Metabolic, Cardiovascular, and Cerebrovascular Outcomes in Growth Hormone-Deficient Subjects with Previous Cushing's Disease or Non-Functioning Pituitary Adenoma

Context: Previous exposure to hypercortisolism due to Cushing's disease ( CD) may adversely affect long-term metabolic and cardiovascular outcomes. In particular, metabolic and cardiovascular outcomes of patients with previous CD who require GH replacement have not been fully established. Objective: The aim of the study was to compare the prevalence and incidence of metabolic syndrome ( Adult Treatment Panel III criteria), diabetes mellitus, cardiovascular disease, and cerebrovascular disease in GH-treated subjects with previous CD with GH-treated subjects with previous nonfunctioning pituitary adenoma (NFPA). Design: We conducted post hoc analysis of the observational Hypopituitary Control and Complications Study conducted at 362 international centers (1995-2006). Subjects: We studied adult-onset GH-deficient subjects with previous CD (n = 160) or NFPA (n = 879). All subjects received GH replacement therapy and were GH naive at enrollment. Multiple pituitary deficits were prevalent in both groups. Main Outcome Measures: We measured the prevalence and incidence of metabolic syndrome, diabetes mellitus, cardiovascular disease, and cerebrovascular disease at baseline and at 3 yr, standardized for age and sex differences between groups. Results: Compared with subjects with previous NFPA, subjects with previous CD had a significantly greater 3-yr incidence of metabolic syndrome (CD, 23.4%; NFPA, 9.2%; P = 0.01), baseline ( CD, 6.3%; NFPA, 2.2%; P < 0.01) and 3-yr (CD, 7.6%; NFPA, 3.9%; P = 0.04) prevalence of cardiovascular disease, and baseline (CD, 6.4%; NFPA, 1.8%; P = 0.03) and 3-yr (CD, 10.2%; NFPA, 2.9%; P = 0.01) prevalence of cerebrovascular disease. Conclusions: Previous hypercortisolism may predispose GH-treated, GH-deficient subjects with prior CD to an increased risk of metabolic syndrome, cardiovascular disease, and cerebrovascular disease. ( J Clin Endocrinol Metab 95: 630-638, 2010

Flavin Reductase Contributes to Pneumococcal Virulence by Protecting from Oxidative Stress and Mediating Adhesion and Elicits Protection Against Pneumococcal Challenge.

Pneumococcal flavin reductase (FlaR) is known to be cell-wall associated and possess age dependent antigenicity in children. This study aimed at characterizing FlaR and elucidating its involvement in pneumococcal physiology and virulence. Bioinformatic analysis of FlaR sequence identified three-conserved cysteine residues, suggesting a transition metal-binding capacity. Recombinant FlaR (rFlaR) bound Fe2+ and exhibited FAD-dependent NADP-reductase activity, which increased in the presence of cysteine or excess Fe2+ and inhibited by divalent-chelating agents. flaR mutant was highly susceptible to H2O2 compared to its wild type (WT) and complemented strains, suggesting a role for FlaR in pneumococcal oxidative stress resistance. Additionally, flaR mutant demonstrated significantly decreased mice mortality following intraperitoneal infection. Interestingly, lack of FlaR did not affect the extent of phagocytosis by primary mouse peritoneal macrophages but reduced adhesion to A549 cells compared to the WT and complemented strains. Noteworthy are the findings that immunization with rFlaR elicited protection in mice against intraperitoneal lethal challenge and anti-FlaR antisera neutralized bacterial virulence. Taken together, FlaR's roles in pneumococcal physiology and virulence, combined with its lack of significant homology to human proteins, point towards rFlaR as a vaccine candidate