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Biomedical subjects

K Uhl

Publications and source records attributed to K Uhl.

At least 19 recordsLinked to original sources
PubMed2000

A newly created splice donor site in exon 25 of the MyBP-C gene is responsible for inherited hypertrophic cardiomyopathy with incomplete disease penetrance.

BACKGROUND: Hypertrophic cardiomyopathy is a myocardial disorder resulting from inherited sarcomeric dysfunction. We report a mutation in the myosin-binding protein-C (MyBP-C) gene, its clinical consequences in a large family, and myocardial tissue findings that may provide insight into the mechanism of disease. METHODS AND RESULTS: History and clinical status (examination, ECG, and echocardiography) were assessed in 49 members of a multigeneration family. Linkage analysis implicated the MyBP-C gene on chromosome 11. Myocardial mRNA, genomic MyBP-C DNA, and the myocardial proteins of patients and healthy relatives were analyzed. A single guanine nucleotide insertion in exon 25 of the MyBP-C gene resulted in the loss of 40 bases in abnormally processed mRNA. A 30-kDa truncation at the C-terminus of the protein was predicted, but a polypeptide of the expected size ( approximately 95 kDa) was not detected by immunoblot testing. The disease phenotype in this family was characterized in detail: only 10 of 27 gene carriers fulfilled diagnostic criteria. Five carriers showed borderline hypertrophic cardiomyopathy, and 12 carriers were asymptomatic, with normal ECG and echocardiograms. The age of onset in symptomatic patients was late (29 to 68 years). In 2 patients, outflow obstruction required surgery. Two family members experienced premature sudden cardiac death, but survival at 50 years was 95%. CONCLUSIONS: Penetrance of this mutation was incomplete and age-dependent. The large number of asymptomatic carriers and the good prognosis support the interpretation of benign disease.

Adult↗
PubMed2000

Genomic structure and fine mapping of the two human filamin gene paralogues FLNB and FLNC and comparative analysis of the filamin gene family.

The genomic structure of the filamin gene paralogues FLNB and FLNC was determined and related to FLNA. FLNB consists of 45 exons and 44 introns and spans approximately 80 kb of genomic DNA. FLNC is divided into 48 exons and 47 introns and covers approximately 29.5 kb of genomic DNA. A previously unknown intron was found in FLNA. The comparison of all three filamin gene paralogues revealed a highly conserved exon-intron structure with significant differences in the exons 32 of all paralogues encoding the hinge I region, as well as the insertion of a novel exon 40A in FLNC only. Gene organization does not correlate with the domain structures of the respective proteins. To improve candidate gene cloning approaches, FLNB was precisely mapped at 3p14 in an interval of 0.81 cM between WI3771 and WI6691 and FLNC at 7q32 in an interval of 2.07 cM between D7S530 and D7S649.

Animals↗
PubMed2000

Delayed-type hypersensitivity skin reactions caused by subcutaneous unfractionated and low-molecular-weight heparins: tolerance of a new recombinant hirudin.

BACKGROUND: Eczema-like infiltrated plaques at subcutaneous heparin injection sites are well-documented side effects of these anticoagulants. However, surgical interventions may be problematic if heparin is urgently needed in these patients. OBJECTIVE: The aims of this study were to perform extensive allergy skin testing in 24 patients, including a pregnant woman in whom subcutaneous infiltrated plaques developed after subcutaneous heparin injections, and to find safe therapeutic alternatives for this group of patients. METHODS: Patch, intradermal, and subcutaneous tests were performed with a panel of unfractionated heparins (UFHs), low-molecular-weight heparins (LMWHs), and heparinoids. Since 1997, we have also been performing allergy studies in 8 patients with lepirudin, a new recombinant heparinoid; tolerance of lepirudin was investigated by means of subcutaneous and intravenous injections. The allergy investigations in the pregnant woman were limited to patch tests with heparins and intradermal and subcutaneous tests with pentosanpolysulfate, which are not contraindicated during pregnancy. RESULTS: In our study population 19 of 23 patients were sensitized to all the UFHs and LMWHs tested when intracutaneous and subcutaneous test results were read at up to 96 hours. LMWH was found to be a possible substitute in 4 patients. Five patients were also sensitized to the heparinoid pentosanpolysulfate. Sensitization to the heparinoid danaparoid was observed in 12 of the 13 patients who were tested with this substance. The administration of an intravenous bolus containing a therapeutic dose of lepirudin after negative subcutaneous provocation was tolerated without any side effects in all 8 patients. The pregnant woman was sensitized to LMWH but tolerated subcutaneous pentosanpolysulfate without any side effects. CONCLUSION: Extensive allergy skin testing should be performed to find safe alternatives. With few exceptions, all patients react to both UFHs and LMWHs, as well as to danaparoid. The subcutaneous provocation test is the most reliable diagnostic measure. Intravenous lepirudin, and in some cases subcutaneous pentosanpolysulfate, appears to be a safe alternative in patients with eczema-like infiltrated plaques at subcutaneous heparin-injection sites.

Anticoagulants↗
PubMed1999

S100-Beta, melanoma-inhibiting activity, and lactate dehydrogenase discriminate progressive from nonprogressive American Joint Committee on Cancer stage IV melanoma.

PURPOSE: Monitoring advanced malignant melanoma, serum levels of S100-beta (S100beta) and melanoma-inhibiting activity (MIA) were assessed for the ability to discriminate progressive from nonprogressive disease. S100beta and MIA were supposed to be superior to conventional variables, such as lactate dehydrogenase (LDH) level. PATIENTS AND METHODS: Seventy-one patients with stage IV malignant melanoma according to the criteria of the American Joint Committee on Cancer (AJCC) were included in the study. Results of restaging examinations were used as an independent reference standard for diagnosing progressive disease, and S100beta, MIA, LDH level, and erythrocyte sedimentation rate (ESR) were determined in venous blood just before restaging. Sensitivities and specificities of the parameters were calculated by logistic regression analysis. Discrimination ability was assessed by Somers' D(xy) rank correlation and the area under the receiver-operating characteristic curve (ROC-AUC). RESULTS: All tested serum parameters were significantly elevated in patients with progressive disease. The highest sensitivities according to the established thresholds were found for S100beta and MIA (91% and 88%, respectively). LDH had the highest specificity (92%). ESR was dropped from the analysis because of low specificity. In calculating Somers' D(xy) and ROC-AUC values, S100beta, MIA, and LDH showed high discrimination ability. By multiple logistic regression, LDH was identified to be the only statistically significant marker for progressive disease. S100beta and MIA did not provide additional significant information because of their high correlation with LDH with respect to clinical outcome. CONCLUSION: Elevated serum levels of S100beta, MIA, and LDH indicate current disease progression in AJCC stage IV melanoma. LDH was the most relevant overall parameter.

Adult↗
PubMed1998

A high risk phenotype of hypertrophic cardiomyopathy associated with a compound genotype of two mutated beta-myosin heavy chain genes.

Hypertrophic cardiomyopathy (HCM) is a genetically and clinically heterogeneous myocardial disease that is in most cases familial and transmitted in a dominant fashion. The most frequently affected gene codes for the cardiac (ventricular) beta-myosin heavy chain. We have investigated the genetic cause of an isolated case of HCM, which was marked by an extremely severe phenotype and a very early age of onset. HCM is normally not a disease of small children. The proband was a boy who had suffered cardiac arrest at the age of 6.5 years (resuscitation by cardioconversion). Upon screening of the beta-myosin heavy chain gene as a candidate, two missense mutations, one in exon 19 (Arg719Trp) and a second in exon 12 (Met349Thr), were identified. The Arg719Trp mutation was de novo, as it was not found in the parents. In contrast, the Met349Thr mutation was inherited through the maternal grandmother. Six family members were carriers of this mutation but only the proband was clinically affected. Segregation and molecular analysis allowed us to assign the Met349Thr mutation to the maternal and the Arg719Trp de novo mutation to the paternal beta-myosin allele. Thus, the patient has no normal myosin. We interpret these findings in terms of compound heterozygosity of a dominant (Arg719Trp) and a recessive (Met349Thr) mutation. Whereas a single mutated Arg719Trp allele would be sufficient to cause HCM, the concurrent Met349Thr mutation alone does not apparently induce the disease. Nevertheless, it conceivably contributes to the particularly severe phenotype.

Age of Onset↗
PubMed1990

Isolation of isoproteins from monoclonal antibodies and recombinant proteins by chromatofocusing.

A fast protein liquid chromatographic method for the preparative separation of the various isoproteins is described. Highly purified human monoclonal antibodies, recombinant human superoxide dismutase and human superoxide dismutase from erythrocytes were used as starting material. The isoproteins were separated by chromatofocusing on Mono P columns. A very narrow pH gradient was applied to achieve complete separation of the isoproteins. The prepurification steps and the pretreatment of the samples to achieve optimum resolution are described in detail. The method is also applicable to extremely basic monoclonal antibodies (pI = 9). The successful separation was checked by isoelectric focusing in immobilized pH gradients (Immobilines). The future of these methods is discussed, because for many different biochemical and biophysical investigations pure and homogeneous isoproteins are necessary.

Antibodies, Monoclonal↗
PubMed1980

[On the question of endocrine side effects in patients on medication for renal calcium stone disease (author's transl)].

In patients with recurrent idiopathic nephrolithiasis we studied whether treatment with sodium cellulose phosphate leading to decreased intestinal calcium absorption could induce secondary hyperparathyroidism and whether thiazides which diminish calciuria would impair glucose tolerance. After removal of a actual kidney stone, 74 patients were treated for one year as follows: 25 (group 1) received conventional therapy (Nieron), 22 (group 2) received sodium cellulose phosphate, and 27 (group 3) received sodium cellulose phosphate plus hydrochlorothiazide. The period of one year was too short to evaluate the effectiveness of treatment regarding stone recurrence, however, a significant decrease in calciuria only was seen in group 3. With respect to the possibility to develop secondary hyperparathyroidism, group 2 and group 3 did not reveal any hints. In group 3, the thiazide treatment did not worsen glucose tolerance. Therefore, longer lasting studies with these drugs could be performed without evident danger to develop the mentioned side effects.

Calcium↗
PubMedDate not supplied

Effects of Plasmodium berghei infection on cytochromes P-450 2E1 and 3A2.

Metabolism and disposition of most drugs used to treat malaria are substantially altered in malaria infection. Few data are available that specify effects of malaria infection on drug metabolism pathways in humans or animal model systems. In this report, studies were undertaken to determine the effect of Plasmodium berghei infection on cytochrome P-450 (CYP450) 2E1 and 3A2-mediated metabolism and enzyme expression in rat liver microsomes. Malaria infection (MAL) resulted in significant decreases in total cytochrome P-450 content (56%, P < 0.05) and NADPH cytochrome P-450 reductase activity (32%, P < 0.05) as compared to control (CON) rats. Chlorzoxazone 4-hydroxylase activity (CYP2E1-mediated) showed no significant difference between CON and MAL microsomes while testosterone 6-beta-hydroxylase activity (CYP3A2-mediated) was reduced by 41% (P < 0.05) in MAL. Enzyme kinetic studies and immunoblot analysis indicate that the loss of activity for CYP3A2 in malaria infection is due to significantly decreased CYP3A2 protein expression. The altered expression of CYP450s in malaria infection should be taken into account when treating patients with malaria in order to minimize drug-drug interactions or toxicity.

Animals↗