A low renal threshold for glucose in diabetic patients with a mutation in the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene.

One form of maturity-onset diabetes of the young, Type 3 (MODY3), results from mutations in the gene coding for hepatocyte nuclear factor-1alpha (HNF-1alpha), a transcription factor first described in the liver. MODY3 is characterized by a defective glucose-stimulated insulin secretion. Earlier observations of glycosuria with normal blood glucose levels in some MODY families suggest an additional renal manifestation of the respective genetic defect.

[Sclerosing in multiple familial glomangiomas].

Glomus tumors (glomangiomata) are benign tumors arising from glomus cells. Multiple glomangiomata are less frequent and less painful than the solitary variant, which is usually located subungually. Nonetheless multiple glomangiomata--sometimes being sensitive to pressure and changes in temperature--may cause considerable discomfort.

[Granuloma eosinophilicum faciei--successful cryosurgery treatment of 6 patients].

Six patients with granuloma faciale, including patients with multiple lesions, were treated successfully with cryosurgery. Granuloma faciale is known to be difficult to treat. Cryosurgery is an effective and minimally invasive therapy for this granulomatous inflammation of the skin.

Endothelial expression of endothelin-converting enzyme-1 beta mRNA is regulated by the transcription factor Ets-1.

Cleavage of big endothelins (ETs) by endothelin-converting enzymes (ECEs) represents the final step in the biosynthesis of ETs. ECE-1 is expressed predominantly in endothelial cells and exists in two isoforms, termed alpha and beta, differing in their 5' termini. We have recently shown that isoform-specific mRNA expression is directed by alternative promoters.

Evidence of alternative promoters directing isoform-specific expression of human endothelin-converting enzyme-1 mRNA in cultured endothelial cells.

The endothelins, a family of closely related vasoactive and mitogenic peptides, are thought to play an important role in cardiovascular pathophysiology. The conversion of the inactive precursor "big endothelin" to the biologically active peptide is catalyzed in vitro and in vivo by endothelin-converting enzymes (ECE). Recently the cDNA cloning of two homologous proteins, termed ECE-1 and ECE-2, has been reported.

Mutations in the hepatocyte nuclear factor-1alpha gene in MODY and early-onset NIDDM: evidence for a mutational hotspot in exon 4.

We have recently shown that mutations in the gene encoding the transcription factor hepatocyte nuclear factor (HNF)-1alpha are the cause of one form of maturity-onset diabetes of the young (MODY3). Here, we report the exon-intron organization and partial sequence of the human HNF-1alpha gene. In addition, we have screened the ten exons and flanking introns of this gene for mutations in a group of 25 unrelated white subjects from Germany who presented with NIDDM before 35 years of age and had a first-degree relative with NIDDM.

Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1).

The disease maturity-onset diabetes of the young (MODY) is a genetically heterogeneous monogenic form of non-insulin-dependent (type 2) diabetes mellitus (NIDDM), characterized by early onset, usually before 25 years of age and often in adolescence or childhood, and by autosomal dominant inheritance. It has been estimated that 2-5% of patients with NIDDM may have this form of diabetes mellitus. Clinical studies have shown that prediabetic MODY subjects have normal insulin sensitivity but suffer from a defect in glucose-stimulated insulin secretion, suggesting that pancreatic beta-cell dysfunction rather than insulin resistance is the primary defect in this disorder.

Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3).

The disease non-insulin-dependent (type 2) diabetes mellitus (NIDDM) is characterized by abnormally high blood glucose resulting from a relative deficiency of insulin. It affects about 2% of the world's population and treatment of diabetes and its complications are an increasing health-care burden. Genetic factors are important in the aetiology of NIDDM, and linkage studies are starting to localize some of the genes that influence the development of this disorder.

Altered insulin secretory responses to glucose in diabetic and nondiabetic subjects with mutations in the diabetes susceptibility gene MODY3 on chromosome 12.

One form of maturity-onset diabetes of the young (MODY) results from mutations in a gene, designated MODY3, located on chromosome 12 in band q24. The present study was undertaken to define the interactions between glucose and insulin secretion rate (ISR) in subjects with mutations in MODY3. Of the 13 MODY3 subjects, six subjects with normal fasting glucose and glycosylated hemoglobin and seven overtly diabetic subjects were studied as were six nondiabetic control subjects.

Isolation and characterization of rat liver microsomal R-ibuprofenoyl-CoA synthetase.

Microsomal long-chain acyl-CoA synthetase (EC 6.1.2.

Searching for NIDDM susceptibility genes: studies of genes with triplet repeats expressed in skeletal muscle.

The expansion of trinucleotide repeats has been associated with late-onset neurodegenerative disorders. Although the genes harbouring the triplet expansions may be widely expressed, the pathological expression of these diseases is restricted to specific tissues. Non-insulin-dependent diabetes mellitus (NIDDM) shares several features with diseases resulting from such dynamic mutations including late-onset and specific but limited sites of tissue pathology-muscle, fat, liver and insulin-secreting pancreatic beta cells.

A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2.

Non-insulin-dependent (type 2) diabetes mellitus (NIDDM) is a common disorder of middle-aged individuals characterized by high blood glucose levels which, if untreated, can cause serious medical complications and lead to early death. Genetic factors play an important role in determining susceptibility to this disorder. However, the number of genes involved, their chromosomal location and the magnitude of their effect on NIDDM susceptibility are unknown.

An approach for identifying simple sequence repeat DNA polymorphisms near cloned cDNAs and genes. Linkage studies of the islet amyloid polypeptide/amylin and liver glycogen synthase genes and NIDDM.

Genetic factors contribute to the development of NIDDM, and genes involved in regulating pancreatic beta-cell function and insulin's effects on glucose metabolism are good candidates for being NIDDM susceptibility loci. However, testing candidate genes for linkage to NIDDM depends on the identification of highly informative DNA polymorphisms in or near the candidate locus. Here we describe an approach for identifying highly polymorphic markers near candidate genes that utilizes the emerging physical map of the human genome.

Stereospecific determination of tiaprofenic acid in plasma: problems with drug degradation.

A sensitive stereospecific high-performance liquid chromatographic assay for the quantification of tiaprofenic acid in human plasma was developed. The procedure involved extraction of tiaprofenic acid from acidified plasma into hexanediethyl ether (8:2, v/v). Stereospecific separation was achieved with a prepacked alpha1-acid glycoprotein column without derivatization.

Localization of MODY3 to a 5-cM region of human chromosome 12.

Maturity-onset diabetes of the young (MODY) is a heterogeneous disorder that appears to be characterized by a primary defect in insulin secretion. Mutations in an unknown locus (MODY1) on chromosome 20 and the glucokinase gene (MODY2) on chromosome 7 can cause this form of non-insulin-dependent diabetes. Recent genetic studies have identified a third locus on chromosome 12 (MODY3) that is linked to MODY in a group of French families.

2-Arylpropionyl-CoA epimerase: partial peptide sequences and tissue localization.

The R-enantiomers of 2-arylpropionic acids (2-APAs) such as ibuprofen (IBU) exhibit the phenomenon of species- and substrate-dependent metabolic chiral inversion. Only R-enantiomers are activated to acyl-CoA-thioesters by an acyl-CoA-synthetase via an adenylate intermediate. The acyl-CoA-thioesters are substrates for an epimerase, which is responsible for chiral inversion.

Pharmacokinetics of ketoprofen enantiomers after different doses of the racemate.

The pharmacokinetics of the enantiomers of ketoprofen after oral administration of 12.5 mg, 25 mg and 50 mg and i.v.

Isolation of a cDNA clone encoding a KATP channel-like protein expressed in insulin-secreting cells, localization of the human gene to chromosome band 21q22.1, and linkage studies with NIDDM.

The metabolism of glucose in insulin-secreting cells leads to closure of ATP-sensitive K+ channels (KATP), an event that initiates the insulin secretory process. Defects in insulin secretion are a common feature of non-insulin-dependent diabetes mellitus (NIDDM), and the beta-cell KATP that couples metabolism and membrane potential is a candidate for contributing to the development of this clinically and genetically heterogeneous disorder. We screened a hamster insulinoma cDNA library by low-stringency hybridization with a probe coding for the G-protein-coupled inwardly rectifying K+ channel GIRK1/KGA and isolated clones encoding a protein, KATP-2, whose sequence is 90% similar to that of the recently described KATP-1, an ATP-sensitive K+ channel expressed in heart and other tissues.

Tonic versus phasic pain: dose-related effects of ketoprofen.

Only recently has a new experimental technique been developed which combines tonic and phasic painful stimulation. By means of this technique the non-steroidal anti-inflammatory drug (NSAID) ibuprofen has been shown to produce a dose-related decrease in heterotopically applied phasic and tonic pain. The present study aimed to investigate the dose-related effects of the NSAID ketoprofen (50, 100, and 150 mg i.

Localization of the gene encoding a neutral amino acid transporter-like protein to human chromosome band 19q13.3 and characterization of a simple sequence repeat DNA polymorphism.

The gene encoding a human neutral amino acid transporter-like protein (SLC1A5) was mapped to chromosome band 19q13.3 by fluorescence in situ hybridization to metaphase chromosomes. A simple sequence repeat DNA polymorphism of the form (GT)n was identified in the 3'-untranslated region of SLC1A5 mRNA.

Is the formation of R-ibuprofenyl-adenylate the first stereoselective step of chiral inversion?

Coenzyme A thioester formation is reported to be the first step of chiral inversion of R-ibuprofen. In order to investigate the mechanism of this reaction adenylate derivatives of the ibuprofen enantiomers were synthesized chemically. R- and S-ibuprofenyl-adenylates as well as free acids were incubated with rat liver mitochondria in the presence of coenzyme A, MgCl2 with or without ATP.

Stereoselective disposition of flurbiprofen in healthy subjects following administration of the single enantiomers.

Plasma concentrations of the enantiomers of flurbiprofen were measured following oral administration of (S)-flurbiprofen 50 mg and (R)-flurbiprofen 50 mg and 100 mg to sixteen healthy subjects. Chiral inversion did not occur to a measurable extent. Significantly higher values of AUC (55.

Is the inversion from R- to S-ketoprofen concentration dependent? Investigations in rats in vivo and in vitro.

The effects of dose on the pharmacokinetics of ketoprofen (KT) enantiomers were investigated in rats in vivo and in hepatoma cells in continuous culture in vitro following administration of the optically pure enantiomers and the racemate of KT. With the exception of AUC (area under the curve) no pharmacokinetic differences could be found following i.v.

Localization of the glucagon receptor gene to human chromosome band 17q25.

The gene encoding the human glucagon receptor (GCGR) was mapped to chromosome band 17q25 by fluorescence in situ hybridization to metaphase chromosomes. An Alu variable poly(A) DNA polymorphism was identified in this gene. Studies in the CEPH families showed significant evidence of linkage between DNA polymorphism and markers localized to the distal long arm of chromosome 17.