Pandemics pose unique risks to people in correctional facilities. Among other vulnerabilities, incarcerated populations often have high rates of mental disorders and substance use disorders, which ...may increase risks for morbidity and mortality during a pandemic. California's San Quentin State Prison (SQSP) experienced multiple outbreaks during the 1918 influenza pandemic, and, a century later, the prison faces a new pandemic. This Open Forum describes the modification of mental health services in SQSP during the early stages of the COVID-19 pandemic. The authors explore the challenges of reducing risks of viral contagion while maintaining high-quality mental health care in a correctional setting.
Background Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases. Objective We sought to determine, in terms of their sputum cellular and mediator profiles, the extent to ...which they represent distinct or overlapping conditions supporting either the “British” or “Dutch” hypotheses of airway disease pathogenesis. Methods We compared the clinical and physiological characteristics and sputum mediators between 86 subjects with severe asthma and 75 with moderate-to-severe COPD. Biological subgroups were determined using factor and cluster analyses on 18 sputum cytokines. The subgroups were validated on independent severe asthma (n = 166) and COPD (n = 58) cohorts. Two techniques were used to assign the validation subjects to subgroups: linear discriminant analysis, or the best identified discriminator (single cytokine) in combination with subject disease status (asthma or COPD). Results Discriminant analysis distinguished severe asthma from COPD completely using a combination of clinical and biological variables. Factor and cluster analyses of the sputum cytokine profiles revealed 3 biological clusters: cluster 1: asthma predominant, eosinophilic, high TH 2 cytokines; cluster 2: asthma and COPD overlap, neutrophilic; cluster 3: COPD predominant, mixed eosinophilic and neutrophilic. Validation subjects were classified into 3 subgroups using discriminant analysis, or disease status with a binary assessment of sputum IL-1β expression. Sputum cellular and cytokine profiles of the validation subgroups were similar to the subgroups from the test study. Conclusions Sputum cytokine profiling can determine distinct and overlapping groups of subjects with asthma and COPD, supporting both the British and Dutch hypotheses. These findings may contribute to improved patient classification to enable stratified medicine.
Adipocyte progenitor cells (APCs) provide the reservoir of regenerative cells to produce new adipocytes, although their identity in humans remains elusive. Using FACS analysis, gene expression ...profiling, and metabolic and proteomic analyses, we identified three APC subtypes in human white adipose tissues. The APC subtypes are molecularly distinct but possess similar proliferative and adipogenic capacities. Adipocytes derived from APCs with high CD34 expression exhibit exceedingly high rates of lipid flux compared with APCs with low or no CD34 expression, while adipocytes produced from CD34− APCs display beige-like adipocyte properties and a unique endocrine profile. APCs were more abundant in gluteofemoral compared with abdominal subcutaneous and omental adipose tissues, and the distribution of APC subtypes varies between depots and in patients with type 2 diabetes. These findings provide a mechanistic explanation for the heterogeneity of human white adipose tissue and a potential basis for dysregulated adipocyte function in type 2 diabetes.
Display omitted
•Identification of three distinct human adipocyte progenitor cell (APC) subtypes•APC subtypes have unique molecular profiles but similar adipogenic capacities•Adipocytes from APC subtypes have distinguishing metabolic and endocrine profiles•APC composition varies according to anatomical location and type 2 diabetes status
Raajendiran et al. report the identification of three adipocyte progenitor cell (APC) subtypes that reside in human adipose tissues. These APCs have distinct molecular phenotypes yet retain similar adipogenic potential. The APCs give rise to adipocytes with divergent metabolic and endocrine capacities and their distribution varies in type 2 diabetes patients.
...observational evidence that seemed to suggest that vitamin E is protective for cardiovascular disease, beta-carotene for cancer, and, more recently, oestrogen for dementia, has now been refuted 4. ...Since only candidate causes with the strongest observational support tend to be followed up in RCTs when these are possible, it is likely that many more reported observational findings are not actually causal 5. In practice, one can never be sure that the relevant confounders have been identified and accounted for. Besides the fact that RCTs are not feasible or ethical for many exposures of public health relevance, such as toxins, physical activity, or complex nutritional regimes, observational studies also have some advantages over RCTs; for example, the subjects in the latter are not always representative of the population for which an intervention is being considered 6.
To further investigate susceptibility loci identified by genome-wide association studies, we genotyped 5,500 SNPs across 14 associated regions in 8,000 samples from a control group and 3 diseases: ...type 2 diabetes (T2D), coronary artery disease (CAD) and Graves' disease. We defined, using Bayes theorem, credible sets of SNPs that were 95% likely, based on posterior probability, to contain the causal disease-associated SNPs. In 3 of the 14 regions, TCF7L2 (T2D), CTLA4 (Graves' disease) and CDKN2A-CDKN2B (T2D), much of the posterior probability rested on a single SNP, and, in 4 other regions (CDKN2A-CDKN2B (CAD) and CDKAL1, FTO and HHEX (T2D)), the 95% sets were small, thereby excluding most SNPs as potentially causal. Very few SNPs in our credible sets had annotated functions, illustrating the limitations in understanding the mechanisms underlying susceptibility to common diseases. Our results also show the value of more detailed mapping to target sequences for functional studies.
Adolescent obesity is a common and serious health problem affecting more than 5 million young people in the United States alone. Bariatric surgery is being evaluated as a possible treatment option. ...Laparoscopic adjustable gastric banding (gastric banding) has the potential to provide a safe and effective treatment.
To compare the outcomes of gastric banding with an optimal lifestyle program on adolescent obesity.
A prospective, randomized controlled trial of 50 adolescents between 14 and 18 years with a body mass index (BMI) higher than 35, recruited from the Melbourne, Australia, community, assigned either to a supervised lifestyle intervention or to undergo gastric banding, and followed up for 2 years. The study was performed between May 2005 and September 2008.
Weight loss. Secondary outcomes included change in metabolic syndrome, insulin resistance, quality of life, and adverse outcomes.
Twenty-four of 25 patients in the gastric banding group and 18 of 25 in lifestyle group completed the study. Twenty-one (84%) in the gastric banding and 3 (12%) in the lifestyle groups lost more than 50% of excess weight, corrected for age. Overall, the mean changes in the gastric banding group were a weight loss of 34.6 kg (95% CI, 30.2-39.0), representing an excess weight loss of 78.8% (95% CI, 66.6%-91.0%), 12.7 BMI units (95% CI, 11.3-14.2), and a BMI z score change from 2.39 (95% CI, 2.05-2.73) to 1.32 (95% CI, 0.98-1.66). The mean losses in the lifestyle group were 3.0 kg (95% CI, 2.1-8.1), representing excess weight loss of 13.2% (95% CI, 2.6%-21.0%), 1.3 BMI units (95% CI, 0.4-2.9), and a BMI z score change from 2.41 (95% CI, 2.21-2.66) to 2.26 (95% CI, 1.91-2.43). At entry, 9 participants (36%) in the gastric banding group and 10 (40%) in the lifestyle group had the metabolic syndrome. At 24 months, none of the gastric banding group had the metabolic syndrome (P = .008; McNemar chi(2)) compared with 4 of the 18 completers (22%) in the lifestyle group (P = .13). The gastric banding group experienced improved quality of life with no perioperative adverse events. However, 8 operations (33%) were required in 7 patients for revisional procedures either for proximal pouch dilatation or tubing injury during follow-up.
Among obese adolescent participants, use of gastric banding compared with lifestyle intervention resulted in a greater percentage achieving a loss of 50% of excess weight, corrected for age. There were associated benefits to health and quality of life.
ANZCTR Identifier: 12605000160639.
Glucocorticoids are essential for life, but are also implicated in disease pathogenesis and may produce unwanted effects when given in high doses. Glucocorticoid receptor (GR) transcriptional ...activity and clinical outcome have been linked to its oligomerization state. Although a point mutation within the GR DNA-binding domain (GRdim mutant) has been reported as crucial for receptor dimerization and DNA binding, this assumption has recently been challenged. Here we have analyzed the GR oligomerization state in vivo using the number and brightness assay. Our results suggest a complete, reversible, and DNA-independent ligand-induced model for GR dimerization. We demonstrate that the GRdim forms dimers in vivo whereas adding another mutation in the ligand-binding domain (I634A) severely compromises homodimer formation. Contrary to dogma, no correlation between the GR monomeric/dimeric state and transcriptional activity was observed. Finally, the state of dimerization affected DNA binding only to a subset of GR binding sites. These results have major implications on future searches for therapeutic glucocorticoids with reduced side effects.
Mucopolysaccharidosis (MPS) II is a rare, X-linked lysosomal storage disease. Approximately two-thirds of patients have central nervous system involvement with some demonstrating progressive ...cognitive impairment (neuronopathic disease). The natural history of cognitive and adaptive function in patients with MPS II is not well-defined. This 2-year, prospective, observational study evaluated the neurodevelopmental trajectories of boys with MPS II aged greater than or equal to 2 years and < 18 years. Overall, 55 patients were enrolled. At baseline, mean (standard deviation SD) age was 5.60 (3.32) years; all patients were receiving intravenous idursulfase. Cognitive and adaptive function were assessed using the Differential Ability Scales, Second Edition (DAS-II) General Conceptual Ability (GCA) and the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Adaptive Behavior Composite (ABC) scores, respectively. Baseline mean (SD) DAS-II GCA and VABS-II ABC scores were 78.4 (19.11) and 83.7 (14.22), respectively, indicating low cognitive function and moderately low adaptive behavior. Over 24 months, modest deteriorations in mean (SD) scores were observed for DAS-II GCA (-3.8 12.7) and VABS-II ABC (-2.0 8.07). Changes in DAS-II GCA scores varied considerably, and data suggested the existence of four potential patient subgroups: (1) patients with marked early impairment and rapid subsequent decline, (2) patients with marked early impairment then stabilization, (3) patients with mild early impairment then stabilization, and (4) patients without impairment who remained stable. Subgroup analyses revealed numerically greater DAS-II GCA score reductions from baseline in patients aged < 7 years at baseline (vs. those aged greater than or equal to 7 years) and in patients with DAS-II GCA scores less than or equal to 70 at baseline (vs. those with scores > 70); between-group differences were nonsignificant. No clear subgroups or patterns were identified for individual changes in VABS-II ABC scores. In total, 49 patients (89.1%) reported greater than or equal to 1 adverse event (AE) and nine patients (16.4%) reported serious AEs. Some patients with MPS II had rapid declines in cognitive ability, whereas others remained relatively stable after an initial decline. These insights provide a basis for more detailed analyses of different patient subgroups, which may enhance the definition and understanding of factors that influence cognitive and adaptive function in MPS II.
PDF
