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W Krone

Publications and source records attributed to W Krone.

At least 91 records · Page 5Linked to original sources
PubMed1995

Analysis of an alternatively spliced exon of the neurofibromatosis type 1 gene in cultured melanocytes from patients with neurofibromatosis 1.

Neurofibromatosis type 1 (NF1) is characterized by clinical features that primarily affect tissues derived from the neural crest (neurofibromas, café-aulait macules). Because aberrant regulation of alternative splicing in the NF1 gene transcript may be of functional significance, cultured melanocytes from café-aulait macules (CALM), as an example of benign NF1 lesions, were examined for the expression of the different alternative splice products of this gene. Both kinds of NF1 messengers (type 1 and 2) were found not only in CALM melanocytes but also in keratinocytes, fibroblasts and blood cells. Except in blood cells, there was a predominance of the type 2 transcript. Melanocytes from NF1 patients and healthy donors showed similar expression patterns under several culture conditions. Our results suggest that the development of CALM does not correlate with a switch in the ratio of type 1 to type 2 NF1 messenger RNA.

Alternative Splicing↗
PubMed1995

A clonal translocation t(10;21) in an optic glioma of a patient with neurofibromatosis type 1 (NF 1).

An 11-year-old boy affected by neurofibromatosis type 1 is presented with severely impaired vision on the right eye (0.1). MRI demonstrated a 2.3 x 1.8 cm tumour of the optic chiasma. After open biopsy cytogenetic analysis was performed on primary cultures of this optic glioma (grade I). A clonal translocation t(10;21)(q21.2;21.1) was detected in 66% of the metaphases analysed. The boy received fractioned irradiation with a total tumour dose of 60 Gy. The ultimate MRI taken 18 months after radiotherapy showed no residual tumour. The vision on the right improved to 0.2, but decreased on the left to 0.6. The patient attends high school with no impairment in his daily life.

Adolescent↗
PubMed1995

Stimulation of alpha-adrenoceptors inhibits cholesterol synthesis in freshly isolated human mononuclear leukocytes.

Specific agonists and antagonists for alpha 1- and alpha 2-adrenoceptors were used to determine an alpha-adrenoceptor-mediated action of adrenaline on the rate of sterol synthesis from [14C]acetate in freshly isolated human mononuclear leukocytes. In the presence of the beta-adrenergic blocker propranolol (1 microM), adrenaline (100 microM) and noradrenaline (100 microM) suppressed sterol synthesis by 36% and 38%, respectively, suggesting an action via alpha-adrenoceptors. The catecholamine effect could be mimicked by alpha 2-selective beta-phenethylamines including alpha-methylnoradrenaline, but not by imidazolines. alpha 1-Selective agonists like phenylephrine and methoxamine had no effect on the pathway. Accordingly, the effects of adrenaline and the alpha 2-selective agonist alpha-methylnoradrenaline on sterol synthesis were attenuated by the unselective alpha-antagonist phentolamine and the selective alpha 2-antagonist yohimbine, but not by the alpha 1-antagonist prazosin. The results provide evidence that catecholamines can affect sterol synthesis in human mononuclear leukocytes by stimulating alpha-adrenoceptors of the alpha 2-subtype.

Cholesterol↗
PubMed1995

On unequal allelic expression of the neurofibromin gene in neurofibromatosis type 1.

The autosomal dominantly inherited disease neurofibromatosis type 1 (NF1) is caused by mutations of a large gene comprising 59 exons, which code for a protein with 2818 amino acids called neurofibromin. Employing an expressed polymorphic site in exon 5 of the neurofibromin gene, the expression of its alleles was analysed quantitatively by scanning radioactive RT-PCR fragments of this exon prepared from the RNA of fibroblast cell cultures from 15 NF1 patients and of white blood cells from one NF1 patient. Thirteen of the RNA preparations yielded unequal amounts of the allelic messages. The deviations of the expression ratios (A2:A1) from 1.0 ranged from -0.9 to +25.8. The allelic messages were equally represented in the RNA preparations from five informative healthy donors. Apart from fibroblasts this phenomenon could also be detected in keratinocytes, melanocytes from normally pigmented skin and melanocytes from a café-au-lait spot of one patient. Only one of three patients affected by stop mutations exhibited unequal allelic expression. When nuclear RNA from 10 of the 13 patients was examined, equal amounts of the primary transcripts were found (average ratio A2/A1: 1.08 +/- 0.07 S.E.M.), indicating that unequal expression on the level of mRNA was not caused by mutations affecting transcriptional regulation. The ratio of the amount of neurofibromin to that of p120 GAP did not seem to be correlated with the extent of unequal allelic expression.

Alleles↗
PubMed1995

Neurofibromatosis type 1: pathology, clinical features and molecular genetics.

Neurofibromatosis type 1 (NF1) or von Recklinghausen neurofibomatosis, is a common heritable neurocutaneous disorder. This disorder appears to affect all races, with a prevalence estimated to be 1 in 3000. Approximately half of all cases of NF1 represent new mutations. The characteristics of NF1, which include cafe-au-lait spots, neurofibromas, Lisch nodules, optic glioma, osseous lesions, macrocephaly, short stature and mental retardation suggest that the genetic lesion affects the proper development of multiple organ systems. Within the past few years, the gene causing NF1 has been identified and the protein encoded by this gene, neurofibromin, has been the subject of detailed investigation. The NF1 gene spans over 350 kb of genomic DNA and encodes a protein product of 2818 amino acids. Neurofibromin is expressed in many different tissues. It is now known that one role of neurofibromin is as a GTPase activating protein (GAP), very likely in the same pathway of signal transduction as ras. Absence of neurofibromin in mice homozygously mutant for the NF1 gene results in profound developmental abnormalities. In mice that are heterozygous for NF1, an accelerated onset of tumor formation is observed. Combined with studies of tumors from NF1 patients showing homozygous deletions in the NF1 gene, these data suggest a role for NF1 as a "tumor suppressor". Evidence suggesting other roles played by neurofibromin, in control of proliferation in some situations and differentiation in others, is gradually bringing the previously hazy picture of this genetic disorder into sharper focus.

Brain Neoplasms↗
PubMed1995

Plasma catecholamines, thrombocyte alpha 2- and lymphocyte beta 2-adrenoceptor densities in hypertensive patients with low or normal plasma renin concentrations.

The sympathetic nervous system is unique in the regulation of plasma renin, for it can stimulate or suppress renin release by activation of either renal beta- or alpha 2-adrenoceptors. The authors studied plasma renin concentration (PRC), noradrenalin and adrenalin levels in plasma, and the densities of lymphocyte beta 2-adrenoceptors and thrombocyte alpha 2-adrenoceptors in 25 hypertensive patients with either normal (11-40 mU/L; n = 9) or low PRC (0-10 mU/L; n = 14). There were no differences in plasma catecholamine levels and adrenoceptor densities between the two patient groups. A positive correlation (r = 0.66; P < 0.005) between beta 2-adrenoceptor density and PRC in the patient group with low PRC, and a negative correlation (r = -0.72; P < 0.01) between alpha 2-adrenoceptor density and plasma renin in patients with normal PRC were found. They conclude that adrenoceptor densities on blood elements and plasma catecholamines do not differ in low and normal renin hypertension. The significant correlations between adrenoceptor densities and PRCs may indicate that adrenoceptors on blood elements mirror adrenoceptor densities in the kidney and that tonic suppression of renin release through alpha 2-adrenoceptors is preserved in hypertensive patients with normal plasma renin levels.

Adult↗
PubMed1995

Ras-GTP regulation is not altered in cultured melanocytes with reduced levels of neurofibromin derived from patients with neurofibromatosis 1 (NF1).

As derivatives of the neural crest, epidermal melanocytes are supposed to be clinically affected by NF1 gene defects. The NF1 gene shares sequence homology with the p120 GTPase activating protein (p120-GAP) and neurofibromin has been shown to participate in Ras-regulation. By immunoprecipitation and Western blotting, neurofibromin was found to be expressed in melanocytes from the unaffected skin and café au lait macules of NF1 patients, but the intensity of the neurofibromin band was decreased compared to control cultures. The Ras-GTP/Ras-GDP ratios of NF1 derived melanocyte cultures were comparable to those derived from healthy donors. Furthermore, the total GAP-activity of cell lysates was not altered in NF1 melanocyte cultures compared to controls. However, lysates of proliferating melanocytes, both from NF1 patients and from healthy donors, showed an about 2-fold higher GAP-activity than poorly growing cells. Neurofibromin contributed approximately one third of total GAP-activity, in both control and NF1 melanocytes, indicating that it is not the major regulator of Ras in these cells. These results suggest that the function of neurofibromin in melanocytes is not limited to regulation of Ras activity.

Adult↗
PubMed1995

Increase of protooncogene c-myc mRNA levels by low density lipoprotein in vascular smooth muscle cells.

The effect of low density lipoprotein (LDL) on the intracellular mRNA concentration of the protooncogene c-myc was studied in freshly isolated bovine vascular smooth muscle cells and in the rat aortic smooth muscle cell line A7r5. Northern analysis showed that LDL increased the mRNA levels of c-myc in both cell lines, the stimulation being 2-fold after 2 h incubation at a concentration of 50 micrograms LDL-protein/ml. High density lipoprotein (HDL) had no effect on c-myc mRNA levels in A7r5 cells. These results demonstrate that LDL, but not HDL, increases intracellular concentrations of c-myc in two different aortic smooth muscle cell lines.

Animals↗
PubMed1995

[Insulin resistance and arterial hypertension].

Insulin resistance and reactive hyperinsulinemia occur not only in patients with obesity, impaired glucose tolerance or non-insulin-dependent (Type 2) diabetes mellitus, but also in many non-obese, non-diabetic individuals with essentiell hypertension and their normotensive, lean young offsprings. The common coexistance of a genetic predisposition for hypertension with insulin resistance helps to explain the frequent occurrence of hypertension as well as dyslipidemia, obesity and diabetes Type 2 in a given individual. In the pathogenesis of hypertension, inappropriate vasoconstriction and/or a structural vasculopathy appears to be an important and ultimate causative event. Several pressor mechanisms are discussed and a distinct sodium retention appears to be almost obligatory associated with diabetes mellitus, while essential and particularly obesity-associated hypertension involves predominantly a tendency for sympathetic activation. Acute hyperinsulinemia on one hand causes arterial vasodilation and on the other hand enhances renal sodium reabsorption and sympathetic activity. Chronically, hyperinsulinemia may promote cardiovascular muscle cell proliferation and atherogenesis. Insulin resistance affecting certain transmembrane cation transporters might lead to an elevation of intracellular cytosolic calcium levels thereby inducing inappropriate vasoconstriction. Nevertheless, whether insulin resistance and hyperinsulinemia contribute to the pathogenesis of hypertension per se is still unproven. Considering antihypertensive drugs, thiazide diuretics given in medium or high dosage as well as beta-blockers appear to promote insulin resistance, reactive hyperinsulinemia and dyslipidemia. Almost all calcium antagonists and the conventional sympthatolytics are metabolically neutral, while ACE-inhibitors and alpha 1-blockers tend to improve insulin resistance. In Type 2 diabetic patients, ACE-inhibitors exert in addition to their antihypertensive a potentially useful anti-diabetic effect. Nevertheless, the prognostic relevance of the metabolic side effects of antihypertensive drugs awaits further clarification.

Antihypertensive Agents↗
PubMed1995

[Disorders of lipid metabolism in insulin resistance].

Insulin resistance with consecutive hyperinsulinemia is associated with dyslipidemia in individuals with metabolic syndrome or "syndrome x". This dyslipidemia is characterized by a hypertriglyceridemia and reduced levels of HDL-(high density lipoprotein)cholesterol in plasma. Table 1 summarizes the alterations of lipoproteins in insulin resistance. In severe forms of insulin resistance LDL-(low density lipoprotein)cholesterol can be elevated as well. The hypertriglyceridemia is caused by an elevated synthesis and secretion of VLDL (very low density lipoprotein) in the liver and by reduced metabolism, mediated e.g. by lipoprotein lipase. The alterations of VLDL-metabolism are associated with a reduced concentration of HDL-cholesterol. In addition the composition of lipoprotein particles can be altered, which might interfere with their normal metabolism. Furthermore addition direct effects of insulin on cellular cholesterol metabolism have been described. These alterations in lipid metabolism which are due to an insulin resistance and hyperinsulinemia might be related to the increased coronary risk which has been observed in patients with metabolic syndrome. Therefore the diagnostic approach in patients with hypertriglyceridemia should consider the possibility of an underlying glucose intolerance or Type 2 diabetes. Therapeutic aims and strategies are discussed. In accordance to guidelines of the American Heart Association the goals of lipid-lowering therapy take into account the prevalence of various cardiovascular risk factors in an individual patient (Table 2). Principle actions of lipid-lowering drugs on plasma lipids are outlined in Table 3. Table 4 summarizes the effect of antihypertensive drugs on plasma lipids and lipoproteins, which should be considered in the treatment of patients with dyslipidemia.

Adult↗
PubMed1994

Melatonin inhibits LDL receptor activity and cholesterol synthesis in freshly isolated human mononuclear leukocytes.

There is some indirect evidence that the pineal hormone melatonin can suppress plasma levels of cholesterol in hypercholesterolemic rats. We have examined the effects of the hormone on cellular cholesterol metabolism in freshly isolated human mononuclear leukocytes. Incubation of cells for up to 20 h in a lipid-free medium resulted in an increase in the rate of cholesterol synthesis from [14C]acetate and the high affinity accumulation and degradation of [125I]labeled low density lipoprotein (LDL). Addition of melatonin in increasing concentrations to the incubation medium at zero time inhibited cholesterol synthesis and the specific accumulation and degradation of [125I]labeled LDL; at a concentration of 100 microM, the inhibitions were 38%, 42%, and 48%, respectively. Similar results were obtained using [14C]mevalonate as precursor. Fatty acid synthesis was not altered under these conditions. In contrast to cholesterol, the synthesis of the first cyclic compound lanosterol was not affected by the pineal hormone. These results implicate that melatonin inhibits this pathway between lanosterol and cholesterol. The action of melatonin on LDL receptor activity appeared to be mediated by a decrease in the number of LDL receptors and not by a change in binding affinity. Pharmacological characterization of the potential melatonin receptor site using several analogs like tryptamine, 5-hydroxytryptamine,N-acetyl-5-hydroxytryptamine, 5-methoxytryptamine, and 6-chloromelatonin indicated that the 5-methoxy group is indispensible for the hormone action on cholesterol synthesis. The data provide evidence that melatonin can modulate cholesterol metabolism in human cells.

5-Methoxytryptamine↗
PubMed1994

Spontaneous chromosomal aberrations in cell cultures from patients with neurofibromatosis 1.

Neurofibroma-derived cell cultures, skin fibroblast strains from NF1 patients, melanocyte cultures from café-au-lait spots and melanocytes from skin overlying neurofibroma were investigated with regard to the frequencies of spontaneous chromosomal aberrations. A 3.4-fold increased rate of stable and unstable chromosome aberrations in 34 neurofibroma cultures of 18 NF1 patients was noticed in comparison to 17 skin biopsy-derived cultures of healthy probands. Fibroblast strains from the unaffected skin of nine NF1 patients revealed a 2.6-fold higher rate of chromosome breakage compared with the control cultures. Likewise, an increase of spontaneous chromosomal instability by a factor of 13.5 was found in cultured melanocytes from café-au-lait spots and by a factor of 11.9 in the skin-melanocyte cultures of six NF1 patients in comparison to foreskin-derived melanocyte strains of five unaffected persons. Analyses of the distribution of chromatid and chromosome breaks along the chromosomes revealed a significant clustering of these events in the centromeric regions specifically in the four kinds of NF1-derived cultures.

Adult↗
PubMed1994

A deletion in the 5'-region of the neurofibromatosis type 1 (NF1) gene.

A new mutation, the first one close to the 5'-end of the neurofibromatosis type 1 (NF1) gene, was found when RNA preparations from various cell types of 15 NF1 patients were analysed by reverse transcription and subsequent multiplex polymerase chain reaction. This mutation removes the 84 bp of exon 3 precisely from the cDNA. Genomic Southern blots revealed a larger deletion with breakpoints within the introns flanking exon 3. This mutation suggests that the amino-terminal region of neurofibromin is functionally significant. When using this mutation to distinguish the wild type and mutant alleles, their expression could be analysed in neurofibroma fibroblasts, melanocytes from the unaffected skin, and those from a café-au-lait macule. In all these cell types, the products of both alleles were detected, confirming similar results obtained with a different NF1 gene mutation.

Adult↗
PubMed1994

ACE-inhibition with perindopril in essential hypertensive patients with concomitant diseases. The Perindopril Therapeutic Safety Collaborative Research Group.

PURPOSE: Many hypertensive patients have other, usually long-term diseases. Antihypertensive therapy may interfere with these diseases and their therapies. In the present study, the possible interactions of the ACE-inhibitor perindopril with several of the most common long-term diseases was evaluated. PATIENTS AND METHODS: In a multicenter, double-blind, randomized, placebo-controlled trial, the effect of perindopril was evaluated in 490 patients with mild essential hypertension and any one of the following concomitant diseases: hyperlipidemia, type II diabetes mellitus, ischemic heart disease, cardiac arrhythmia, peripheral arterial occlusive disease, nephropathy with proteinuria, chronic obstructive pulmonary disease, or degenerative joint disease treated with nonsteroidal anti-inflammatory drugs (NSAIDs). After a 3-week single-blind placebo run-in, the patients received either perindopril (4 mg/d) or matching placebo for 6 weeks. RESULTS: Blood pressure was effectively reduced by perindopril irrespective of the associated disease. The rate of spontaneously reported side effects was low. Treatment with perindopril was free from adverse interactions with the concomitant diseases and therapies. Moreover, favorable actions could be observed in patients with ischemic heart disease (reduction of maximal ST-segment depression during peak exercise and decrease in the number of angina attacks), in patients with proteinuria (decrease in albuminuria in patients with normal serum creatinine levels), and in patients with NSAID-treatment (increase in prostaglandin E2 concentration in gastric mucosa suggesting gastric cytoprotection). CONCLUSION: This trial shows that ACE-inhibition with perindopril represents a simple, safe, and effective short-term therapeutic option for the large proportion of patients with mild essential hypertension and concomitant diseases and therapies.

Adult↗
PubMed1994

Inhibition of fatty acid synthesis by stimulation of alpha- and beta-adrenergic receptors in human mononuclear leukocytes.

Selective alpha- and beta-adrenergic agonists and antagonists were used to determine the action of catecholamines on fatty acid biosynthesis in freshly isolated human mononuclear leukocytes. Incubation of cells for 22 h in a lipid-free medium resulted in a 4-fold increase in the incorporation of [14C]acetate into fatty acids. Addition of (-)-epinephrine in increasing concentrations to the incubation medium inhibited the rate of fatty acid synthesis by 42% at a concentration of 0.1 M. Similar effects were observed using (-)-norepinephrine and the beta-agonist isoproterenol. The catecholamine action was diminished by the unselective beta-blocker propranolol and mimicked by dibutyryl cyclic AMP. Since human mononuclear leukocytes possess beta 2-, but not beta 1-adrenoceptors (Brodde, Engel and Hoyer 1981), catecholamines may act via beta-adrenergic receptors of the beta 2-subtype. In addition, it appears that stimulation of alpha-adrenergic receptors inhibits fatty acid synthesis, too. In the presence of a beta-blockade by 1 microM propranolol, the alpha 2-agonist alpha-methylnorepinephrine, but not the alpha 1-agonist phenylephrine inhibited fatty acid synthesis rate. Accordingly, the epinephrine effect was attenuated by the alpha 2-antagonist yohimbine, but not by the alpha 1-antagonist prazosin. The results provide evidence that catecholamines may inhibit the synthesis rate of fatty acids by stimulation of both, beta 2- and alpha 2-adrenergic receptors.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1994

Effects of perindopril on serum lipids in hypertensive patients with hyperlipidemia.

The effect of the angiotensin-converting enzyme (ACE)-inhibitor perindopril on serum lipids and apolipoprotein concentrations were assessed in a multicenter, randomized, double-blind, placebo-controlled study in 51 hyperlipidemic patients treated for mild hypertension. Perindopril was given as a single morning dose (4 mg) for 6 weeks. During the treatment period, blood pressure (BP) was significantly (p < 0.001) reduced from 159/99 to 148/90 mm Hg by verum treatment and from 158/101 to 151/95 mm Hg (NS) by placebo treatment. Neither total cholesterol and triglycerides nor high-density-lipoprotein and apolipoprotein AI and B levels were significantly altered by drug treatment as compared with placebo. Although perindopril had good antihypertensive effect in patients with mild hypertension and hyperlipidemia, it had no adverse effects on lipid metabolism in these patients. Therefore, perindopril is recommended for antihypertensive treatment, especially in hypertensive patients with concomitant hyperlipidemia.

Adult↗