Effect of LKB1 deficiency on mitochondrial content, fibre type and muscle performance in the mouse diaphragm.

AIM: The liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signalling pathway is a major regulator of skeletal muscle metabolic processes. During exercise, LKB1-mediated phosphorylation of AMPK leads to its activation, promoting mitochondrial biogenesis and glucose transport, among other effects. The roles of LKB1 and AMPK have not been fully characterized in the diaphragm. METHODS: Two methods of AMPK activation were used to characterize LKB1/AMPK signalling in diaphragms from muscle-specific LKB1 knockout (KO) and littermate control mice: (1) acute injection of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) and (2) 5-min direct electrical stimulation of the diaphragm. Diaphragms were excised 60 min post-AICAR injection and immediately after electrical stimulation. RESULTS: AMPK phosphorylation increased with AICAR and electrical stimulation in control but not KO mice. Acetyl CoA carboxylase phosphorylation increased with AICAR in control but not KO mice, but increased in both genotypes with electrical stimulation. While the majority of mitochondrial protein levels were lower in KO diaphragms, uncoupling protein 3, complex I and cytochrome oxidase IV protein levels were not different between genotypes. KO diaphragms have a lower percentage of IIx fibres and an elevated percentage of IIb fibres when compared with control diaphragms. While in vitro peak force generation was similar between genotypes, KO diaphragms fatigued more quickly and had an impaired ability to recover. CONCLUSION: LKB1 regulates AMPK phosphorylation, mitochondrial protein expression, fibre type distribution, as well as recovery of the diaphragm from fatigue.

Continuous subcutaneous insulin infusion (CSII) in the Veneto region: efficacy, acceptability and quality of life.

AIM: To study the effect of continuous subcutaneous insulin infusion (CSII) on metabolic control and well-being in patients with Type 1 diabetes. METHODS: Efficacy, safety and interference with everyday life associated with CSII were studied retrospectively in 138 diabetic patients from the Veneto region treated for 7.4 +/- 0.4 years. RESULTS: Glycosylated haemoglobin decreased during the first year of CSII from 9.3 +/- 0.2% to 7.9 +/- 0.1% (P < 0.0001), and then remained unchanged. Serious hypoglycaemia decreased from 0.31 +/- 0.07/year to 0.09 +/- 0.02/year (P < 0.003), as did ketoacidosis (from 0.41 +/- 0.12/year to 0.11 +/- 0.03/year, P < 0.013). During the first year of therapy daily insulin requirement decreased from 49 +/- 1 to 42 +/- 2 U/day (P < 0.0001) and did not change thereafter. The number of out-patient consultations and hospital admissions per year also decreased significantly. CSII was associated with a progressive increase of body weight (P < 0.05) and with 0.2 +/- 0.04 infections/patient per year at the infusion site. Infection was rated as mild in 72%, moderate in 18%, severe in 10%. Patients reported that CSII improved metabolic control (71%), sense of well-being (41%), and allowed more freedom (40%). Quality of life, assessed using the DQOL, after 7 years of CSII was rated as good by patients (score of 73.0 +/- 1.8 on a scale from 0 to 100). CONCLUSIONS: This retrospective analysis suggests that CSII improves metabolic control in Type 1 diabetic patients, reduces hypoglycaemic and ketoacidotic events, is well accepted, allows a good quality of life and decreases out-patient consultations and hospital admissions.

The safety and efficacy of granulocyte-macrophage colony-stimulating factor (Sargramostim) added to indinavir- or ritonavir-based antiretroviral therapy: a randomized double-blind, placebo-controlled trial.

Sargramostim is a yeast-derived, recombinant human granulocyte-macrophage colony-stimulating factor with therapeutic potential in human immunodeficiency virus (HIV) infection. Its safety and activity when used in combination with protease inhibitors were evaluated in a randomized, double-blind trial in which 20 HIV-infected subjects on stable antiretroviral regimens, including indinavir or ritonavir, received sargramostim or placebo 3 times a week for 8 weeks. Analysis of HIV virus load excluded any 0. 5 log10 increase due to sargramostim (95% confidence interval, -0.68 to 0.44). Sargramostim was well tolerated, and inflammatory cytokines and surrogate markers of disease progression, such as serum levels of interleukin-10 and soluble tumor necrosis factor receptors types Iota and IotaIota, remained stable in subjects receiving sargramostim. Sargramostim treatment was associated with a trend toward decreased HIV RNA (>0.5 log10) and increased CD4+ cell count (>30%). These results became statistically significant only when subjects with baseline virus loads within the limits of detection or baseline CD4 cell count >50 were analyzed. No difference in indinavir pharmacokinetics was observed before or after sargramostim therapy.

Does ethanol intake interfere with the evaluation of glycated hemoglobins?

Ethanol and/or its metabolites interfere with the chromatographic assay of glycated hemoglobins. Fasting plasma glucose, blood ethanol, HbA(1), HbA(1c), HbA(1a+b), MCV and GGT were determined in 22 control subjects; 22 alcoholics, 22 diabetic patients and 22 alcoholic diabetic patients. Fasting plasma glucose and all hemoglobin fractions were lower in alcoholic subjects and, except for HbA(1a+b), higher in diabetic patients and in alcoholic diabetic patients. HbA(1), and HbA(1c) correlated well with plasma glucose but not with blood ethanol, MCV and GGT. Glycated hemoglobin was not found to be a useful marker for alcohol abuse. With the chromatographic method we used, the evaluation of glycated hemoglobin fractions, chiefly HbA(1c), confirms its usefulness in monitoring the metabolic control of diabetic subjects, even in case of ethanol abuse.

Lipopolysaccharide from a gram-negative marine bacterium.

A lipopolysaccharide molecule was isolated from a marine bacterium. The molecule seems to be composed of lipid A and the hexoses, glucose and galactose.