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Human but not mouse islets transplanted into immunodeficient NSG mice effectively accumulate lipid droplets (LDs). Because chronic lipid exposure is associated with islet β-cell dysfunction, we investigated LD accumulation in the intact human and mouse pancreas over a range of ages and states of diabetes. Very few LDs were found in normal human juvenile pancreatic acinar and islet cells, with numbers subsequently increasing throughout adulthood. While accumulation appeared evenly distributed in postjuvenile acinar and islet cells in donors without diabetes, LDs were enriched in islet α- and β-cells from donors with type 2 diabetes (T2D). LDs were also found in the islet β-like cells produced from human embryonic cell-derived β-cell clusters. In contrast, LD accumulation was nearly undetectable in the adult rodent pancreas, even in hyperglycemic and hyperlipidemic models or 1.5-year-old mice. Taken together, there appear to be significant differences in pancreas islet cell lipid handling between species, and the human juvenile and adult cell populations. Moreover, our results suggest that LD enrichment could be impactful to T2D islet cell function.
© 2019 by the American Diabetes Association.
BACKGROUND - Patient-specific and disease-specific factors shape the course of chronic rhinosinusitis (CRS) and its response to treatment, with optimal management involving interventions tailored to these factors. Recent evidence suggests CRS inflammatory signatures depend on age. The objective of this study was to determine whether age also influences quality-of-life (QOL) and postoperative outcomes.
METHODS - Retrospective analysis of prospectively collected QOL data from 403 adults with medically refractory CRS who underwent functional endoscopic sinus surgery (FESS) at a tertiary care medical center between 2014 and 2018 was undertaken. Total and subdomain scores from the 22-item Sino-Nasal Outcome Test (SNOT-22) and the Short Form 8 Health Survey (SF-8) measure of general health completed at preoperative and postoperative visits were reviewed.
RESULTS - Patients were divided into young (18 to 39 years, n = 100), middle-aged (40 to 59 years, n = 172), and elderly (≥60 years, n = 131) groups. Baseline total SNOT-22 scores differed between groups (p = 0.01), with middle-aged patients having the highest symptom burden and elderly patients having the lowest. Similar patterns were observed for SNOT-22 subdomains. Elderly patients reported smaller improvements and were less likely to achieve a minimally important clinical difference. CRS patients had worse SF-8 scores compared to the general population, and elderly patients were the least likely to match population norms following surgery. Age was an independent predictor of QOL outcomes after FESS.
CONCLUSION - Age may play a significant role in CRS pathophysiology, symptom burden, and surgical outcomes. Elderly patients report smaller improvements in disease-specific and general health QOL after surgery. CRS management in the elderly population should incorporate age-dependent differences in symptom burden and expectations into treatment algorithms.
© 2019 ARS-AAOA, LLC.
BACKGROUND - Sex differences mediating predisposition to kidney injury are well known, with evidence indicating lower CKD incidence rates and slower decline in renal function in nondiabetic CKD for premenopausal women compared with men. However, signaling pathways involved have not been elucidated to date. The EGF receptor (EGFR) is widely expressed in the kidney in glomeruli and tubules, and persistent and dysregulated EGFR activation mediates progressive renal injury.
METHODS - To investigate the sex differences in response to renal injury, we examined EGFR expression in mice, in human kidney tissue, and in cultured cell lines.
RESULTS - In wild type mice, renal mRNA and protein EGFR levels were comparable in males and females at postnatal day 7 but were significantly lower in age-matched adult females than in adult males. Similar gender differences in renal EGFR expression were detected in normal adult human kidneys. In Dsk5 mutant mice with a gain-of-function allele that increases basal EGFR kinase activity, males had progressive glomerulopathy, albuminuria, loss of podocytes, and tubulointerstitial fibrosis, but female Dsk5 mice had minimal kidney injury. Oophorectomy had no effect on renal EGFR levels in female Dsk5 mice, while castration protected against the kidney injury in male Dsk5 mice, in association with a reduction in EGFR expression to levels seen in females. Conversely, testosterone increased EGFR expression and renal injury in female Dsk5 mice. Testosterone directly stimulated EGFR expression in cultured kidney cells.
CONCLUSIONS - These studies indicate that differential renal EGFR expression plays a role in the sex differences in susceptibility to progressive kidney injury that may be mediated at least in part by testosterone.
Copyright © 2019 by the American Society of Nephrology.
Background The relationship of coronary artery calcium (CAC) with adverse cardiac remodeling is not well established. We aimed to study the association of CAC in middle age and change in CAC from early adulthood to middle age with left ventricular (LV) function. Methods CAC score was measured by computed tomography at CARDIA study (Coronary Artery Risk Development in Young Adults) year-15 examination and at year-25 examination (Y25) in 3043 and 3189 participants, respectively. CAC score was assessed as a continuous variable and log-transformed to account for nonlinearity. Change in CAC from year-15 examination to Y25 was evaluated as the absolute difference of log-transformed CAC from year-15 examination to Y25. LV structure and function were evaluated by echocardiography at Y25. Results At Y25, mean age was 50.1±3.6 years, 56.6% women, 52.4% black. In the multivariable analysis at Y25, higher CAC was related to higher LV mass (β=1.218; adjusted P=0.007), higher LV end-diastolic volume (β=0.811; adjusted P=0.007), higher LV end-systolic volume (β=0.350; adjusted P=0.048), higher left atrial volume (β=0.214; adjusted P=0.009), and higher E/e' ratio (β=0.059; adjusted P=0.014). CAC was measured at both year-15 examination and Y25 in 2449 individuals. Higher change in CAC score during follow-up was independently related to higher LV mass index in blacks (β=4.789; adjusted P<0.001), but not in whites (β=1.051; adjusted P=0.283). Conclusions Higher CAC in middle age is associated with higher LV mass and volumes and worse LV diastolic function. Being free of CAC from young adulthood to middle age correlates to better LV function at middle age. Higher change in CAC score during follow-up is independently related to higher LV mass index in blacks.
INTRODUCTION - Evidence of human papillomavirus (HPV) vaccine impact on anogenital warts (AGWs) by race or urbanicity in the US is lacking. We evaluated HPV vaccine impact in Tennessee by assessing AGW trends among Tennessee Medicaid (TennCare) enrollees aged 15-39 years from 2006-2014.
METHODS - Persons with incident AGWs were identified using diagnosis/pharmacy codes from TennCare billing claims. We calculated sex-specific annual AGW incidence by age group, race, and urbanicity; estimated annual percent changes (APCs) using log-linear models; and performed pairwise comparisons by race and urbanicity.
RESULTS - AGW incidence decreased among females aged 15-19 (APC = -10.6; P < 0.01) and 20-24 years (APC = -3.9; P = 0.02). Overall trends were similar between Whites and Blacks, and between those living in metropolitan statistical areas (MSAs) and non-MSAs. Rates among males aged 15-19 years began decreasing after 2010. Among enrollees aged 25-39 years, rates increased or were stable.
CONCLUSIONS - Following introduction of the HPV vaccine in 2006, AGWs decreased among age groups most likely to be vaccinated. The change in trend among young males after 2010 suggests early herd effects. Our findings indicate vaccine effects and support the importance of improving adherence to current vaccination recommendations for preventing AGWs and other HPV-related diseases.
Copyright © 2019. Published by Elsevier B.V.
Integrin-linked kinase (ILK) is a critical intracellular signaling node for integrin receptors. Its role in liver development is complex, as ILK deletion at E10.5 (before hepatocyte differentiation) results in biochemical and morphological differences that resolve as mice age. Nevertheless, mice with ILK depleted specifically in hepatocytes are protected from the hepatic insulin resistance during obesity. Despite the potential importance of hepatocyte ILK to metabolic health, it is unknown how ILK controls hepatic metabolism or glucoregulation. The present study tested the role of ILK in hepatic metabolism and glucoregulation by deleting it specifically in hepatocytes, using a cre-lox system that begins expression at E15.5 (after initiation of hepatocyte differentiation). These mice develop the most severe morphological and glucoregulatory abnormalities at 6 wk, but these gradually resolve with age. After identifying when the deletion of ILK caused a severe metabolic phenotype, in depth studies were performed at this time point to define the metabolic programs that coordinate control of glucoregulation that are regulated by ILK. We show that 6-wk-old ILK-deficient mice have higher glucose tolerance and decreased net glycogen synthesis. Additionally, ILK was shown to be necessary for transcription of mitochondrial-related genes, oxidative metabolism, and maintenance of cellular energy status. Thus, ILK is required for maintaining hepatic transcriptional and metabolic programs that sustain oxidative metabolism, which are required for hepatic maintenance of glucose homeostasis.
OBJECTIVE - The primary aim of this study is to evaluate the safety, efficacy, and execution of major open laryngotracheal operations for patients in the advanced decades.
STUDY DESIGN - Case series with chart review.
SETTING - Multidisciplinary clinic at a tertiary care academic hospital.
SUBJECTS AND METHODS - Patient characteristics, operative course, and postoperative outcomes were retrospectively recorded for all airway reconstruction operations performed between 1999 and 2016 on patients aged ≥60 years Long-term success was defined as prosthesis-free survival at last follow-up. Descriptive statistics were performed.
RESULTS - Twenty-nine patients met inclusion criteria, and the median age was 71 years (interquartile range, 63-74). Tracheal resection was the most common procedure (13 patients), followed by laryngotracheal reconstruction (7 patients). Fifteen patients began their operation with a tracheostomy, 6 of whom underwent decannulation prior to leaving the operating room. Three additional patients underwent decannulation at follow-up appointments and were prosthesis-free at most recent follow-up. The mean time to decannulation among these patients was 3 months. Of the 14 patients beginning their procedure without a tracheostomy, only 2 required permanent airway prosthesis. The overall long-term rate of prosthesis-free survival was 72.4% (21 of 29 patients). Factors suggestive of long-term success include lower McCaffrey grade and lack of pulmonary disease, hypertension, or diabetes, as well as decreased red blood cell distribution width on preoperative complete blood count.
CONCLUSION - Through careful patient selection, preoperative workup, and meticulous postoperative care, airway reconstruction procedures in patients aged ≥60 years are reasonably successful. Of 29 patients, 21 (72.4%) were successfully breathing long-term without airway prosthesis.
OBJECTIVE - Necrotizing enterocolitis (NEC) is the most common surgical emergency in preterm infants, and pathogenesis associates with changes in the fecal microbiome. As fecal samples incompletely represent microbial communities in intestinal mucosa, we sought to determine the NEC tissue-specific microbiome and assess its contribution to pathogenesis.
DESIGN - We amplified and sequenced the V1-V3 hypervariable region of the bacterial 16S rRNA gene extracted from intestinal tissue and corresponding fecal samples from 12 surgical patients with NEC and 14 surgical patients without NEC. Low quality and non-bacterial sequences were removed, and taxonomic assignment was made with the Ribosomal Database Project. Operational taxonomic units were clustered at 97%. We tested for differences between NEC and non-NEC samples in microbiome alpha- and beta-diversity and differential abundance of specific taxa between NEC and non-NEC samples. Additional analyses were performed to assess the contribution of other demographic and environmental confounding factors on the infant tissue and fecal microbiome.
RESULTS - The fecal and tissue microbial communities were different. NEC was associated with a distinct microbiome, which was characterized by low diversity, higher abundances of Staphylococcus and Clostridium_sensu_stricto, and lower abundances of Actinomyces and Corynebacterium. Infant age and vancomycin exposure correlated with shifts in the tissue microbiome.
CONCLUSION - The observed low diversity in NEC tissues suggests that NEC is associated with a bacterial bloom and a distinct mucosal bacterial community. The exact bacterial species that constitute the bloom varied by infant and were strongly influenced by age and exposure to vancomycin.
BACKGROUND - Blood transfusions are administered to children and adults with sickle cell anemia (SCA) for secondary stroke prevention, or as treatment for recurrent pain crises or acute anemia, but transfusion effects on cerebral hemodynamics and metabolism are not well-characterized.
PURPOSE - To compare blood transfusion-induced changes in hemometabolic parameters, including oxygen extraction fraction (OEF) and cerebral blood flow (CBF), within and between adults and children with SCA.
STUDY TYPE - Prospective, longitudinal study.
SUBJECTS - Adults with SCA (n = 16) receiving simple (n = 7) or exchange (n = 9) transfusions and children with SCA (n = 11) receiving exchange transfusions were scanned once when hematocrit was near nadir and again within 7 days of transfusion. Adult controls without SCA or sickle trait (n = 7) were scanned twice on separate days.
FIELD STRENGTH/SEQUENCE - 3.0T T -weighted, T -weighted, and T -relaxation-under-spin-tagging (TRUST) imaging, and phase contrast angiography.
ASSESSMENT - Global OEF was computed as the relative difference between venous oxygenation (from TRUST) and arterial oxygenation (from pulse oximetry). Global CBF was computed as total blood flow to the brain normalized by intracranial tissue volume.
STATISTICAL TESTS - Hemometabolic variables were compared using two-sided Wilcoxon signed-rank tests; associations were analyzed using two-sided Spearman's correlation testing.
RESULTS - In adults with SCA, posttransfusion OEF = 0.38 ± 0.05 was lower (P = 0.001) than pretransfusion OEF = 0.45 ± 0.09. A change in OEF was correlated with increases in hematocrit (P = 0.02; rho = -0.62) and with pretransfusion hematocrit (P = 0.02; rho = 0.65). OEF changes after transfusion were greater (P = 0.002) in adults receiving simple versus exchange transfusions. Posttransfusion CBF = 77.7 ± 26.4 ml/100g/min was not different (P = 0.27) from pretransfusion CBF = 82.3 ± 30.2 ml/100g/min. In children with SCA, both posttransfusion OEF = 0.28 ± 0.04 and CBF = 76.4 ± 26.4 were lower than pretransfusion OEF = 0.36 ± 0.06 (P = 0.004) and CBF = 96.4 ± 16.5 (P = 0.004).
DATA CONCLUSION - Cerebral OEF reduces following transfusions in adults and children with SCA. CBF reduces following transfusions more often in children compared to adults, indicating that vascular reserve capacity may remain near exhaustion posttransfusion in many adults.
LEVEL OF EVIDENCE - 2 Technical Efficacy Stage 5 J. Magn. Reson. Imaging 2019;49:466-477.
© 2018 International Society for Magnetic Resonance in Medicine.