PubMed Health⌕ Search

Biomedical subjects

M Kasten

Publications and source records attributed to M Kasten.

At least 19 recordsLinked to original sources
PubMed2003

Increased frequency of migraine in narcoleptic patients: a confirmatory study.

Previously we have reported an increased prevalence of migraine in narcoleptic patients. Because of the theoretical and clinical implications of this finding we recruited an independent new study sample of 100 patients with proven narcolepsy and conducted a structured 26-item interview based on the international diagnostic criteria for headache disorders, the Kiel Headache Questionnaire. Narcolepsy symptoms were measured by means of the Stanford Centre for Narcolepsy Sleep Inventory. Migraine prevalence was twofold to fourfold increased in the narcoleptic patients and amounted to 44.4% in women and 28.3% in men. The onset of narcolepsy symptoms was 12.3 +/- 11.4 years before the onset of migraine symptoms. The results might be regarded as indicative of a common pathophysiological pathway relevant to both of the two disorders.

Adult↗
PubMed2001

ApoE polymorphisms in narcolepsy.

BACKGROUND: Narcolepsy is a common neuropsychiatric disorder characterized by increased daytime sleepiness, cataplexy and hypnagogic hallucinations. Deficiency of the hypocretin neurotransmitter system was shown to be involved in the pathogenesis of narcolepsy in animals and men. There are several hints that neurodegeneration of hypocretin producing neurons in the hypothalamus is the pathological correlate of narcolepsy. The ApoE4 allele is a major contributing factor to early-onset neuronal degeneration in Alzheimer disease and other neurodegenerative diseases as well. METHODS: To clarify whether the ApoE4 phenotype predisposes to narcolepsy or associates with an earlier disease onset, we have genotyped the ApoE gene in 103 patients with narcolepsy and 101 healthy controls. RESULTS: The frequency of the E4 allele of the ApoE gene was 11% in the patient and 15% in the control groups. Furthermore, the mean age of onset did not differ between the ApoE4+ and ApoE4- patient groups. CONCLUSION: Our results exclude the ApoE4 allele as a major risk factor for narcolepsy.

Journal Article↗
PubMed2001

Cdk10, a Cdc2-related kinase, associates with the Ets2 transcription factor and modulates its transactivation activity.

Cdk10 is a Cdc2-related kinase that may play a role in regulating the G2/M phase of the cell cycle. However little is known about the proteins that interact with this putative kinase and contribute to its function in the cell. We report in this study that Cdk10 interacts with the N-terminus of the Ets2 transcription factor, which contains the highly conserved Pointed domain and transactivation domain. The Pointed domain has been implicated in protein-protein interactions and we find that Ets2 requires an intact Pointed domain to bind Cdk10. The Pointed domain of Ets1 is highly similar to Ets2, however Cdk10 does not recognize Ets1 in a two-hybrid assay thereby demonstrating significant binding specificity on the part of Cdk10. We find that Cdk10 binds full length Ets2 in vitro and in vivo and inhibits Ets2 transactivation in mammalian cells.

Binding Sites↗
PubMed2001

A prepro-orexin gene polymorphism is associated with narcolepsy.

The orexin (hypocretin) neurotransmitter system was recently shown to be directly involved in the pathogenesis of narcolepsy in two animal models. Furthermore, decreased levels of orexin A in the CSF were shown in narcoleptic patients. To define any genetic contribution of orexin to the etiology of narcolepsy, the authors screened the entire prepro-orexin gene for mutations or polymorphisms in 133 patients suffering from narcolepsy. They report an association of a rare polymorphism in the prepro-orexin gene with narcolepsy in a cohort of 178 patients.

DNA Primers↗
PubMed2001

Increased prevalence of obesity in narcoleptic patients and relatives.

Increased Body Mass Indices (BMIs), increased prevalences of non insulin-dependent diabetes and sleep apnoe syndrome have been reported to be associated with narcolepsy. Our objective was to explore and possibly confirm the association of narcolepsy and increased BMI. In addition, we addressed the question whether increased BMIs also occur in relatives of narcoleptic patients. Together with narcolepsy-related clinical parameters we measured body weight and height of 132 narcoleptic patients who agreed to participate in our narcolepsy research program. In addition, 52 first degree relatives of 22 index patients, mostly from multiplex families, were included in the study. Data were compared to published general population surveys, recently conducted in Germany and Switzerland as well as to collective of 104 psychiatric inpatients. Narcoleptic patients had significantly increased BMIs in comparison to general populations or psychiatric controls. BMIs of first degree relatives were lower than those of index patients but significantly higher than those found in the general population. BMIs were not related to symptom severity or to medication status. Thus, the elevated BMIs appeared not to be secondary to behavioral consequences of narcolepsy but may reflect a trait at least partially common to index patients and relatives.

Adult↗
PubMed1999

Regulatory functions of Cdk9 and of cyclin T1 in HIV tat transactivation pathway gene expression.

HIV-1 gene expression relies upon a complex machinery that is primarily controlled by two viral regulatory proteins, Tat and Rev. Rev is involved in regulating post-transcriptional events of HIV-1 gene expression. The Tat protein transactivates transcription from the HIV-1 5' long terminal repeat (LTR) and acts in synergy with specific cellular factors. Recently, it has been shown that one set of these cellular factors is a protein kinase activity termed TAK (Tat-associated kinase), which activates transcription by hyperphosphorylation of the carboxyl-terminal domain (CTD) of the large subunit of RNA polymerase II. TAK also enhances transcription of HIV-2, together with the retroviral transactivator, Tat-2. The TAK activity appears to be related to the CTD kinase P-TEFb, which stabilizes transcription elongation of many genes and was originally isolated from Drosophila extracts. Both TAK and P-TEFb contain at least two subunits: the cyclin-dependent kinase, CDK9 (PITALRE), the catalytic subunit, and the regulatory subunit, cyclin T1. CDK9 and cyclin T1 are ubiquitous factors that affects many cellular processes, including cell differentiation and apoptosis. The involvement of TAK in HIV-1 and HIV-2 gene expression is an important aspect in the biology of these two retroviruses, and may lead to the development of novel antiretroviral drugs and/or gene therapy approaches for the treatment of patients with AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Alpha3beta4 subunit-containing nicotinic receptors dominate function in rat medial habenula neurons.

Regional-specific differences in nicotinic acetylcholine receptors (nAChRs) were examined using the whole-cell patch clamp technique in rat medial habenula (MHb) slices. The majority of cells in the ventral two thirds of the MHb responded robustly to local pressure application of nAChR agonists. Mean agonist potency profiles in the middle and ventral thirds of the MHb were similar: cytisine was the most potent agonist and DMPP the weakest, consistent with a significant contribution of the beta4 subunit to functional nAChRs in all areas of the MHb. In acutely isolated MHb neurons, the alpha3beta4-selective toxin alpha-CTx-AuIB (1 microM) reversibly blocked approximately 75% of the nicotine-induced currents, as expected for cells solely expressing alpha3beta4 nAChRs. However, the alpha3beta2-selective toxin, alpha-CTx-MII (100 nM), blocked a variable fraction (0-90%) of the MHb nicotinic response implying that beta2 subunits may contribute to some functional receptors. We suggest that the effects of alpha-CTx-MII may arise from interaction with alpha3beta2beta4 subunit-containing nAChRs. This idea is supported by the findings (1) that alpha-CTx-MII antagonizes receptors comprised of alpha3, beta2 and beta4 subunits in Xenopus oocytes, and (2) that a mutant alpha-CTx-MII toxin[H12A], which blocks alpha3beta2beta4 receptors but not alpha3beta2 or alpha3beta4 nAChRs, also reduces nicotinic currents in some MHb neurons. Overall these data imply that most functional nAChRs on MHb cells contain at least alpha3 and beta4 subunits, and that a variable subpopulation additionally contains the beta2 subunit.

Animals↗
PubMed1998

The RB family of cell cycle regulatory factors.

The intense investigation of the retinoblastoma "tumor suppressor family" members, pRb, pRb2/p130, and p107, has revealed impressive mechanisms evolved to safeguard development and homeostasis in higher eukaryotes. Members of the retinoblastoma family are involved in implementing and controlling three major aspects of cellular life: (1) proliferative growth, (2) differentiation, and (3) apoptosis. The activities of these proteins are highly regulated, enabling them to precisely establish control. The pRb protein is well understood in its regulatory abilities and is considered a classical tumor suppressor. The role of pRb2/p130 protein in growth suppression and its potential as a tumor suppressor have been established during the last few years. The p107 protein, structurally and functionally similar to, but yet distinctive from, pRb2/p130, is characterized at a more rudimentary level. In this report, we review the latest data on the retinoblastoma protein family and its web of regulatory mechanisms.

Animals↗
PubMed1989

A spectroscopic collagenase assay using peroxidase-labeled collagen.

A quantitative collagenase assay detecting soluble collagen fragments is described in this paper. Using the reagent N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP) type I collagen was conjugated with horseradish peroxidase (POD) which was employed as a reporter enzyme. POD was preferentially linked to the TC B fragment in a ratio of 1.4 mol POD/mol collagen. The conjugation product was immobilized on AH-Sepharose via carbodiimide coupling to form the final collagenase substrate used in the assay. POD activity in the supernatants caused by liberated TC B fragments exhibited a linear relationship for collagenase concentrations up to 100 micrograms/ml bacterial collagenase. Over an incubation period of 4 h the lowest detection limits found were 20 ng/100 microliters for bacterial collagenase and 60 ng/100 microliters for human leukocyte collagenase. Incubation of the assay mixture with 5 micrograms trypsin resulted in 3.8% of the activity released by the equivalent amount of leukocyte collagenase. The assay developed here has been shown to be sensitive and specific for collagenase, with the additional advantage that this method is suited for simple and economic handling.

Chromatography, Gel↗
PubMed1988

Interaction of polymorphonuclear leukocytes with cartilage in vitro. Catabolic effects of serine proteases and oxygen radicals.

The ability of purified PMN serine proteases as well as oxygen-derived free radicals (ODFR) generated by activated phagocytes to damage cartilage matrix has been thoroughly investigated in vitro. The question in the present study was the extent to which enzymatic and ODFR-mediated mechanisms can contribute to the degradation of bovine cartilage slices by zymosan-stimulated PMN. Tissue destruction as assessed by mechanical parameters of stability as well as by liberation of uronic acids from matrix proteoglycans was not inhibitable by the radical scavengers superoxide dismutase (SOD) and catalase (CAT), while serine protease inhibitors led to a significant reduction of matrix degradation. Thus an enzymatic mechanism may play a major part in PMN-induced cartilage damage. Besides this predominant role of especially serine proteases a direct, non-zymosan-dependent stimulatory effect of cartilage matrix on PMN to release elastase into the incubation medium was detected. Hence an as-yet unknown mechanism of PMN activation is indicated, while unspecific effects by bacterial contamination, complement factors, or endotoxin could be excluded as an explanation for the observed phenomenon.

Animals↗
PubMed1987

Purification and characterization of a serine proteinase inhibitor from human articular cartilage.

An inhibitor of serine proteinases from human articular cartilage was purified to homogeneity by sequential ultrafiltration and ion exchange chromatography on CM-Sephadex C-50. The apparent molecular weight of the cationic glycoprotein (pI greater than 10) was determined to be 16.5 X 10(3) by SDS gel electrophoresis. The inhibitor blocked the activity of leukocyte elastase, cathepsin G and trypsin but not leukocyte collagenase. In kinetic studies for the interactions with leukocyte elastase a firm enzyme-inhibitor binding was obtained. Amino acid analyses did not reveal homologies with other serine proteinase inhibitors already purified from human tissues.

Amino Acids↗
PubMed1987

Interference of cartilage surface with interaction of granulocyte elastase with alpha 1-proteinase inhibitor. An in vitro model of enzyme inhibition in the joint space.

Synovial fluids of patients suffering from rheumatoid arthritis contain elevated levels of granulocyte (PMN) elastase in complex with alpha 1-proteinase inhibitor (alpha 1-PI), whereas free-elastase activity is usually not detectable. This absence of free enzymatic activity in joint effusions has cast some doubt on the pathophysiological relevance of PMN elastase in inflammatory joint destruction. Our in vitro experiments using bovine nasal cartilage demonstrate that incubation with elastase and alpha 1-PI in equimolar concentrations to or even in excess of the serum proteinase inhibitor resulted in significant tissue destruction as assessed by histological staining for proteoglycans, release of uronic acid from the matrix and loss of mechanical stability. Though in the supernatants containing alpha 1-PI, free-elastase activity was not detectable, immunofluorescent staining for elastase evidenced penetration of the enzyme into the matrix. Simultaneous measurements of the incubation media employing a sandwich enzyme-linked immunoadsorption assay (ELISA) revealed PMN elastase in complex with alpha 1-PI but without correlation to the parameters of tissue degradation. In comparison with the results obtained using the chromogenic substrate Suc-Ala-Ala-Ala-pNA (SAPA) for titration of alpha 1-PI against elastase, the employment of cartilage matrix showed that a fourfold increase in inhibitor concentration was necessary to achieve 100% enzyme inhibition. Hence, cartilage surface obviously interferes with the interaction between alpha 1-PI and elastase. Measurements of elastase-inhibitor concentrations or free enzymatic activity in synovial fluid seem to have limited value in predicting cartilage destruction.

Animals↗