Functional genomics of the endocrine pancreas: the pancreas clone set and PancChip,new resources for diabetes research

Over the past 5 years, microarrays have greatly facilitated large-scale analysis of gene expression levels. Although these arrays were not specifically geared to represent tissues and pathways known to be affected by diabetes, they have been used in both type 1 and type 2 diabetes research. To prepare a tool that is particularly useful in the study of type 1 diabetes, we have assembled a nonredundant set of 3,400 clones representing genes expressed in the mouse pancreas or pathways known to be affected by diabetes. We have demonstrated the usefulness of this clone set by preparing a cDNA glass microarray, the PancChip, and using it to analyze pancreatic gene expression from embryonic day 14.5 through adulthood in mice. The clone set and corresponding array are useful resources for diabetes research.     

The second activating glucokinase mutation (A456V): implications for glucose homeostasis and diabetes therapy

In this study, a second case of hyperinsulinemic hypoglycemia due to activation of glucokinase is reported. The 14-year-old proband had a history of neonatal hypoglycemia, treated with diazoxide. He was admitted with coma and convulsions due to nonketotic hypoglycemia. His BMI was 34 kg/m(2), and his fasting blood glucose ranged from 2.1 to 2.7 mmol/l, associated with inappropriately high serum levels of insulin, C-peptide, and proinsulin. An oral glucose tolerance test (OGTT) showed exaggerated responses of these peptides followed by profound hypoglycemia. Treatment with diazoxide and chlorothiazide was effective. His mother never had clinical hypoglycemic symptoms, even though her fasting blood glucose ranged from 2.9 to 3.5 mmol/l. Increases in serum insulin, C-peptide, and proinsulin in response to an OGTT suggested a lower threshold for glucose-stimulated insulin release (GSIR). Screening for mutations in candidate genes revealed a heterozygous glucokinase mutation in exon 10, substituting valine for alanine at codon 456 (A456V) in the proband and his mother. The purified recombinant glutathionyl S-transferase fusion protein of the A456V glucokinase revealed a decreased glucose S(0.5) (the concentration of glucose needed to achieve the half-maximal rate of phosphorylation) from 8.04 (wild-type) to 2.53 mmol/l. The mutant's Hill coefficient was decreased, and its maximal specific activity k(cat) was increased. Mathematical modeling predicted a markedly lowered GSIR threshold of 1.5 mmol/l. The theoretical and practical implications are manifold and significant.     

The discovery of renal contrast media in Berlin

After X-rays were detected and cystoscopes had become available, progress in nephrology depended on the development of contrast media which would permit imaging of the kidneys and the urinary system. We describe how A. Binz and C. R?th, two chemists at the Agricultural Academy in Berlin, synthesized iodinated derivatives which were potent chemotherapeutics. Moses Swick tested the substances in the clinics of L. Lichtwitz (Hamburg) and A. von Lichtenberg (Berlin) and discovered a rapid renal excretion. He also observed that an iodinated N-acetylated derivative, later named Uro-Selectan, amplified X-ray contrast after intravenous application. With this substance and other derivatives which were produced by Schering-Kahlbaum AG, the door was open for excretion urography.     

5,10-Methylenetetrahydrofolate reductase genotype determines the plasma homocysteine-lowering effect of supplementation with 5-methyltetrahydrofolate or folic acid in healthy young women

BACKGROUND: Elevated plasma total homocysteine (tHcy) is a risk factor for vascular disease and neural tube defects. The polymorphism in the gene encoding 5,10-methylenetetrahydrofolate reductase (FADH(2)) (MTHFR) influences the tHcy concentration and the response to tHcy-lowering therapy. Supplementation with folic acid (FA) decreases plasma tHcy, but limited data are available on the effect of 5-methyltetrahydrofolate (MTHF). OBJECTIVE: We evaluated the tHcy-lowering potential of low-dose FA and of MTHF with respect to the MTHFR genotype. DESIGN: In this randomized, placebo-controlled, double-blind study, 160 women received 400 microg FA, the equimolar amount of MTHF (480 microg, racemic mixture), or a placebo daily during an 8-wk treatment period. Blood samples were collected at baseline and at 4 and 8 wk. RESULTS: Changes in plasma tHcy concentration depended on the supplemented folate derivative and the MTHFR genotype. Supplementation with FA significantly decreased tHcy concentrations by > or = 13% in women of all 3 genotypes after both 4 and 8 wk. The greatest decrease was 20% (P < 0.05) in the women with the TT genotype after 4 wk. MTHF supplementation also decreased tHcy, but only the women with the CT genotype had a significant decrease after 4 wk (7%; P < 0.05). The largest nonsignificant reduction (15%) occurred in the women with the TT genotype after 4 wk of MTHF supplementation. CONCLUSIONS: The response to tHcy-lowering therapy is influenced by MTHFR genotype. Women with the TT genotype seem to benefit the most from supplementation with either FA or MTHF. In women with the CT or CC genotype, FA is more effective than MTHF in lowering plasma tHcy.     

Tanapox: first report in a European traveller and identification by PCR

Tanapox is a rare pox disease endemic in East Africa. We report the first case of tanapox in a European traveller who contracted the disease in 1999 during a short visit to Tanzania. The diagnosis was made on clinical grounds and confirmed by electron microscopy and a tanapox virus-specific PCR assay.     

Energy metabolism of young rats after early postnatal overnutrition

Early postnatal overnutrition (PNO) induced by restricting litter size in rats leads to increased body-weight (BW) and body-fat gain in later life. PNO rats are used as an animal model of moderate obesity and early hyperinsulinism. We investigated whether the increased adiposity could be due to a decreased energy expenditure. Male newborn Wistar rats were raised in litters of either two (SL) or twelve pups (NL), weaned at 4 weeks of age and subsequently fed ad libitum. BW was recorded continuously until 12 weeks of age. Daily energy intake, total daily energy expenditure (EE, measured by indirect calorimetry) and body composition were measured in weaned pups at 5, 8 and 12 weeks of age. SL rats displayed increased BW compared with NL rats from week 2 to 5 and again from week 10 to 12. Lean body mass, body fat and protein content and total EE were increased in SL rats at week 5. The same linear correlation described the relationship between BW and total EE in NL and SL rats. At week 8 to 12 no differences in energy metabolism could be found, but the total fat content was increased in SL rats at week 12. Energy balance, i.e. assimilated energy minus EE, was no different between SL and NL at any time that it was measured. We conclude that although PNO rats display increased adiposity in early life, there seem to be no long-lasting effects on energy metabolism in later life, even if a tendency to increased adiposity can still be detected.     

Trends of research and practice in "occupational risk prevention" as seen in Germany

Hypothesis and scenarios of future developments in ORP and ORP research are derived. Based on an analysis of events in the past, on the content and process of research projects in the German "humanization" program, on literature analysis and expert interviews 19 anamnesis to diagnosis relationships are formulated concentrating on the following topics: 1. Innovation potentials and value systems of ORP research, 2. Fields and topics of ORP research of the future, 3. Service-oriented systems of actors in ORP, 4. Demands and limits for research transfer. So the creative potential of the ORP community in Germany was used to conclude on recommendations for ORP developments.     

High dietary iron concentrations enhance the formation of cholesterol oxidation products in the liver of adult rats fed salmon oil with minimal effects on antioxidant status

The aim of this study was to investigate the effect of high dietary iron concentrations on the antioxidant status of rats fed two different types of fat. Four groups of male adult Sprague-Dawley rats were fed diets with adequate (50 mg iron supplemented per kg diet) or high (500 mg iron supplemented per kg diet) iron concentrations with either lard or salmon oil as dietary fat at 100 g/kg for 12 wk. The antioxidant status of the rats was profoundly influenced by the type of fat. Rats fed salmon oil diets had higher concentrations of thiobarbituric acid-reactive substances (TBARS) (P < 0.001), various cholesterol oxidation products (COP) (P < 0.001), total and oxidized glutathione (P < 0.05) and a lower concentration of alpha-tocopherol (P < 0.05) in liver and plasma than rats fed lard diets. The iron concentration of the diet did not influence the concentrations of TBARS, the activities of superoxide dismutase and glutathione peroxidase or the concentration of alpha-tocopherol in plasma or liver. The activity of catalase (P < 0.01) and the concentrations of total, oxidized and reduced glutathione (P < 0.05) in liver were slightly but significantly higher in rats fed high iron diets than in rats fed adequate iron diets, irrespective of the dietary fat. Rats fed the high iron diets with salmon oil, moreover, had higher concentrations of various COP in the liver (P < 0.001) than rats fed adequate iron diets with salmon oil. These results suggest that feeding a high iron diet does not generally affect the antioxidant status of rats but enhances the formation of COP, particularly if the diet is rich in polyunsaturated fatty acids.