Elizabeth J. Brown

Bio: Elizabeth J. Brown is an academic researcher from University of Texas Southwestern Medical Center. The author has contributed to research in topics: Focal segmental glomerulosclerosis & Minimal change disease. The author has an hindex of 19, co-authored 42 publications receiving 6698 citations. Previous affiliations of Elizabeth J. Brown include Harvard University & Christiana Care Health System.

The hormone resistin links obesity to diabetes

Abstract: Diabetes mellitus is a chronic disease that leads to complications including heart disease, stroke, kidney failure, blindness and nerve damage. Type 2 diabetes, characterized by target-tissue resistance to insulin, is epidemic in industrialized societies and is strongly associated with obesity; however, the mechanism by which increased adiposity causes insulin resistance is unclear. Here we show that adipocytes secrete a unique signalling molecule, which we have named resistin (for resistance to insulin). Circulating resistin levels are decreased by the anti-diabetic drug rosiglitazone, and increased in diet-induced and genetic forms of obesity. Administration of anti-resistin antibody improves blood sugar and insulin action in mice with diet-induced obesity. Moreover, treatment of normal mice with recombinant resistin impairs glucose tolerance and insulin action. Insulin-stimulated glucose uptake by adipocytes is enhanced by neutralization of resistin and is reduced by resistin treatment. Resistin is thus a hormone that potentially links obesity to diabetes.

A family of tissue-specific resistin-like molecules

Abstract: We have identified a family of resistin-like molecules (RELMs) in rodents and humans. Resistin is a hormone produced by fat cells. RELMα is a secreted protein that has a restricted tissue distribution with highest levels in adipose tissue. Another family member, RELMβ, is a secreted protein expressed only in the gastrointestinal tract, particularly the colon, in both mouse and human. RELMβ gene expression is highest in proliferative epithelial cells and is markedly increased in tumors, suggesting a role in intestinal proliferation. Resistin and the RELMs share a cysteine composition and other signature features. Thus, the RELMs together with resistin comprise a class of tissue-specific signaling molecules.

Individualized behavioral and environmental care for the very low birth weight preterm infant at high risk for bronchopulmonary dysplasia: neonatal intensive care unit and developmental outcome

Abstract: We hypothesize that the respiratory and functional states of the very low birth weight infant with bronchopulmonary dysplasia can be improved in the neonatal intensive care unit by prevention of inappropriate sensory input. To test this hypothesis, we developed for preterm newborns a behavior observation method that catalogues specific reaction patterns according to putative stress and relaxation behaviors. We then collected behavioral information and heart rate, respiratory rate, and transcutaneous PO2 readings before, during, and after routine care-giving interventions. Eight control and eight experimental infants were selected for study based on the following criteria: birth weight less than 1,250 g, gestational age less than 28 weeks, on the respirator greater than 24 hours in first 48 hours of life at greater than or equal to 0.60 FiO2 for more than two hours during first 48 hours of life. Additionally, the two groups were comparable on other medical and demographic variables, including severity of respiratory status for the first ten days and incidence of intraventricular hemorrhage, patent ductus arteriosus, and socioeconomic status. Systematic observations were conducted on days 10, 20, and 30 after birth and at 36 and 40 weeks postconception. For the intervention infants, our observations were discussed with the infants' primary nurses, and individualized modifications for each infant's care plan were implemented based on these observations. Experimental infants showed significantly briefer stays on the respirator (P less than .01) and in increased FiO2 (P less than .05). Their feeding behavior was normalized significantly earlier (P less than .01). Experimental infants also showed significantly better behavioral regulation scores at 1 month after their mothers' estimated dates of confinement (post-EDC), as measured with the Assessment of Preterm Infants' Behavior, significantly better Mental and Psychomotor Developmental Indices at 3, 6, and 9 months post-EDC, as measured with the Bayley Scales of Infant Development, and significantly better behavioral regulation scores at 9 months post-EDC, as measured in a videotaped play observation. Measurements of weight, height, and head circumference at 3, 6, and 9 months post-EDC showed no differences. All assessments were performed by one of two trained testers not familiar with the goals of the study or the group status of the infant. These results support the hypothesis that very low birth weight preterm babies profit significantly both medically and developmentally from individualized behavioral care in the neonatal intensive care unit.

Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis

Abstract: Focal segmental glomerulosclerosis (FSGS) is a pattern of kidney injury observed either as an idiopathic finding or as a consequence of underlying systemic conditions. Several genes have been identified that, when mutated, lead to inherited FSGS and/or the related nephrotic syndrome. These findings have accelerated the understanding of glomerular podocyte function and disease, motivating our search for additional FSGS genes. Using linkage analysis, we identified a locus for autosomal-dominant FSGS susceptibility on a region of chromosome 14q. By sequencing multiple genes in this region, we detected nine independent nonconservative missense mutations in INF2, which encodes a member of the formin family of actin-regulating proteins. These mutations, all within the diaphanous inhibitory domain of INF2, segregate with FSGS in 11 unrelated families and alter highly conserved amino acid residues. The observation that alterations in this podocyte-expressed formin cause FSGS emphasizes the importance of fine regulation of actin polymerization in podocyte function.

Risk factors for Clostridium difficile toxin-associated diarrhea.

Abstract: The hospital-wide attack rate for Clostridium difficile-associated diarrhea at our tertiary-care university hospital was 002 per 100 patient discharges (002%) in 1982, but 041% and 147% in 1986 and 1987, respectively, with a peak incidence of 225% in the fourth quarter of 1987 Hospital antibiotic usage patterns showed concurrent increased use of third-generation cephalosporins, and intravenous vancomycin and metronidazole Thirty-seven cases selected for study were older than 37 control patients, more likely to have an underlying malignancy and less likely hospitalized on the obstetrics/gynecology service Their mean duration of hospitalization prior to diagnosis was 21 days, versus a mean total length of stay of eight days for controls All cases received antibiotics, compared to 24 of the controls Cases were given more antibiotics for longer periods, and more often received clindamycin, third-generation cephalosporins, aminoglycosides and vancomycin Gender, race, duration of hospitalization, prior surgery and antiulcer therapy were not significant by logistic regression analysis Epidemiologic variables with significantly different adjusted odds ratios (95% confidence intervals) were age greater than 65 years (141, 14-141), intensive care unit residence (392, 22-713), gastrointestinal procedure (232, 21-255) and more than ten antibiotic days (summation of days of each antibiotic administered) (161, 22-117) Control measures included encouraging earlier isolation and treatment of suspected cases and formulary restriction of clindamycin, with use of metronidazole for therapy of anaerobic infections By the second half of 1988, the attack rate had dropped progressively to 074%

Adipose Tissue as an Endocrine Organ

Abstract: Adipose tissue is a complex, essential, and highly active metabolic and endocrine organ. Besides adipocytes, adipose tissue contains connective tissue matrix, nerve tissue, stromovascular cells, and immune cells. Together these components function as an integrated unit. Adipose tissue not only responds to afferent signals from traditional hormone systems and the central nervous system but also expresses and secretes factors with important endocrine functions. These factors include leptin, other cytokines, adiponectin, complement components, plasminogen activator inhibitor-1, proteins of the renin-angiotensin system, and resistin. Adipose tissue is also a major site for metabolism of sex steroids and glucocorticoids. The important endocrine function of adipose tissue is emphasized by the adverse metabolic consequences of both adipose tissue excess and deficiency. A better understanding of the endocrine function of adipose tissue will likely lead to more rational therapy for these increasingly prevalent disorders. This review presents an overview of the endocrine functions of adipose tissue.

Insulin signalling and the regulation of glucose and lipid metabolism

Abstract: The epidemic of type 2 diabetes and impaired glucose tolerance is one of the main causes of morbidity and mortality worldwide. In both disorders, tissues such as muscle, fat and liver become less responsive or resistant to insulin. This state is also linked to other common health problems, such as obesity, polycystic ovarian disease, hyperlipidaemia, hypertension and atherosclerosis. The pathophysiology of insulin resistance involves a complex network of signalling pathways, activated by the insulin receptor, which regulates intermediary metabolism and its organization in cells. But recent studies have shown that numerous other hormones and signalling events attenuate insulin action, and are important in type 2 diabetes.

The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity

Abstract: Adiponectin is an adipocyte-derived hormone. Recent genome-wide scans have mapped a susceptibility locus for type 2 diabetes and metabolic syndrome to chromosome 3q27, where the gene encoding adiponectin is located. Here we show that decreased expression of adiponectin correlates with insulin resistance in mouse models of altered insulin sensitivity. Adiponectin decreases insulin resistance by decreasing triglyceride content in muscle and liver in obese mice. This effect results from increased expression of molecules involved in both fatty-acid combustion and energy dissipation in muscle. Moreover, insulin resistance in lipoatrophic mice was completely reversed by the combination of physiological doses of adiponectin and leptin, but only partially by either adiponectin or leptin alone. We conclude that decreased adiponectin is implicated in the development of insulin resistance in mouse models of both obesity and lipoatrophy. These data also indicate that the replenishment of adiponectin might provide a novel treatment modality for insulin resistance and type 2 diabetes.

Increased oxidative stress in obesity and its impact on metabolic syndrome

Abstract: Obesity is a principal causative factor in the development of metabolic syndrome. Here we report that increased oxidative stress in accumulated fat is an important pathogenic mechanism of obesity-associated metabolic syndrome. Fat accumulation correlated with systemic oxidative stress in humans and mice. Production of ROS increased selectively in adipose tissue of obese mice, accompanied by augmented expression of NADPH oxidase and decreased expression of antioxidative enzymes. In cultured adipocytes, elevated levels of fatty acids increased oxidative stress via NADPH oxidase activation, and oxidative stress caused dysregulated production of adipocytokines (fat-derived hormones), including adiponectin, plasminogen activator inhibitor-1, IL-6, and monocyte chemotactic protein-1. Finally, in obese mice, treatment with NADPH oxidase inhibitor reduced ROS production in adipose tissue, attenuated the dysregulation of adipocytokines, and improved diabetes, hyperlipidemia, and hepatic steatosis. Collectively, our results suggest that increased oxidative stress in accumulated fat is an early instigator of metabolic syndrome and that the redox state in adipose tissue is a potentially useful therapeutic target for obesity-associated metabolic syndrome.