Faculty Bibliography

Functional zonation of the adrenal cortex is a consequence of the zone-specific expression of P450c17 (CYP17A1) and its cofactors. Activin and inhibin peptides are differentially produced within the zones of the adrenal cortex and have been implicated in steroidogenic control. In this study, we investigated whether activin and inhibin can function as intermediates in functional zonation of the human adrenal cortex. Activin A suppressed CYP17A1 expression and P450c17 function in adrenocortical cell lines as well as in primary adrenal cell cultures. Inhibin βA-subunit mRNA and activin A protein levels were found to be increased up to 1,900-fold and 49-fold, respectively, after protein kinase C (PKC) stimulation through PMA or angiotensin II in H295R adrenocortical carcinoma cells. This was confirmed in HAC15 cells and for PMA in primary adrenal cell cultures. Both PMA and Ang II decreased CYP17A1 expression in the adrenocortical cell lines, whereas PMA concurrently suppressed CYP17A1 levels in the primary cultures. Inhibition of activin signaling during PKC stimulation through silencing of the inhibin βA-subunit or blocking of the activin type I receptor opposed the PMA-induced downregulation of CYP17A1 expression and P450c17 function. In contrast, PKA stimulation through adrenocorticotrophin or forskolin increased expression of the inhibin α-subunit and betaglycan, both of which are antagonists of activin action. These data indicate that activin A acts as a PKC-induced paracrine factor involved in the suppression of CYP17A1 in the zona glomerulosa and can thereby contribute to functional adrenocortical zonation.

BACKGROUND:Adrenal Cushing's syndrome caused by ACTH-independent macronodular adrenocortical hyperplasia (AIMAH) can be accompanied by aberrant responses to hormonal stimuli. We investigated the prevalence of adrenocortical reactions to these stimuli in a large cohort of AIMAH patients, both in vivo and in vitro. METHODS:In vivo cortisol responses to hormonal stimuli were studied in 35 patients with ACTH-independent bilateral adrenal enlargement and (sub-)clinical hypercortisolism. In vitro, the effects of these stimuli on cortisol secretion and steroidogenic enzyme mRNA expression were evaluated in cultured AIMAH and other adrenocortical cells. Arginine-vasopressin (AVP) receptor mRNA levels were determined in the adrenal tissues. RESULTS:Positive serum cortisol responses to stimuli were detected in 27/35 AIMAH patients tested, with multiple responses within individual patients occurring for up to four stimuli. AVP and metoclopramide were the most prevalent hormonal stimuli triggering positive responses in vivo. Catecholamines induced short-term cortisol production more often in AIMAH cultures compared to other adrenal cells. Short- and long-term incubation with AVP increased cortisol secretion in cultures of AIMAH cells. AVP also increased steroidogenic enzyme mRNA expression, among which an aberrant induction of CYP11B1. AVP type 1a receptor was the only AVPR expressed and levels were high in the AIMAH tissues. AVPR1A expression was related to the AVP-induced stimulation of CYP11B1. CONCLUSIONS:Multiple hormonal signals can simultaneously induce hypercortisolism in AIMAH. AVP is the most prevalent eutopic signal and expression of its type 1a receptor was aberrantly linked to CYP11B1 expression.

The prizes -- $250,000 in each category -- were announced Monday; the winners will be honored at a luncheon in Manhattan on Sept. 20. Since the foundation began making the awards, in 1942, 83 laureates have also won Nobel Prizes

Sensory neuropathy is a common but difficult to quantify complication encountered during treatment of various cancers with taxane-containing regimens. Docetaxel, paclitaxel, and its nanoparticle albumin-bound formulation have been extensively studied in randomized clinical trials comparing various dose and schedules for the treatment of breast, lung, and ovarian cancers. This review highlights differences in extent of severe neuropathies encountered in such randomized trials and seeks to draw conclusions in terms of known pharmacologic factors that may lead to neuropathy. This basic knowledge provides an essential background for exploring pharmacogenomic differences among patients in relation to their susceptibility of developing severe manifestations. In addition, the differences highlighted may lead to greater insight into drug and basic host factors (such as age, sex, and ethnicity) contributing to axonal injury from taxanes. Clin Cancer Res; 19(17); 4570-7. (c)2013 AACR.

David Oshinsky reviews "A Wild Justice: The Death and Resurrection of Capital Punishment in America," a book by John Jay College of Criminal Justice Professor Evan Mandery

To use optical coherence tomography (OCT) and contrast letter acuity to characterize vision loss in Friedreich ataxia (FRDA). High- and low-contrast letter acuity and neurological measures were assessed in 507 patients with FRDA. In addition, OCT was performed on 63 FRDA patients to evaluate retinal nerve fiber layer (RNFL) and macular thickness. Both OCT and acuity measures were analyzed in relation to genetic severity, neurologic function, and other disease features. High- and low-contrast letter acuity was significantly predicted by age and GAA repeat length, and highly correlated with neurological outcomes. When tested by OCT, 52.7 % of eyes (n = 110) had RNFL thickness values below the fifth percentile for age-matched controls. RNFL thickness was significantly lowest for those with worse scores on the Friedreich ataxia rating scale (FARS), worse performance measure composite Z 2 scores, and lower scores for high- and low-contrast acuity. In linear regression analysis, GAA repeat length and age independently predicted RNFL thickness. In a subcohort of participants, 21 % of eyes from adult subjects (n = 29 eyes) had macular thickness values below the first percentile for age-matched controls, suggesting that macular abnormalities can also be present in FRDA. Low-contrast acuity and RNFL thickness capture visual and neurologic function in FRDA, and reflect genetic severity and disease progression independently. This suggests that such measures are useful markers of neurologic progression in FRDA.

BACKGROUND:As the Veterans Health Administration (VHA) reorganizes providers into the patient-centered medical home, questions remain whether this model of care can demonstrate improved patient outcomes and cost savings. OBJECTIVE:We measured adoption of medical home features by VHA primary care clinics prior to widespread implementation of the patient-centered medical home and examined if they were associated with lower risk and costs of potentially avoidable hospitalizations. DESIGN/METHODS:Secondary patient data was linked to clinic administrative and survey data. Patient and clinic factors in the baseline year (FY2009) were used to predict patient outcomes in the follow-up year. PARTICIPANTS/METHODS:2,853,030 patients from 814 VHA primary care clinics MAIN MEASURES/METHODS:Patient outcomes were measured by hospitalizations for an ambulatory care sensitive condition (ACSC) and their costs and identified through diagnosis and procedure codes from inpatient records. Clinic adoption of medical home features was obtained from the American College of Physicians Medical Home Builder®. KEY RESULTS/RESULTS:The overall mean home builder score in the study clinics was 88 (SD = 13) or 69%. In adjusted analyses an increase of 10 points in the medical home adoption score in a clinic decreased the odds of an ACSC hospitalization for patients by 3% (P = 0.032). By component, higher access and scheduling (P = 0.004) and care coordination and transitions (P = 0.020) component scores were related to lower risk of an ACSC hospitalization, and higher population management was related to higher risk (P = 0.023). Total medical home features was not related to ACSC hospitalization costs among patients with at least one (P = 0.074). CONCLUSION/CONCLUSIONS:Greater adoption of medical home features by VHA primary care clinics was found to be significantly associated with lower risk of avoidable hospitalizations with access and scheduling and care coordination/transitions in care as key factors.