Vanadate (sodium orthovanadate), an inhibitor of phosphotyrosine phosphatases (PTPs), mimics many of the metabolic actions of insulin in vitro and in vivo. The potential of vanadate to stimulate glucose transport independent of the early steps in insulin signaling prompted us to test its effectiveness in an in vitro model of insulin resistance. In primary rat adipocytes cultured for 18 h in the presence of high glucose (15 mM) and insulin (10 ؊7 M), sensitivity to insulin-stimulated glucose transport was decreased. In contrast, there was a paradoxical enhanced sensitivity to vanadate of the insulinresistant cells (EC 50 for control, 325 ؎ 7.5 M; EC 50 for insulin-resistant, 171 ؎ 32 M; p < 0.002). Enhanced sensitivity was also present for vanadate stimulation of insulin receptor kinase activity and autophosphorylation and Akt/protein kinase B Ser-473 phosphorylation consistent with more effective PTP inhibition in the resistant cells. Investigation of this phenomenon revealed that 1) depletion of GSH with buthionine sulfoximine reproduced the enhanced sensitivity to vanadate while preincubation of resistant cells with N-acetylcysteine (NAC) prevented it, 2) intracellular GSH was decreased in resistant cells and normalized by NAC, 3) exposure to high glucose and insulin induced an increase in reactive oxygen species, which was prevented by NAC, 4) EPR (electron paramagnetic resonance) spectroscopy showed a decreased amount of vanadyl (؉4) in resistant and buthionine sulfoximine-treated cells, which correlated with decreased GSH and increased vanadate sensitivity, while total vanadium uptake was not altered, and 5) inhibition of recombinant PTP1B in vitro was more sensitive to vanadate (؉5) than vanadyl (؉4). In conclusion, the parodoxical increased sensitivity to vanadate in hyperglycemia-induced insulin resistant adipocytes is due to oxidative stress and decreased reduction of vanadate (؉5) to vanadyl (؉4). Thus, sensitivity of PTP inhibition and glucose transport to vanadate is regulated by cellular redox state.
Long-term cold exposure (5-7 days) is known to induce concomitant increases in the levels of adrenomedullary tyrosine hydroxylase (TH) RNA, protein, and enzyme activity. In this report, we compare the time courses of these changes and investigate the effects of cold exposure on the levels of biopterin, the cofactor required for tyrosine hydroxylation. After only 1 h of cold exposure, TH mRNA abundance increased 71% compared with nonstressed controls. Increases in total cellular TH RNA levels were maximal (threefold over control values) within 3-6 h of cold exposure and remained elevated throughout the duration of the experiment (72 h). TH protein levels increased rapidly after 24 h of cold exposure and reached a maximal value threefold above that of controls at 48-72 h. Despite the relatively rapid and large elevations in TH RNA and protein content, only modest increases in TH activity were detected during the initial 48 h of cold exposure. Adrenomedullary biopterin increased rapidly after the onset of cold exposure, rising to a level approximately twofold that of the nonstressed controls at 24 h, and remained at this level throughout the duration of the stress period. Taken together, the results of this time course study indicate that cold-induced alterations in adrenal TH activity are mediated by multiple cellular control mechanisms, which may include pre- and posttranslational regulation. Our findings also suggest that cold stress-induced increases in the levels of the TH cofactor may represent another key event in the sympathoadrenal system's response to cold stress.
A pilot candidate gene association study was conducted to investigate the role of three common functional genetic polymorphisms of the low-affinity Fc gamma receptors, FCGR2A (131H/R), FCGR3A (158F/V) and FCGR3B (NA1/NA2) in Cryptococcus neoformans infections in individuals not infected with HIV. The FCGR2A 131RR and FCGR3A 158VV genotypes were over-represented [OR: 1.67 (1.05-2.63) and 2.04 (1.06-4.00), respectively] whereas the FCGR3B NA2NA2 was under-represented in patients with cryptococcosis (28% vs. 40% in controls). An analysis of haplotypes showed a significant difference in distribution between cases and controls overall and in Caucasians.
Cryptococcus neoformans is a fungal pathogen associated with advanced HIV disease and other disorders associated with immune dysfunction. The pulmonary and the central nervous system are the most common manifestations of the disease. Localised osteomyelitis as the sole manifestation of extrapulmonary disease is rare. Herein, we present five cases of Cryptococcus osteomyelitis as the only manifestation of extrapulmonary disease. We also identified 84 additional cases of isolated cryptococcal osteomyelitis in the literature. Using these data, we have made some general recommendations regarding an approach to treatment of this uncommon clinical entity.
Quality improvement initiatives combined with pulsed xenon ultraviolet room disinfection were implemented to reduce surgical site infections (SSIs) in patients undergoing total joint procedures. After 12 months, knee SSIs were reduced from 4 to 0 (P = .03) and hip SSIs were reduced from 3 to 0 (P = .15) for a combined prevention of 7 SSIs (P = .01) and a savings of $290,990.
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