Active transforming growth factor-β is associated with phenotypic changes in granulomas after drug treatment in pulmonary tuberculosis

Background: Tuberculosis (TB) chemotherapy clears bacterial burden in the lungs of patients and allows the tuberculous lesions to heal through a fibrotic process. The healing process leaves pulmonary scar tissue that can impair lung function. The goal of this study was to identify fibrotic mediators as a stepping-stone to begin exploring mechanisms of tissue repair in TB. Methods: Hematoxylin and eosin staining and Masson's trichrome stain were utilized to determine levels of collagenization in tuberculous granulomas from non-human primates. Immunohistochemistry was then employed to further interrogate these granulomas for markers associated with fibrogenesis, including transforming growth factor-β (TGFβ), α-smooth muscle actin (αSMA), phosphorylated SMAD-2/3, and CD163. These markers were compared across states of drug treatment using one-way ANOVA, and Pearson's test was used to determine the association of these markers with one another. Results: TGFβ and αSMA were present in granulomas from primates with active TB disease. These molecules were reduced in abundance after TB chemotherapy. Phosphorylated SMAD-2/3, a signaling intermediate of TGFβ, was observed in greater amounts after 1 month of drug treatment than in active disease, suggesting that this particular pathway is blocked in active disease. Collagen production during tissue repair is strongly associated with TGFβ in this model, but not with CD163+ macrophages. Conclusions: Tissue repair and fibrosis in TB that occurs during drug treatment is associated with active TGFβ that is produced during active disease. Further work will identify mechanisms of fibrosis and work towards mitigating lung impairment with treatments that target those mechanisms

Gonadotropins for pubertal induction in males with hypogonadotropic hypogonadism: systematic review and meta-analysis.

OBJECTIVE: Hypogonadotropic hypogonadism is characterized by inadequate secretion of pituitary gonadotropins, leading to absent, partial, or arrested puberty. In males, classical treatment with testosterone promotes virilization but not testicular growth or spermatogenesis. To quantify treatment practices and efficacy, we systematically reviewed all studies investigating gonadotropins for the achievement of pubertal outcomes in males with hypogonadotropic hypogonadism. DESIGN: Systematic review and meta-analysis. METHODS: A systematic review of Medline, Embase, Global Health, and PsycINFO databases in December 2022. Risk of Bias 2.0/Risk Of Bias In Non-randomized Studies of Interventions/National Heart, Lung, and Blood Institute tools for quality appraisal. Protocol registered on PROSPERO (CRD42022381713). RESULTS: After screening 3925 abstracts, 103 studies were identified including 5328 patients from 21 countries. The average age of participants was <25 years in 45.6% (n = 47) of studies. Studies utilized human chorionic gonadotropin (hCG) (n = 93, 90.3% of studies), human menopausal gonadotropin (n = 42, 40.8%), follicle-stimulating hormone (FSH) (n = 37, 35.9%), and gonadotropin-releasing hormone (28.2% n = 29). The median reported duration of treatment/follow-up was 18 months (interquartile range 10.5-24 months). Gonadotropins induced significant increases in testicular volume, penile size, and testosterone in over 98% of analyses. Spermatogenesis rates were higher with hCG + FSH (86%, 95% confidence interval [CI] 82%-91%) as compared with hCG alone (40%, 95% CI 25%-56%). However, study heterogeneity and treatment variability were high. CONCLUSIONS: This systematic review provides convincing evidence of the efficacy of gonadotropins for pubertal induction. However, there remains substantial heterogeneity in treatment choice, dose, duration, and outcomes assessed. Formal guidelines and randomized studies are needed

Proton Magnetic Resonance Spectroscopic Evidence of Glial Effects of Cumulative Lead Exposure in the Adult Human Hippocampus

BACKGROUND: Exposure to lead is known to have adverse effects on cognition in several different populations. Little is known about the underlying structural and functional correlates of such exposure in humans. OBJECTIVES: We assessed the association between cumulative exposure to lead and levels of different brain metabolite ratios in vivo using magnetic resonance spectroscopy (MRS). METHODS: We performed MRS on 15 men selected from the lowest quintile of patella bone lead within the Department of Veterans Affairs’ Normative Aging Study (NAS) and 16 from the highest to assess in the hippocampal levels of the metabolites N-acetylaspartate, myoinositol, and choline, each expressed as a ratio with creatine. Bone lead concentrations—indicators of cumulative lead exposure—were previously measured using K-X-ray fluorescence spectroscopy. MRS was performed on the men from 2002 to 2004. RESULTS: A 20-μg/g bone and 15-μg/g bone higher patella and tibia bone lead concentration—the respective interquartile ranges within the whole NAS—were associated with a 0.04 [95% confidence interval (CI), 0.00–0.08; p = 0.04] and 0.04 (95% CI, 0.00–0.08; p = 0.07) higher myoinositol-to-creatine ratio in the hippocampus. After accounting for patella bone lead declines over time, analyses adjusted for age showed that the effect of a 20-μg/g bone higher patella bone lead level doubled (0.09; 95% CI, 0.01–0.17; p = 0.03). CONCLUSIONS: Cumulative lead exposure is associated with an increase in the myinositol-to-creatine ratio. These data suggest that, as assessed with MRS, glial effects may be more sensitive than neuronal effects as an indicator of cumulative exposure to lead in adults

On the shopfloor: exploring the impact of teacher trade unions on school-based industrial relations

Teachers are highly unionised workers and their trade unions exert an important influence on the shaping and implementation of educational policy. Despite this importance there is relatively little analysis of the impact of teacher trade unions in educational management literature. Very little empirical research has sought to establish the impact of teacher unions at school level. In an era of devolved management and quasi-markets this omission is significant. New personnel issues continue to emerge at school level and this may well generate increased trade union activity at the workplace. This article explores the extent to which devolved management is drawing school-based union representation into a more prominent role. It argues that whilst there can be significant differences between individual schools, increased school autonomy is raising the profile of trade union activity in the workplace, and this needs to be better reflected in educational management research

Representation of Women in Stroke Clinical Trials: A Review of 281 Trials Involving More Than 500,000 Participants

Background and ObjectivesWomen have been underrepresented in cardiovascular disease clinical trials but there is less certainty over the level of disparity specifically in stroke. We examined the participation of women in trials according to stroke prevalence in the population.MethodsPublished randomized controlled trials with ≥100 participants enrolled between 1990 and 2020 were identified from ClinicalTrials.gov. To quantify sex disparities in enrollment, we calculated the participation to prevalence ratio (PPR), defined as the percentage of women participating in a trial vs the prevalence of women in the disease population.ResultsThere were 281 stroke trials eligible for analyses with a total of 588,887 participants, of whom 37.4% were women. Overall, women were represented at a lower proportion relative to their prevalence in the underlying population (mean PPR 0.84; 95% confidence interval [CI] 0.81-0.87). The greatest differences were observed in trials of intracerebral hemorrhage (PPR 0.73; 95% CI 0.71-0.74), trials with a mean age of participants <70 years (PPR 0.81; 95% CI 0.78-0.84), nonacute interventions (PPR 0.80; 95% CI 0.76-0.84), and rehabilitation trials (PPR 0.77; 95% CI 0.71-0.83). These findings did not significantly change over the period from 1990 to 2020 (p for trend = 0.201).DiscussionWomen are disproportionately underrepresented in stroke trials relative to the burden of disease in the population. Clear guidance and effective implementation strategies are required to improve the inclusion of women and thus broader knowledge of the impact of interventions in clinical trials

Controlled interfacial assembly of 2D curved colloidal crystals and jammed shells

Assembly of colloidal particles on fluid interfaces is a promising technique for synthesizing two-dimensional micro-crystalline materials useful in fields as diverse as biomedicine1, materials science2, mineral flotation3 and food processing4. Current approaches rely on bulk emulsification methods, require further chemical and thermal treatments, and are restrictive with respect to the materials employed5-9. The development of methods that exploit the great potential of interfacial assembly for producing tailored materials have been hampered by the lack of understanding of the assembly process. Here we report a microfluidic method that allows direct visualization and understanding of the dynamics of colloidal crystal growth on curved interfaces. The crystals are periodically ejected to form stable jammed shells, which we refer to as colloidal armour. We propose that the energetic barriers to interfacial crystal growth and organization can be overcome by targeted delivery of colloidal particles through hydrodynamic flows. Our method allows an unprecedented degree of control over armour composition, size and stability.Comment: 18 pages, 5 figure

Scientists Want More Children

Scholars partly attribute the low number of women in academic science to the impact of the science career on family life. Yet, the picture of how men and women in science – at different points in the career trajectory – compare in their perceptions of this impact is incomplete. In particular, we know little about the perceptions and experiences of junior and senior scientists at top universities, institutions that have a disproportionate influence on science, science policy, and the next generation of scientists. Here we show that having fewer children than wished as a result of the science career affects the life satisfaction of science faculty and indirectly affects career satisfaction, and that young scientists (graduate students and postdoctoral fellows) who have had fewer children than wished are more likely to plan to exit science entirely. We also show that the impact of science on family life is not just a woman's problem; the effect on life satisfaction of having fewer children than desired is more pronounced for male than female faculty, with life satisfaction strongly related to career satisfaction. And, in contrast to other research, gender differences among graduate students and postdoctoral fellows disappear. Family factors impede talented young scientists of both sexes from persisting to research positions in academic science. In an era when the global competitiveness of US science is at risk, it is concerning that a significant proportion of men and women trained in the select few spots available at top US research universities are considering leaving science and that such desires to leave are related to the impact of the science career on family life. Results from our study may inform university family leave policies for science departments as well as mentoring programs in the sciences

The Epidemiology of Lead Toxicity in Adults: Measuring Dose and Consideration of Other Methodologic Issues

We review several issues of broad relevance to the interpretation of epidemiologic evidence concerning the toxicity of lead in adults, particularly regarding cognitive function and the cardiovascular system, which are the subjects of two systematic reviews that are also part of this mini-monograph. Chief among the recent developments in methodologic advances has been the refinement of concepts and methods for measuring individual lead dose in terms of appreciating distinctions between recent versus cumulative doses and the use of biological markers to measure these parameters in epidemiologic studies of chronic disease. Attention is focused particularly on bone lead levels measured by K-shell X-ray fluorescence as a relatively new biological marker of cumulative dose that has been used in many recent epidemiologic studies to generate insights into lead’s impact on cognition and risk of hypertension, as well as the alternative method of estimating cumulative dose using available repeated measures of blood lead to calculate an individual’s cumulative blood lead index. We review the relevance and interpretation of these lead biomarkers in the context of the toxico-kinetics of lead. In addition, we also discuss methodologic challenges that arise in studies of occupationally and environmentally exposed subjects and those concerning race/ethnicity and socioeconomic status and other important covariates

Biophysically Realistic Filament Bending Dynamics in Agent-Based Biological Simulation

An appealing tool for study of the complex biological behaviors that can emerge from networks of simple molecular interactions is an agent-based, computational simulation that explicitly tracks small-scale local interactions – following thousands to millions of states through time. For many critical cell processes (e.g. cytokinetic furrow specification, nuclear centration, cytokinesis), the flexible nature of cytoskeletal filaments is likely to be critical. Any computer model that hopes to explain the complex emergent behaviors in these processes therefore needs to encode filament flexibility in a realistic manner. Here I present a numerically convenient and biophysically realistic method for modeling cytoskeletal filament flexibility in silico. Each cytoskeletal filament is represented by a series of rigid segments linked end-to-end in series with a variable attachment point for the translational elastic element. This connection scheme allows an empirically tuning, for a wide range of segment sizes, viscosities, and time-steps, that endows any filament species with the experimentally observed (or theoretically expected) static force deflection, relaxation time-constant, and thermal writhing motions. I additionally employ a unique pair of elastic elements – one representing the axial and the other the bending rigidity– that formulate the restoring force in terms of single time-step constraint resolution. This method is highly local –adjacent rigid segments of a filament only interact with one another through constraint forces—and is thus well-suited to simulations in which arbitrary additional forces (e.g. those representing interactions of a filament with other bodies or cross-links / entanglements between filaments) may be present. Implementation in code is straightforward; Java source code is available at www.celldynamics.org

Mechanistic Basis of Branch-Site Selection in Filamentous Bacteria

Many filamentous organisms, such as fungi, grow by tip-extension and by forming new branches behind the tips. A similar growth mode occurs in filamentous bacteria, including the genus Streptomyces, although here our mechanistic understanding has been very limited. The Streptomyces protein DivIVA is a critical determinant of hyphal growth and localizes in foci at hyphal tips and sites of future branch development. However, how such foci form was previously unknown. Here, we show experimentally that DivIVA focus-formation involves a novel mechanism in which new DivIVA foci break off from existing tip-foci, bypassing the need for initial nucleation or de novo branch-site selection. We develop a mathematical model for DivIVA-dependent growth and branching, involving DivIVA focus-formation by tip-focus splitting, focus growth, and the initiation of new branches at a critical focus size. We quantitatively fit our model to the experimentally-measured tip-to-branch and branch-to-branch length distributions. The model predicts a particular bimodal tip-to-branch distribution results from tip-focus splitting, a prediction we confirm experimentally. Our work provides mechanistic understanding of a novel mode of hyphal growth regulation that may be widely employed