Association of Steroid 5α-Reductase Type 3 Congenital Disorder of Glycosylation With Early-Onset Retinal Dystrophy

Importance: Steroid 5α-reductase type 3 congenital disorder of glycosylation (SRD5A3-CDG) is a rare disorder of N-linked glycosylation. Its retinal phenotype is not well described but could be important for disease recognition because it appears to be a consistent primary presenting feature. Objective: To investigate a series of patients with the same mutation in the SRD5A3 gene and thereby characterize its retinal manifestations and other associated features. Design, Setting and Participants: Seven affected individuals from 4 unrelated families with early-onset retinal dystrophy as a primary manifestation underwent comprehensive ophthalmic assessment, including retinal imaging and electrodiagnostic testing. Developmental and systemic findings were also recorded. Molecular genetic approaches, including targeted next-generation sequencing, autozygosity mapping, and apex microarray, were tried to reach a diagnosis; all participants were mutation negative. Whole-exome sequencing or whole-genome sequencing was used to identify the causative variant. Biochemical profiling was conducted to confirm a CDG type I defect. Patient phenotype data were collected over the course of ophthalmic follow-up, spanning a period of 20 years, beginning March 20, 1997, through September 15, 2016. Main Outcomes and Measures: Detailed clinical phenotypes as well as genetic and biochemical results. Results: The cohort consisted of 7 participants (5 females and 2 males) whose mean (SD) age at the most recent examination was 17.1 (3.9) years and who were all of South Asian ethnicity. Whole-exome sequencing and whole-genome sequencing identified the same homozygous SRD5A3 c.57G>A, p.(Trp19Ter) variant as the underlying cause of early-onset retinal dystrophy in each family. Detailed ocular phenotyping identified early-onset (aged ≤3 years) visual loss (mean [SD] best-corrected visual acuity, +0.95 [0.34] logMAR [20/180 Snellen]), childhood-onset nyctalopia, myopia (mean [SD] refractive error, -6.71 [-4.22]), and nystagmus. Six of the 7 patients had learning difficulties and psychomotor delay. Fundus autofluorescence imaging and optical coherence tomographic scans were abnormal in all patients, and electrodiagnostic testing revealed rod and cone dysfunction in the 5 patients tested. Conclusions and Relevance: Mutations in the SRD5A3 gene may cause early-onset retinal dystrophy, a previously underdescribed feature of the SRD5A3-CDG disorder that is progressive and may lead to serious visual impairment. SRD5A3 and other glycosylation disorder genes should be considered as a cause of retinal dystrophy even when systemic features are mild. Further delineation of SRD5A3-associated eye phenotypes can help inform genetic counseling for prognostic estimation of visual loss and disease progression

Transcriptomics and adaptive genomics of the asymptomatic bacteriuria Escherichia coli strain 83972

Escherichia coli strains are the major cause of urinary tract infections in humans. Such strains can be divided into virulent, UPEC strains causing symptomatic infections, and asymptomatic, commensal-like strains causing asymptomatic bacteriuria, ABU. The best-characterized ABU strain is strain 83972. Global gene expression profiling of strain 83972 has been carried out under seven different sets of environmental conditions ranging from laboratory minimal medium to human bladders. The data reveal highly specific gene expression responses to different conditions. A number of potential fitness factors for the human urinary tract could be identified. Also, presence/absence data of the gene expression was used as an adaptive genomics tool to model the gene pool of 83972 using primarily UPEC strain CFT073 as a scaffold. In our analysis, 96% of the transcripts filtered present in strain 83972 can be found in CFT073, and genes on six of the seven pathogenicity islands were expressed in 83972. Despite the very different patient symptom profiles, the two strains seem to be very similar. Genes expressed in CFT073 but not in 83972 were identified and can be considered as virulence factor candidates. Strain 83972 is a deconstructed pathogen rather than a commensal strain that has acquired fitness properties

Eucapnic Voluntary Hyperpnea: Gold Standard for Diagnosing Exercise-Induced Bronchoconstriction in Athletes?

In athletes, a secure diagnos is of exercise-induced bronchoconstriction (EIB) is dependent on objective testing. Evaluating spirometric indices of airflow before and following an exercise bout is intuitively the optimal means for the diagnosis; however, this approach is recognized as having several key limitations. Accordingly, alternative indirect bronchoprovocation tests have been recommended as surrogate means for obtaining a diagnosis of EIB. Of these tests, it is often argued that the eucapnic voluntary hyperpnea (EVH) challenge represents the ‘gold standard’. This article provides a state-of-the-art review of EVH, including an overview of the test methodology and its interpretation. We also address the performance of EVH against the other functional and clinical approaches commonly adopted for the diagnosis of EIB. The published evidence supports a key role for EVH in the diagnostic algorithm for EIB testing in athletes. However, its wide sensitivity and specificity and poor repeatability preclude EVH from being termed a ‘gold standard’ test for EIB

Falls, Depression and Antidepressants in Later Life: A Large Primary Care Appraisal

BACKGROUND: Depression and falls are common and co-exist for older people. Safe management of each of these conditions is important to quality of life. METHODS: A cross-sectional survey was used to examine medication use associated with injurious and non-injurious falls in 21,900 community-dwelling adults, aged 60 years or over from 383 Australian general practices recruited for the DEPS-GP Project. Falls and injury from falls, medication use, depressive symptoms (Primary Health Questionnaire (PHQ-9)), clinical morbidity, suicidal ideation and intent, health status (SF-12 Health Survey), demographic and lifestyle information was reported in a standardised survey. FINDINGS: Respondents were 71.8 years (sd 7.7) of age and 58.4% were women. 24% 11% and 8% reported falls, fall related injury, and sought medical attention respectively. Antidepressant use (odds ratio, OR: 1.46; 95% confidence interval, 95%CI: 1.25, 1.70), questionable depression (5-14 on PHQ OR: 1.32, 95%CI: 1.13, 1.53) and clinically significant symptoms of depression (15 or more on PHQ OR: 1.70, 95%CI: 1.14, 1.50) were independently associated with multiple falls. SSRI use was associated with the highest risk of multiple falls (OR: 1.66, 95%CI: 1.36, 2.02) amongst all psychotropic medications. Similar associations were observed for injurious falls. Over 60% of those with four accumulated risk factors had multiple falls in the previous year (OR: 3.40, 95%CI: 1.79, 6.45); adjusted for other demographic and health factors. INTERPRETATION: Antidepressant use (particularly SSRIs) was strongly associated with falls regardless of presence of depressive symptoms. Strategies to prevent falls should become a routine part of the management of older people with depression

Сельскохозяйственная кооперация Урала за 1926-27 хозяйственный год и за I квартал 1927-28 г.: материалы к III собранию уполномоченных Уралселькустсоюза

0|7|Общие условия и итоги работы с.-х. кооперации за отчетный период [c. 7]0|11|Направление и темп кооперирования [c. 11]0|13|Союзное строительство [c. 13]0|13|Социальный состав пайщиков и его регулирование [c. 13]0|16|Итоги перевыборной кампании [c. 16]0|17|Аппарат системы [c. 17]0|18|Направление и характер организационной работы системы [c. 18]0|19|Культработа [c. 19]0|20|Массовая работа [c. 20]0|20|Колхозное строительство [c. 20]0|22|Кредитная работа [c. 22]0|26|Торгово-посредническая деятельность [c. 26]0|30|Финансы [c. 30]0|33|Производственная деятельность [c. 33]0|34|Агрикультурная работа [c. 34]0|35|Кустарно-промысловая кооперация в системе сел.-хоз. кооперации [c. 35]0|38|Состояние и работа системы в I кв. 1927-28 г. [c. 38]0|39|Рост колхозного движения [c. 39]0|40|Товарооборот с.-х. кооперации [c. 40]0|41|Финансовое состояние системы [c. 41]0|41|Итоги и перспективы [c. 41]0|45|Таблицы [c. 45]1|45|Сельско-хозяйственная кооперация в 1926-28 году [c. 45]2|45|Организационное состояние [c. 45]3|46|Сеть кооперативов в районах деятельности союзов сельско-хоз. и куст. пром. кооперации Уралобласти по видам [c. 46]3|47|Число всех кооперативов и членов в них в районах деятельности отдельных союзов сел.-хоз. и куст.-пром. кооперации и процент кооперированности хозяйств по округам [c. 47]3|49|Социально-имущественный состав членов-пайщиков сел.-хоз. кредитных товариществ на 1 октября 1927 года [c. 49]3|50|Состав правлений и ревкомиссий низовой сети сельско-хозяйственной кооперации до и после перевыборов 1927-28 г. [c. 50]2|51|Финансовое состояние [c. 51]3|52|Сводные балансы по отдельным видам сельско-хозяйственных кооперативов на 1-Х-1926 г. и 1-Х-1927 г. [c. 52]3|53|Сводные балансы сельско-хозяйственных кредитных товариществ на 1 октября 1927 года по союзам [c. 53]3|54|Балансы (нетто) союзов сел.-хоз. куст.-пром. кооперации на 1 октября 26 г. и на 1 октября 27 г. [c. 54]3|56|Балансы Уралселькустсоюза на 1-Х-1926 г. и 1-Х-1927 года [c. 56]3|57|Использование фондов кооперирования бедноты в 1926-27 г. и создание таковых из прибылей 1926-27 г. по низовой сети [c. 57]2|59|Хозяйственная работа и ее результаты [c. 59]3|61|Оброт по продаже товаров отдельных звеньев сельско-хозяйственной кооперации по сортиментным группам за 1926-27 год [c. 61]3|62|Распределение торговых оборотов сель.-хоз, кредитных товариществ по контрагентам в 1926-27 г. [c. 62]3|63|Общеторговые расходы сел.-хоз. кредитных товариществ за 1926-27 год [c. 63]3|64|Доходы сельско-хозяйственных кредитных товариществ за 1926-1927 год [c. 64]3|65|Агрономические предприятия низовой сети сель.-хоз кооперации на 1-Х 1927 год [c. 65]3|66|Промышленные предприятия низовой сети сельско-хозяйственной кооперации на 1-Х-1927 г. [c. 66]3|67|Товарооборот союзов сельско-хозяйственной и кустарно-промысловой кооперации за 1926-27 год [c. 67]3|68|Покупка и продажа товаров по снабжению союзами с.-х. куст. промысл. кооперации с разбивкой на контрагентов в 1926-27 г. [c. 68]3|69|Покупка и продажа товаров по сбыту союзами сел.-хоз. куст. пром. кооперации с разбивкой на контрагентов в 1926-27 году [c. 69]3|70|Доходы и обще-торговые расходы союзов сел.-хоз. и куст.-пром. кооперации в 1926-1927 году [c. 70]3|71|Наложение на себестоимость товаров в 1927-28 году [c. 71]2|72|Сельско-хозяйственная кооперация в I квартале 1927-28 года [c. 72]3|73|Сеть кооперативов в районе деятельности окружных и районных союзов, входящих в систему областного союза сел.-хоз. кооперации на 1-Х-27 г. и 1-I-1928 г. [c. 73]3|74|Число всех кооперативов и членов в них по отдельным союзам и процент кооперированости хозяйств по округам [c. 74]3|75|Сводные балансы с.-хоз. кредитных товариществ на 1 октября 27 г. и 1 января 1928 г. [c. 75]3|76|Сводные балансы (нетто) 1-ти окружных и районных союзов сел.-хоз. кооперации на 1-Х-27 и 1-I -28 г. [c. 76]3|78|Балансы (нетто) Уралселькустсоюза на 1/I-27 г., 1/I-28 г. и 1-IV-28 г. [c. 78]3|80|Оборот по продаже товаров союзов сельско-хозяйственной кооперации за I кварта 1927-28 года [c. 80]3|81|Обще-торговые расходы союзов сел.-хоз. кооперации в I квартале 1927-28 года [c. 81]3|82|Товарооборот и обще-торговые расходы союзов сел.-хоз. кооперации [c. 82]2|83|Текущие кампании [c. 83]3|84|Паевая кампания [c. 84]3|85|Перевыборная кампания 1927-28 г. [c. 85]3|85|Общие перевыборные собрания членов пайщиков сел.-хоз. кооперации в 1927-1928 году [c. 85]3|86|Перевыборные собрания уполномоченных сельско-хозяйственных к-вово в 1917-28 году [c. 86]0|87|Пояснения к таблицам [c. 87]0|90|Оглавление [c. 90

Cryptococcal Cell Morphology Affects Host Cell Interactions and Pathogenicity

Cryptococcus neoformans is a common life-threatening human fungal pathogen. The size of cryptococcal cells is typically 5 to 10 µm. Cell enlargement was observed in vivo, producing cells up to 100 µm. These morphological changes in cell size affected pathogenicity via reducing phagocytosis by host mononuclear cells, increasing resistance to oxidative and nitrosative stress, and correlated with reduced penetration of the central nervous system. Cell enlargement was stimulated by coinfection with strains of opposite mating type, and ste3aΔ pheromone receptor mutant strains had reduced cell enlargement. Finally, analysis of DNA content in this novel cell type revealed that these enlarged cells were polyploid, uninucleate, and produced daughter cells in vivo. These results describe a novel mechanism by which C. neoformans evades host phagocytosis to allow survival of a subset of the population at early stages of infection. Thus, morphological changes play unique and specialized roles during infection

Acoustic Oddball during NREM Sleep: A Combined EEG/fMRI Study

Background: A condition vital for the consolidation and maintenance of sleep is generally reduced responsiveness to external stimuli. Despite this, the sleeper maintains a level of stimulus processing that allows to respond to potentially dangerous environmental signals. The mechanisms that subserve these contradictory functions are only incompletely understood. Methodology/Principal Findings: Using combined EEG/fMRI we investigated the neural substrate of sleep protection by applying an acoustic oddball paradigm during light NREM sleep. Further, we studied the role of evoked K-complexes (KCs), an electroencephalographic hallmark of NREM sleep with a still unknown role for sleep protection. Our main results were: (1) Other than in wakefulness, rare tones did not induce a blood oxygenation level dependent (BOLD) signal increase in the auditory pathway but a strong negative BOLD response in motor areas and the amygdala. (2) Stratification of rare tones by the presence of evoked KCs detected activation of the auditory cortex, hippocampus, superior and middle frontal gyri and posterior cingulate only for rare tones followed by a KC. (3) The typical high frontocentral EEG deflections of KCs were not paralleled by a BOLD equivalent. Conclusions/Significance: We observed that rare tones lead to transient disengagement of motor and amygdala responses during light NREM sleep. We interpret this as a sleep protective mechanism to delimit motor responses and to reduce the sensitivity of the amygdala towards further incoming stimuli. Evoked KCs are suggested to originate from a brain state wit

Dust polarized emission observations of NGC 6334: BISTRO reveals the details of the complex but organized magnetic field structure of the high-mass star-forming hub-filament network

Context. Molecular filaments and hubs have received special attention recently thanks to new studies showing their key role in star formation. While the (column) density and velocity structures of both filaments and hubs have been carefully studied, their magnetic field (B-field) properties have yet to be characterized. Consequently, the role of B-fields in the formation and evolution of hub-filament systems is not well constrained. Aims. We aim to understand the role of the B-field and its interplay with turbulence and gravity in the dynamical evolution of the NGC 6334 filament network that harbours cluster-forming hubs and high-mass star formation. Methods. We present new observations of the dust polarized emission at 850 μm toward the 2 pc × 10 pc map of NGC 6334 at a spatial resolution of 0.09 pc obtained with the James Clerk Maxwell Telescope (JCMT) as part of the B-field In STar-forming Region Observations (BISTRO) survey. We study the distribution and dispersion of the polarized intensity (PI), the polarization fraction (PF), and the plane-of-The-sky B-field angle (χB_POS) toward the whole region, along the 10 pc-long ridge and along the sub-filaments connected to the ridge and the hubs. We derived the power spectra of the intensity and χBPOS along the ridge crest and compared them with the results obtained from simulated filaments. Results. The observations span 3 orders of magnitude in Stokes I and PI and 2 orders of magnitude in PF (from 0.2 to 20%). A large scatter in PI and PF is observed for a given value of I. Our analyses show a complex B-field structure when observed over the whole region ( 10 pc); however, at smaller scales (1 pc), χBPOS varies coherently along the crests of the filament network. The observed power spectrum of χBPOS can be well represented with a power law function with a slope of-1.33 ± 0.23, which is 20% shallower than that of I. We find that this result is compatible with the properties of simulated filaments and may indicate the physical processes at play in the formation and evolution of star-forming filaments. Along the sub-filaments, χBPOS rotates frombeing mostly perpendicular or randomly oriented with respect to the crests to mostly parallel as the sub-filaments merge with the ridge and hubs. This variation of the B-field structure along the sub-filaments may be tracing local velocity flows of infalling matter in the ridge and hubs. Our analysis also suggests a variation in the energy balance along the crests of these sub-filaments, from magnetically critical or supercritical at their far ends to magnetically subcritical near the ridge and hubs. We also detect an increase in PF toward the high-column density (NH2 â 1023 cm-2) star cluster-forming hubs. These latter large PF values may be explained by the increase in grain alignment efficiency due to stellar radiation from the newborn stars, combined with an ordered B-field structure. Conclusions. These observational results reveal for the first time the characteristics of the small-scale (down to 0.1 pc) B-field structure of a 10 pc-long hub-filament system. Our analyses show variations in the polarization properties along the sub-filaments that may be tracing the evolution of their physical properties during their interaction with the ridge and hubs. We also detect an impact of feedback from young high-mass stars on the local B-field structure and the polarization properties, which could put constraints on possible models for dust grain alignment and provide important hints as to the interplay between the star formation activity and interstellar B-fields

First BISTRO Observations of the Dark Cloud Taurus L1495A-B10: The Role of the Magnetic Field in the Earliest Stages of Low-mass Star Formation

We present BISTRO Survey 850 μm dust emission polarization observations of the L1495A-B10 region of the Taurus molecular cloud, taken at the James Clerk Maxwell Telescope (JCMT). We observe a roughly triangular network of dense filaments. We detect nine of the dense starless cores embedded within these filaments in polarization, finding that the plane-of-sky orientation of the core-scale magnetic field lies roughly perpendicular to the filaments in almost all cases. We also find that the large-scale magnetic field orientation measured by Planck is not correlated with any of the core or filament structures, except in the case of the lowest-density core. We propose a scenario for early prestellar evolution that is both an extension to, and consistent with, previous models, introducing an additional evolutionary transitional stage between field-dominated and matter-dominated evolution, observed here for the first time. In this scenario, the cloud collapses first to a sheet-like structure. Uniquely, we appear to be seeing this sheet almost face on. The sheet fragments into filaments, which in turn form cores. However, the material must reach a certain critical density before the evolution changes from being field dominated to being matter dominated. We measure the sheet surface density and the magnetic field strength at that transition for the first time and show consistency with an analytical prediction that had previously gone untested for over 50 yr

The JCMT BISTRO-2 Survey: Magnetic Fields of the Massive DR21 Filament

We present 850 μm dust polarization observations of the massive DR21 filament from the B-fields In STar-forming Region Observations (BISTRO) survey, using the POL-2 polarimeter and the SCUBA-2 camera on the James Clerk Maxwell Telescope. We detect ordered magnetic fields perpendicular to the parsec-scale ridge of the DR21 main filament. In the subfilaments, the magnetic fields are mainly parallel to the filamentary structures and smoothly connect to the magnetic fields of the main filament. We compare the POL-2 and Planck dust polarization observations to study the magnetic field structures of the DR21 filament on 0.1-10 pc scales. The magnetic fields revealed in the Planck data are well-aligned with those of the POL-2 data, indicating a smooth variation of magnetic fields from large to small scales. The plane-of-sky magnetic field strengths derived from angular dispersion functions of dust polarization are 0.6-1.0 mG in the DR21 filament and ∼0.1 mG in the surrounding ambient gas. The mass-to-flux ratios are found to be magnetically supercritical in the filament and slightly subcritical to nearly critical in the ambient gas. The alignment between column density structures and magnetic fields changes from random alignment in the low-density ambient gas probed by Planck to mostly perpendicular in the high-density main filament probed by James Clerk Maxwell Telescope. The magnetic field structures of the DR21 filament are in agreement with MHD simulations of a strongly magnetized medium, suggesting that magnetic fields play an important role in shaping the DR21 main filament and subfilaments