Large Family With Maturity-Onset Diabetes of the Young and a Novel V121I Mutation in HNF4A

Maturity-onset diabetes of the young (MODY) is a subtype of early-onset diabetes mellitus which is characterized by autosomal dominant inheritance. Several genes are known to induce MODY : HNF4A/MODY1, GCK/MODY2, TCF1/MODY3, IPF1/MODY4, TCF2/MODY5 and NEUROD1/MODY6. We studied a Swiss family with 13 diabetic patients over 3 generations. The average age at diagnosis was 35 +/- 15 years (7 subjects before 30). In addition, 2 individuals had an abnormal oral glucose tolerance. The mutation present in this family was located in the DNA binding domain of HNF4A, a strongly conserved region across almost all species, and segregated in all the MODY patients. Identification of this missense mutation allowed for presymptomatic diagnosis in the younger generations and will improve medical follow-up of the predisposed individuals.     

Energy cost of running during a specific transition in duathlon]

The aim of the present study was to investigate the variability of the energy cost of running (Cr) during a simulated duathlon performed in outdoor conditions by elite duathletes. This duathlon consisted of 5 km of running, 30 km of cycling, and 5 km of running. The main result was the lack of significant difference in Cr between the two running bouts (210 +/- 10 mL d'O2.km-1.kg-1 vs. 217 +/- 10 mL d'O2.km-1.kg-1). This result is different from those observed during a triathlon, where an increase of energy cost of running bout has been reported. Furthermore, during a short-distance duathlon performed by well-trained subjects, none of the physiological (ventilation alteration, metabolic changes, or dehydration) or biomechanical factors that are classically evoked in triathlon research to explain Cr variability seem to be affected by the run-cycle-run transition. These results seem to minimize the negative effect of the cycle-to-run transition during a short-duration event in well-trained subjects.     

Quantification of plasma and intracellular levels of the HIV protease inhibitor ritonavir by competitive ELISA

The HIV protease inhibitor ritonavir (Norvir; ABT-578), currently used in combination with nucleoside analogs and other protease inhibitors in anti-HIV therapy, has previously been quantified by an HPLC procedure. Here, we report the first convenient one-step competitive ELISA for measuring plasma and intracellular ritonavir in HIV patients. Anti-ritonavir antibody was raised in rabbits using ritonavir-KLH conjugate as immunogen, and the enzymatic tracer was prepared by coupling the drug to acetylcholine esterase. Samples for analysis were first extracted with methanol. Bound/free separation was achieved in a microtiter plate previously coated with anti rabbit IgG monoclonal antibody. Fifty percent inhibition was observed at 1 ng/ml ritonavir and the method accurately and specifically detected as little as 3-4 ng/ml of plasma ritonavir as well as intracellular drug in the peripheral blood mononuclear cells of patients undergoing ritonavir therapy. Within-run and day to day coefficients of variation were below 10% and the drugs currently used in HIV therapy did not interfere with the test. The ELISA was applied to the measurement of plasma ritonavir and to the determination of the extracellular/intracellular drug level ratios in HIV patients receiving long-term multidrug therapy.     

Origin and filiation of human plasmacytoid dendritic cells

Human plasmacytoid dendritic cells represent a rare population of leukocytes which produce high amounts of type I interferon in response to certain viruses. Although those cells were first described in 1958, there are still unsolved issues related to their origin and function. Recently, a leukemic counterpart of plasmacytoid dendritic cells was identified. Molecular approaches using either normal or leukemic plasmacytoid dendritic cells provide some new insights into the controversial lymphoid origin of those cells. The need for specific markers is still a critical aspect for the identification of plasmacytoid dendritic cells, whatever stage of differentiation, in normal as well as in pathological conditions. Hopefully, novel markers will allow delineation of the relationships between dendritic cells at different stages of differentiation/maturation along the myeloid and lymphoid lineages.     

Dysferlin mutations in LGMD2B, Miyoshi myopathy, and atypical dysferlinopathies

DYSF encoding dysferlin is mutated in Miyoshi myopathy and Limb-Girdle Muscular Dystrophy type 2B, the two main phenotypes recognized in dysferlinopathies. Dysferlin deficiency in muscle is the most relevant feature for the diagnosis of dysferlinopathy and prompts the search for mutations in DYSF. DYSF, located on chromosome 2p13, contains 55 coding exons and spans 150 kb of genomic DNA. We performed a genomic analysis of the DYSF coding sequence in 34 unrelated patients from various ethnic origins. All patients showed an absence or drastic decrease of dysferlin expression in muscle. A primary screening of DYSF using SSCP or dHPLC of PCR products of each of 55 exons of the gene was followed by sequencing whenever a sequence variation was detected. All together, 54 sequence variations were identified in DYSF, 50 of which predicting either a truncated protein or one amino-acid substitution and most of them (34 out of 54) being novel. In 23 patients, we identified two pathogenic mutations, while only one was identified in 11 patients. These mutations were widely spread in the coding sequence of the gene without any mutational "hotspot."     

Influence of plyometric training on the mechanical impedance of the human ankle joint

The objective of this work was to study the effects of plyometric training on the mechanical properties of the ankle joint in humans. Changes in the mechanical parameters of this musculo-articular structure were quantified with the aid of a sinusoidal perturbation technique. This technique allowed the expression of the mechanical impedance of the musculo-articular system in terms of stiffness, viscosity and inertia. Measurements were performed under passive conditions and when the subject performed plantar flexion. A 7-week period of training induced a decrease in the slope of the relationship between stiffness and plantar flexion torque, whereas passive stiffness was increased. A slight decrease in viscosity and an invariability in inertia were also found. These results are interpreted in terms of the possible adaptations of the musculo-articular structure and ultrastructure involved in the performance of plantar flexion. Accepted: 11 April 1997     

Immunologically silent autochthonous acute hepatitis E virus infection in France

Hepatitis E is an acute and self-limiting hepatitis, and the causative agent, hepatitis E virus, is excreted in feces and orally transmitted. The disease is common in Asia and Africa, causing outbreaks or sporadic cases. In Europe, the infection is generally observed after a history of travel in an area of endemicity. We report on an autochthonous case in southwestern France in which the diagnosis was based on molecular tools rather than serological testing.     

Lower serum vitamin E concentrations in major depression. Another marker of lowered antioxidant defenses in that illness

OBJECTIVE: Major depression is associated with defective antioxidant defenses. Vitamin E is the major fat soluble antioxidant in the body. The aim of the present study is to examine serum vitamin E concentrations in major depressed patients versus normal volunteers. METHOD: Serum vitamin E concentrations were measured in 26 healthy volunteers and 42 major depressed patients by means of HPLC. Since vitamin E is a fat soluble vitamin, and serum vitamin E concentrations are strongly related to these of low-density-lipoprotein cholesterol (LDL-C) and triglycerides, we have adjusted the results for possible differences in these lipids. The numbers of peripheral blood leukocytes were measured. RESULTS: Patients with major depression had significantly lower serum vitamin E concentrations than healthy controls. The area under the ROC (receiver operating characteristics) curve was 83%. There were significant and negative correlations between serum vitamin E and number of total leukocytes and neutrophils. CONCLUSIONS: Major depression is accompanied by significantly lower serum vitamin E concentrations, suggesting lower antioxidant defenses against lipid peroxidation. The results could, in part, explain previous findings, which suggest increased lipid peroxidation in major depression.