The purpose of this study, in part, was to determine the ability of cholecystokinin (CCK-33/39 and CCK-8) to penetrate the blood cerebrospinal fluid (CSF) barrier in dogs by measuring these forms of CCK in plasma and in CSF. In addition, the effectiveness of centrally administered bombesin in releasing brain CCK-33/39 and CCK-8 was evaluated. Six groups of five dogs each were studied. Each group received one of the following: (1) intravenous infusion of CCK-33/39 (1.3 micrograms/kg/hr); (2) intravenous infusion of CCK-8 (0.4 micrograms/kg/hr); (3) intrathecal infusion of CCK-33/39 (1.3 micrograms/kg/hr); (4) intrathecal infusion of CCK-8 (0.5 micrograms/kg/hr); (5) intravenous infusion of bombesin (1 micrograms/kg/hr); and (6) intrathecal infusion of bombesin (1 microgram/kg/hr). Plasma concentrations of CCK-33/39 significantly increased during intravenous infusion of CCK-33/39 (from basal of 84 +/- 8 to 142 +/- 2 pg/ml) or bombesin (from basal of 78 +/- 13 to 325 +/- 87 pg/ml); however, CSF perfusate concentrations of CCK-33/39 did not increase. CCK-33/39 levels of the CSF perfusate increased significantly (P less than .05) from 211 +/- 84 to 9,873 +/- 3,368 pg/ml during intrathecal infusion of CCK-33/39, but failed to rise simultaneously in the systemic circulation. Similarly, intravenous infusion of CCK-8 caused a fivefold elevation in plasma CCK-8 levels and no change in CSF perfusate levels of CCK-8; moreover, intrathecal infusion of CCK-8 failed to elevate peripheral CCK-8 levels, despite CSF perfusate CCK-8 levels of 92,300 +/- 18,598 pg/ml. Intrathecal concentrations of neither CCK-33 nor CCK-8 were affected by intravenous or intrathecal administration of bombesin. We conclude that CCK-33/39 and CCK-8 do not penetrate the blood-cerebrospinal fluid barrier in dogs, and centrally administered bombesin is ineffective in causing release of cholecystokinin from brain tissue into the CSF.
Previously, we showed that ADAM10 is necessary for HIV-1 replication in primary human macrophages and immortalized cell lines. Silencing ADAM10 expression interrupted the HIV-1 life cycle prior to nuclear translocation of viral cDNA. Furthermore, our data indicated that HIV-1 replication depends on the expression of ADAM15 and γ-secretase, which proteolytically processes ADAM10. Silencing ADAM15 or γ-secretase expression inhibits HIV-1 replication between reverse transcription and nuclear entry. Here, we show that ADAM10 expression also supports replication in CD4+ T lymphocytes. The intracellular domain (ICD) of ADAM10 associates with the HIV-1 pre-integration complex (PIC) in the cytoplasm and immunoprecipitates and co-localizes with HIV-1 integrase, a key component of PIC. Taken together, our data support a model whereby ADAM15/γ-secretase processing of ADAM10 releases the ICD, which then incorporates into HIV-1 PIC to facilitate nuclear trafficking. Thus, these studies suggest ADAM10 as a novel therapeutic target for inhibiting HIV-1 prior to nuclear entry.
Malnutrition is a common cause of impeding recovery in patients with acute alcoholic hepatitis (AAH). Previous reports have shown that appropriate nutritional supplementation reduce short and long-term mortality in patients with AAH. Despite these clear recommendations, the element of nutrition in AAH is often neglected. We designed a quality improvement project to evaluate and improve compliance with appropriate nutrition in patients presenting with AAH at our institution. Patients admitted with AAH between December 2015 to December 2016 were included. Our primary outcome was compliance with appropriate nutrition. Secondary outcomes included nutrition consultation and hepatology consultation. A total of fifty-four patients were included. Nine of the 53 patients (17%) received high calorie and high protein diets. Hepatology was consulted in 72% (38/53) of the patients, and 21% (8/38) of these patients received appropriate nutrition as compared to only 8.3% (1/12) in whom hepatology was not consulted. Nutrition was consulted in 55% (29/53) of these patients and 67% (19/28) of those patients received appropriate nutrition. In conclusion, our compliance of appropriate nutrition in AAH is low. Our initial investigation suggests that hepatology and nutrition consultation improved compliance with appropriate nutrition. The next step will be to implement protocolized care for appropriate nutrition in AAH by incorporating consultation of hepatology and nutrition services, assess the effect on adherence to appropriate nutrition, and determine the impact on patient outcomes.
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