Fecal lactate and short bowel syndrome

In patients with short bowel syndrome (SBS), the carbohydrate overload to the colon may disturb the normal pattern of colonic fermentation with production ofd-lactic acid and subsequent development of a metabolicd-lactic acidosis. We measuredd-lactic acid in blood, urine, and feces, as well as the composition of fecal water and fecal reducing substances from 11 patients with SBS, comparing the results with those from normal subjects. The fecal water from patients with SBS was characterized by low pH, potassium, and volatile fatty acids, high osmotic gap, and high concentration ofl- andd-lactic acid. Five of 11 had abnormal amounts of fecal reducing substances. Fecald-lactic acid was increased in nine of 11 patients. However, none of these patients showedd-lactic acid in urine, and only one had a very low concentration in plasma. These results show thatd-lactic acid was overproduced in the colon of most of the patients with SBS. However, other factors such as absorption or impairedd-lactic acid metabolism may be necessary for a plasmatic increase ofd-lactic acid.Unidad de Terapia Nutricional, Hospital de Niños Sor Maria Ludovica, La Plata, Provincia de Buenos Aires, Argentina.Part of this work was presented at the International Symposium on Short Chain Fatty Acids, Strasbourg, France, September 1993.     

L-carnitine supplementation and physical exercise restore age-associated decline in some mitochondrial functions in the rat

In mammals, during the aging process, an atrophy of the muscle fibers, an increase in body fat mass, and a decrease in skeletal muscle oxidative capacities occur. Compounds and activities that interact with lipid oxidative metabolism may be useful in limiting damages that occur in aging muscle. In this study, we evaluated the effect of L-carnitine and physical exercise on several parameters related to muscle physiology. We described that supplementing old rats with L-carnitine at 30 mg/kg body weight for 12 weeks (a) allowed the restoration of L-carnitine level in muscle cells, (b) restored muscle oxidative activity in the soleus, and (c) induced positive changes in body composition: a decrease in abdominal fat mass and an increase in muscle capabilities without any change in food intake. Moderate physical exercise was also effective in (a) limiting fat mass gain and (b) inducing an increase in the capacities of the soleus to oxidize fatty acids.     

Hidden Genetic Variation in LCA9‐Associated Congenital Blindness Explained by 5′UTR Mutations and Copy‐Number Variations of NMNAT1

Leber congenital amaurosis (LCA) is a severe autosomal‐recessive retinal dystrophy leading to congenital blindness. A recently identified LCA gene is NMNAT1, located in the LCA9 locus. Although most mutations in blindness genes are coding variations, there is accumulating evidence for hidden noncoding defects or structural variations (SVs). The starting point of this study was an LCA9‐associated consanguineous family in which no coding mutations were found in the LCA9 region. Exploring the untranslated regions of NMNAT1 revealed a novel homozygous 5′UTR variant, c.‐70A>T. Moreover, an adjacent 5′UTR variant, c.‐69C>T, was identified in a second consanguineous family displaying a similar phenotype. Both 5′UTR variants resulted in decreased NMNAT1 mRNA abundance in patients’ lymphocytes, and caused decreased luciferase activity in human retinal pigment epithelial RPE‐1 cells. Second, we unraveled pseudohomozygosity of a coding NMNAT1 mutation in two unrelated LCA patients by the identification of two distinct heterozygous partial NMNAT1 deletions. Molecular characterization of the breakpoint junctions revealed a complex Alu‐rich genomic architecture. Our study uncovered hidden genetic variation in NMNAT1‐associated LCA and emphasized a shift from coding to noncoding regulatory mutations and repeat‐mediated SVs in the molecular pathogenesis of heterogeneous recessive disorders such as hereditary blindness.     

Therapeutic Benefit and Gene Network Regulation by Combined Gene Transfer of Apelin,FGF2, and SERCA2a into Ischemic Heart

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Induction of Multidrug Tolerance in Plasmodium falciparum by Extended Artemisinin Pressure

Plasmodium falciparum resistance to artemisinin derivatives in Southeast Asia threatens global malaria control strategies. Whether delayed parasite clearance, which exposes larger parasite numbers to artemisinins for longer times, selects higher-grade resistance remains unexplored. We investigated whether long-lasting artemisinin pressure selects a novel multidrug-tolerance profile. Although 50% inhibitory concentrations for 10 antimalarial drugs tested were unchanged, drug-tolerant parasites showed higher recrudescence rates for endoperoxides, quinolones, and an antifolate, including partner drugs of recommended combination therapies, but remained susceptible to atovaquone. Moreover, the age range of intraerythrocytic stages able to resist artemisinin was extended to older ring forms and trophozoites. Multidrug tolerance results from drug-induced quiescence, which enables parasites to survive exposure to unrelated antimalarial drugs that inhibit a variety of metabolic pathways. This novel resistance pattern should be urgently monitored in the field because this pattern is not detected by current assays and represents a major threat to antimalarial drug policy.     

Buruli Ulcer in Traveler from Suriname,South America,to the Netherlands

We report Buruli ulcer in a man in the Netherlands. Phenotyping of samples indicate the Buruli pathogen was acquired in Suriname and activated by trauma on return to the Netherlands. Awareness of this disease by clinicians in non–Buruli ulcer–endemic areas is critical for identification.