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Biomedical subjects

W Krone

Publications and source records attributed to W Krone.

At least 19 recordsLinked to original sources
PubMed1992

[Dyslipoproteinemia and metabolic syndrome. Effects of insulin resistance and hyperinsulinemia on lipid metabolism].

Insulin resistance and consecutive hyperinsulinemia in individuals with the metabolic syndrome are associated with dyslipidemia. This latter is characterised by hypertriglyceridemia and a diminishment of high-density lipoprotein (HDL) cholesterol in the plasma. In severe forms of insulin resistance, low density lipoprotein (LDL) cholesterol may also be elevated. Hypertriglyceridemia is due to an increase in the rate of synthesis of very low density lipoproteins (VLDL) in the liver, and a reduction in their breakdown by the lipoprotein lipase in non-hepatic tissue. Changes in VLDL metabolism are associated with a reduction in HDL concentrations. In addition, direct effects of insulin on the lipid metabolism have been described. Changes in lipid metabolism due to insulin resistance and hyperinsulinemia may be of significance for the atherosclerosis risk in patients with the metabolic syndrome.

Cholesterol↗
PubMed1992

[Does the captopril test improve the diagnosis of primary hyperaldosteronism?].

Plasma concentrations of renin and aldosterone were measured before and 60 min after taking 25 mg captopril in 242 patients with arterial hypertension (124 men, 118 women, aged 51.9 +/- 12.7 years; unilateral aldosterone-producing adrenal adenoma in 8, idiopathic hyperaldosteronism in 16 and essential hypertension in 189). Basal plasma aldosterone levels were twice as high in those with adenoma or hyperaldosteronism (216.9 +/- 99.1 pg/ml and 256 +/- 123 pg/ml, respectively) as in those with essential hypertension (117.7 +/- 115 pg/ml). Basal renin levels in adenoma and idiopathic hyperaldosteronism (1 +/- 0.8 microU/ml and 2.6 +/- 1.9 microU/ml, respectively) were decreased compared with those in essential hypertension (13.1 +/- 14.2 microU/ml). The basal aldosterone/renin ratio was higher in adenoma (436 +/- 370 pg/microU) and idiopathic hyperaldosteronism (615 +/- 950 pg/microU) than in essential hypertension (52.9 +/- 151.3 pg/microU). The sensitivity of this ratio in combination with the aldosterone concentration was 100% for recognizing an adrenal adenoma, its specificity 92.7%. The mean plasma aldosterone level after captopril administration did not change in adenoma patients, but fell to 162 +/- 85 pg/ml (P less than 0.001) in those with idiopathic hyperaldosteronism. These data indicate that the captopril test contributes to distinguishing primary from idiopathic hyperaldosteronism.

Adenoma↗
PubMed1992

Analysis of segregation and expression of an identified mutation at the neurofibromatosis type 1 locus.

A previously identified complex mutation, affecting exon 28 of the neurofibromatosis type 1 gene, was employed for the analysis of the expression pattern in primary cultures of neurofibroma cells and melanocytes from a café-au-lait macule of the patient, respectively. Reverse transcription and subsequent polymerase chain reaction amplification of the segment carrying the mutation revealed that both alleles were expressed in both cell types analysed, thus excluding loss of heterozygosity in this particular instance. Segregation of the alleles of the intragenic Alu sequence length-polymorphism disclosed the paternal origin of the mutated allele. Detection of this mutation was also used for presymptomatic direct DNA diagnosis in the younger child of the patient.

Adult↗
PubMed1992

Cytogenetic studies of skin fibroblast cultures from a karyotypically normal female with dyskeratosis congenita.

Skin fibroblast cultures from a female patient with dyskeratosis congenita revealed markedly increased frequencies of chromosomal breaks, hypodiploidy, and premature centromere disjunction. The frequencies of mitotic disturbances, like ana- and telophase bridges, lagging chromosomes, and micronuclei were almost as dramatically elevated as in cultures from two severely affected patients with Fanconi anemia. Provided that our patient is representative for an autosomal form of dyskeratosis congenita, this type of the disease seems to be characterized by chromosomal instability with a characteristic pattern of cytogenetic abnormalities.

Adult↗
PubMed1992

Human immunodeficiency virus type 1 clones chimeric for the envelope V3 domain differ in syncytium formation and replication capacity.

Chimeric human immunodeficiency virus type 1 (HIV-1) molecular clones differing only in the envelope V3 region were constructed. The V3 regions were derived from two HIV-1 isolates with a non-syncytium-inducing, non-T-cell-tropic phenotype and from four HIV-1 isolates with a syncytium-inducing, T-cell-tropic phenotype. When assayed in SupT1 cells, the two chimeric viruses with a V3 region derived from the non-syncytium-inducing isolates did not induce syncytia and showed a low level of replication. The four chimeric viruses with a V3 region derived from the syncytium-inducing isolates did induce syncytia and replicated efficiently in SupT1 cells. In A3.01 cells, which do not support syncytium formation, the V3 loop affected replication similarly. Upon prolonged culture in SupT1 cells, the phenotype of a non-syncytium-inducing, low-replicating chimeric HIV-1 converted into a syncytium-inducing, high-replicating phenotype. Mutations within the usually conserved GPGR tip of the loop, which were shown to be responsible for the conversion into the syncytium-inducing, high-replicating phenotype, had occurred. In vitro mutagenesis showed that coupled changes of amino acids at both sides of the tip of the V3 loop were able to convert the viral phenotype from non-syncytium-inducing, low replicating into syncytium inducing, high replicating. Our data show that the V3 loop is involved in both syncytium forming and replicative capacity of HIV-1.

Amino Acid Sequence↗
PubMed1992

Cholera toxin diminishes tyrosine kinase activity of the insulin receptor.

We have examined the effect of cholera toxin (CT) on the insulin receptor tyrosine kinase. Incubation of intact rat hepatoma cells FaO with CT (1 microgram/ml/2h) inhibited insulin-induced receptor autophosphorylation by 30% in vivo. This effect persisted after receptor purification in vitro. CT did not alter hormone binding of the insulin receptor, indicating that the toxin affects signal transduction of insulin at the level of the receptor kinase. Experiments using chinese hamster ovary (CHO) cells transfected either with the human insulin receptor (HIR) or a mutant lacking the last 43 amino acids of the receptor beta-subunit (HIR delta CT) showed, that the carboxy-terminal tail of the insulin receptor does not play a role in the suppressive effect of the toxin on the insulin receptor kinase.

Animals↗
PubMed1991

Pertussis toxin inhibits autophosphorylation and activation of the insulin receptor kinase.

Pertussis toxin is an ADP-ribosyltransferase which alters the function of some of the GTP-binding proteins and inhibits some actions of insulin. In vivo, pertussis toxin (2 micrograms/ml/2h) inhibited insulin-stimulated tyrosyl autophosphorylation of the insulin receptor by 50% in FaO cells, and nearly completely inhibited phosphorylation of the cellular insulin receptor substrate pp185. Similarly, insulin-stimulated autophosphorylation and kinase activity of the insulin receptor purified on wheat germ agglutinin-agarose from pertussis toxin-treated FaO cells was diminished 50%; however, treatment of cells with the catalytically inactive B-oligomer of the toxin had no effect on receptor tyrosine kinase activity in vitro. Pertussis toxin did not alter insulin binding or the cellular levels of ATP, cAMP, and cGMP. Furthermore, immunoprecipitation of the insulin receptor from intact cells with anti-insulin receptor antibodies showed that pertussis toxin did not increase the phosphorylation of serine or threonine residues in the insulin receptor. These results suggest that pertussis toxin can modulate signal transduction of insulin at the level of the insulin receptor kinase.

Animals↗
PubMed1991

A small deletion and an adjacent base exchange in a potential stem-loop region of the neurofibromatosis 1 gene.

A single-strand conformational polymorphism found in the DNA of a patient with neurofibromatosis 1 (NF1) was shown to be caused by a deletion of a CCACC or CACCT sequence and an adjacent transversion, located about 500 base pairs downstream from the region that codes for a functional domain of the NF1 gene product. This mutation could also be detected in the patient and in his affected daughter by heteroduplex analysis. The deletion removes the proximal half of a small potential stem-loop and interrupts the reading frame in exon 1. A severely truncated protein with a grossly altered carboxy terminus lacking one third of its sequence is expected to be formed from the mutant allele.

Adult↗
PubMed1991

Increased melanogenesis in cultured epidermal melanocytes from patients with neurofibromatosis 1 (NF 1).

Melanocyte cultures from the normally pigmented skin of patients with neurofibromatosis 1 (NF 1) have a higher melanin content than those from the skin of healthy donors. An additional increase in the amount of melanin per cell was found in 5 out of 6 lines of melanocytes derived from café au lait macules of NF 1 patients. Omission of the tumor promoter phorbol-12-myristate-13-acetate from the culture medium brings about a comparable increase in the melanin content in all three kinds of melanocyte cultures. Cultures of NF 1 melanocytes show a higher tyrosine hydroxylase activity than those of control melanocytes, and incorporate larger amounts of dihydroxyphenylalanine than the latter. We conclude that melanogenesis in epidermis melanocytes is affected by defective alleles of the NF 1 gene. Our findings do not contradict the hypothesis that the defect underlying NF 1 impairs the inhibition of a wild-type RAS oncogene by interfering with the GTPase-activating function of the NF 1 gene product.

Adolescent↗
PubMed1991

The size of small polydisperse circular DNA (spcDNA) in angiofibroma-derived cell cultures from patients with tuberous sclerosis (TSC) differs from that in fibroblasts.

Cell cultures were derived from angiofibromas of three patients with tuberous sclerosis (TSC), from the unaffected skin of these patients, and from the skin of five healthy donors. The length distributions of the small polydisperse circular DNA (spcDNA) fraction of these cell cultures were then analyzed. Nearly half the spcDNA molecules from the angiofibroma cultures were longer than 0.4 micron, whereas only about 7% exceeded this threshold in the spcDNA preparations from the skin fibroblast cultures. The percentage of the larger size class of spcDNA showed an increase at higher numbers of in vitro passages in all three types of cultures, but this effect was much more conspicuous in the angiofibroma-derived cultures than in those from the skin fibroblasts. An age-dependent increase in the overall amount of spcDNA was only seen in the angiofibroma-derived cultures. Our earlier finding of elevated amounts of spcDNA in angiofibroma cultures was confirmed in cultures from an additional TSC patient.

Adult↗
PubMed1990

Cytogenetic studies in tuberous sclerosis.

A cytogenetic study was performed with cultures derived from peripheral blood, unaffected skin, and angiofibromas of four patients suffering from the sporadic form of tuberous sclerosis (TSC). Increased frequencies of unstable chromosomal anomalies were found in lymphocytes and in fibroblasts from unaffected skin of the patients. The slight increase of the overall rate of unstable anomalies observed in angiofibroma-derived cultures above that of lymphocytes and skin fibroblasts, respectively, could almost entirely be attributed to a higher frequency of dicentric chromosomes. Of the 17 facial angiofibromas from which a total of 20 cell cultures were established, nine showed a normal karyotype, while eight exhibited stable chromosomal rearrangements, among which 19 clonal types could be identified. Unbalanced forms of various translocations caused partial trisomies of the long arms of chromosomes 1, 3, 7, 10, and 15. There was no clustering of breakpoints to a particular chromosomal region, nor was one particular chromosome preferentially involved. Frequencies and kinds of rearrangements varied between cultures derived from different angiofibromas from the same patient and between different culture charges from the same tumor. Tetraploidy was not generally more abundant in the angiofibroma-derived cultures, but there were a few culture charges with exceedingly high rates of tetraploid cells. The occurrence of premature centromere disjunction (PCD), either affecting all chromosomes or only part of them in angiofibroma-derived cultures, first described in TSC by Scappaticci et al. could be confirmed.

Chromosome Aberrations↗
PubMed1990

Hyperlipidaemia and hypertension.

Hyperlipidaemia and hypertension are commonly found in the population and are independent risk factors for cardiovascular complications. The combined presence of hypertension and hypercholesterolaemia increases considerably the risk for cardiovascular complications. These high-risk patients have to be identified early and treated appropriately in order to avoid complications. The goal of antihypertensive therapy is to reduce the average levels of diastolic pressure to below 90 mm Hg and the systolic pressure to below 140 mm Hg. The goals set for lipid levels in these patients are total cholesterol less than or equal to 200 mg/dl, LDL cholesterol less than or equal to 135 mg/dl and triglycerides less than or equal to 200 mg/dl. The first step in the treatment of patients with both hyperlipidaemia and hypertension is to seek underlying causes and to take appropriate therapeutic measures for both diseases. Non-pharmacological treatment of these high-risk patients includes weight reduction, appropriate dietary measures including alcohol and salt restriction, cessation of smoking and increasing physical activity. If pharmacological antihypertensive treatment is needed, drugs without adverse effects on lipid and lipoprotein levels should be preferred. If, in addition to dietary measures, drug treatment is necessary to reduce high cholesterol levels, bile acid sequestrants are the drug of first choice at present. If long-term safety can be established for HMG CoA reductase inhibitors, these drugs will represent a major advance in the therapy of hypercholesterolaemia.

Antihypertensive Agents↗
PubMed1990

Evidence for rapid selection and deletion of HIV-1 subpopulations in vivo by V3-specific neutralizing antibody: a model of humoral-associated selection.

Emergence in two chimpanzees of HIV-1 HTLV-IIIB variants resistant to neutralization by the pre-existing antibody is described. Viruses isolated from the HTLV-IIIB gp120 vaccinated and challenged animal were more resistant to neutralization, had more heterogenic genomes and showed more pronounced antigenic drift as determined by serotypic neutralization analysis than viruses isolated from the naive infected animal, indicating immune pressure as the selective mechanism. The earliest selecting antibody population detected in the chimpanzees appeared to be conformationally dependent. This was demonstrated by its ability to neutralize only the most replication-competent sub-populations of the HTLV-IIIB inoculum strain, yet was found to bind a HTLV-IIIB common nonapeptide (IQRGPGRAF) derived from the gp120 isolate-specific 3rd variable domain (V3) also known to induce isolate-specific neutralization in multiple species. Each of the recovered isolates had become resistant to neutralization by both a monoclonal (0.5 beta) and polyclonal HTLV-IIIB gp120 V3-specific antibody by as much as 16 to 256-fold. Amplification of the V3 coding sequence by polymerase chain reaction and subsequent sequence analysis of the neutralization-resistant variants obtained from in vivo infected animals indicated that resistance to neutralization was conferred by changes outside the direct binding site for the selective neutralizing antibody. Further studies indicated that apparent neutralization-resistant variants, yielded after in vitro passage through chimpanzee and human peripheral blood mononuclear cell cultures void of HIV-specific antibody, result from the homogenic amplification of the more replication competent sub-population pre-existing in the original viral stock. These faster replicating sub-populations appear to dominate initially and therefore are the initial prime targets recognized by the chimpanzee humoral immune system upon infection in vivo and thus eliminated. The described finding of virus escape due to a conformationally-induced flexibility of the major neutralization epitope termed "conformational-V3 hypervariability", coupled to the known primary amino acid hypervariability of this epitope (V3) termed "linear-V3 hypervariability", may be all that is required by the virus to survive in an otherwise effective humoral immune system.

Amino Acid Sequence↗
PubMed1989

Restriction analysis of chromosomal sequences homologous to single-copy fragments cloned from small polydisperse circular DNA (spcDNA).

Restriction fragments from the fraction of small polydisperse circular DNA (spcDNA) were cloned in pBR322. The spcDNA was prepared from cell cultures derived from an angiofibroma of a patient with tuberous sclerosis (TS). Such cultures have been shown previously to contain increased amounts of spcDNA. Four cloned spcDNA fragments containing single-copy sequences were chosen to characterize the homologous chromosomal DNA segments by restriction analysis. When used as hybridization probes, these four fragments generate well-defined nonvariable patterns in the chromosomal DNA from healthy donors. The restriction patterns obtained with one of the fragments (D-C4) can best be interpreted by assuming the presence of two copies of the homologous sequences in chromosomal DNA. A second sequence, A-B4, occurs at least 30-50 times in the haploid human genome. In both cases the duplicated regions span relatively large segments of DNA.

Base Sequence↗
PubMed1989

Metabolic changes during antihypertensive therapies.

There is controversy whether various classes of antihypertensive drugs can reduce significantly cardiovascular morbidity and mortality in primary prevention. A failure to show this in many studies was attributed, at least in part, to deleterious effects of these drugs on lipid metabolism. Especially adrenergic antihypertensives cause marked effects on lipoprotein levels in plasma. A review of the literature revealed that beta-blockers increase triglycerides and VLDL (very low density lipoprotein)-cholesterol and may lower plasma HDL (high density lipoprotein) levels. In contrast alpha 1-adrenergic inhibitors like prazosin, doxazosin and terazosin lower triglycerides, total cholesterol, LDL (low density lipoprotein)- and VLDL-cholesterol and increase plasma HDL levels. The mechanisms by which alpha- and beta-blockers may produce the observed effects on plasma lipids and lipoproteins are not well understood. It has been shown in our laboratory that the activity of the LDL receptor of peripheral cells, a major determinant of cholesterol levels in plasma, is regulated by catecholamines via alpha 2- and beta 2-adrenergic receptors. Accordingly, blockade of these adrenoceptors with alpha- and beta-adrenergic antagonists can reverse the catecholamine effect. In addition these agents may affect lipoprotein lipase, lecithin cholesteryl acyltransferase and cholesterol ester hydrolase. These data may explain, at least in part, the plasma effects. However, long-term studies are needed to clarify the clinical value of antihypertensives with different metabolic profiles.

Adrenergic alpha-Antagonists↗