panlobular pericellular fibrosis, and cirrhosis. Certain copper-associated disorders, such as chronic active hepatitis in Doberman pinschers and Skye terrier hepatitis are characterized by copper retention secondary to the underlying disease, thus resembling primary biliary cirrhosis in humans. Copper-associated liver disease has increasingly being recognized in Dalmatians. Copper-associated liver diseases in Dalmatians and Long Evans Cinnamom rats share many morphologic features. Fulminant hepatic failure in Dalmatians is characterized by high serum activities of alanine aminotransferase and aspartate aminotransferase, and severe necrosis of centrilobular areas (periacinar, zone 3) hepatocytes. Macrophages and surviving hepatocytes contain copper-positive material. Liver disease associated with periacinar copper accumulation has also been described in Siamese cats. Many questions regarding copper metabolism in mammals, genetic background, pathogenesis and treatment of copper-associated liver diseases remain to be answered. This review describes the similarities between the clinico-pathological features of spontaneous copper-associated diseases in humans and domestic animals.


Efficacy of artemisinin-based and quinine-based treatments for uncomplicated falciparum malaria in pregnancy: a protocol for systematic review and individual patient data (IPD) meta-analysis.
Pregnant women are more vulnerable to malaria leading to adverse impact on both mothers and fetuses. However, knowledge on the efficacy and safety of antimalarials in pregnancy is limited by the paucity of randomised control trials and the lack of standardised protocols in this special subpopulation. Pooling individual patient data (IPD) for meta-analysis could address in part these limitations to summarise accurately the currently available evidence on treatment efficacy and risk factors for treatment failure. To assess the treatment efficacy of artemisinin-based and quinine-based treatments for uncomplicated falciparum malaria in pregnancy, seven databases (Medline, Embase, Global Health, Cochrane Library, Scopus, Web of Science and Literatura Latino Americana em Ciências da Saúde) and two clinical trial registries (International Clinical Trials Registry Platform and ClinicalTrial.gov) were searched. Both interventional and observational cohort studies following up for at least 28 days will be included. IPD of the identified eligible published or unpublished studies will be sought by inviting principal investigators. Raw IPD will be shared through the web-based secure platform developed by the WorldWide Antimalarial Resistance Network using the established methodology. The primary objective is to compare the risk of PCR-corrected treatment failure among different treatments and to find the risk factors. One-stage IPD meta-analysis by Cox model with shared frailty will be conducted. A risk of bias assessment will be conducted to address the impact of unshared potential data and of the quality of individual studies. Potential limitations include difficulty in acquiring the IPD and heterogeneity of the study designs due to the lack of standard. This IPD meta-analysis consists of secondary analyses of existing anonymous data and meets the criteria for waiver of ethics review by the Oxford Tropical Research Ethics Committee. The results of this IPD meta-analysis will be disseminated through open-access publications at peer-reviewed journals. The study results will lead to a better understanding of malaria treatment in pregnancy, which can be used for clinical decision-making and conducting further studies. CRD42018104013.


Analysis of chemical constituents and antinociceptive potential of essential oil of Teucrium Stocksianum bioss collected from the North West of Pakistan.
Medicinal plants are used for the treatment of different diseases in almost all cultures. Teucrium species grow wildly at different geographical locations around the world. Teucrium stocksianum is used in folk medicine for the treatment of diarrhea, cough, jaundice and abdominal pain. Scientific study on Teucrium stocksianum shows that it possesses anthelmintic, cytotoxic and antispasmodic activity. The aim of our present study is to identify the chemical composition and antinociceptive potential of the essential oil extracted from Teucrium stocksianum bioss. Essential oil (EO) from the aerial parts of Teucrium stocksianum were extracted by hydrodistillation process. The qualitative and quantitative composition of essential oil was determined with Gas chromatography/Mass spectrometer. Antinociceptive activity was determined by acetic acid induced writhing method. Percent inhibition of writhes of the test concentration was determined by comparing it with that of control. Tween-80 emulsion 2.5% (5 ml/kg b.w) was used as a control while Diclofenic sodium 50 mg/kg (b.w) was used as a standard drug. The chromatogram of the essential oil of Teucrium stocksianum shows differences both qualitatively and quantatively from essential oil composition reported in other countries. Hydrodistillation of Teucrium stocksianum yielded 0.4% (v/w), pale yellowish oil on dry basis. A total of 26 chemicals were identified by GC-MS accounting for 90.28% of the oil. The major components of essential oil were δ-cadinene (12.92%), α-pinene (10.3%), myrcene (8.64%), β-caryophyllene (8.23%), germacrene D (5.18%) and limonene (2.36%). Essential oil of Teucrium stocksianum has shown outstanding antinociceptive activity. It has been observed that increase in percent writhe inhibition (PWI) occurred from 20-80 mg/kg (b.w) and maximum writhe inhibition has been noted at a concentration of 80 mg/kg (b.w), but PWI decreased at 160 mg/kg, which may be due to some toxic effect of higher dose. ED50 value for Teucrium stocksianum was calculated as 31.5 ± 1.72415 mg/kg (b.w). Our results indicate that there is a lot of variation in the composition of essential oil of Teucrium stocksianum boiss, which may be due to different climatic and experimental conditions. Secondly, the essential oil possesses strong antinociceptive activity and could be used in analgesic preparations especially for topical use.


Traffic-related air pollution and prostate cancer risk: a case-control study in Montreal, Canada.
There is a paucity of information on environmental risk factors for prostate cancer. We conducted a case-control study in Montreal to estimate associations with exposure to ground-level nitrogen dioxide (NO2), a marker for traffic-related air pollution. Cases were 803 men with incident prostate cancer, ≤75 years of age, and diagnosed across all French hospitals in Montreal. Concurrently, 969 controls were drawn from electoral lists of French-speaking individuals residing in the same electoral districts as the cases and frequency-matched by age. Concentrations of NO2 were measured across Montreal in 2005-2006. We developed a land use regression model to predict concentrations of NO2 across Montreal for 2006. These estimates were back-extrapolated to 1996. Estimates were linked to residential addresses at the time of diagnosis or interview. Unconditional logistic regression was used, adjusting for potential confounding variables. For each increase of 5 parts per billion of NO2, as estimated from the original land use regression model in 2006, the OR5ppb adjusted for personal factors was 1.44 (95% CI 1.21 to 1.73). Adding in contextual factors attenuated the OR5ppb to 1.27 (95% CI 1.03 to 1.58). One method for back-extrapolating concentrations of NO2 to 1996 (about 10 years before the index date) gave the following OR5ppb: 1.41 (95% CI 1.24 to 1.62) when personal factors were included, and 1.30 (95% CI 1.11 to 1.52) when contextual factors were added. Exposure to ambient concentrations of NO2 at the current address was associated with an increased risk of prostate cancer. This novel finding requires replication.


Bridging the resolution gap: Imaging the same transcription factories in cryosections by light and electron microscopy.
The resolution of conventional light microscopy is limited to approximately 200 nm in the x- and y-axes and >500 nm in the z-axis. A simple way of improving z-axis resolution is to analyze thin sections of 100-200 nm. The utility of such an approach is illustrated by reference to transcription sites imaged in cryosections of human nuclei. Cells are permeabilized, allowed to extend nascent transcripts in Br-UTP, fixed, cryosectioned, and Br-RNA-immunolabeled with fluorochromes and gold particles. As expected, physical sectioning improves resolution and brings other advantages. First, sections allow improved antibody access and better immunolabeling. Second, more sites (with a more representative range of intensities) can now be resolved against lower backgrounds, facilitating quantitative analysis. Third, problems associated with chromatic aberration when two differently colored images of the same objects are collected can be sidestepped by refocusing between image collection. Fourth, exactly the same sites can be imaged by light and electron microscopy, allowing direct comparison between the two techniques. Immunogold labeling and electron microscopy provided the most accurate counts of site number. The results confirm that nascent transcripts in the nucleoplasm are confined to several thousand sites, or "factories," with diameters of approximately 40 nm. (J Histochem Cytochem 47:471-480, 1999)


Comparison of different preparation methods of biological samples for FIB milling and SEM investigation.
When a new approach in microscopy is introduced, broad interest is attracted only when the sample preparation procedure is elaborated and the results compared with the outcome of the existing methods. In the work presented here we tested different preparation procedures for focused ion beam (FIB) milling and scanning electron microscopy (SEM) of biological samples. The digestive gland epithelium of a terrestrial crustacean was prepared in a parallel for FIB/SEM and transmission electron microscope (TEM). All samples were aldehyde-fixed but followed by different further preparation steps. The results demonstrate that the FIB/SEM samples prepared for conventional scanning electron microscopy (dried) is suited for characterization of those intracellular morphological features, which have membranous/lamellar appearance and structures with composition of different density as the rest of the cell. The FIB/SEM of dried samples did not allow unambiguous recognition of cellular organelles. However, cellular organelles can be recognized by FIB/SEM when samples are embedded in plastic as for TEM and imaged by backscattered electrons. The best results in terms of topographical contrast on FIB milled dried samples were obtained when samples were aldehyde-fixed and conductively stained with the OTOTO method (osmium tetroxide/thiocarbohydrazide/osmium tetroxide/thiocarbohydrazide/osmium tetroxide). In the work presented here we provide evidence that FIB/SEM enables both, detailed recognition of cell ultrastructure, when samples are plastic embedded as for TEM or investigation of sample surface morphology and subcellular composition, when samples are dried as for conventional SEM.


Using relationship styles based on attachment theory to improve understanding of specialty choice in medicine.
Patient-provider relationships in primary care are characterized by greater continuity and depth than in non-primary care specialties. We hypothesized that relationship styles of medical students based on attachment theory are associated with specialty choice factors and that such factors will mediate the association between relationship style and ultimately matching in a primary care specialty. We determined the relationship styles, demographic characteristics and resident specialty match of 106 fourth-year medical students. We assessed the associations between 1) relationship style and specialty choice factors; 2) specialty choice factors and specialty match, and 3) relationship style and specialty match. We also conducted mediation analyses to determine if factors examined in a specialty choice questionnaire mediate the association between relationship style and ultimately matching in a primary care specialty. Prevalence of attachment styles was similar to that found in the general population and other medical school settings with 59% of students rating themselves as having a secure relationship style. Patient centeredness was directly associated, and career rewards inversely associated with matching in a primary care specialty. Students with a self-reliant relationship style were significantly more likely to match in a non-primary care specialty as compared to students with secure relationship style (OR = 5.3, 95% CI 1.8, 15.6). There was full mediation of the association between relationship style and specialty match by the specialty choice factor characterized by patient centeredness. Assessing relationship styles based on attachment theory may be a potentially useful way to improve understanding and counsel medical students about specialty choice.


Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions.
5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) belongs to a group of naturally-occurring psychoactive indolealkylamine drugs. It acts as a nonselective serotonin (5-HT) agonist and causes many physiological and behavioral changes. 5-MeO-DMT is O-demethylated by polymorphic cytochrome P450 2D6 (CYP2D6) to an active metabolite, bufotenine, while it is mainly inactivated through the deamination pathway mediated by monoamine oxidase A (MAO-A). 5-MeO-DMT is often used with MAO-A inhibitors such as harmaline. Concurrent use of harmaline reduces 5-MeO-DMT deamination metabolism and leads to a prolonged and increased exposure to the parent drug 5-MeO-DMT, as well as the active metabolite bufotenine. Harmaline, 5-MeO-DMT and bufotenine act agonistically on serotonergic systems and may result in hyperserotonergic effects or serotonin toxicity. Interestingly, CYP2D6 also has important contribution to harmaline metabolism, and CYP2D6 genetic polymorphism may cause considerable variability in the metabolism, pharmacokinetics and dynamics of harmaline and its interaction with 5-MeO-DMT. Therefore, this review summarizes recent findings on biotransformation, pharmacokinetics, and pharmacological actions of 5-MeO-DMT. In addition, the pharmacokinetic and pharmacodynamic drug-drug interactions between harmaline and 5-MeO-DMT, potential involvement of CYP2D6 pharmacogenetics, and risks of 5-MeO-DMT intoxication are discussed.


The pathogenic role of IgA1 O-linked glycosylation in the pathogenesis of IgA nephropathy.
Numerous abnormalities of the IgA immune system have been reported in IgAN but the most consistent finding remains aberrant IgA1 O-linked glycosylation of the IgA1 hinge region. The defect comprises reduced galactosylation of O-linked N-acetylgalactosamine residues with or without changes in the terminal sialylation of the O-linked sugars. Aberrant O-galactosylation has been found in serum IgA1, in IgA1 isolated from tonsillar lymphocytes, and in IgA1 eluted from mesangial deposits. There is evidence that changes in IgA1 O-galactosylation lead to IgA immune complex formation and mesangial IgA deposition. Mesangial cells exposed to these IgA immune complexes proliferate and adopt a pro-inflammatory phenotype; they secrete cytokines, chemokines, growth factors and extracellular matrix components promoting glomerular inflammation and glomerulosclerosis. Recent evidence suggests that the control of IgA1 O-glycosylation is linked to class switching from IgD to IgA1 synthesis and that the pattern of IgA1 O-glycosylation may be programmed at the time of initial antigen encounter. IgA1 glycosylation varies between systemic and mucosal sites and the association of aberrant IgA1 galactosylation with low affinity, polymeric IgA1 antibodies against mucosal antigens suggests undergalactosylated IgA1 may in fact be a mucosal glycoform of IgA1. Although suited to the mucosal compartment, when these IgA1 glycoforms enter the systemic circulation in appreciable quantities they deposit in the mesangium and trigger glomerular inflammation. This review will discuss the evidence for the role of IgA1 O-glycosylation in the pathogenesis of IgAN and propose an explanation for the presence of aberrantly O-glycosylated IgA1 in the circulation of patients with IgAN.


A cohort study of lymphatic filariasis on socio economic conditions in Andhra Pradesh, India.
To assess the impact of socioeconomic variables on lymphatic filariasis in endemic villages of Karimnagar district, Andhra Pradesh, India. A pilot scale study was conducted in 30 villages of Karimnagar district from 2004 to 2007. These villages were selected based on previous reports from department of health, Government of Andhra Pradesh, epidemiology, entomology and socioeconomic survey was conducted as per protocol. Collected data were analysed statistically by Chi square test, Principal Component Analysis, Odds ratio, Bivariate, multivariate logistic regression analysis. Total of 5,394 blood samples collected and screened for microfilaria, out of which 199 were found to be positive (3.7%). The socioeconomic data of these respondents/participants were correlated with MF prevalence. The socioeconomic variables like educational status (Odds Ratio (OR) = 2.6, 95% Confidence Interval (CI) = 1.1-6.5), house structure (hut OR = 1.9, 95% CI = 1.2-3.1; tiled OR = 1.3, 95% CI = 0.8-2) and participation in mass drug administration program (OR = 1.8, 95% CI = 1.3-2.6) were found to be highly associated with the occurrence of filarial disease. The socioeconomic index was categorized into low (3.6%; OR-1.1, 95% CI: 0.7-1.5) medium (4.9%; OR-1.5, 95% CI = 1-2.1) and high (3.3%) in relation to percentage of filarial parasite prevalence. A significant difference was observed among these three groups while comparing the number of cases of filaria with the type of socioeconomic conditions of the respondents (P = 0.067). From this study it is inferred that age, education of family, type of house structure and awareness about the filarial disease directly influenced the disease prevalence. Beside annual mass drug administration program, such type of analysis should be undertaken by health officials to target a few socioeconomic factors to reduce the disease burden. Health education campaigns in the endemic villages and imparting of protection measures against mosquitoes using insecticide treated bed nets would substantially reduce the disease in these villages.


Immunotoxins: a clinical review of their use in the treatment of malignancies.
Immunotoxins are a new class of antitumor agents consisting of tumor-selective ligands (generally monoclonal antibodies [MoAbs]) linked to highly toxic protein molecules that have been modified to remove their normal tissue-binding domains. These immuno-conjugates combine the potency of the parent toxin with the specificity of the attached ligand. Toxins used in the construction of immunotoxins belong to a group of peptides that catalytically inhibit the elongation step of protein synthesis, and include ricin, abrin, pokeweed antiviral protein, gelonin, Pseudomonas exotoxin A, diptheria toxin, and alpha-sarcin. To synthesize immunotoxins, the normal cell-binding function must be removed by chemical cleavage or modification, or in the case of toxins that have been cloned, genetic engineering used to delete amino acids critical to cell binding. Covalent linkage of toxin to ligand generally involves a disulfide or thioether bond, though recently, recombinant toxin molecules with ligands that are genetically engineered into the protein have been made. The most successful clinical application of immunotoxins has been in the depletion of T cells from allogeneic bone marrow grafts to prevent graft-versus-host disease (GVHD). Clinical trials have been conducted using immunotoxins for the systemic treatment of chronic lymphocytic leukemia (CLL), GVHD, and selected solid tumors. With the possible exception of GVHD, responses have been limited. Obstacles have included rapid systemic clearance, poor delivery to extravascular tumor deposits, and humoral immune responses to the immunotoxin. Research to overcome these problems is in progress and should lead to a better definition of the role of immunotoxins in the therapy of malignancies.


Toroidal dipolar response in a metamaterial.
Toroidal multipoles are fundamental electromagnetic excitations different from those associated with the familiar charge and magnetic multipoles. They have been held responsible for parity violation in nuclear and particle physics, but direct evidence of their existence in classical electrodynamics has remained elusive. We report on the observation of a resonant electromagnetic response in an artificially engineered medium, or metamaterial, that cannot be attributed to magnetic or charge multipoles and can only be explained by the existence of a toroidal dipole. Our direct experimental evidence of the toroidal response brings attention to the often ignored electromagnetic interactions involving toroidal multipoles, which could be present in naturally occurring systems, especially at the macromolecule level, where toroidal symmetry is ubiquitous.


The methamphetamine epidemic among persons who inject heroin in Hai Phong, Vietnam.
To describe the current methamphetamine (MA) use epidemic among persons who inject heroin (PWID) in Hai Phong, Vietnam, and consider possibilities for mitigating adverse effects of methamphetamine use. This study conducted surveys of PWID in 2016, 2017, and 2018 (N = 1383, 1451, and 1445, respectively). Trained interviewers administered structured interviews covering drug use histories, current drug use, and related risk behaviors. The study used urinalysis to confirm current drug use, and conducted HIV and HCV testing. Participants were predominantly male (95%), mean age of 40, and all reported injecting heroin. Respondents' reports of initiating MA use were rare up through early 2000s but increased exponentially through the mid-2010s. MA use was predominantly "smoking," heating the drug and inhaling the vapor using a pipe; injecting MA was rare. Current (past 30 day) MA use appears to have plateaued in 2016-2018 with 53-58% of participants reporting no use in the last 30 days, 37-41% reporting low to moderate use (1 to 19 days in last 30 days), and 5-7% reporting very frequent use (20 or more days in last 30 days). This plateau reflects a rough balance between new users and individuals ceasing use. MA use has become a substantial public health problem among PWID in Hai Phong. Initiation into MA use rose exponentially from 2005 to about 2015. Use of MA will likely continue for a substantial number of PWID. Currently, no medication is approved for treating MA disorders in Vietnam. Current psychosocial treatment requires highly trained counselors and months of treatment, so that psychosocial treatment for all PWID with MA disorders is likely beyond the resources available in a middle-income country such as Vietnam. Harm reduction programs implemented by community-based organization staff may provide a way to rapidly address aspects of the current MA epidemic. Such programs could emphasize social support for reducing use where possible and for avoiding escalation of use among persons continuing to use.


Medication adherence in patients with diabetes and dyslipidemia: associated factors and strategies for improvement.
Dyslipidemia and diabetes mellitus are commonly coincident, and together contribute to the development of atherosclerotic disease. Medication therapy is the mainstay of treatment for dyslipidemia. Optimal medication therapy for dyslipidemia in patients with diabetes reduces cardiovascular events but necessitates patients take multiple medications. As a result, sub-optimal adherence to medication therapy is common. Factors contributing to medication non-adherence in patients taking multiple medications are complex and can be grouped into patient-, social and economic-, medication therapy-, and health provider and health system-related factors. Strategies aimed at improving medication adherence may target the patient, health care providers, or health systems. Recent data suggest medication non-adherence contributes to racial health disparities. In addition, health literacy, cost-related medication non-adherence, and patient beliefs regarding medication therapy have all been recently described as factors affecting medication adherence. Data from within the last year support an important role for regular contact between patients and health care providers to effectively address these factors. Cost-related barriers to medication adherence have recently been addressed through examination of health system approaches to decreasing cost-related non-adherence.


Human dopamine transporter: the first implementation of a combined in silico/in vitro approach revealing the substrate and inhibitor specificities.
Parkinson's disease (PD) is characterized by the loss of dopamine-generating neurons in the substantia nigra and corpus striatum. Current treatments alleviate PD symptoms rather than exerting neuroprotective effect on dopaminergic neurons. New drugs targeting the dopaminergic neurons by specific uptake through the human dopamine transporter (hDAT) could represent a viable strategy for establishing selective neuroprotection. Molecules able to increase the bioactive amount of extracellular dopamine, thereby enhancing and compensating a loss of dopaminergic neurotransmission, and to exert neuroprotective response because of their accumulation in the cytoplasm, are required. By means of homology modeling, molecular docking, and molecular dynamics simulations, we have generated 3D structure models of hDAT in complex with substrate and inhibitors. Our results clearly reveal differences in binding affinity of these compounds to the hDAT in the open and closed conformations, critical for future drug design. The established in silico approach allowed the identification of promising substrate compounds that were subsequently analyzed for their efficiency in inhibiting hDAT-dependent fluorescent substrate uptake, through in vitro live cell imaging experiments. Taken together, our work presents the first implementation of a combined in silico/in vitro approach enabling the selection of promising dopaminergic neuron-specific substrates.


Aquimarina rubra sp. nov., isolated from sediment of a sea cucumber culture pond.
A Gram-stain-negative, non-motile, rod-shaped, red-pigmented, facultatively anaerobic bacterium, designated SS2-9T, was isolated from sediment collected from a sea cucumber culture pond located in Rongcheng, Shandong province, China. Cells of strain SS2-9T were approximately 0.3-0.5 µm in width and 1.5-6.0 µm in length. The strain was able to grow at 10-37 °C, at pH 6.5-8.5 and in the presence of 0.5-6.0 % (w/v) NaCl. It grew optimally at 28 °C and in the presence of 2.0 % (w/v) NaCl. The DNA G+C content was 34.5 mol% and the sole respiratory quinone was menaquinone 6 (MK-6). The predominant cellular fatty acids were C15 : 0, iso-C15 : 1 G, iso-C15 : 0 and iso-C17 : 0 3-OH. The major polar lipids were phosphatidylethanolamine, an unidentified phospholipid, two unidentified aminolipids and four unidentified lipids. Phylogenetic analyses based on 16S rRNA gene sequences revealed that strain SS2-9T was phylogenetically related to members of the genus Aquimarina and was closely related to Aquimarina amphilecti 92VT (97.29 % similarity). On the basis of phenotypic, chemotaxonomic and phylogenetic data, strain SS2-9T was considered to represent a novel species of the genus Aquimarina, for which the name Aquimarina rubra sp. nov. is proposed. The type strain is SS2-9T (=KCTC 52274T=MCCC 1H00142T).


The information-motivation-behavioral skills model of antiretroviral adherence and its applications.
Suboptimal adherence to highly active antiretroviral therapy (HAART) may have serious consequences for HIV patients, and for public health overall. The Information-Motivation-Behavioral Skills (IMB) model of HAART adherence can be used to understand the dynamics of HAART adherence and to intervene with patients to promote more optimal levels of adherence. This article reviews the core hypotheses of the IMB model of HAART adherence and describes available correlational and experimental evaluations of the model, outcomes of adherence intervention trials that applied the model, and IMB model-based interventions that are currently under evaluation. It then explores one potential promising application of the model that uses a protocol originally developed and demonstrated as a structured patient-centered, provider-delivered risk reduction intervention to deliver information, motivation, and behavioral skills-based adherence-promotion strategies. This protocol could be incorporated into clinical practice as a valuable tool in working with patients individually.


The Gulf War Women's Health Cohort: Study Design and Protocol.
Military service and deployment affect women differently than men, underscoring the need for studies of the health of women veterans and their receipt of health care services. Despite the large numbers of women who served during the 1990-1991 Gulf War, few studies have evaluated Gulf War illness (GWI) and other medical conditions specifically as they affect women veterans of the 1991 Gulf War. The objectives of the Gulf War Women's Health Cohort study are: (1) to establish the Gulf War women's cohort (GWWC), a large sample of women veterans who served in the 1990-1991 Gulf War and a comparison group of women who served in other locations during that period; and (2) to provide current, comprehensive data on the health status of women who served during the 1990-1991 Gulf War, and identify any specific conditions that affect Gulf War women veterans at excess rates. The study will utilize both existing datasets and newly collected data to examine the prevalence and patterns of Gulf War Illness symptoms, diagnosed medical conditions, reproductive health, birth outcomes and other health issues among women who served during the Gulf War. The Gulf War Women's Health Cohort study will address the need for information about the comprehensive health of women veterans who were deployed to the Gulf War, and other wars during the Gulf War era.


Effectiveness of the First step Program delivered by professionals versus peers.
To compare the effectiveness of a theory-based lifestyle physical activity (PA) program delivered to individuals with type 2 diabetes in diabetes education centers by professionals and peers. Changes over 16 weeks in PA (steps/day) and related variables (weight, waist girth, resting heart rate, systolic and diastolic blood pressures) were compared (RMANOVA) for two groups: 157 participants led by 13 different professionals versus 63 participants led by 5 peer leaders. Overall, the 81 male and 139 female participants (age = 55.7 +/- 7.3 years, BMI = 35.2 +/- 6.6) showed an incremental change of 4,059 +/- 3,563 steps/day, which translates into an extra 37 minutes of daily walking (P < .001). Statistically significant improvements were also seen in weight, waist girth, and blood pressure (all P < .001) and resting heart rate (P < .05). There were no significant differences in outcomes between professional and peer-led groups. A theory-based behavior modification program featuring simple feedback and monitoring tools, and with a proven element of flexibility in delivery, can be effective under real-world conditions while addressing inevitable concerns about resource allocation. Program delivery by peer leaders, in particular, could address a potential obstacle to dissemination by helping to alleviate existing high caseload demands on diabetes educators.