Stem compression reversibly reduces phloem transport in Pinus sylvestris trees.
Manipulating tree belowground carbon (C) transport enables investigation of the ecological and physiological roles of tree roots and their associated mycorrhizal fungi, as well as a range of other soil organisms and processes. Girdling remains the most reliable method for manipulating this flux and it has been used in numerous studies. However, girdling is destructive and irreversible. Belowground C transport is mediated by phloem tissue, pressurized through the high osmotic potential resulting from its high content of soluble sugars. We speculated that phloem transport may be reversibly blocked through the application of an external pressure on tree stems. Thus, we here introduce a technique based on compression of the phloem, which interrupts belowground flow of assimilates, but allows trees to recover when the external pressure is removed. Metal clamps were wrapped around the stems and tightened to achieve a pressure theoretically sufficient to collapse the phloem tissue, thereby aiming to block transport. The compression's performance was tested in two field experiments: a (13)C canopy labelling study conducted on small Scots pine (Pinus sylvestris L.) trees [2-3 m tall, 3-7 cm diameter at breast height (DBH)] and a larger study involving mature pines (∼15 m tall, 15-25 cm DBH) where stem respiration, phloem and root carbohydrate contents, and soil CO2 efflux were measured. The compression's effectiveness was demonstrated by the successful blockage of (13)C transport. Stem compression doubled stem respiration above treatment, reduced soil CO2 efflux by 34% and reduced phloem sucrose content by 50% compared with control trees. Stem respiration and soil CO2 efflux returned to normal within 3 weeks after pressure release, and (13)C labelling revealed recovery of phloem function the following year. Thus, we show that belowground phloem C transport can be reduced by compression, and we also demonstrate that trees recover after treatment, resuming C transport in the phloem.


Human Cytomegalovirus UL135 Interacts with Host Adaptor Proteins To Regulate Epidermal Growth Factor Receptor and Reactivation from Latency.
Human cytomegalovirus, HCMV, is a betaherpesvirus that establishes a lifelong latent infection in its host that is marked by recurrent episodes of reactivation. The molecular mechanisms by which the virus and host regulate entry into and exit from latency remain poorly understood. We have previously reported that UL135 is critical for reactivation, functioning in part by overcoming suppressive effects of the latency determinant UL138 We have demonstrated a role for UL135 in diminishing cell surface levels and targeting epidermal growth factor receptor (EGFR) for turnover. The attenuation of EGFR signaling promotes HCMV reactivation in combination with cellular differentiation. In this study, we sought to define the mechanisms by which UL135 functions in regulating EGFR turnover and viral reactivation. Screens to identify proteins interacting with pUL135 identified two host adaptor proteins, CIN85 and Abi-1, with overlapping activities in regulating EGFR levels in the cell. We mapped the amino acids in pUL135 necessary for interaction with Abi-1 and CIN85 and generated recombinant viruses expressing variants of pUL135 that do not interact with CIN85 or Abi-1. These recombinant viruses replicate in fibroblasts but are defective for reactivation in an experimental model for latency using primary CD34+ hematopoietic progenitor cells (HPCs). These UL135 variants have altered trafficking of EGFR and are defective in targeting EGFR for turnover. These studies demonstrate a requirement for pUL135 interactions with Abi-1 and CIN85 for regulation of EGFR and mechanistically link the regulation of EGFR to reactivation.IMPORTANCE Human cytomegalovirus (HCMV) establishes a lifelong latent infection in the human host. While the infection is typically asymptomatic in healthy individuals, HCMV infection poses life-threatening disease risk in immunocompromised individuals and is the leading cause of birth defects. Understanding how HCMV controls the lifelong latent infection and reactivation of replication from latency is critical to developing strategies to control HCMV disease. Here, we identify the host factors targeted by a viral protein that is required for reactivation. We define the importance of this virus-host interaction in reactivation from latency, providing new insights into the molecular underpinnings of HCMV latency and reactivation.


The neural basis of romantic love.
The neural correlates of many emotional states have been studied, most recently through the technique of fMRI. However, nothing is known about the neural substrates involved in evoking one of the most overwhelming of all affective states, that of romantic love, about which we report here. The activity in the brains of 17 subjects who were deeply in love was scanned using fMRI, while they viewed pictures of their partners, and compared with the activity produced by viewing pictures of three friends of similar age, sex and duration of friendship as their partners. The activity was restricted to foci in the medial insula and the anterior cingulate cortex and, subcortically, in the caudate nucleus and the putamen, all bilaterally. Deactivations were observed in the posterior cingulate gyrus and in the amygdala and were right-lateralized in the prefrontal, parietal and middle temporal cortices. The combination of these sites differs from those in previous studies of emotion, suggesting that a unique network of areas is responsible for evoking this affective state. This leads us to postulate that the principle of functional specialization in the cortex applies to affective states as well.


Antipsychotic-like profile of CIQ isomers in animal models of schizophrenia.
Earlier, we have shown the efficacy of racemic (±) CIQ, a positive allosteric modulator of GluN2C/2D receptor against MK-801 induced impairment of prepulse inhibition as well as working memory. The present study investigated the antipsychotic-like profile of different CIQ (±, +, -) isomers against schizophrenia-like symptoms in series of behavioural animal models like apomorphine climbing, social isolation behaviour and NMDA receptor antagonist MK-801 induced cognitive deficits. Further, we also tested CIQ (±, +, -) isomers in neurodevelopmental model against MK-801induced deficits using open field test, Y-maze test and novel object recognition test. CIQ (±, +, -) isomers decreased climbing behaviour, increased social interaction and improved the MK-801 induced deficits in working memory in Y-maze. Further, CIQ (±, +) but not CIQ (-) improved the recognition memory in novel object recognition test as well as reduced hyperlocomotion and stereotyped behaviour. We conclude that CIQ (±, +) but not CIQ (-) exhibit the significant antipsychotic-like profile.


Integrative analysis of single-cell expression data reveals distinct regulatory states in bidirectional promoters.
Bidirectional promoters (BPs) are prevalent in eukaryotic genomes. However, it is poorly understood how the cell integrates different epigenomic information, such as transcription factor (TF) binding and chromatin marks, to drive gene expression at BPs. Single-cell sequencing technologies are revolutionizing the field of genome biology. Therefore, this study focuses on the integration of single-cell RNA-seq data with bulk ChIP-seq and other epigenetics data, for which single-cell technologies are not yet established, in the context of BPs. We performed integrative analyses of novel human single-cell RNA-seq (scRNA-seq) data with bulk ChIP-seq and other epigenetics data. scRNA-seq data revealed distinct transcription states of BPs that were previously not recognized. We find associations between these transcription states to distinct patterns in structural gene features, DNA accessibility, histone modification, DNA methylation and TF binding profiles. Our results suggest that a complex interplay of all of these elements is required to achieve BP-specific transcriptional output in this specialized promoter configuration. Further, our study implies that novel statistical methods can be developed to deconvolute masked subpopulations of cells measured with different bulk epigenomic assays using scRNA-seq data.


Alternative splicing of human inducible nitric-oxide synthase mRNA. tissue-specific regulation and induction by cytokines.
Human inducible nitric-oxide synthase (iNOS) is responsible for nitric oxide synthesis in response to inflammatory mediators. The human iNOS gene, containing 26 exons, encodes a protein of 131 kDa. This study was aimed at investigating the presence of alternative splicing of human iNOS mRNA. Total RNA from human alveolar macrophages, nasal and bronchial epithelial cells, and several human tissues was transcribed to cDNA and analyzed using polymerase chain reaction with specific primers for segmental analysis of the iNOS gene. Four sites of alternative splicing were identified by sequence analysis; these included deletion of: (i) exon 5; (ii) exons 8 and 9; (iii) exons 9, 10, and 11; and (iv) exons 15 and 16. The deduced amino acid sequences of the novel iNOS cDNAs predict one truncated protein (resulting from exon 5 deletion) and three iNOS proteins with in-frame deletions. Southern analyses of polymerase chain reaction products were consistent with tissue-specific regulation of alternative splicing. In cultured cells, iNOS induction by cytokines and lipopolysaccharide was associated with an increase in alternatively spliced mRNA transcripts. Because iNOS is active as a dimer, the novel forms of alternatively spliced iNOS may be involved in regulation of nitric oxide synthesis.


Fluoroscopic registration and localization for image-guided cranial neurosurgical procedures: a feasibility study.
Frameless image-guided neurosurgical techniques can achieve high degrees of accuracy when skull-implanted fiducials are used for registration. However, fiducial placement is invasive and uncomfortable for patients. Development of a noninvasive registration method for accurate image-guided functional neurosurgery such as deep brain stimulator placement would therefore be highly desirable. We performed an initial series of experiments using a commercially available fluoroscopic registration package to assess the feasibility of this approach for image-guided functional neurosurgery. We also evaluated the accuracy of landmark placement in the fluoroscopic images using the navigational capability of the software. A fluoroscopic target was created by etching a hexagonal pattern of 1-mm diameter holes on a copper-clad board (0.0254-mm copper cladding on fiberglass). The target was then mounted in a plastic phantom skull, oriented in a mid-sagittal plane. Five implantable fiducial markers were screwed into the phantom in positions which approximated those commonly used clinically. 1.25-mm CT slices were obtained, uploaded to a Stealthstation neuronavigational system and were displayed using the Fluoromerge software package. Lateral and AP images were generated with 2 approximately orthogonal views of the phantom. Registration was carried out both fluoroscopically and using the implanted fiducials. Targets were localized using both methods and the localization errors recorded. Localization error was less than 1 mm using fiducial-based registration, and between 0.8 and 2.9 mm using fluoroscopic registration. Error varied depending on location within the volume of the phantom. Initial experiments show that fluoroscopic registration is feasible for the performance of frameless functional neurosurgical procedures, although accuracy is still insufficient. Intraoperative verification of lead location was also shown to be feasible in one case.


Evaluation of Risk Factors for Peste des Petits Ruminants Virus in Sheep and Goats at the Wildlife-Livestock Interface in Punjab Province, Pakistan.
Peste des petits ruminants virus (PPRV) is causing infectious disease with high morbidity and mortality rate in domestic and wild small ruminants of Pakistan with valuable economical losses. The present study was carried out to investigate risk factors of PPRV in domestic small ruminants which were present in the vicinity of wildlife parks. A total of 265 sera samples (27 wild ruminants and 238 domesticated small ruminants) from apparently healthy animals from two different wildlife parks were collected and analysed for PPRV antibodies. Also, 20 nasal swabs from domestic small ruminants showing respiratory signs were collected to check for presence of PPRV antigen. Competitive ELISA revealed highest proportions of anti-PPRV antibodies in domestic small ruminants around the Wildlife Park at Lahore (35%) as compared to Faisalabad (13%), with no existence of PPRV antibodies in tested serum of wild ruminants at these parks. Higher seropositivity was observed in females (25.6%) than in males (5.1%) and in goats (34.5%) compared to sheep (11.2%). The results of N-gene based RT-PCR highlight the absence of PPRV due to lack of current PPR outbreak in the region during study period. Even though grazing was not a significant risk factor, there is still a possibility of wildlife-livestock interactions for feed and water reservoirs, resulting in spillover of PPR to wildlife. Keeping in view the high seropositivity and risk of PPR, vaccination should be adopted to avoid circulation of PPRV among wild and domestic small ruminants (sheep and goats).


Attentional selection and action selection in the ventral and orbital prefrontal cortex.
Different accounts of the ventral and orbital prefrontal cortex (PFv+o) have emphasized either its role in learning conditional rules for action selection or the attentional selection of behaviorally relevant stimuli. Although the accounts are not mutually exclusive, it is possible that the involvement of PFv+o in conditional action selection is a consequence of its role in selecting relevant stimuli or that its involvement in attentional selection is a consequence of the conditional rules present in many attentional paradigms. Five macaques learned a conditional action-selection task in which the difficulty of identifying the stimulus relevant for guiding action selection was varied in a simple manner by either altering its distance from the action or presenting additional distracting stimuli. Simply increasing the spatial separation between the instructing stimulus led to slower responses. Experiment 1 showed that bilateral PFv+o lesions impaired conditional action selection even when attentional demands were kept to a minimum, but there was evidence that the impairment was exacerbated by manipulating stimulus selection difficulty. Experiment 2 confirmed the importance of PFv+o for conditional action selection even when stimulus selection difficulty was minimal. Experiments 3 and 4 demonstrated that the action-selection impairment was significantly increased by making identification of the behaviorally relevant stimulus difficult. PFv+o is central to the use of conditional rules when selecting courses of action, but conditional rules are also represented in premotor and striatal regions. A special contribution of PFv+o may be initial selection of behaviorally relevant stimuli.


Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial.
The Women's Health Initiative Estrogen-Alone Trial was stopped early after a mean of 7.1 years of follow-up because of an increased risk of stroke and little likelihood of altering the balance of risk to benefit by the planned trial termination date. Postintervention health outcomes have not been reported. To examine health outcomes associated with randomization to treatment with conjugated equine estrogens (CEE) among women with prior hysterectomy after a mean of 10.7 years of follow-up through August 2009. The intervention phase was a double-blind, placebo-controlled, randomized clinical trial of 0.625 mg/d of CEE compared with placebo in 10,739 US postmenopausal women aged 50 to 79 years with prior hysterectomy. Follow-up continued after the planned trial completion date among 7645 surviving participants (78%) who provided written consent. The primary outcomes were coronary heart disease (CHD) and invasive breast cancer. A global index of risks and benefits included these primary outcomes plus stroke, pulmonary embolism, colorectal cancer, hip fracture, and death. The postintervention risk (annualized rate) for CHD among women assigned to CEE was 0.64% compared with 0.67% in the placebo group (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.75-1.25), 0.26% vs 0.34%, respectively, for breast cancer (HR, 0.75; 95% CI, 0.51-1.09), and 1.47% vs 1.48%, respectively, for total mortality (HR, 1.00; 95% CI, 0.84-1.18). The risk of stroke was no longer elevated during the postintervention follow-up period and was 0.36% among women receiving CEE compared with 0.41% in the placebo group (HR, 0.89; 95% CI, 0.64-1.24), the risk of deep vein thrombosis was lower at 0.17% vs 0.27%, respectively (HR, 0.63; 95% CI, 0.41-0.98), and the risk of hip fracture did not differ significantly and was 0.36% vs 0.28%, respectively (HR, 1.27; 95% CI, 0.88-1.82). Over the entire follow-up, lower breast cancer incidence in the CEE group persisted and was 0.27% compared with 0.35% in the placebo group (HR, 0.77; 95% CI, 0.62-0.95). Health outcomes were more favorable for younger compared with older women for CHD (P = .05 for interaction), total myocardial infarction (P = .007 for interaction), colorectal cancer (P = .04 for interaction), total mortality (P = .04 for interaction), and global index of chronic diseases (P = .009 for interaction). Among postmenopausal women with prior hysterectomy followed up for 10.7 years, CEE use for a median of 5.9 years was not associated with an increased or decreased risk of CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality. A decreased risk of breast cancer persisted. clinicaltrials.gov Identifier: NCT00000611.


Short-acting insulin analogues versus regular human insulin for adult, non-pregnant persons with type 2 diabetes mellitus.
The use of short-acting insulin analogues (insulin lispro, insulin aspart, insulin glulisine) for adult, non-pregnant people with type 2 diabetes is still controversial, as reflected in many scientific debates. To assess the effects of short-acting insulin analogues compared to regular human insulin in adult, non-pregnant people with type 2 diabetes mellitus. For this update we searched CENTRAL, MEDLINE, Embase, the WHO ICTRP Search Portal, and ClinicalTrials.gov to 31 October 2018. We placed no restrictions on the language of publication. We included all randomised controlled trials with an intervention duration of at least 24 weeks that compared short-acting insulin analogues to regular human insulin in the treatment of people with type 2 diabetes, who were not pregnant. Two review authors independently extracted data and assessed the risk of bias. We assessed dichotomous outcomes by risk ratios (RR), and Peto odds ratios (POR), with 95% confidence intervals (CI). We assessed continuous outcomes by mean differences (MD) with 95% CI. We assessed trials for certainty of the evidence using the GRADE approach. We identified 10 trials that fulfilled the inclusion criteria, randomising 2751 participants; 1388 participants were randomised to receive insulin analogues and 1363 participants to receive regular human insulin. The duration of the intervention ranged from 24 to 104 weeks, with a mean of about 41 weeks. The trial populations showed diversity in disease duration, and inclusion and exclusion criteria. None of the trials were blinded, so the risk of performance bias and detection bias, especially for subjective outcomes, such as hypoglycaemia, was high in nine of 10 trials from which we extracted data. Several trials showed inconsistencies in the reporting of methods and results.None of the included trials defined all-cause mortality as a primary outcome. Six trials provided Information on the number of participants who died during the trial, with five deaths out of 1272 participants (0.4%) in the insulin analogue groups and three deaths out of 1247 participants (0.2%) in the regular human insulin groups (Peto OR 1.66, 95% CI 0.41 to 6.64; P = 0.48; moderate-certainty evidence). Six trials, with 2509 participants, assessed severe hypoglycaemia differently, therefore, we could not summarise the results with a meta-analysis. Overall, the incidence of severe hypoglycaemic events was low, and none of the trials showed a clear difference between the two intervention arms (low-certainty evidence).The MD in glycosylated haemoglobin A1c (HbA1c) change was -0.03% (95% CI -0.16 to 0.09; P = 0.60; 9 trials, 2608 participants; low-certainty evidence). The 95% prediction ranged between -0.31% and 0.25%. The MD in the overall number of non-severe hypoglycaemic episodes per participant per month was 0.08 events (95% CI 0.00 to 0.16; P = 0.05; 7 trials, 2667 participants; very low-certainty evidence). The 95% prediction interval ranged between -0.03 and 0.19 events per participant per month. The results provided for nocturnal hypoglycaemic episodes were of questionable validity. Overall, there was no clear difference between the two short-acting insulin analogues and regular human insulin. Two trials assessed health-related quality of life and treatment satisfaction, but we considered the results for both outcomes to be unreliable (very low-certainty evidence).No trial was designed to investigate possible long term effects (all-cause mortality, microvascular or macrovascular complications of diabetes), especially in participants with diabetes-related complications. No trial reported on socioeconomic effects. Our analysis found no clear benefits of short-acting insulin analogues over regular human insulin in people with type 2 diabetes. Overall, the certainty of the evidence was poor and results on patient-relevant outcomes, like all-cause mortality, microvascular or macrovascular complications and severe hypoglycaemic episodes were sparse. Long-term efficacy and safety data are needed to draw conclusions about the effects of short-acting insulin analogues on patient-relevant outcomes.


Epidemiology of rib fractures in older men: Osteoporotic Fractures in Men (MrOS) prospective cohort study.
To study the causes and consequences of radiologically confirmed rib fractures (seldom considered in the context of osteoporosis) in community dwelling older men. Prospective cohort study (Osteoporotic Fractures in Men (MrOS) Study). 5995 men aged 65 or over recruited in 2000-2 from six US sites; 99% answered mailed questionnaires about falls and fractures every four months for a mean 6.2 (SD 1.3) year follow-up. New fractures validated by radiology reports; multivariate Cox proportional hazard ratios were used to evaluate factors independently associated with time to incident rib fracture; associations between baseline rib fracture and incident hip and wrist fracture were also evaluated. The incidence of rib fracture was 3.5/1000 person years, and 24% (126/522) of all incident non-spine fractures were rib fractures. Nearly half of new rib fractures (48%; n=61) followed falling from standing height or lower. Independent risk factors for an incident rib fracture were age 80 or above, low bone density, difficulty with instrumental activities of daily living, and a baseline history of rib/chest fracture. Men with a history of rib/chest fracture had at least a twofold increased risk of an incident rib fracture (adjusted hazard ratio 2.71, 95% confidence interval 1.86 to 3.95), hip fracture (2.05, 1.33 to 3.15), and wrist fracture (2.06, 1.14 to 3.70). Only 14/82 of men reported being treated with bone specific drugs after their incident rib fracture. Rib fracture, the most common incident clinical fracture in men, was associated with classic risk markers for osteoporosis, including old age, low hip bone mineral density, and history of fracture. A history of rib fracture predicted a more than twofold increased risk of future fracture of the rib, hip, or wrist, independent of bone density and other covariates. Rib fractures should be considered to be osteoporotic fractures in the evaluation of older men for treatment to prevent future fracture.


[Interobserver reproducibility in the pathologic diagnosis of borderline ductal proliferative breast diseases].
The aim of this study involving general pathologists was to assess interobserver reproducibility in the pathologic diagnosis of borderline ductal proliferative breast diseases. Ten general pathologists independently reviewed 43 specimens chosen to represent the spectrum of borderline ductal proliferative breast lesions. All slides were blindly reviewed without given standardized criteria, and were classified as either mild usual hyperplasia, moderate-severe usual hyperplasia, mild atypical hyperplasia, moderate-severe atypical hyperplasia, ductal carcinoma in situ, or ductal carcinoma in situ with invasion. According to the years of training, these 10 general pathologists were divided into the experienced group and the less trained group. Interobserver agreement was statistically analyzed using Kappa statistic. Then, by comparing all the diagnoses of individual pathologist with the consensus opinion confirmed by two breast pathologists in terms of Page standard, we acquired the diagnostic accuracy and ascertained the undue diagnosis. The ten general pathologists' interobserver reproducibility in the diagnosis of borderline ductal proliferative breast diseases was rather low, especially that in their diagnosis of atypical hyperplasia. The reproducibility and accuracy were slightly higher in the experienced pathologists than in the less trained pathologists. Some pathologists made over-diagnosis or under-diagnosis of the lesions to different degrees. However, when the categories of diagnostic terms were simplified, the interobserver reproducibility increased. The use of standardized criteria is an important approach to increasing the diagnostic reproducibility and accuracy.


Novel recA-Independent Horizontal Gene Transfer in Escherichia coli K-12.
In bacteria, mechanisms that incorporate DNA into a genome without strand-transfer proteins such as RecA play a major role in generating novelty by horizontal gene transfer. We describe a new illegitimate recombination event in Escherichia coli K-12: RecA-independent homologous replacements, with very large (megabase-length) donor patches replacing recipient DNA. A previously uncharacterized gene (yjiP) increases the frequency of RecA-independent replacement recombination. To show this, we used conjugal DNA transfer, combining a classical conjugation donor, HfrH, with modern genome engineering methods and whole genome sequencing analysis to enable interrogation of genetic dependence of integration mechanisms and characterization of recombination products. As in classical experiments, genomic DNA transfer begins at a unique position in the donor, entering the recipient via conjugation; antibiotic resistance markers are then used to select recombinant progeny. Different configurations of this system were used to compare known mechanisms for stable DNA incorporation, including homologous recombination, F'-plasmid formation, and genome duplication. A genome island of interest known as the immigration control region was specifically replaced in a minority of recombinants, at a frequency of 3 X 10(-12) CFU/recipient per hour.


Comparing Breast Cancer Outcomes Between Medicaid and the Ohio Breast and Cervical Cancer Early Detection Program.
To compare outcomes between women enrolling in Medicaid after being diagnosed with breast cancer and those referred to Medicaid through the Ohio Breast and Cervical Cancer Early Detection Program (BCCEDP). Using linked data from the 2002 to 2008 Ohio Cancer Incidence Surveillance System, Medicaid, the BCCEDP database, and Ohio death certificates (through 2010), we identified women 40 to 64 years of age diagnosed with incident invasive breast cancer during the study years and enrolled in Medicaid 3 months before or after cancer diagnosis. We compared the following outcomes across BCCEDP one-time and repeat participants and nonparticipants: (1) cancer stage at diagnosis, (2) treatment delays, (3) receipt of standard treatment, and (4) survival. We conducted multivariable logistic regression and survival analysis to examine the association between BCCEDP participation and the outcomes of interest, controlling for potential confounders. We identified 427 and 654 BCCEDP participants and nonparticipants, respectively; 28.5% of BCCEDP women were repeat participants. Compared with nonparticipants, BCCEDP one-time and repeat participants were significantly less likely to be diagnosed with advanced-stage cancer (one-time: adjusted odds ratio [AOR], 0.64; 95% CI, 0.49 to 0.85; repeat: AOR, 0.34; 95% CI, 0.23 to 0.52), or experience delays in treatment initiation (one-time: adjusted hazard ratio [AHR], 1.29; 95% CI, 1.09 to 1.51; repeat: AHR, 1.38; 95% CI, 1.11 to 1.72). In addition, although we observed no difference in receipt of standard cancer treatment, BCCEDP participants experienced cancer-specific and overall survival benefits. Compared with nonparticipants, BCCEDP participants experienced earlier breast cancer stage at diagnosis, shorter time to treatment initiation, and survival benefits.


On the feasibility of polyurethane based 3D dosimeters with optical CT for dosimetric verification of low energy photon brachytherapy seeds.
To investigate the feasibility of and challenges yet to be addressed to measure dose from low energy (effective energy <50 keV) brachytherapy sources (Pd-103, Cs-131, and I-125) using polyurethane based 3D dosimeters with optical CT. The authors' evaluation used the following sources: models 200 (Pd-103), CS-1 Rev2 (Cs-131), and 6711 (I-125). The authors used the Monte Carlo radiation transport code MCNP5, simulations with the ScanSim optical tomography simulation software, and experimental measurements with PRESAGE(®) dosimeters/optical CT to investigate the following: (1) the water equivalency of conventional (density = 1.065 g/cm(3)) and deformable (density = 1.02 g/cm(3)) formulations of polyurethane dosimeters, (2) the scatter conditions necessary to achieve accurate dosimetry for low energy photon seeds, (3) the change in photon energy spectrum within the dosimeter as a function of distance from the source in order to determine potential energy sensitivity effects, (4) the optimal delivered dose to balance optical transmission (per projection) with signal to noise ratio in the reconstructed dose distribution, and (5) the magnitude and characteristics of artifacts due to the presence of a channel in the dosimeter. Monte Carlo simulations were performed using both conventional and deformable dosimeter formulations. For verification, 2.8 Gy at 1 cm was delivered in 92 h using an I-125 source to a PRESAGE(®) dosimeter with conventional formulation and a central channel with 0.0425 cm radius for source placement. The dose distribution was reconstructed with 0.02 and 0.04 cm(3) voxel size using the Duke midsized optical CT scanner (DMOS). While the conventional formulation overattenuates dose from all three sources compared to water, the current deformable formulation has nearly water equivalent attenuation properties for Cs-131 and I-125, while underattenuating for Pd-103. The energy spectrum of each source is relatively stable within the first 5 cm especially for I-125. The inherent assumption of radial symmetry in the TG43 geometry leads to a linear increase in sample points within the 3D dosimeter as a function of distance away from the source, which partially offsets the decreasing signal. Simulations of dose reconstruction using optical CT showed the feasibility of reconstructing dose out to a radius of 10 cm without saturating projection images using an optimal dose and high dynamic range scanning; the simulations also predicted that reconstruction artifacts at the channel surface due to a small discrepancy in refractive index should be negligible. Agreement of the measured with calculated radial dose function for I-125 was within 5% between 0.3 and 2.5 cm from the source, and the median difference of measured from calculated anisotropy function was within 5% between 0.3 and 2.0 cm from the source. 3D dosimetry using polyurethane dosimeters with optical CT looks to be a promising application to verify dosimetric distributions surrounding low energy brachytherapy sources.


Surgical versus conservative interventions for treating acromioclavicular dislocation of the shoulder in adults.
Dislocation of the acromioclavicular joint is one of the most common shoulder injuries in a sport-active population. The question of whether surgery should be used remains controversial. This is an update of a Cochrane Review first published in 2010. To assess the effects (benefits and harms) of surgical versus conservative (non-surgical) interventions for treating acromioclavicular dislocations in adults. We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (to June 2019), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2019, Issue 6), MEDLINE (1946 to June 2019), Embase (1980 to June 2019), and LILACS (1982 to June 2019), trial registries, and reference lists of articles. There were no restrictions based on language or publication status. We included all randomised and quasi-randomised trials that compared surgical with conservative treatment of acromioclavicular dislocation in adults. At least two review authors independently performed study screening and selection, 'Risk of bias' assessment, and data extraction. We pooled data where appropriate and used GRADE to assess the quality of evidence for each outcome. We included five randomised trials and one quasi-randomised trial. The included trials involved 357 mainly young adults, the majority of whom were male, with acute acromioclavicular dislocation. The strength of the findings in all studies was limited due to design features, invariably lack of blinding, that carry a high risk of bias. Fixation of the acromioclavicular joint using hook plates, tunnelled suspension devices, coracoclavicular screws, acromioclavicular pins, or (usually threaded) wires was compared with supporting the arm in a sling or similar device. After surgery, the arm was also supported in a sling or similar device in all trials. Where described in the trials, both groups had exercise-based rehabilitation. We downgraded the evidence for all outcomes at least two levels, invariably for serious risk of bias and serious imprecision.Low-quality evidence from two studies showed no evidence of a difference between groups in shoulder function at one year, assessed using the Disability of the Arm, Shoulder, and Hand questionnaire (DASH) (0 (best function) to 100 (worst function)): mean difference (MD) 0.73 points, 95% confidence interval (CI) -2.70 to 4.16; 112 participants. These results were consistent with other measures of function at one-year or longer follow-up, including non-validated outcome scores reported by three studies. There is low-quality evidence that function at six weeks may be better after conservative treatment, indicating an earlier recovery. Very low-quality evidence from one trial found no difference between groups in participants reporting pain at one year: risk ratio (RR) 1.32, 95% CI 0.54 to 3.19; 79 participants. There is very low-quality evidence that surgery may not reduce the risk of treatment failure, usually resulting in non-routine secondary surgery: 14/168 versus 15/174; RR 0.99, 95% CI 0.51 to 1.94; 342 participants, 6 studies. The main source of treatment failure was complications related to surgical implants in the surgery group and persistent symptoms, mainly discomfort, due to the acromioclavicular dislocation in the conservatively treated group.There is low-quality evidence from two studies that there may be little or no difference between groups in the return to former activities (sports or work) at one year: 57/67 versus 62/70; RR 0.96, 95% CI 0.85 to 1.10; 137 participants, 2 studies. Low-quality but consistent evidence from four studies indicated an earlier recovery in conservatively treated participants compared with those treated with surgery. There is low-quality evidence of no clinically important difference between groups at one year in quality of life scores, measured using the 36-item or 12-item Short Form Health Survey (SF-36 or SF-12) (0-to-100 scale, where 100 is best score), in either the physical component (MD -0.63, 95% CI -2.63 to 1.37; 122 participants, 2 studies) or mental component (MD 0.47 points, 95% CI -1.51 to 2.44; 122 participants). There is very low-quality and clinically heterogenous evidence of a greater risk of an adverse event after surgery: 45/168 versus 16/174; RR 2.82, 95% CI 1.65 to 4.82; 342 participants, 6 studies; I2 = 48%. Common adverse outcomes were hardware complications or discomfort (18.5%) and infection (8.7%) in the surgery group and persistent symptoms (7.1%), mainly discomfort, in the conservatively treated group. The majority of surgical complications occurred in older studies testing now-outdated devices known for their high risk of complications. The very low-quality evidence from one study (70 participants) means that we are uncertain whether there is a between-group difference in patient dissatisfaction with cosmetic results.It is notable that the evidence for function, return to former activities, and quality of life came from the two most recently conducted studies, which tested currently used devices and interventions in clearly defined participant populations that represented the commonly perceived population for which there is uncertainty over the use of surgery. There were insufficient data to conduct subgroup analysis relating to type of injury and whether surgery involved ligament reconstruction or not. There is low-quality evidence that surgical treatment has no additional benefits in terms of function, return to former activities, and quality of life at one year compared with conservative treatment. There is, however, low-quality evidence that people treated conservatively had improved function at six weeks compared with surgical management. There is very low-quality evidence of little difference between the two treatments in pain at one year, treatment failure usually resulting in secondary surgery, or patient satisfaction with cosmetic result. Although surgery may result in more people sustaining adverse events, this varied between the trials, being more common in techniques such as K-wire fixation that are rarely used today. There remains a need to consider the balance of risks between the individual outcomes: for example, surgical adverse events, including wound infection or dehiscence and hardware complication, against risk of adverse events that may be more commonly associated with conservative treatment such as persistent symptoms or discomfort, or both.There is a need for sufficiently powered, good-quality, well-reported randomised trials of currently used surgical interventions versus conservative treatment for well-defined injuries.


Quality improvement in forensic mental health: the East London forensic violence reduction collaborative.
Ward-based violence is the most significant cause of reported safety incidents at East London NHS Foundation Trust (ELFT). It impacts on patient and staff safety, well-being, clinical care and the broader hospital community in various direct and indirect ways. The contributing factors are varied and complex. Several factors differentiate the forensic setting, which has been identified as a particularly stressful work environment. Staff must constantly balance addressing therapeutic needs with robust risk management in a complex patient cohort. ELFT identified reducing inpatient physical violence on mental health wards as a major quality improvement (QI) priority. The aim was to use a QI methodology to reduce incidents of inpatient violence and aggression across two secure hospital sites by at least 30% between July 2016 and March 2018. Collaborative learning was central to this project. It sought to foster a culture of openness within the organisation around violence and to support service users and staff to work together to understand and address it. A QI methodology was applied in medium and low secure inpatient settings. A change bundle was tested for effectiveness, which included: safety huddles, safety crosses and weekly community safety discussions. Operational definitions for non-physical violence, physical violence and sexual harassment were developed and used. Reductions of 8% and 16.6% in rates of physical and non-physical violent incidents, respectively, were achieved and sustained. Compared with baseline, this equated to one less incident of physical and 17 less of non-physical violence per week averaged across seven wards. Three wards achieved at least a 30% reduction in incidents of physical violence per week. Five wards achieved at least a 30% reduction in incidents of non-physical violence per week. This collaborative brought significant improvements and a cultural shift towards openness around inpatient violence.


Assessment of immunization data management practices in Cameroon: unveiling potential barriers to immunization data quality.
One crucial obstacle to attaining universal immunization coverage in Sub-Saharan Africa is the paucity of timely and high-quality data. This challenge, in part, stems from the fact that many frontline immunization staff in this part of the world are commonly overburdened with multiple data-related responsibilities that often compete with their clinical tasks, which in turn could affect their data collection practices. This study assessed the data management practices of immunization staff and unveiled potential barriers impacting immunization data quality in Cameroon. A descriptive cross-sectional study was conducted, involving health districts and health facilities in all 10 regions in Cameroon selected by a multi-stage sampling scheme. Structured questionnaires and observation checklists were used to collect data from Expanded Program of Immunization (EPI) staff, and data were analyzed using STATA VERSION 13.0 (StataCorp LP. 2015. College Station, TX). A total of 265 facilities in 68 health districts were assessed. There was limited availability of some data recording tools like vaccination cards (43%), maintenance registers (8%), and stock cards (57%) in most health facilities. Core data collection tools were incompletely filled in a significant proportion of facilities (37% for registers and 81% for tally sheets). Almost every health facility (89%) did not adhere to the recommendation of filling tally sheets during vaccination; the filling was instead done either before (51% of facilities) or after (25% of facilities) vaccinating several children. Moreso, about 8% of facilities did not collect data on vaccine administration. About a third of facilities did not collect data on stock levels (35%), vaccine storage temperatures (21%), and vaccine wastage (39%). Our findings unveil important gaps in data collection practices at the facility level that could adversely affect Cameroon's immunization data quality. It highlights the urgent need for systematic capacity building of frontline immunization staff on data management capacity, standardizing data management processes, and building systems that ensure constant availability of data recording tools at the facility level.


Multiple conical intersections in small linear parameter Jahn-Teller systems: the DMBE potential energy surface of ground-state C3 revisited.
A new single-sheeted DMBE potential energy surface for ground-state C3 is reported. The novel analytical form accurately describes the three symmetry-equivalent C2v disjoint seams, in addition to the symmetry-required D3h one, over the entire configuration space. The present formalism warrants by built-in construction the confluence of the above crossings, and the rotation-in-plane of the C2v seams when the perimeter of the molecule fluctuates. Up to 1050 ab initio energies have been employed in the calibration procedure, of which 421 map the loci of intersection. The calculated energies have been scaled to account for the incompleteness of the basis set and truncation of the MRCI expansion, and fitted analytically with chemical accuracy. The novel form is shown to accurately mimic the region defined by the 4 conical intersections, while exhibiting similar attributes to the previously reported one [J. Chem. Phys., 2015, 143, 074302] at the regions of configuration space away from the crossing seams. Despite being mainly addressed to C3, the present approach should be applicable to adiabatic PESs of any X3 system experiencing similar topological attributes, in particular the small-linear-parameter Jahn-Teller molecules.


Accurate image reconstruction from few-view and limited-angle data in diffraction tomography.
We present a method for obtaining accurate image reconstruction from highly sparse data in diffraction tomography (DT). A practical need exists for reconstruction from few-view and limited-angle data, as this can greatly reduce required scan times in DT. Our method does this by minimizing the total variation (TV) of the estimated image, subject to the constraint that the Fourier transform of the estimated image matches the measured Fourier data samples. Using simulation studies, we show that the TV-minimization algorithm allows accurate reconstruction in a variety of few-view and limited-angle situations in DT. Accurate image reconstruction is obtained from far fewer data samples than are required by common algorithms such as the filtered-backpropagation algorithm. Overall our results indicate that the TV-minimization algorithm can be successfully applied to DT image reconstruction under a variety of scan configurations and data conditions of practical significance.


Testing language effects in psychiatric epidemiology surveys with randomized experiments: results from the National Latino and Asian American Study.
To evaluate the prevalence of mental disorders for persons of non-English-language origin, it is essential to use translated diagnostic interviews. The equivalence of translated surveys is rarely tested formally. In the National Latino and Asian American Study (NLAAS), the authors tested whether a carefully translated mental health survey administered in Spanish produced results equivalent to those obtained by the original English version, using a randomized survey experiment. The NLAAS is a nationally representative survey carried out in the United States in 2002-2003. Bilingual respondents from the Latino section of the NLAAS (n = 332) were randomly assigned to receive either a Spanish- or English-language version of the World Mental Health Survey Composite International Diagnostic Interview. In tests of differences in lifetime and 12-month prevalences of 11 diagnoses and four higher-order aggregate disorder categories, in only one case was there an apparent difference between randomized language groups: Lifetime reports of generalized anxiety disorder were more prevalent in the bilingual group assigned to English than in the group interviewed in Spanish. Detailed follow-up analyses did not implicate any specific question in the generalized anxiety disorder protocol. Translation and back-translation of surveys does not guarantee that response probabilities are exactly equivalent. Randomized survey experiments should be incorporated into cross-cultural psychiatric surveys when possible.


Cochlear outer hair cells undergo an apical circumference remodeling constrained by the hair bundle shape.
Epithelial cells acquire diverse shapes relating to their different functions. This is particularly relevant for the cochlear outer hair cells (OHCs), whose apical and basolateral shapes accommodate the functioning of these cells as mechano-electrical and electromechanical transducers, respectively. We uncovered a circumferential shape transition of the apical junctional complex (AJC) of OHCs, which occurs during the early postnatal period in the mouse, prior to hearing onset. Geometric analysis of the OHC apical circumference using immunostaining of the AJC protein ZO1 and Fourier-interpolated contour detection characterizes this transition as a switch from a rounded-hexagon to a non-convex circumference delineating two lateral lobes at the neural side of the cell, with a negative curvature in between. This shape tightly correlates with the 'V'-configuration of the OHC hair bundle, the apical mechanosensitive organelle that converts sound-evoked vibrations into variations in cell membrane potential. The OHC apical circumference remodeling failed or was incomplete in all the mouse mutants affected in hair bundle morphogenesis that we tested. During the normal shape transition, myosin VIIa and myosin II (A and B isoforms) displayed polarized redistributions into and out of the developing lobes, respectively, while Shroom2 and F-actin transiently accumulated in the lobes. Defects in these redistributions were observed in the mutants, paralleling their apical circumference abnormalities. Our results point to a pivotal role for actomyosin cytoskeleton tensions in the reshaping of the OHC apical circumference. We propose that this remodeling contributes to optimize the mechanical coupling between the basal and apical poles of mature OHCs.


Effect of human auditory efferent feedback on cochlear gain and compression.
The mammalian auditory system includes a brainstem-mediated efferent pathway from the superior olivary complex by way of the medial olivocochlear system, which reduces the cochlear response to sound (Warr and Guinan, 1979; Liberman et al., 1996). The human medial olivocochlear response has an onset delay of between 25 and 40 ms and rise and decay constants in the region of 280 and 160 ms, respectively (Backus and Guinan, 2006). Physiological studies with nonhuman mammals indicate that onset and decay characteristics of efferent activation are dependent on the temporal and level characteristics of the auditory stimulus (Bacon and Smith, 1991; Guinan and Stankovic, 1996). This study uses a novel psychoacoustical masking technique using a precursor sound to obtain a measure of the efferent effect in humans. This technique avoids confounds currently associated with other psychoacoustical measures. Both temporal and level dependency of the efferent effect was measured, providing a comprehensive measure of the effect of human auditory efferents on cochlear gain and compression. Results indicate that a precursor (>20 dB SPL) induced efferent activation, resulting in a decrease in both maximum gain and maximum compression, with linearization of the compressive function for input sound levels between 50 and 70 dB SPL. Estimated gain decreased as precursor level increased, and increased as the silent interval between the precursor and combined masker-signal stimulus increased, consistent with a decay of the efferent effect. Human auditory efferent activation linearizes the cochlear response for mid-level sounds while reducing maximum gain.


Sun-related knowledge and attitudes of primary and secondary schoolchildren in western Switzerland.
Switzerland, particularly its western region, has the highest incidence of melanoma in Europe. Although the risk of melanoma increases with sun overexposure during childhood, sun-related knowledge and attitudes of Swiss children are scarcely documented. We report the first investigation of the knowledge of the danger of ultraviolet radiation, attitudes towards a suntan and parental influence of schoolchildren in western Switzerland. All fifth, eighth and eleventh graders (average ages of 9, 12 and 15, respectively) in the 18 primary (fifth grade, n=431) and secondary (eighth and eleventh grades, n=837) public schools of La Chaux-de-Fonds were surveyed during regular school classes. The response rate was 91% (1154/1268). Sun-related knowledge was high overall. Eight out of 10 children knew about the risk of skin cancer and recognized the most susceptible phototype. Knowledge increased significantly with age. Girls, older children, fair-skinned participants and those who preferred a tanned skin obtained the highest knowledge score. The main source of information on ultraviolet radiation and sun protection was their parents (76%), followed by the school (11%) and the media (9%). Multivariate logistic regression analyses identified higher sun-related knowledge, lower familial socioprofessional status and skin phototypes III-IV to be associated with a tan-seeking attitude. Parental sensitization (56%) and encouragement (61%) towards sun protection were more common among fair-skinned children and those of higher familial socioprofessional status. The high awareness of the risk of skin cancer among Swiss schoolchildren does not translate into appropriate attitudes. Community-wide intervention programmes involving parents, teachers, peers and primary care clinicians could be considered for Swiss prevention campaigns to improve children's sun behaviour and change their current pro-tan attitude.


Clomethiazole acute stroke study (CLASS): results of a randomized, controlled trial of clomethiazole versus placebo in 1360 acute stroke patients.
The efficacy and safety of the neuroprotective drug clomethiazole was tested in a double blind placebo controlled trial in patients with a clinical diagnosis of acute hemispheric stroke. Patients with symptom onset of </=12 hours before the start of treatment were included in the study. Clomethiazole (75 mg/kg) or placebo was given as an intravenous infusion over a 24-hour period. Patients were followed up for 90 days. The primary efficacy variable was the proportion of patients reaching relative functional independence (>/=60 points on the Barthel Index) at 90 days. A total of 1360 patients were included. In the main efficacy analysis (n=1353), 56.1% of patients taking clomethiazole and 54.8% of placebo patients reached relative functional independence. The difference was not statistically significant. An analysis of the effect of time since onset of symptoms showed no difference between the treatment groups. Clomethiazole was generally well tolerated and appeared safe in the population studied. Sedation was the most common adverse event, leading to treatment withdrawal that occurred in 15.6% of clomethiazole-treated patients compared with 4.2% of placebo-treated patients. In a subgroup classified before randomization as having total anterior circulation syndrome (TACS) (n=545, or 40% of all randomized patients), the percentage of those reaching relative functional independence was 40.8% on clomethiazole and 29.8% on placebo, a difference of approximately 11 percentage units. TACS patients have clinical symptoms suggesting a "large" stroke. Clomethiazole had no adverse or beneficial effect on long-term outcome for all patients but produced sedation. The hypothesis that clomethiazole is effective in patients with large strokes will be tested in a further study.


Parallel phase-shifting digital holography with adaptive function using phase-mode spatial light modulator.
Parallel phase-shifting digital holography using a phase-mode spatial light modulator (SLM) is proposed. The phase-mode SLM implements spatial distribution of phase retardation required in the parallel phase-shifting digital holography. This SLM can also compensate dynamically the phase distortion caused by optical elements such as beam splitters, lenses, and air fluctuation. Experimental demonstration using a static object is presented.


Functional analysis of transcription factor binding sites in human promoters.
The binding of transcription factors to specific locations in the genome is integral to the orchestration of transcriptional regulation in cells. To characterize transcription factor binding site function on a large scale, we predicted and mutagenized 455 binding sites in human promoters. We carried out functional tests on these sites in four different immortalized human cell lines using transient transfections with a luciferase reporter assay, primarily for the transcription factors CTCF, GABP, GATA2, E2F, STAT, and YY1. In each cell line, between 36% and 49% of binding sites made a functional contribution to the promoter activity; the overall rate for observing function in any of the cell lines was 70%. Transcription factor binding resulted in transcriptional repression in more than a third of functional sites. When compared with predicted binding sites whose function was not experimentally verified, the functional binding sites had higher conservation and were located closer to transcriptional start sites (TSSs). Among functional sites, repressive sites tended to be located further from TSSs than were activating sites. Our data provide significant insight into the functional characteristics of YY1 binding sites, most notably the detection of distinct activating and repressing classes of YY1 binding sites. Repressing sites were located closer to, and often overlapped with, translational start sites and presented a distinctive variation on the canonical YY1 binding motif. The genomic properties that we found to associate with functional TF binding sites on promoters -- conservation, TSS proximity, motifs and their variations -- point the way to improved accuracy in future TFBS predictions.


Chronic exposure to sulfide causes accelerated degradation of cytochrome c oxidase in ethylmalonic encephalopathy.
Ethylmalonic encephalopathy (EE) is an autosomal recessive, invariably fatal disorder associated with mutations in ETHE1, a gene encoding a mitochondrial sulfur dioxygenase (SDO). The main consequence of the absence of Ethe1-SDO is the accumulation of sulfide (H(2)S) in critical tissues, including colonic mucosa, liver, muscle, and brain. To make progress in the elucidation of the biochemical mechanisms leading to cytochrome c oxidase (COX) deficiency, we (i) generated tissue-specific conditional Ethe1 knockout mice to clarify the different contributions of endogenous and exogenous H(2)S production, and (ii) studied the development of H(2)S-driven COX deficiency in Ethe1(-/-) mouse tissues and human cells. Ethe1(-/-) conditional animals displayed COX deficiency limited to the specific targeted tissue. The accumulation of H(2)S over time causes progressive COX deficiency in animal tissues and human cells, which is associated with reduced amount of COX holoenzyme, and of several COX subunits, including mitochondrially encoded cytochrome c oxidase 1 (MTCO1), MTCO2, COX4, and COX5A. This reduction is not paralleled by consistent downregulation in expression of the corresponding mRNAs. Tissue-specific ablation of Ethe1 causes COX deficiency in targeted organs, suggesting that failure in neutralizing endogenous, tissue-specific production of H(2)S is sufficient to cause the biochemical defect but neither to determine a clinical impact nor to induce the biomarker profile typical of EE. The mechanism by which H(2)S causes COX deficiency consists of rapid heme a inhibition and accelerated long-term degradation of COX subunits. However, the pleiotropic devastating effects of H(2)S accumulation in EE cannot be fully explained by the sole defect of COX in critical tissues, but are likely consequent to several toxic actions on a number of enzymatic activities in different tissues, including endothelial lining of the small vessels, leading to multiorgan failure.


Substance Use among Adolescents Involved in Bullying: A Cross-Sectional Multilevel Study.
Being involved in bullying as a victim or perpetrator could have deleterious health consequences. Even though there is some evidence that bullies and victims of bullying have a higher risk for drug use, less is known about bystanders. The aim of this research was to study the association between bullying experience (as victims, bullies, or bystanders) and substance use. We gathered complete information from a nationally representative sample of 36,687 students (51.4% female) attending 756 schools in Chile. We used a self-reported questionnaire which was developed based on similar instruments used elsewhere. This questionnaire was piloted and presented to an expert panel for approval. We used multilevel multivariate logistic regression analyses, controlling for several variables at the individual (e.g., school membership, parental monitoring) and school levels (e.g., school type, school denomination). This study shows that bullies and bully-victims have a high risk for cigarette, alcohol, and cannabis use than bystanders. This is one of the few studies exploring the association between witnessing bullying and substance use. These findings add new insights to the study of the co-occurrence of bullying and substance use. Other factors, such as higher academic performance, stronger school membership, and better parental monitoring reduced the risk of any substance use, while the experience of domestic violence and the perception of social disorganization in the neighborhood, increased the risk. These findings may help the design of preventive interventions.


[Prevalence of selected musculoskeletal conditions in Germany: results of the German Health Interview and Examination Survey for Adults (DEGS1)].
The term musculoskeletal condition (MSKC) comprises inflammatory and degenerative diseases of joints and bones. They are among the most common conditions in older age and cause of severe long-term pain, physical disability, and decrease in quality of life. Data from the German Health Interview and Examination Survey for Adults (DEGS1) were used to estimate the life-time prevalence of osteoarthritis, rheumatoid arthritis (RA) and osteoporosis in Germany. A total of 7,988 persons aged 18-79 years (osteoporosis 50-79 years) were asked to report doctor-diagnosed MSKC in face-to-face interviews. Women were more likely to report all MSKC and all prevalences increase with age. Osteoarthritis is reported by 22.3 % of women and 18.1 % of men, RA by 3.2 % of women and 1.9 % of men, and osteoporosis by 13.1 % of women and 3.2 % of men. MSKC are of great relevance for older adults in Germany. Data from DEGS1 provide a lot of information along to MSKC and hereby allow a closer description of the health situation of older adults. An English full-text version of this article is available at SpringerLink as supplemental.


Utility of bronchoscopy with bronchoalveolar lavage in diagnosing pulmonary infection in hospitalized patients with underlying malignancy.
To evaluate the clinical utility of bronchoscopy with bronchoalveolar lavage (BAL) for diagnosing pulmonary infection in patients with underlying malignancy and to evaluate the impact of positive microbiology results on antimicrobial therapy. Retrospective chart review. University-affiliated downtown teaching hospital in Toronto. All patients who underwent bronchoscopy with BAL from November 1990 to September 1992. One hundred and thirty-nine BALs were performed, of which 82 (59%) were positive for microorganisms. These 82 charts were reviewed. The main underlying diagnosis was hemotogenous malignancy (70 of 82). Primary indiction for bronchoscopy was the presence of pulmonary symptoms with or without radiographic abnormality. Common organisms identified were fungi (n=50), primarily Candida albicans and cytomegalovirus (CMV) (27), and 16 'usual' pathogens. Less common were herpes simplex virus (six), Pneumoncystis carinii pneumonia (PCP) (four), Legionella pneumoniae and Mycoplasma pneumoniae (one each). Eighty-seven per cent of patients were on broad spectrum antibiotics at the time of bronchoscopy. Although antiibiotic therapy was altered postbronchoscopy in 47 of the 82 cases, only 26 instances could be directly attributed to the results of BAL. Pathogens that commonly initiated specific therapy were CMV (16 of 27) and PCP (three of four). Diagnostic yield was highest in allogenic bone marrow transplant recipients (BMT). They comprised only 49% (40 of 82) of the cases but accounted for 85% (22 of 26) of those whose therapy was directly altered by the results of BAL. Of these 22 cases, 20 were attributed to the isolation of CMV. The overall raw diagnostic yield from bronchoscopy with BAL was high at 59%. Of those with positive BAL cultures, a change in antimicrobial management occurred in 32% of cases. In a patient poulation with underlying hematogenous malignancy, particularly BMT recipients, bronchoscopy with BAL is useful for a specfic diagnosis of pulmonary infection.


Vicious circles: positive feedback in major evolutionary and ecological transitions.
Evolutionary biologists and ecologists often focus on equilibrium states that are subject to forms of negative feedback, such as optima for phenotypic traits or regulation of population sizes. However, recent theoretical and empirical studies show how positive feedback can be instrumental in driving many of the most important and spectacular processes in evolutionary ecology, including the evolution of sex and genetic systems, mating systems, life histories, complex cooperation in insects and humans, ecological specialization, species diversity, species ranges, speciation and extinction. Taken together, this work suggests that positive feedback is more common than is generally appreciated, and that its self-reinforcing dynamics generate the conditions for changes that might otherwise be difficult or impossible for selection or other mechanisms to achieve. Testing for positive feedback requires analysing each causal link in feedback loops, tracking genetic, character and population-dynamic changes across generations, and elucidating the conditions that can result in self-reinforcing change.


A 2.8-Mb clone contig of the multiple endocrine neoplasia type 1 (MEN1) region at 11q13.
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder that results in parathyroid, anterior pituitary, and pancreatic and duodenal endocrine tumors in affected individuals. The MEN1 locus is tightly linked to the marker PYGM on chromosome 11q13, and linkage analysis has placed the MEN1 gene within a 2-Mb interval flanked by D11S1883 and D11S449. As a step toward cloning the MEN1 gene, we have constructed a 2.8-Mb clone contig consisting of YAC and bacterial clones (PAC, BAC, and P1) for the D11S480 to D11S913 region. The bacterial clones alone represent nearly all of the 2.8-Mb contig. The contig was assembled based on a high-density STS-content analysis of 79 genomic clones (YAC, PAC, BAC, and P1) with 118 STSs. The STSs included 22 polymorphic markers and 20 transcripts, with the remainder primarily derived from the end sequences of the genomic clones. An independent cosmid contig for the 1-Mb PYGM-SEA region was also generated. Support for correctness of the 2.8-Mb contig map comes from an independent ordering of the clones by fiber-FISH. This sequence-ready contig will be a useful resource for positional cloning of MEN1 and other disease genes whose loci fall within this region.


Stability of noisy Metropolis-Hastings.
Pseudo-marginal Markov chain Monte Carlo methods for sampling from intractable distributions have gained recent interest and have been theoretically studied in considerable depth. Their main appeal is that they are exact, in the sense that they target marginally the correct invariant distribution. However, the pseudo-marginal Markov chain can exhibit poor mixing and slow convergence towards its target. As an alternative, a subtly different Markov chain can be simulated, where better mixing is possible but the exactness property is sacrificed. This is the noisy algorithm, initially conceptualised as Monte Carlo within Metropolis, which has also been studied but to a lesser extent. The present article provides a further characterisation of the noisy algorithm, with a focus on fundamental stability properties like positive recurrence and geometric ergodicity. Sufficient conditions for inheriting geometric ergodicity from a standard Metropolis-Hastings chain are given, as well as convergence of the invariant distribution towards the true target distribution.


Crossbridge scheme and the kinetic constants of elementary steps deduced from chemically skinned papillary and trabecular muscles of the ferret.
Elementary steps of the crossbridge cycle in chemically skinned ferret myocardium were investigated with sinusoidal analysis. The muscle preparations were activated at pCa 4.82 and an ionic strength of 200 mM, and the effects of the change in the MgATP (S) and phosphate (Pi) concentrations on three exponential processes were studied at 20 degrees C. Results are consistent with the following crossbridge scheme: [formula: see text] where A is actin, M is myosin, D is MgADP, and Det includes all detached states (MS and MDP) and weakly attached states (AMS and AMDP). From our studies, we obtained K1a = 0.99 mM-1 (MgATP association), k1b = 270 s-1 (ATP isomerization), k-1b = 280 s-1 (reverse isomerization), K1b = k1b/k-1b = 0.95, k2 = 48 s-1 (crossbridge detachment), k-2 = 14 s-1 (reverse detachment), K2 = 3.5, k4 = 11 s-1 (crossbridge attachment), k-4 = 107 s-1 (reverse attachment), K4 = 0.11, and K5 = 0.06 mM-1 (Pi association). K6 is the rate-limiting step, and it is the slowest forward reaction in the cycle, which results in the rigor-like AM state. K1a (MgATP binding) is four times that of rabbit psoas, and K5 (Pi binding) is 0.3 times that of psoas, demonstrating that crossbridges in myocardium bind MgATP more and Pi less than psoas. The rate constants of ATP isomerization (k1b, k-1b), crossbridge detachment (k2, k-2), and crossbridge attachment (k4) steps are generally an order of magnitude slower than rabbit psoas. The reverse attachment step (k-4) is similar to that in psoas, indicating that this step may occur irrespective of the myosin type and possibly spontaneously. The above scheme with the deduced kinetic constants predicts the following crossbridge distributions at 5 mM MgATP2- and 8 mM Pi:AM (3%), AM S (15%), AM*S (14%), Det (50%), AM*DP (6%), and AM*D (12%). The actual number of attached crossbridges was measured to be 51 +/- 4% by the stiffness ratio during activation and after rigor induction, and a strong correlation was seen with the prediction. Our results are consistent with the hypothesis that force generation occurs at the Det-->AM*DPi transition, and the same force is maintained after the release of Pi.


Effect of caffeine on meiotic maturation of porcine oocytes.
This study was conducted to evaluate the effect of caffeine on the meiotic maturation of porcine oocytes. Oocyte-cumulus complexes were collected from slaughterhouse-derived ovaries and cultured for 24, 32 or 48 h in medium 199 supplemented with 10% fetal calf serum, 10 microg/ml FSH, 50 microg/ml sodium pyruvate and 50 microg/ml gentamicin in the presence or absence of 2.5 mM caffeine. Caffeine inhibited the meiotic resumption of pig oocytes effectively after 24 h of culture, and 95.5% of oocytes were arrested at the germinal vesicle (GV) stage (control 17.8%, p < 0.05). Prolonged culture with caffeine up to 32 h or 48 h, however, resulted in a significant decrease in the inhibitory effect (GV: 13.8% and 8.2%). The number of oocytes at metaphase II after 48 h of culture in the presence of caffeine was significantly lower than that in the control medium (65.3% vs 94.7%, p < 0.05). The withdrawal of caffeine after 24 h of culture resulted in the resumption of meiotic maturation, and the oocytes reached metaphase II after 48 h. However, the ability of caffeine-treated oocytes to develop to blastocysts after artificial activation was lower than that of the control (5.5% vs 9.1%, p < 0.05). Caffeine treatment significantly increased cAMP levels in the oocytes after 24 h of culture, while both Cdc2 kinase and MAP kinase activation were inhibited in the oocytes. These results suggest that caffeine, similarly to other purine derivatives, prolongs the meiotic arrest of porcine oocytes at the GV stage, perhaps by its action of increasing the cAMP level and by the suppression of Cdc2 kinase and MAP kinase activities in the oocytes.


Neural substrates of cognitive control under the belief of getting neurofeedback training.
Learning to modulate one's own brain activity is the fundament of neurofeedback (NF) applications. Besides the neural networks directly involved in the generation and modulation of the neurophysiological parameter being specifically trained, more general determinants of NF efficacy such as self-referential processes and cognitive control have been frequently disregarded. Nonetheless, deeper insight into these cognitive mechanisms and their neuronal underpinnings sheds light on various open NF related questions concerning individual differences, brain-computer interface (BCI) illiteracy as well as a more general model of NF learning. In this context, we investigated the neuronal substrate of these more general regulatory mechanisms that are engaged when participants believe that they are receiving NF. Twenty healthy participants (40-63 years, 10 female) performed a sham NF paradigm during fMRI scanning. All participants were novices to NF-experiments and were instructed to voluntarily modulate their own brain activity based on a visual display of moving color bars. However, the bar depicted a recording and not the actual brain activity of participants. Reports collected at the end of the experiment indicate that participants were unaware of the sham feedback. In comparison to a passive watching condition, bilateral insula, anterior cingulate cortex and supplementary motor and dorsomedial and lateral prefrontal areas were activated when participants actively tried to control the bar. In contrast, when merely watching moving bars, increased activation in the left angular gyrus was observed. These results show that the intention to control a moving bar is sufficient to engage a broad frontoparietal and cingulo-opercular network involved in cognitive control. The results of the present study indicate that tasks such as those generally employed in NF training recruit the neuronal correlates of cognitive control even when only sham NF is presented.


[Depression in schizophrenia: prevalence and relationship to quality of life].
This study aimed to investigate the prevalence of depression in schizophrenia and associated factors, including quality of life. A cross-sectional study was conducted with 150 outpatients. The Calgary Depression Scale for Schizophrenia measured depression, and the Quality of Life Scale-Brazil measured quality of life. Major depression was found in 56% of patients with schizophrenia. Patients with major depression had low quality of life according to both the global scale and the occupational subscale. Global quality of life was important for separating the decision-tree statistical analyses. In patients with low quality of life, three factors were associated with depression: presence of schizophrenic symptoms, number of medications, and lack of household activities. In patients with better quality of life scores, only duration of the illness was significant. The study shows a high prevalence of depression in schizophrenia, besides highlighting its repercussions on quality of life. When evaluating quality of life, the presence of depression should be taken into consideration.


Cessation of intensive treatment with recombinant human erythropoietin is followed by secondary anemia.
Little information is available on the evolution of erythropoiesis after interruption of recombinant human erythropoietin (rHuEpo) therapy. Iron-overloaded rats received 20 daily injections of rHuEpo. During treatment, reticulocytes, soluble transferrin receptor (sTfR), and hematocrit increased progressively. This was accompanied by a substantial expansion of spleen erythropoiesis but a decrease in the bone marrow. Five weeks after treatment, rats developed a significant degree of a regenerative anemia. Erythropoietic activity, as assessed by reticulocytes, sTfR, erythroid cellularity, iron incorporation into heme, and the number of erythroid colonies, was severely depressed 3 weeks after cessation of rHuEpo. This was followed by regeneration of erythroblasts and reticulocytes at weeks 6 to 7 post-Epo, but erythroid progenitors recovered only partially by that time. The anemia was definitely corrected 2 months after cessation of rHuEpo treatment. Serum Epo levels remained elevated for several weeks, but the sensitivity of marrow erythroid precursors to Epo was preserved. No rat antibodies to rHuEpo were detected, and serum from post-Epo animals did not exert any inhibitory activity on erythropoiesis. In conclusion, after cessation of intensive rHuEpo therapy, there was a strong inhibition of erythropoietic activity with secondary anemia followed by late recovery. This was not due to antibodies or other soluble inhibitory factors, a defect in endogenous Epo production, or a loss of sensitivity to Epo. This may rather represent intrinsic erythroid marrow exhaustion, mostly at the level of erythroid progenitors but also at later stages of erythropoiesis.


Sporting programs aimed at inactive population groups in the Netherlands: factors influencing their long-term sustainability in the organized sports setting.
The organized sports sector has received increased interest as a setting to stimulate physical activity among inactive target groups. To include many inactive people and to obtain population health benefits, it is important that effective sporting programs are sustained (i.e. continuation of program activities) over a long period of time. This study identified the factors influencing the long-term sustainability of these kind of sporting programs located within local sports clubs in the Netherlands. Fourteen Dutch sporting programs aimed at increasing physical activity levels of inactive population groups and funded within the National Action Plan for Sport and Exercise (NAPSE) were the focus of this study. The programs were developed by ten Dutch National Sports Federations (NSFs) and implemented by different sports clubs in the Netherlands within a three-year funded implementation period (2008-2011). This research consisted of semi-structured face-to-face interviews with the program coordinators of the NSFs (n = 14) and semi-structured telephone interviews with representatives of sports clubs that provided the programs (n = 17 continued the program, n = 11 discontinued the program) six and a half years after the funding period ended (November 2017-March 2018). A sustainability framework with five pre-specified main themes (i.e. program design, implementation, trainer/coach, organizational setting, broader community environment) guided data collection and (deductive) thematic analysis. Ten of the fourteen NAPSE funded sporting programs were sustained at the level of the NSFs. Most factors facilitating (+) and impeding (-) the long-term sustainability of the programs were common to both NSFs and sports clubs, like program adaptation (+) and a lack of program financing (-). Program evaluation (+) and high program costs (-) were specific factors mentioned by NSFs, while factors related to human resources (e.g. lack of volunteers (-)) or the sports club nature (e.g. social aspect in program design (+)) applied to sports clubs. The factors were summarized in the form of a checklist. Key factors influencing the long-term sustainability of the sporting programs were identified. The results can be used to develop strategies to promote long-term sustainability of these kind of programs and inform funding guidelines in countries with a similar organized sports infrastructure.


Vitamin D for health: a global perspective.
It is now generally accepted that vitamin D deficiency is a worldwide health problem that affects not only musculoskeletal health but also a wide range of acute and chronic diseases. However, there remains cynicism about the lack of randomized controlled trials to support the association studies regarding the nonskeletal health benefits of vitamin D. This review was obtained by searching English-language studies published up to April 1, 2013, in PubMed, MEDLINE, and the Cochrane Central Register of Controlled Trials (search terms: vitamin D and supplementation) and focuses on recent challenges regarding the definition of vitamin D deficiency and how to achieve optimal serum 25-hydroxyvitamin D concentrations from dietary sources, supplements, and sun exposure. The effect of vitamin D on fetal programming epigenetics and gene regulation could potentially explain why vitamin D has been reported to have such wide-ranging health benefits throughout life. There is potentially a great upside to increasing the vitamin D status of children and adults worldwide for improving musculoskeletal health and reducing the risk of chronic illnesses, including some cancers, autoimmune diseases, infectious diseases, type 2 diabetes mellitus, neurocognitive disorders, and mortality.


Myocardial infarction in pregnancy and postpartum in the UK.
Cardiac disease is a leading cause of maternal death in the developed world, responsible for one-fifth of all maternal deaths in the UK. The aim of this study was to estimate the incidence of myocardial infarction (MI) in pregnancy and up to one week postpartum in the UK and describe risk factors, management and outcomes. A prospective population-based study with nested case control analysis used the UK Obstetric Surveillance System to identify all women in the UK with MI in pregnancy (in the years 2005-2010). A control group of 1360 women was used for comparison. Multivariable unconditional logistic regression was conducted to identify potential risk factors for MI in pregnancy and calculate adjusted odds ratios with 95% confidence intervals. Twenty-five cases of MI in pregnancy were reported, giving an estimated incidence of 0.7 per 100,000 maternities (95%CI 0.5-1.1). Maternal age, smoking, hypertension, twin pregnancy and pre-eclampsia were independently associated with MI in pregnancy. Fifteen (60%) women underwent coronary angiography; nine (60%) had coronary atherosclerosis, three (21%) had coronary artery dissection, one (7%) had a coronary thrombus and two (13%) had normal coronary arteries. Nine women had angioplasty +/- stenting and two were thrombolysed. No women died. Many risk factors are both recognisable and modifiable. Management of MI in pregnancy was highly variable indicating a clear need for further information regarding the safety and outcomes of different interventions. The addition of pregnancy status as a compulsory field in cardiac audit databases would enable routine collection of this information.


The effect of the volatile oil from ginger rhizomes (Zingiber officinale), its fractions and isolated compounds on the 5-HT3 receptor complex and the serotoninergic system of the rat ileum.
A contribution of the volatile oil from ginger rhizomes (Zingiber officinale Roscoe) on inhabiting the 5-HT3 receptor complex had been shown. In the present study a possible interaction of some compounds of the volatile oil with the 5-HT3 receptor system expressed in N1E-115 cells and with the serotoninergic system of the rat ileum was investigated. The volatile oil was obtained by steam distillation and fractionated using a silica gel column resulting in five fractions. Compounds of the fractions were identified by GC-MS. The influence of the volatile oil, its fractions and pure components on serotonin-induced [14C]guanidinium influx into N1E-115 cells was measured indicating the inhibitory interaction with the 5-HT3 receptor channel system. Most potent inhibitors of cation influx were the volatile oil, fraction 4, beta-pinene, terpinolene, alpha-copaene and alpha-phellandrene. The volatile oil and fractions 1 and 4 were not able to significantly influence either serotonin (10 microM)-induced maximum contraction of the rat ileum or the second phase of the biphasic contraction 2.5 min after serotonin addition. However, beta-pinene, terpinolene and alpha-phellandrene reduced both contractions. In conclusion, the volatile oil and distinct compounds such as terpinolene, beta-pinene and alpha-phellandrene interact with 5-HT3 receptor channel system and possess an antispasmodic effect at the rat ileum.


Open Framework Structures Based on Sex2- Fragments: Synthesis of (Ph4P)[M(Se6)2] (M = Ga, In, TI) in Molten (Ph4P)2Sex.
Polychalcogenide compounds with open polymeric frameworks are rare, and they represent a class of compounds in which microporosity might be achieved. Microporous frameworks that are not oxide-based are now attracting interest because of the combination of catalytic and electronic properties they may simultaneously possess. Three new compounds that may be forerunners to such materials have been discovered and are reported here. The reaction of gallium (Ga), indium (In), and thallium (TI) metal with (Ph(4)P)(2)Se(5) (Ph, phenyl) and an excess of elemental selenium (Se) in a sealed, evacuated Pyrex tube at 200 degrees C yielded small red crystals of (Ph(4)P)[Ga(Se(6))(2)] (I), (Ph(4)P)[In(Se(6))(2)] (II), and (Ph(4)P)[TI(Se(6))(2)] (III), respectively. The [M(Se(6))(2)](-) (M = Ga, In, TI) ions form a two-dimensional, open framework filled with Ph(4)P(+) ions. The [M(Se(6))(2)](n)(n-) structure consists of tetrahedral M(3+) centers and bridging Se(6)(2-) ligands, leading to an extended structure in two dimensions. These layers stack perfectly one on top of the other giving rise to one-dimensional channels running down the c axis that are filled with Ph(4)P(+) cations. These cations are situated in the layers, as opposed to between the layers, and the whole structure can be viewed as a template. Compound II shows remarkable thermal stability and melts congruently at 242 degrees C. Upon cooling to room temperature it gives a glassy phase that recrystallizes upon subsequent heating to 160 degrees C.


Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus.
Metformin is an oral anti-hyperglycemic agent that has been shown to reduce total mortality compared to other anti-hyperglycemic agents, in the treatment of type 2 diabetes mellitus. Metformin, however, is thought to increase the risk of lactic acidosis, and has been considered to be contraindicated in many chronic hypoxemic conditions that may be associated with lactic acidosis, such as cardiovascular, renal, hepatic and pulmonary disease, and advancing age. To assess the incidence of fatal and nonfatal lactic acidosis, and to evaluate blood lactate levels, for those on metformin treatment compared to placebo or non-metformin therapies. A comprehensive search was performed of electronic databases to identify studies of metformin treatment. The search was augmented by scanning references of identified articles, and by contacting principal investigators. Prospective trials and observational cohort studies in patients with type 2 diabetes of least one month duration were included if they evaluated metformin, alone or in combination with other treatments, compared to placebo or any other glucose-lowering therapy. The incidence of fatal and nonfatal lactic acidosis was recorded as cases per patient-years, for metformin treatment and for non-metformin treatments. The upper limit for the true incidence of cases was calculated using Poisson statistics. In a second analysis lactate levels were measured as a net change from baseline or as mean treatment values (basal and stimulated by food or exercise) for treatment and comparison groups. The pooled results were recorded as a weighted mean difference (WMD) in mmol/L, using the fixed-effect model for continuous data. Pooled data from 347 comparative trials and cohort studies revealed no cases of fatal or nonfatal lactic acidosis in 70,490 patient-years of metformin use or in 55,451 patients-years in the non-metformin group. Using Poisson statistics the upper limit for the true incidence of lactic acidosis per 100,000 patient-years was 4.3 cases in the metformin group and 5.4 cases in the non-metformin group. There was no difference in lactate levels, either as mean treatment levels or as a net change from baseline, for metformin compared to non-metformin therapies. There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other anti-hyperglycemic treatments.


I-J restrictions on the activation and interaction of parental and F1-derived TS3 suppressor cells.
An experimental system was developed to independently analyze the H-2 and Igh genetic restrictions at two steps of the 4-hydroxy-3-nitrophenylacetyl hapten (NP) suppressor cell pathway. This experimental system allowed genetic analysis of the activation of TS3 cells by hybridoma-derived TsF2 and independent analysis of the genetic restrictions that controlled the interaction of the TS3 cells with their target population. Thus, TS3 cells were activated in vitro with monoclonal H-2b or H-2k-derived TsF2. The activated TS3 cells were then adoptively transferred to TS3-depleted (cyclophosphamide-treated) recipients of various genotypes. When the TS3-containing lymph node population was activated in vitro for 2 h, suppressive activity was only noted in combinations of TSF2, TS3, and recipients that were matched at both the I-J and Igh gene complexes. The data indicate that TsF2 can activate TS3 cells and that both the activation and the interaction of TS3 cells are I-J and Igh restricted. Using (B10 x B10.BR)F1 mice as TS3 donors, we noted that H-2b-derived TsF2 activated these F1 TS3 cells to suppress NP-specific cutaneous sensitivity responses in H-2b but not in H-2k recipients. Reciprocal experiments using H-2k-derived TsF2 demonstrated that only an H-2k-restricted population was activated in the F1-derived TS3 cells. The simplest explanation to account for these observations is that two distinct populations, each of which is restricted to a parental I-J determinants, exists in the heterozygous F1 TS3 population. Furthermore, we demonstrated that both I-Jb and I-Jk determinants are expressed on F1-derived TS3 cells. These observations are discussed in terms of the mechanisms involved in immunoregulation.


Solitary dilated duct identified at mammography: outcomes analysis.
The purpose of this study is to review the clinical and pathologic outcomes for cases of solitary dilated duct identified at mammography. For all screening mammography examinations during a 22-year period and all diagnostic mammography examinations during the last 10 of these years, the radiologists recorded the principal finding of each abnormal mammographic examination during image interpretation. Only examinations with the recorded finding of solitary dilated duct were studied. We examined radiology records to determine imaging follow-up and pathology records to determine histologic diagnosis, and we performed linkage with our regional tumor registry to identify cancers not biopsied at our institution. The finding of solitary dilated duct was recorded for nine (0.0038%) of 235,209 consecutive screenings and for 12 (0.041%) of 29,267 consecutive diagnostic mammography examinations. Five screening and five diagnostic cases were stable at follow-up (minimum interval, 2 years) and did not undergo biopsy; tumor registry linkage showed no subsequent cancer diagnosis. Biopsy was performed for four (44%) of nine screening and seven (58%) of 12 diagnostic cases. One cancer each (ductal carcinoma in situ) was identified from the screening and diagnostic populations, yielding positive predictive values of 11% (1/9) and 8% (1/12), respectively. Solitary dilated duct is a rare mammographic finding, this series being the largest reported to date. Although few cases are studied, solitary dilated duct appears to have a greater than 2% likelihood of malignancy, sufficiently high to suggest that a suspicious (BI-RADS 4a) assessment may be appropriate.


Glycosylation site-specific analysis of HIV envelope proteins (JR-FL and CON-S) reveals major differences in glycosylation site occupancy, glycoform profiles, and antigenic epitopes' accessibility.
The HIV-1 envelope (Env) is a key determinant in mediating viral entry and fusion to host cells and is a major target for HIV vaccine development. While Env is typically about 50% glycan by mass, glycosylation sites are known to evolve, with some glycosylation profiles presumably being more effective at facilitating neutralization escape than others. Thus, characterizing glycosylation patterns of Env and native virions and correlating glycosylation profiles with infectivity and Env immunogenicity are necessary first steps in designing effective immunogens. Herein, we describe a mass spectrometry-based strategy to determine HIV-1 Env glycosylation patterns and have compared two mammalian cell expressed recombinant Env immunogens, one a limited immunogen and one that induces cross-clade neutralizing antibodies. We have used a glycopeptide-based mass mapping approach to identify and characterize Env's glycosylation patterns by elucidating which sites are utilized and what type of glycan motif is present at each glycosylation site. Our results show that the immunogens displayed different degrees of glycosylation as well as a different characteristic set of glycan motifs. Thus, these techniques can be used to (1) define glycosylation profiles of recombinant Env proteins and Env on mature virions, (2) define specific carbohydrate moieties at each glycosylation site, and (3) determine the role of certain carbohydrates in HIV-1 infectivity and in modulation of Env immunogenicity.


An internet-based adolescent depression preventive intervention: study protocol for a randomized control trial.
The high prevalence of major depressive disorder in adolescents and the low rate of successful treatment highlight a pressing need for accessible, affordable adolescent depression prevention programs. The Internet offers opportunities to provide adolescents with high quality, evidence-based programs without burdening or creating new care delivery systems. Internet-based interventions hold promise, but further research is needed to explore the efficacy of these approaches and ways of integrating emerging technologies for behavioral health into the primary care system. We developed a primary care Internet-based depression prevention intervention, Competent Adulthood Transition with Cognitive Behavioral Humanistic and Interpersonal Training (CATCH-IT), to evaluate a self-guided, online approach to depression prevention and are conducting a randomized clinical trial comparing CATCH-IT to a general health education Internet intervention. This article documents the research framework and randomized clinical trial design used to evaluate CATCH-IT for adolescents, in order to inform future work in Internet-based adolescent prevention programs. The rationale for this trial is introduced, the current status of the study is reviewed, and potential implications and future directions are discussed. The current protocol represents the only current, systematic approach to connecting at-risk youth with self-directed depression prevention programs in a medical setting. This trial undertakes the complex public health task of identifying at-risk individuals through mass screening of the general primary care population, rather than solely relying on volunteers recruited over the Internet, and the trial design provides measures of both symptomatic and diagnostic clinical outcomes. At the present time, we have enrolled N = 234 adolescents/expected 400 and N = 186 parents/expected 400 in this trial, from N = 6 major health systems. The protocol described here provides a model for a new generation of interventions that blend substantial computer-based instruction with human contact to intervene to prevent mental disorders such as depression. Because of the potential for broad generalizability of this model, the results of this study are important, as they will help develop the guidelines for preventive interventions with youth at-risk for the development of depressive and other mental disorders. NCT01893749 date 6 May 2012.


Free-space regular optical interconnections: a mathematical analysis.
The matrix descriptions for three types of free-space regular optical interconnection networks, the perfect shuffle, the banyan, and the crossover, are given. Some new properties of the perfect shuffle are presented in matrix equations, and the equivalence of the three types of interconnection networks is simply shown.


Ragout-a reference-assisted assembly tool for bacterial genomes.
Bacterial genomes are simpler than mammalian ones, and yet assembling the former from the data currently generated by high-throughput short-read sequencing machines still results in hundreds of contigs. To improve assembly quality, recent studies have utilized longer Pacific Biosciences (PacBio) reads or jumping libraries to connect contigs into larger scaffolds or help assemblers resolve ambiguities in repetitive regions of the genome. However, their popularity in contemporary genomic research is still limited by high cost and error rates. In this work, we explore the possibility of improving assemblies by using complete genomes from closely related species/strains. We present Ragout, a genome rearrangement approach, to address this problem. In contrast with most reference-guided algorithms, where only one reference genome is used, Ragout uses multiple references along with the evolutionary relationship among these references in order to determine the correct order of the contigs. Additionally, Ragout uses the assembly graph and multi-scale synteny blocks to reduce assembly gaps caused by small contigs from the input assembly. In simulations as well as real datasets, we believe that for common bacterial species, where many complete genome sequences from related strains have been available, the current high-throughput short-read sequencing paradigm is sufficient to obtain a single high-quality scaffold for each chromosome. The Ragout software is freely available at: https://github.com/fenderglass/Ragout.