The dynamics of human bone marrow adipose tissue in response to feeding and fasting.

BACKGROUNDAdipocytes were long considered inert components of the bone marrow niche, but mouse and human models suggest bone marrow adipose tissue (BMAT) is dynamic and responsive to hormonal and nutrient cues.METHODSIn this study of healthy volunteers, we investigated how BMAT responds to acute nutrient changes, including analyses of endocrine determinants and paracrine factors from marrow aspirates. Study participants underwent a 10-day high-calorie protocol, followed by a 10-day fast.RESULTSWe demonstrate (a) vertebral BMAT increased significantly during high-calorie feeding and fasting, suggesting BMAT may have different functions in states of caloric excess compared with caloric deprivation; (b) ghrelin, which decreased in response to high-calorie feeding and fasting, was inversely associated with changes in BMAT; and (c) in response to high-calorie feeding, resistin levels in the marrow sera, but not the circulation, rose significantly. In addition, TNF-α expression in marrow adipocytes increased with high-calorie feeding and decreased upon fasting.CONCLUSIONHigh-calorie feeding, but not fasting, induces an immune response in bone marrow similar to what has been reported in peripheral adipose tissue. Understanding the immunomodulatory regulators in the marrow may provide further insight into the homeostatic function of this unique adipose tissue depot.FUNDINGNIH grant R24 DK084970, Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, NIH, award UL 1TR002541), and NIH grants P30 DK040561 and U19 AG060917S1.

Sex and Race-Ethnic Disparities in Door-to-CT Time in Acute Ischemic Stroke: The Florida Stroke Registry.

Background Less than 40% of acute stroke patients have computed tomography (CT) imaging performed within 25 minutes of hospital arrival. We aimed to examine the race-ethnic and sex differences in door-to-CT (DTCT) ≤25 minutes in the FSR (Florida Stroke Registry). Methods and Results Data were collected from 2010 to 2018 for 63 265 patients with acute ischemic stroke from the FSR and secondary analysis was performed on 15 877 patients with intravenous tissue plasminogen activator-treated ischemic stroke. Generalized estimating equation models were used to determine predictors of DTCT ≤25. DTCT ≤25 was achieved in 56% of cases of suspected acute stroke, improving from 36% in 2010 to 72% in 2018. Women (odds ratio [OR], 0.90; 95% CI, 0.87-0.93) and Black (OR, 0.88; CI, 0.84-0.94) patients who had strokes were less likely, and Hispanic patients more likely (OR, 1.07; CI, 1.01-1.14), to achieve DTCT ≤25. In a secondary analysis among intravenous tissue plasminogen activator-treated patients, 81% of patients achieved DTCT ≤25. In this subgroup, women were less likely to receive DTCT ≤25 (0.85, 0.77-0.94) whereas no significant differences were observed by race or ethnicity. Conclusions In the FSR, there was considerable improvement in acute stroke care metric DTCT ≤25 in 2018 in comparison to 2010. However, sex and race-ethnic disparities persist and require further efforts to improve performance and reduce these disparities.

Targeting Microglial Polarization to Improve TBI Outcomes.

Traumatic Brain Injury (TBI) is still the worldwide leading cause of mortality and morbidity in young adults. Improved safety measures and advances in critical care have increased chances of surviving a TBI, however, numerous secondary mechanisms contribute to the injury in the weeks and months that follow TBI. The past 4 decades of research have addressed many of the metabolic impairments sufficient to mitigate mortality, however, an enduring secondary mechanism, i.e. neuroinflammation, has been intractable to current therapy. Neuroinflammation is particularly difficult to target with pharmacological agents due to lack of specificity, the blood brain barrier, and an incomplete understanding of the protective and pathologic influences of inflammation in TBI. Recent insights into TBI pathophysiology have established microglial activation as a hallmark of all types of TBI. The inflammatory response to injury is necessary and beneficial while the death of activated microglial is not. This review presents new insights on the therapeutic and maladaptive features of the immune response after TBI with an emphasis on microglial polarization, followed by a discussion of potential targets for pharmacologic and non-pharmacologic treatments. In aggregate, this review presents a rationale for guiding TBI inflammation towards neural repair and regeneration rather than secondary injury and degeneration, which we posit could improve outcomes and reduce lifelong disease burden in TBI survivors.

Genotype-Phenotype Correlation for Predicting Cochlear Implant Outcome: Current Challenges and Opportunities.

The use and utility of cochlear implantation has rapidly increased in recent years as technological advances in the field have expanded both the efficacy and eligible patient population for implantation. This review aims to serve as a general overview of the most common hearing disorders that have favorable auditory outcomes with cochlear implants (CI). Hearing loss in children caused by congenital cytomegalovirus infection, syndromic conditions including Pendred Syndrome, and non-syndromic genetic conditions such as hearing impairment associated with GJB2 mutations have shown to be successfully managed by CI. Furthermore, cochlear implantation provides the auditory rehabilitation for the most common etiology of hearing loss in adults and age-related hearing loss (ARHL) or presbycusis. However, in some cases, cochlear implantation have been associated with some challenges. Regarding implantation in children, studies have shown that sometimes parents seem to have unrealistic expectations regarding the ability of CI to provide auditory rehabilitation and speech improvement. Given the evidence revealing the beneficial effects of early intervention via CI in individuals with hearing disorders especially hearing loss due to genetic etiology, early auditory and genetic screening efforts may yield better clinical outcomes. There is a need to better understand genotype-phenotype correlations and CI outcome, so that effective genetic counseling and successful treatment strategies can be developed at the appropriate time for hearing impaired individuals.

Generalized granuloma annulare associated with essential thrombocythemia.

The only myeloproliferative neoplasm associated with generalized granuloma annulare (GA) is chronic myelogenous leukemia (CML). We present the first reported case of GA in a patient with essential thrombocythemia (ET). Future work investigating the shared pathophysiology of GA-associated CML and ET may improve our understanding of GA pathophysiology and treatment.

Red and White Blood Cell Counts Are Associated With Bone Marrow Adipose Tissue, Bone Mineral Density, and Bone Microarchitecture in Premenopausal Women.

Bone marrow adipose tissue (BMAT) resides within the bone marrow microenvironment where its function remains poorly understood. BMAT is elevated in anorexia nervosa, a disease model of chronic starvation, despite depletion of other fat depots. In addition to BMAT, the marrow microenvironment also consists of osteoblast and hematopoietic progenitors. BMAT is inversely associated with bone mineral density (BMD) in multiple populations including women with anorexia nervosa, and regulates hematopoiesis in animal models. We hypothesized that BMAT would be associated with circulating populations of hematopoietic cells (red and white blood cells) in humans and performed a post hoc analysis of two studies-a cross-sectional study and a longitudinal study-to investigate this hypothesis. We studied 89 premenopausal women cross-sectionally (median age [interquartile range], 27 [24.5, 31.7] years), including 35 with anorexia nervosa. We investigated associations between red blood cell (RBC) and white blood cell (WBC) counts and BMAT assessed by 1 H-magnetic resonance spectroscopy, BMD assessed by DXA, and bone microarchitecture assessed by HR-pQCT. In addition, we analyzed longitudinal data in six premenopausal women with anorexia nervosa treated with transdermal estrogen for 6 months and measured changes in BMAT and blood cell counts during treatment. Cross-sectionally, BMAT was inversely associated with WBC and RBC counts. In contrast, BMD and parameters of bone microarchitecture were positively associated with WBC and RBC. In women with anorexia nervosa treated with transdermal estrogen for 6 months, decreases in BMAT were significantly associated with increases in both RBC and hematocrit (rho = -0.83, p = 0.04 for both). In conclusion, we show that BMAT is inversely associated with WBC and RBC in premenopausal women, and there is a potential association between longitudinal changes in BMAT and changes in RBC. These associations warrant further study and may provide further insight into the role and function of this understudied adipose depot. © 2020 American Society for Bone and Mineral Research.

The Use of Oral Anticoagulants in Patients with Atrial Fibrillation in the Emergency Department.

BACKGROUND AND AIM: Atrial Fibrillation is the leading cause of embolic stroke, yet less than half of high-risk patients with atrial fibrillation are on adequate stroke prevention with oral anticoagulants. Guidelines for the primary prevention of stroke recognize the emergency department as a location for physicians to identify atrial fibrillation and initiate anticoagulants. We sought to compare anticoagulant prescription rates in patients with atrial fibrillation in various provider settings to identify opportunities for improvement in cardioembolic stroke prevention. METHODS: A retrospective cohort study of 436 patients with atrial fibrillation presenting to the emergency department from 2014 to 2018 was performed. Baseline characteristics, stroke risk, and rates of anticoagulant prescription were compared across 3 groups: (1) patients discharged from the emergency department, (2) patients admitted under observation status, and (3) patients admitted to inpatient hospital service. RESULTS: Among 436 patients (47% women, 51% Hispanic), we identified 105 in the emergency department cohort, 131 in the observation cohort and 200 in the inpatient cohort. The average CHA2DS2-VASc score was 2.5 in the emergency department cohort, 2.6 in the observation cohort and 3.3 in the inpatient cohort. Anticoagulants were prescribed for high-risk patients (CHA2DS2-VASc score ≥ 2) in 17.5% (7/40) of the emergency department cohort compared to 73% (38/52, P< .0001) of the observation cohort and 80% (82/103 P< .0001) of the inpatient cohort. CONCLUSION: Patients with atrial fibrillation are more likely to be prescribed anticoagulants if admitted to inpatient or under observation status compared to the emergency department.

Transdermal Estrogen in Women With Anorexia Nervosa: An Exploratory Pilot Study.

Anorexia nervosa (AN) is a psychiatric disorder characterized by self-induced starvation, low body weight, and elevated levels of bone marrow adipose tissue (BMAT). BMAT is negatively associated with BMD in AN and more than 85% of women with AN have low bone mass and an increased risk of fracture. Although a majority of women with AN are amenorrheic, which is associated with low BMD, oral contraceptive pills, containing supraphysiologic doses of estrogen, are not effective in increasing bone mass. We performed a 6-month, open-label study of transdermal estradiol (0.045 mg/day) + levonorgestrel (0.015 mg/day) in 11 women with AN (mean age ± SEM: 37.2 ± 2.3 years) to investigate the effects of transdermal, physiologic doses of estrogen on BMD and BMAT in women with AN. We measured change in BMD by DXA, change in BMAT at the spine/hip by 1H-magnetic resonance spectroscopy, and change in C-terminal collagen cross-links (CTX), P1NP, osteocalcin, IGF-1, and sclerostin after 3 and 6 months of transdermal estrogen. Lumbar spine (2.0% ± 0.8%; p = 0.033) and lateral spine (3.2% ± 1.1%; p = 0.015) BMD increased after 6 months of transdermal estrogen. Lumbar spine BMAT decreased significantly after 3 months (-13.9 ± 6.0%; p = 0.046). Increases in lateral spine BMD were associated with decreases in CTX (p = 0.047). In conclusion, short-term treatment with transdermal, physiologic estrogen increases spine BMD in women with AN. Future studies are needed to assess the long-term efficacy of this treatment. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Role of microRNAs in inner ear development and hearing loss.

The etiology of hearing loss tends to be multi-factorial and affects a significant proportion of the global population. Despite the differences in etiology, a common physical pathological change that leads to hearing loss is damage to the mechanosensory hair cells of the inner ear. MicroRNAs (miRNAs) have been shown to play a role in inner ear development and thus, may play a role in the development or prevention of hearing loss. In this paper, we review the mechanism of action of miRNAs in the auditory system. We present an overview about the role of miRNAs in inner ear development, summarize the current research on the role of miRNAs in gene regulation, and discuss the effects of both miRNA mutations as well as overexpression. We discuss the crucial role of miRNAs in ensuring normal physiological development of the inner ear. Any deviation from the proper function of miRNA in the cochlea seems to contribute to deleterious damage to the structure of the auditory system and subsequently results in hearing loss. As interest for miRNA research increases, this paper serves as a platform to review current understandings and postulate future avenues for research. A better knowledge about the role of miRNA in the auditory system will help in developing novel treatment modalities for restoring hearing function based on regeneration of damaged inner ear hair cells.

Changes in marrow adipose tissue with short-term changes in weight in premenopausal women with anorexia nervosa.

OBJECTIVE: In anorexia nervosa, a psychiatric disease characterized by self-induced starvation and a model of chronic undernutrition, levels of subcutaneous (SAT) and visceral (VAT) adipose tissue are low, whereas marrow adipose tissue (MAT) levels are elevated compared to normal-weight women. The reason for this paradoxical elevation of an adipose tissue depot in starvation is not known. We sought to understand changes in MAT in response to subacute changes in weight and to compare these changes with those of other fat depots and body composition parameters. DESIGN AND METHODS: We conducted a 12-month longitudinal study including 46 premenopausal women (n = 26 with anorexia nervosa and n = 20 normal-weight controls) with a mean (s.e.m.) age of 28.2 ± 0.8 years. We measured MAT, SAT, VAT and bone mineral density (BMD) at baseline and after 12 months. RESULTS: At baseline, SAT (P < 0.0001), VAT (P < 0.02) and BMD of the spine and hip (P ≤ 0.0002) were significantly lower and vertebral and metaphyseal MAT (P ≤ 0.001) significantly higher in anorexia nervosa compared to controls. Weight gain over 12 months was associated with increases not only in SAT and VAT, but also epiphyseal MAT (P < 0.03). Changes in epiphyseal MAT were positively associated with changes in BMD (P < 0.03). CONCLUSIONS: In contrast to the steady state, in which MAT levels are higher in anorexia nervosa and MAT and BMD are inversely associated, short-term weight gain is associated with increases in both MAT and BMD. These longitudinal data demonstrate the dynamic nature of this fat depot and provide further evidence of its possible role in mineral metabolism.

Predictive Ability of Novel Cardiac Biomarkers ST2, Galectin-3, and NT-ProBNP Before Cardiac Surgery.

BACKGROUND: Current preoperative models use clinical risk factors alone in estimating risk of in-hospital mortality following cardiac surgery. However, novel biomarkers now exist to potentially improve preoperative prediction models. An assessment of Galectin-3, N-terminal pro b-type natriuretic peptide (NT-ProBNP), and soluble ST2 to improve the predictive ability of an existing prediction model of in-hospital mortality may improve our capacity to risk-stratify patients before surgery. METHODS AND RESULTS: We measured preoperative biomarkers in the NNECDSG (Northern New England Cardiovascular Disease Study Group), a prospective cohort of 1554 patients undergoing coronary artery bypass graft surgery. Exposures of interest were preoperative levels of galectin-3, NT-ProBNP, and ST2. In-hospital mortality and adverse events occurring after coronary artery bypass graft were the outcomes. After adjustment, NT-ProBNP and ST2 showed a statistically significant association with both their median and third tercile categories with NT-ProBNP odds ratios of 2.89 (95% confidence interval [CI]: 1.04-8.05) and 5.43 (95% CI: 1.21-24.44) and ST2 odds ratios of 3.96 (95% CI: 1.60-9.82) and 3.21 (95% CI: 1.17-8.80), respectively. The model receiver operating characteristic score of the base prediction model (0.80 [95% CI: 0.72-0.89]) varied significantly from the new multi-marker model (0.85 [95% CI: 0.79-0.91]). Compared with the Northern New England (NNE) model alone, the full prediction model with biomarkers NT-proBNP and ST2 shows significant improvement in model classification of in-hospital mortality. CONCLUSIONS: This study demonstrates a significant improvement of preoperative prediction of in-hospital mortality in patients undergoing coronary artery bypass graft and suggests that biomarkers can be used to identify patients at higher risk.