Analysis of insulin signaling pathways through comparative genomics. Mapping mechanisms for insulin resistance in type 2 (non-insulin-dependent) diabetes mellitus.

The precise molecular cause of insulin resistance has not yet been elucidated. Resistance to the normal action of insulin contributes to the pathogenesis of a number of common human disorders, including type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus, hypertension, and the Metabolic Syndrome X, thus constituting a major public health problem. A disease program aimed at combating this disorder should focus on the identification of targets for therapeutic intervention which may overcome insulin resistance and hence the associated metabolic consequences characteristic of the Metabolic Syndrome. Although the primary defect in the pathogenesis of type 2 diabetes is unknown, genetic and environmental factors are likely to contribute to the manifestation of this progressive metabolic disorder, which is usually not clinically apparent until mid-life. Defects at the level of glucose uptake/phosphorylation characterize insulin resistance in skeletal muscle of type 2 diabetic patients. Identification of putative components of the insulin receptor-signaling pathway may offer insights into mechanisms involved in insulin resistance. Enhanced flux of free fatty acids due to impaired lipid metabolism may contribute to impaired insulin secretion and peripheral insulin resistance. Genes regulating lipolysis are prime candidates for susceptibility towards the metabolic syndrome. Here we describe pathways constituting complex interactions that control glucose homeostasis. We will be considering (1) regulation of glucose uptake by the insulin receptor signaling pathway, and (2) control of adipogenesis and insulin sensitivity by the sterol response element binding protein (SREBP) pathway.     

Penicillium piceum infection: diagnosis and successful treatment in chronic granulomatous disease.

Infections due to Penicillium species other than P.marneffei are rare. We identified a boy with X-linked chronic granulomatous disease (X-CGD) with a pulmonary nodule and adjacent rib osteomyelitis caused by Penicillium piceum. The only sign of infection was an elevated sedimentation rate. P. piceum was isolated by fine needle aspirate and from excised infected tissues. Surgical removal and one year of voriconazole treatment were very well tolerated and led to complete recovery. Microbiological, microscopic and molecular studies support the fungal diagnosis. P. piceum should be considered as a relevant pathogen in immunocompromised patients.     

Lung and heart volumes by three-dimensional ultrasound in normal fetuses at 12-32 weeks' gestation.

OBJECTIVE: To establish reference intervals for the fetal right, left and total lung volumes and heart volume between 12 and 32 weeks of gestation. METHODS: Fetal lung and heart volumes were measured using three-dimensional (3D) ultrasound in 650 normal singleton pregnancies at 12-32 weeks. The VOCAL (Virtual Organ Computer-aided AnaLysis) technique was used to obtain a sequence of six sections of each lung and the heart around a fixed axis, each after a 30 degrees rotation from the previous one. The rotation axis for the lungs extended from the apex to the upper limit of the diaphragm dome, and the rotation axis for the heart extended from its apex to its connection to the great vessels. The contour of each of these organs was drawn manually in the six different rotation planes to obtain the 3D volume measurement. In 60 cases the fetal lungs and heart volumes were measured by the same sonographer twice and also by a second sonographer once in order to compare the measurements and calculate intra- and interobserver agreement. RESULTS: The total lung volume and heart volume increased with gestation, from respective mean values of 1.6 and 0.6 mL at 12 weeks to 10.9 and 4.3 mL at 20 weeks and 49.3 and 26.6 mL at 32 weeks. The right to left lung volume ratio did not change significantly with gestation (median, 0.7), whereas the heart to total lung volume ratio increased with gestation from about 0.3 at 12 weeks to 0.5 at 32 weeks. In the Bland-Altman plot, the difference between paired measurements by two sonographers was, in 95% of the cases, less than 0.05, 0.5 and 1.9 mL for each lung at 12-13, 19-22 and 29-32 weeks, respectively, and the corresponding values for the heart volumes were 0.04, 0.4 and 2.3 mL. CONCLUSIONS: In normal fetuses the lung and heart volumes increase between 12 and 32 weeks of gestation. The extent to which in pathological pregnancies possible deviations in these measurements from normal prove to be useful in the prediction of outcome remains to be determined.