Elizabeth J. Brown

The hormone resistin links obesity to diabetes

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.

Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis

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.

The hospital-wide attack rate for Clostridium difficile-associated diarrhea at our tertiary-care university hospital was 0.02 per 100 patient discharges (0.02%) in 1982, but 0.41% and 1.47% in 1986 and 1987, respectively, with a peak incidence of 2.25% 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 (14.1, 1.4-141), intensive care unit residence (39.2, 2.2-713), gastrointestinal procedure (23.2, 2.1-255) and more than ten antibiotic days (summation of days of each antibiotic administered) (16.1, 2.2-117). 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 0.74%.

Mutations in the INF2 gene account for a significant proportion of familial but not sporadic focal and segmental glomerulosclerosis

Mutations in the inverted formin 2 gene (INF2) have recently been identified as the most common cause of autosomal dominant focal and segmental glomerulosclerosis (FSGS). In order to quantify the contribution of various genes contributing to FSGS, we sequenced INF2 where all mutations have previously been described (exons 2 to 5) in a total of 215 probands and 281 sporadic individuals with FSGS, along with other known genes accounting for autosomal dominant FSGS (ACTN4, TRPC6 and CD2AP) in 213 probands. Variants were classified as disease-causing if they altered the amino acid sequence, were not found in control samples, and in families segregated with disease. Mutations in INF2 were found in a total of 20 of the 215 families (including those previously reported) in our cohort of autosomal dominant familial nephrotic syndrome or FSGS, thereby explaining disease in 9 percent. INF2 mutations were found in 2 of 281 individuals with sporadic FSGS. In contrast, ACTN4 and TRPC6-related disease accounted for 3 and 2 percent of our familial cohort, respectively. INF2-related disease showed variable penetrance, with onset of disease ranging widely from childhood to adulthood and commonly leading to ESRD in the third and fourth decade of life. Thus, mutations in INF2 are more common, although still minor, monogenic cause of familial FSGS when compared to other known autosomal dominant genes associated with FSGS.

Rho activation of mDia formins is modulated by an interaction with inverted formin 2 (INF2).

Inverted formin 2 (INF2) encodes a member of the diaphanous subfamily of formin proteins. Mutations in INF2 cause human kidney disease characterized by focal and segmental glomerulosclerosis. Disease-causing mutations occur only in the diaphanous inhibitory domain (DID), suggesting specific roles for this domain in the pathogenesis of disease. In a yeast two-hybrid screen, we identified the diaphanous autoregulatory domains (DADs) of the mammalian diaphanous-related formins (mDias) mDia1, mDia2, and mDia 3 as INF2_DID-interacting partners. The mDias are Rho family effectors that regulate actin dynamics. We confirmed in vitro INF2_DID/mDia_DAD binding by biochemical assays, confirmed the in vivo interaction of these protein domains by coimmunoprecipitation, and observed colocalization of INF2 and mDias in glomerular podocytes. We investigated the influence of this INF2_DID/mDia_DAD interaction on mDia mediated actin polymerization and on serum response factor (SRF) activation. We find that the interaction of INF2_DID with mDia_DAD inhibited mDia-mediated, Rho-activated actin polymerization, as well as SRF-responsive gene transcriptional changes. Similar assays using the disease-causing E184K and R218Q mutations in INF2_DID showed a decreased effect on SRF activation and gene transcription. The binding of INF2_DID to mDia_DAD may serve as a negative regulatory mechanism for mDias’ function in actin-dependent cell processes. The effects of disease-causing INF2 mutations suggest an important role for this protein and its interaction with other formins in modulating glomerular podocyte phenotype and function.

Cost-benefit and cost-effectiveness analyses of behavioral marital therapy with and without relapse prevention sessions for alcoholics and their spouses

Fifty-nine couples with a newly abstinent alcoholic husband, after participating in weekly behavioral marital therapy (BMT) couples sessions for 5 to 6 months, were randomly assigned to receive or not to receive 15 additional conjoint couples relapse prevention (RP) sessions over the next 12 months. Costs of treatment delivery and health and legal service utilization were measured for the 12 months before and 12 months after BMT. Cost-benefit analysis results for both standard BMT and for the longer and more costly form of BMT with the additional RP sessions showed (a) decreases in health care and legal costs after, as compared to before, treatment, (b) positive cost offsets, and (c) benefit to cost ratios greater than 1, indicating that health and legal system cost savings (i.e., benefits) exceeded the costs of delivering the BMT treatments. In fact, cost savings from reduced utilization were more than 5 times greater than the cost of delivering the standard 5- to 6-month BMT program. Although adding RP to BMT led to less drinking and better marital adjustment, it did not lead to greater cost savings in health and legal service utilization. A trend for subjects with higher baseline costs to incur lower costs at follow-up if they received BMT plus RP suggested additional cost savings from RP may come only for more severe problem patients who have a history of high utilization of services. Cost-effectiveness analyses indicated that BMT only was more cost-effective than BMT plus RP in producing abstinence from drinking, but the 2 treatments were equally cost-effective when marital adjustment outcomes were considered. Since BMT only was actually less effective than BMT plus RP in producing abstinent days, it was the lower cost of BMT only that produced its greater cost-effectiveness in relation to abstinence. Study limitations are discussed.

Genetic testing for nephrotic syndrome and FSGS in the era of next-generation sequencing

The haploid human genome is composed of three billion base pairs, about one percent of which consists of exonic regions, the coding sequence for functional proteins, also now known as the “exome”. The development of next-generation sequencing makes it possible from a technical and economic standpoint to sequence an individual’s exome but at the cost of generating long lists of gene variants that are not straightforward to interpret. Various public consortiums such as the 1000 Genomes Project and the NHLBI Exome Sequencing Project have sequenced the exomes and a subset of entire genomes of over 2500 control individuals with ongoing efforts to further catalogue genetic variation in humans.1 The use of these public databases facilitates the interpretation of these variant lists produced by exome sequencing and, as a result, novel genetic variants linked to disease are being discovered and reported at a record rate. However, the interpretation of these results and their bearing on diagnosis, prognosis, and treatment is becoming ever more complicated. Here, we discuss the application of genetic testing to individuals with focal and segmental glomerulosclerosis (FSGS), taking a historical perspective on gene identification and its clinical implications along with the growing potential of next-generation sequencing.

Racial Disparities In Geographic Access To Primary Care In Philadelphia

Primary care is often thought of as the gateway to improved health outcomes and can lead to more efficient use of health care resources. Because of primary cares cardinal importance, adequate access is an important health policy priority. In densely populated urban areas, spatial access to primary care providers across neighborhoods is poorly understood. We examined spatial variation in primary care access in Philadelphia, Pennsylvania. We calculated ratios of adults per primary care provider for each census tract and included buffer zones based on prespecified drive times around each tract. We found that the average ratio was 1,073; the supply of primary care providers varied widely across census tracts, ranging from 105 to 10,321. We identified six areas of Philadelphia that have much lower spatial accessibility to primary care relative to the rest of the city. After adjustment for sociodemographic and insurance characteristics, the odds of being in a low-access area were twenty-eight times greater for census tracts with a high proportion of African Americans than in tracts with a low proportion of African Americans.

Magnitude and duration of lung response to dexamethasone in fetal sheep

Some cases of respiratory distress syndrome (RDS) occur after optimal prenatal exposure to glucocorticoids. To explore whether some of these cases might be due to a transient effect of glucocorticoids on developing fetal lung, we studied nine chronically catheterized sheep fetuses after infusion of 500 micrograms of dexamethasone phosphate. Daily efflux of disaturated phosphatidylcholine (DSPC) from fetal tracheal fluid was measured. Three cases showed no response, two showed an early sustained rise in DSPC, and four showed an unsustained response. We interpret these data as indicating that the fetus may respond in a variety of ways to glucocorticoids, depending possibly on such factors as stage of maturity, sex, dose, and duration of exposure.

Exploring the Patient and Staff Experience With the Process of Primary Care

PURPOSE Previous studies suggest that the highest-risk patients value accessible, coordinated primary care that they perceive to be of high technical quality. We have limited understanding, however, of how low-income, chronically ill patients and the staff who care for them experience each individual step in the primary care process. METHODS We conducted qualitative interviews with uninsured or Medicaid patients with chronic illnesses, as well as with primary care staff. We interviewed 21 patients and 30 staff members with a variety of job titles from 3 primary care practices (1 federally qualified health center and 2 academically affiliated clinics).] RESULTS The interviews revealed 3 major issues that were present at all stages of a primary care episode: (1) information flow throughout an episode of care is a frequent challenge, despite systems that are intended to improve communication; (2) misaligned goals and expectations among patients, clinicians, and staff members are often an impediment to providing and obtaining care; and (3) personal relationships are highly valued by both patients and staff. CONCLUSIONS Vulnerable populations and the primary care staff who work with them perceive some of the same challenges throughout the primary care process. Improving information flow, aligning goals and expectations, and developing personal relationships may improve the experience of both patients and staff.