Heiner Kentrup

cDNA cloning and characterization of rat Clk3, a LAMMER kinase predominately expressed in testis.

A cDNA clone of a protein kinase with high similarity to the Clk (Cdc2-like kinases) subfamily was isolated from a rat brain library and characterized. Its deduced amino acid sequence exhibited a 99% identity with human Clk3 and was therefore designated rat Clk3. In addition to the protein kinase domain, the sequence (490 amino acids) comprises an N-terminal domain with a strikingly high portion of basic amino acids. A glutathione S-transferase fusion protein of Clk3 catalyzed autophosphorylation of the kinase but not phosphorylation of the exogenous substrates histone or casein. By Northern blot analysis of different rat tissues, mRNA of Clk3 was detected predominately in testis, suggesting that this kinase regulates a predominately testicular function.

Five novel mutations in the SCNN1A gene causing autosomal recessive pseudohypoaldosteronism type 1

BACKGROUND Pseudohypoaldosteronism type 1 (PHA1) is a monogenic disease caused by mutations in the genes encoding the human mineralocorticoid receptor (MR) or the α (SCNN1A), β (SCNN1B) or γ (SCNN1G) subunit of the epithelial Na(+) channel (ENaC). While autosomal dominant mutation of the MR cause renal PHA1, autosomal recessive mutations of the ENaC lead to systemic PHA1. In the latter, affected children suffer from neonatal onset of multi-organ salt loss and often exhibit cystic fibrosis-like pulmonary symptoms. OBJECTIVE We searched for underlying mutations in seven unrelated children with systemic PHA1, all offsprings of healthy consanguineous parents. METHODS AND RESULTS Amplification of the SCNN1A gene and sequencing of all 13 coding exons unraveled mutations in all of our patients. We found five novel homozygous mutations (c.587_588insC in two patients, c.1342_1343insTACA, c.742delG, c.189C>A, c.1361-2A>G) and one known mutation (c.1474C>T) leading to truncation of the αENaC protein. All parents were asymptomatic heterozygous carriers of the respective mutations, confirming the autosomal recessive mode of inheritance. Five out of seven patients exhibited pulmonary symptoms in the neonatal period. CONCLUSION The α subunit is essential for ENaC function and mutations truncating the pore-forming part of the protein leading to systemic PHA1. Based on current knowledge, the pulmonary phenotype cannot be satisfactorily predicted.

Determination of left atrial area and volume by cross-sectional echocardiography in healthy infants and children

Part 1 of the study measured the end-systolic and end-diastolic left atrial (LA) areas and volumes in 30 children through sector echocardiography, and compared these values with those obtained with biplane angiocardiography. A strong correlation exists between the LA area in the frontal plane as determined by apical (r greater than 0.91) and subcostal (r greater than 0.98) echocardiography on the one hand and by angiocardiography on the other. However, there is a slight underestimation of the LA area by the apical 4-chamber view. LA volume as determined by subcostal sector echocardiography in the frontal and sagittal plane also correlated well with LA volume calculated with biplane angiocardiography (r greater than 0.97). Part 2 of the study determined LA areas and volumes in 74 healthy newborns and infants by echocardiography and related them to body weight and body surface area, thus obtaining normal values for this age group. The relation of the LA area and volume measurements in newborns and infants to body weight or surface area was best described by a linear function. The mean of the percentage of systolic-diastolic area diminution was 53 +/- 6% for the apical 4-chamber view and 50 +/- 4% for the subcostal 4-chamber view. LA ejection fraction determined by the subcostal biplane volume measurements was 62 +/- 7% (mean +/- standard deviation). These values were independent of body weight or surface area.

Effect of Cisapride on Acid Gastro-Oesophageal Reflux during Treatment with Caffeine

About 50% of preterm infants and neonates receiving methylxanthines for respiratory stimulation will develop a pathological gastro-oesophageal reflux (GOR) pattern. In the face of potential GOR-related complications the effect of a concomitant treatment with a prokinetic agent, such as cisapride, should be evaluated. In this study 32 formerly preterm infants were studied simultaneously by 24-hour oesophageal pH monitoring and cardio-respirogram before the presumed end of caffeine treatment. In 14 of these infants a reflux index (RI; percentage of recording time) of more than 4% could be detected (pH <4). Ten of them were treated orally with cisapride (0.2 mg/kg t.i.d.). Data of pH monitoring, cardio-respirogram and caffeine serum concentrations were obtained before and 5 days after introducing cisapride. The RI and the frequency of GOR decreased significantly with cisapride. The steady-state serum concentrations of caffeine were not influenced by cisapride and the extent of periodic breathing remained unchanged. In conclusion, cisapride has a positive influence on GOR parameters during caffeine treatment without impairing the oral bioavailability or therapeutic effect of caffeine.

Verbesserung der Glukosetoleranz von Patienten mit Zystischer Fibrose unter pseudomonaswirksamer Chemotherpie

ZusammenfassungFragestellung. Für viele Patienten mit Mukoviszidose wird mit zunehmenden Lebensalter eine Störung der Glukosetoleranz bis hin zum manifesten Diabetes mellitus relevant und behandlungswürdig. Der Einfluss einer pseudomonaswirksamen i.-v.-Chemotherapie auf die Glukosehomöostase bei Zystischer Fibrose wurde untersucht. Patienten und Methode. Bei 14 Mukoviszidosepatienten im Alter von 7–35 Jahren wurden zu Beginn und am Ende einer 14-tägigen, routinemäßig durchgeführten, i.-v.-Chemotherapie ein oraler Glukosetoleranztest mit Erfassung des Blutzuckers und des Seruminsulins unternommen. Ergebnisse. Nach den Kriterien der American Diabetes Association hatten 3 der 14 Patienten eingangs eine gestörte Glukosetoleranz und weitere 3 einen Diabetes mellitus. Von diesen 6 Patienten hatten 4 zu Ende der Antibiotikatherapie eine normale Glukosetoleranz, 1 eine einschränkte Glukosetoleranz und 1 weiterer einen Diabetes mellitus. Gleichzeitig ging die Gesamtinsulinsekretion leicht zurück. Die maximale Insulinsekretion wurde im 2. Test früher erreicht, ohne dass eine Beschleunigung der frühen Insulinantwort festgestellt werden konnte. Schlussfolgerung. Die Therapie der chronischen bronchopulmonalen Infektion von Mukoviszidosepatienten mit pathologischer Glukosetoleranz oder Diabetes mellitus führt über eine Verbesserung der Insulinsensitivität, weniger der Dynamik der Insulinsekretion, zu einer Verbesserung der Glukosehomöostase. Die Erarbeitung diagnostischer Standards zur Früherfassung einer Glukosetoleranzstörung bei Zystischer Fibrose sollte die Abhängigkeit der Ergebnisse von der begleitenden Therapie berücksichtigen.AbstractBackground. For many patients with cystic fibrosis impaired glucose tolerance or even diabetes mellitus is becoming relevant with growing age. The influence of an anti-Pseudomonas chemotherapy on glucose homeostasis of cystic fibrosis patients was investigated. Patients and methods. In fourteen cystic fibrosis patients aged between 7 and 35 years glucose tolerance was tested by standard oral glucose tolerance test in the beginning and at the end of a routine anti-Pseudomonas chemotherapy of fourteen days. Beside the blood glucose serum insulin was determinated. Results. According to the criteria of the American Diabetes Association three of the fourteen patients had an impaired glucose tolerance and another three had diabetes mellitus when tested at the beginning of anti-Pseudomonas chemotherapy. In four of these six patients glucose tolerance was normal at the end of the chemotherapy. Of the remaining two patients one fulfilled the criteria for impaired glucose tolerance and one for diabetes mellitus. In these patients insulin secretion was lower in the second test. Peak insulin was reached earlier while there was no significant improvement of early insulin response. Conclusion. The treatment of chronic airway infection in cystic fibrosis patients with impaired glucose tolerance or diabetes mellitus results in an improvement of glucose homeostasis by a better insulin sensitivity and less by improvement of early insulin response. In developing diagnostic protocols for screening of cystic fibrosis-related diabetes mellitus the impact of the concomitant therapy on glucose homeostasis should be considered.