Beneficial effects of insulin-like growth factor I on epithelial structure and function in parenterally fed rat jejunum

BACKGROUND & AIMS: The functional significance of intestinal hyperplasia stimulated by insulin-like growth factor (IGF)-I is unclear and has not been studied in a model of mucosal atrophy induced by total parenteral nutrition (TPN). The aim of this study was to determine how IGF-I affects intestinal structure and epithelial function in the absence of luminal nutrition caused by TPN. METHODS: Rats were maintained with TPN with or without IGF-I (800 micrograms/day), and jejunal histology and epithelial ion transport were measured after 5 days. In a third TPN group without IGF-I, a short-term dose of IGF-I was added during in vitro flux chamber experiments. RESULTS: Rats given TPN with IGF-I had greater jejunal mucosal weight, greater protein and DNA content, and increased villus height and crypt depth compared with rats given TPN only. TPN increased ionic permeability and ion transport responses to secretory and absorptive agents. IGF-I in vivo reversed most of these changes; IGF-I in vitro enhanced sodium-dependent glucose absorption but had no other effects. CONCLUSIONS: Coinfusion of recombinant human IGF-I with TPN solution stimulates intestinal hyperplasia and attenuates transport changes induced by TPN. The latter effect seems to be primarily associated with the growth state of the epithelium. (Gastroenterology 1996 Dec;111(6):1501-8)     

The volumetric measurement of gastric emptying and gastric secretion by a radioisotope method

Most methods of measurement of gastric emptying rely on the serial estimation of intragastric volume and do not separately account for the volume of fluid which has been added to the meal by gastric secretion, duodenal reflux, or swallowed saliva. The volume emptied is therefore underestimated. A method of measuring gastric emptying using [¹²⁵I]RIHSA and the Volémetron is presented. The volume of fluid added to the meal is taken into consideration in this method, giving a more accurate reflection of gastric emptying. Using this method in the dog, emptying was found to be linear rather than exponential.Supported by South African Medical Research Council grant M14/71/51.     

New predictors of outcome in idiopathic pulmonary arterial hypertension

Idiopathic pulmonary arterial hypertension (PAH) is a rare disease with a poor prognosis. New therapies have improved the outcome of this condition; accordingly, the factors that determine outcome may have changed. We aimed to identify determinants of survival in a cohort of consecutive patients with PAH: which was idiopathic, familial, or associated with anorexigen use. We performed a retrospective cohort study of 84 consecutive patients with PAH who underwent initial evaluation at our center from January 1994 to June 2002. The primary outcome was death or lung transplantation. Survival at 1, 3, and 5 [corrected] years was 87%, 75%, and 61%, respectively. Multivariate analysis showed that being of African-American or Asian descent was associated with an increased risk of death. Warfarin use was associated with a reduced risk of death. Higher serum albumin and cardiac index and acute vasoreactivity were independently associated with improved survival. These data suggest that the determinants of outcome have changed. Race is identified as a new risk factor, which may be attributable to biologic or socioeconomic differences. Cardiac function and acute reactivity of the pulmonary vascular bed remain strong independent predictors of outcome.     

Reduction of Toxoplasma gondii Development Due to Inhibition of Parasite Antioxidant Enzymes by a Dinuclear Iron(III) Compound

Toxoplasma gondii, the causative agent of toxoplasmosis, is an obligate intracellular protozoan that can infect a wide range of vertebrate cells. Here, we describe the cytotoxic effects of the dinuclear iron compound [Fe(HPCINOL)(SO₄)]₂-μ-oxo, in which HPCINOL is the ligand 1-(bis-pyridin-2-ylmethyl-amino)-3-chloropropan-2-ol, on T. gondii infecting LLC-MK2 host cells. This compound was not toxic to LLC-MK2 cells at concentrations of up to 200 μM but was very active against the parasite, with a 50% inhibitory concentration (IC₅₀) of 3.6 μM after 48 h of treatment. Cyst formation was observed after treatment, as indicated by the appearance of a cyst wall, Dolichos biflorus lectin staining, and scanning and transmission electron microscopy characteristics. Ultrastructural changes were also seen in T. gondii, including membrane blebs and clefts in the cytoplasm, with inclusions similar to amylopectin granules, which are typically found in bradyzoites. An analysis of the cell death pathways in the parasite revealed that the compound caused a combination of apoptosis and autophagy. Fluorescence assays demonstrated that the redox environment in the LLC-MK2 cells becomes oxidant in the presence of the iron compound. Furthermore, a reduction in superoxide dismutase and catalase activities in the treated parasites and the presence of reactive oxygen species within the parasitophorous vacuoles were observed, indicating an impaired protozoan response against these radicals. These findings suggest that this compound disturbs the redox equilibrium of T. gondii, inducing cystogenesis and parasite death.     

Preclinical Characterization and In Vivo Efficacy of GSK8853, a Small-Molecule Inhibitor of the Hepatitis C Virus NS4B Protein

The hepatitis C virus (HCV) NS4B protein is an antiviral therapeutic target for which small-molecule inhibitors have not been shown to exhibit in vivo efficacy. We describe here the in vitro and in vivo antiviral activity of GSK8853, an imidazo[1,2-a]pyrimidine inhibitor that binds NS4B protein. GSK8853 was active against multiple HCV genotypes and developed in vitro resistance mutations in both genotype 1a and genotype 1b replicons localized to the region of NS4B encoding amino acids 94 to 105. A 20-day in vitro treatment of replicons with GSK8853 resulted in a 2-log drop in replicon RNA levels, with no resistance mutation breakthrough. Chimeric replicons containing NS4B sequences matching known virus isolates showed similar responses to a compound with genotype 1a sequences but altered efficacy with genotype 1b sequences, likely corresponding to the presence of known resistance polymorphs in those isolates. In vivo efficacy was tested in a humanized-mouse model of HCV infection, and the results showed a 3-log drop in viral RNA loads over a 7-day period. Analysis of the virus remaining at the end of in vivo treatment revealed resistance mutations encoding amino acid changes that had not been identified by in vitro studies, including NS4B N56I and N99H. Our findings provide an in vivo proof of concept for HCV inhibitors targeting NS4B and demonstrate both the promise and potential pitfalls of developing NS4B inhibitors.     

Right ventricular assist device in end-stage pulmonary arterial hypertension: insights from a computational model of the cardiovascular system

BackgroundThe high mortality rate of pulmonary arterial hypertension (PAH) mainly relates to progressive right ventricular (RV) failure. With limited efficacy of medical therapies, mechanical circulatory support for the RV has been considered. However, there is lack of understanding of the hemodynamic effects of mechanical support in this setting.MethodsWe modeled the cardiovascular system, simulated cases of PAH and RV dysfunction and assessed the theoretical effects of a continuous flow micro-pump as an RV assist device (RVAD). RVAD inflow was sourced either from the RV or RA and outflow was to the pulmonary artery. RVAD support was set at various flow rates and additional simulations were carried out in the presence of atrial septostomy (ASD) and tricuspid regurgitation (TR).ResultsRVAD support increased LV filling, thus improving cardiac output and arterial pressure, unloading the RA and RV, while raising pulmonary arterial and capillary pressures in an RVAD flow-dependent manner. These effects diminished with increasing disease severity. The presence of TR did not significantly impact the hemodynamic effects of RVAD support. ASD reduced the efficacy of RVAD support, since right-to-left shunting decreased and ultimately reversed with increasing RVAD support due to the progressive drop in RA pressure.ConclusionsThe results of this theoretical analysis suggest that RVAD support can effectively increase cardiac output and decreases RA pressure with the consequence of increasing pulmonary artery and capillary pressures. Especially in advanced PAH, low RVAD flow rates may mitigate these potentially detrimental effects while effectively increasing systemic hemodynamics.