Insulin resistance and membrane abnormalities.
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Diabetes Mellitus, Type 2↗
Biomedical subjects
P Dittrich
Publications and source records attributed to P Dittrich.
Differential accumulation of the transcripts of 22 novel protein kinase genes in Arabidopsis thaliana.
22 novel members of the Arabidopsis thaliana protein kinase family (AKs) were identified by using degenerate oligonucleotide primers directed to highly conserved amino acid sequences of the protein kinase (PK) catalytic domain. Of these 22 genes, 16 turned out to carry intron sequences. Homologies of AK sequences were detected to S-locus receptor protein kinases (SRKs) from Brassica spp., to SRK-like PKs from maize and A. thaliana and to several other receptor PKs from A. thaliana. Sequence similarity was also detected to Ca(2+)-dependent PKs (CDPKs) from rape and soybean, to SNF1 and to CDC2 homologues. The genomic organization and the accumulation of the mRNAs from these 22 AK genes were investigated.
Amino Acid Sequence↗
Endothelial dysfunction in hypertension.
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Albuminuria↗
Molecular cloning of a novel phytochrome gene of the moss Ceratodon purpureus which encodes a putative light-regulated protein kinase.
The phytochrome gene (phyCer) of the moss Ceratodon purpureus was isolated and characterized. phyCer is composed of three coding exons: exon I of 2035 bp, exon II of 300 bp and exon III of 1574 bp. The deduced polypeptide encoded by exon I and II exhibits substantial sequence homology to the conserved NH2-terminal chromophore domain of known phytochromes. In contrast, the COOH-terminal polypeptide encoded by exon III shows no sequence homology to any phytochrome molecule. phyCer most likely represents a single-copy gene and is expressed in a light-independent manner. From the DNA sequence analysis it can be deduced that the PhyCer polypeptide is composed of 1303 amino acids (including the starting Met) which predicts a molecular mass for PhyCer of 145 kDa. The polypeptide encoded in exon III exhibits striking homology within the 300 carboxy-terminal amino acids to the catalytic domain of protein kinases. The carboxy terminus of PhyCer was found to be most homologous to protein-tyrosine kinases of Dictyostelium discoideum and to the products of retroviral oncogenes which belong to the Raf-Mos serine/threonine kinase family. From the hydropathy profile PhyCer appears to be a soluble protein. The predicted structure suggests that PhyCer represents a soluble light-sensor protein kinase which is linked with a cellular phosphorylating cascade.
Amino Acid Sequence↗
LG 6-101 and LG 6-102, two new propafenone-related antiarrhythmic agents with good oral activity in rats.
LG 6-101 (1-[3-(2-methoxy-3-(2-methylpropylamino)-propoxy)-4-methyl- 2-thienyl]-3-phenyl-1-propanon hydrochloride; MW: 426.02) and LG 6-102 (2-(2-methoxy-3-propylamino-propoxy)-3-phenyl-propiophenon hydrochloride; MW: 391.92) are two new antiarrhythmic substances. They are structurally related to propafenone which is a widely used class Ic-antiarrhythmic drug. In man the oral bioavailability of propafenone is only about 5-40%. Therefore the development of compounds with similar mode of action but higher oral bioavailability seems to be meaningful. Both, LG 6-101 and LG 6-102 proved to be effective in isolated auricles and in experimental animals after intravenous administration. In the present study we tested the antiarrhythmic effects of LG 6-101 and LG 6-102 in rats after oral administration. Animals were treated with LG 6-101 (16, 32, 64, 128, 256 mg kg-1 bodyweight), LG 6-102 (4, 8, 16, 32, 64 mg kg-1 bodyweight) and propafenone (32, 64, 128, 256 mg kg-1 bodyweight) by gavage twice daily during 4 days. Both, LG 6-101 and LG 6-102 showed strong antiarrhythmic effects against arrhythmias induced on the fifth day by infusion of aconitine (10 micrograms kg-1 min-1). LG 6-102 was significantly more effective against cardiac arrest caused by infusion of aconitine (P less than or equal to 0.05) than LG 6-101. Both substances had good effects on the delay of ventricular premature beats.(ABSTRACT TRUNCATED AT 250 WORDS)
Aconitine↗
Renal function after tumor enucleation in a solitary kidney.
Whether extensive ablation of renal mass in humans leads to progressive glomerulosclerosis, proteinuria, and hypertension, as it does in animal models, is a matter of controversy. We have studied kidney function in six patients who underwent enucleation of a renal cell carcinoma in a solitary kidney. Four patients had previously had a nephrectomy. The two others each had one atrophic, nonfunctioning kidney. Serum creatinine levels before surgery were within the normal range (mean, 99.9 mumol/L [1.13 mg/dL]). Two weeks after tumor enucleation, creatinine levels were significantly higher than the preoperative values (mean, 124.6 mumol/L [1.41 mg/dL]). The follow-up period varied from 10 to 23 months. In all patients, kidney function improved during the following months. Serum creatinine levels nearly reached preoperative values in all patients (mean, 105.2 mumol/L [1.19 mg/dL]). None of the patients showed a progressive deterioration in renal function or proteinuria. We found a modest increase in blood pressure in two patients who had been normotensive before surgery. In conclusion, tumor enucleation in a solitary kidney did not cause significant renal injury to the remnant kidneys in our patients, at least in the short term.
Adult↗
[One-stage nose reconstruction using a forehead island flap].
Only part of the nasal skeleton remains after resection of extensive tumours penetrating all layers of the nose. In most cases a multiple-stage procedure is necessary for reconstruction of subtotal and total nasal defects. However, a one-stage reconstruction is needed in old and physically disabled patients who cannot undergo multiple operations for medical or social reasons. Three cases of nasal reconstruction with an inverted forehead island flap are reported. The skin of the inferiorly transposed flap serves as an inner lining for the reconstructed nose; the outer layer of the flap, which forms the surface of the reconstructed nose, is covered by a split thickness skin graft. The advantages of the method are: (1) one-stage reconstruction of the nose after tumour resection without further operations; and (2) the relative stability of the reconstructed nose without cartilaginous or bony implants.
Aged↗
Antiarrhythmic effects of two new propafenone related drugs. A study on four animal models of arrhythmia.
LG 6-101 (1-[3-(2-methoxy-3-(2-methylpropylamino)-propoxy)-4-methyl- 2-thienyl]-3-phenyl-1-propanone, hydrochloride) and LG 6-102 (2-(2-methoxy-3-propylamino-propoxy)-3-phenyl-propiophenone, hydrochloride) are two new antiarrhythmic drugs. They are structurally related to propafenone which is a widely used class 1 antiarrhythmic drug with relatively low bioavailability. Both substances were characterized in four animal models of arrhythmia and compared to propafenone. In isolated guinea pigs left auricles LG 6-101 and LG6-102 were about twice as effective as propafenone regarding the prolongation of the functional refractory period but did not decrease contractility more than propafenone. LG 6-101 was significantly more effective (p less than or equal to 0.002) than propafenone or LG 6-102 in delaying the onset of ventricular premature beats in ouabain induced arrhythmias in guinea pigs. In aconitine induced arrhythmias in rats, LG 6-101 and LG 6-102 did not differ in their antiarrhythmic effects from propafenone, whereas the protection against cardiac arrest was significantly (p less than or equal to 0.003) better for LG 6-101 than for propafenone or LG 6-102. In arrhythmias induced by occlusion of the left descending coronary artery in rats the drugs tested showed as good antiarrhythmic effects as propafenone. In this model the size of the ischemic area was also measured and LG 6-101 was the most effective drug in that respect. These results suggest that both LG 6-101 and LG 6-102 are potent antiarrhythmic substances which in some models were more effective than propafenone.
Aconitine↗
[Double photon absorptiometry in renal osteodystrophy].
Bone mineral content (BMC) of the lumbar spine (L2-L4), femoral neck, Ward's triangle and the trochanteric region was measured in 52 consecutive patients on maintenance haemodialysis. In the whole group the median BMC value as percentage of sex- and age-matched normal means was significantly decreased only in Ward's triangle (91.7%; p less than 0.02). In patients with chronic interstitial nephritis there was a significant decrease in bone density in Ward's triangle and the trochanteric region (p less than 0.02). There was no correlation between BMC and time on dialysis or intact parathormone. BMC value did not predict the type of renal osteodystrophy, according to Delling. 17 patients underwent a second investigation after one year. There was a slight fall in mean BMC of the lumbar spine (-0.9%) and Ward's triangle (-1.1%). The fall in mean BMC of the trochanteric region was pronounced (-3.2%). We believe that the observed low demineralisation, which was more pronounced in patients with interstitial nephritis, may be attributable to early and carefully monitored therapy with vitamin D metabolites.
Absorptiometry, Photon↗
Evaluation of combined effects in dose-response studies by statistical comparison with additive and independent interactions.
An improved method for the evaluation of combined drug effects by means of dose-response curves (DRCs) is described. A drug, A, was tested in the absence and presence of a fixed concentration of another drug, B, mainly in organ-bath experiments with smooth muscle strips from bovine coronary arteries and tracheal muscle. The results of such experiments are expressed in terms of percent of maximum response. Median values, rather than mean values, for each concentration of drug A were determined in order to allow a comparison of observed with expected frequencies above or below median DRCs of additive and independent interactions. This comparison was done with the chi-square goodness-of-fit statistic. Advantage was taken of the curve-fitting program ALLFIT to construct DRCs. However, the method presented does not require a computer program. The results indicate that additive interactions point to actions of drugs at the same site inasmuch as they differ significantly from independent interactions. Overadditive interactions reflect differences between the sites of action. This may either be due to independent actions or to some kind of synergistic "cooperativity", for example, sequential interaction. The effects of the latter significantly exceed the effects expected for independently interacting compounds. This method appears applicable to compounds exerting all kinds of responses that can be described by DRCs.
Animals↗
Evaluation of experimental combined toxicity by use of dose-frequency curves: comparison with theoretical additivity as well as independence.
Dose-frequency curves of toxic effects of a substance A were evaluated in the absence and in the presence of a fixed dose of a second substance B. Data were fitted by the curve-fitting program ALLFIT. Observed combined frequencies of A + B were compared statistically with the expected frequencies of additivity and (or) independence by the phi 2-square goodness-of-fit test. The theoretical dose-frequency curves expected for an additive response were obtained by a solely graphical procedure and the theoretical curves for independent effects were calculated from the effects of B and A at certain doses. In rotarod tests with trained mice, the combined deteriorating effect of ethanol and benzodiazepines were significantly over-additive. However, their lethal interaction appeared underadditive in mice. The lethal underadditive interaction of ethanol and phencyclidine (PCP) can be ascribed largely to independent actions of these compounds. Loss of righting reflex was additively enhanced by PCP, whereas PCP overadditively enhanced the effect of ethanol. The insecticidal action of the cholinesterase inhibitors malathion and parathion appeared additive and significantly different from independent interaction. A comparison of results from dose-response curves with isoboles showed good agreement. The method appears as an attractive alternative or as a complementary procedure to the isobolographic analysis. Combination experiments as described can be carried out and evaluated rather simply, with a minimum of expenditure and a maximum of information.
Animals↗
Renal disease in a patient with hereditary complete deficiency of the fourth component of complement.
Hereditary complete deficiency of the fourth component of complement (C4) is an extremely rare disorder with 17 cases reported so far. Twelve of these patients suffered from a systemic-lupus-erythematosus-like illness. The patient we here describe presented with severe Henoch-Schönlein purpura (HSP) at the age of 17. Immunofluorescence of a kidney biopsy showed granular deposits of IgG, IgA, IgM, C3 and fibrinogen in the mesangium and segmentally along the basement membrane. Six years later, the patient developed hypertension and nephrotic syndrome. Renal function deteriorated rapidly. He was on hemodialysis for 12 months and then received a cadaveric kidney graft. After 2 years of uncomplicated course, microhematuria and proteinuria developed. Immunofluorescence of a transplant biopsy was virtually identical to the pattern in the patient's own kidneys. We thus conclude that the patient had recurrence of his primary disease in the graft. Three and a half years after transplantation hemodialysis had to be restarted. This unique case supports the current view that deficiency of classical pathway components predisposes to the development of immune complex diseases and that the complement system is activated via the alternate pathway in HSP. Furthermore, we assume that complete C4 deficiency was the major cause for the recurrence and unfavorable outcome of HSP in the graft.
Adult↗
Ceftriaxone monotherapy for bacterial meningitis in children.
A total of 33 patients with bacterial meningitis were treated with single daily doses of ceftriaxone (CTR 100 mg/kg/day i.v.) for a median duration of 13 days. Pathogens isolated by culture and/or determined by latex agglutination were 15 Haemophilus influenzae b, 7 Neisseria meningitidis, 2 Streptococcus pneumoniae, 1 group B streptococcus, 2 Streptococcus viridans and 2 Staphylococcus epidermidis. In 4 cases a diagnosis of purulent meningitis could only be made by means of the inflammatory liquor parameters. All cerebrospinal fluid (CSF) drug levels even at the end of the dosing interval were at least 10-fold higher than the MICs of the respective bacterial isolates. The average penetration of CTR into the CSF was 6.6%. Within 12-46 h after the first dose, control spinal taps were performed. Cultures were sterile in all cases. Side effects encountered were diarrhea, exanthema, neutropenia and transient elevation of glutamic oxaloacetic transaminase, but none caused a change of therapy. One patient developed a biliary concrement. No patient died; 5 patients had prolonged fever (greater than 5 days), and 2 were left with persistent hearing deficiencies. CTR can be recommended as a safe and effective antibiotic agent for once daily treatment of bacterial meningitis in children.
Adolescent↗
The effect of concomitantly administered antacids on the bioavailability of lornoxicam, a novel highly potent NSAID.
Antacids are used in the treatment of upper gastrointestinal side-effects during therapy with nonsteroidal anti-inflammatory drugs (NSAIDs). Since pharmacokinetic interactions between antacids and NSAIDs have been reported, it was investigated whether aluminium and magnesium hydroxide (Maalox as oral suspension) or aluminium hydroxide and calcium carbonate (Solugastril as oral gel) influenced the bioavailability of Lornoxicam (rINN), a new potent NSAID from the chemical group of the oxicams. Eighteen male volunteers were given 4 mg of Lornoxicam as a film-coated tablet either alone or together with 10 ml of Maalox or 10 g of Solugastril in an open, randomized, three-way cross-over study. The levels of Lornoxicam in plasma were determined by HPLC following solid-phase extraction. It was found that none of the antacids changed significantly any of the following pharmacokinetic parameters: elimination half-life (t1/2 beta), concentration at peak time (Cmax), time to reach the peak (tmax) and area under the curve to infinity (AUCo-infinity). The results indicate that the concomitant administration of antacids did not influence the pharmacokinetic profile of Lornoxicam. Furthermore they confirm the short elimination half-life of Lornoxicam in man, which is markedly shorter than that of other oxicam-type compounds.
Adult↗
[Deglutition-induced supraventricular tachycardias].
We describe the cases of two patients who exhibited a supraventricular tachycardia induced by swallowing. In both cases we found a systemic hypertension, other cardiac or gastroesophagic abnormalities were absent. The electrophysiologic studies demonstrated in the first case a supraventricular tachycardia with 1 : 1 AV-conduction and an origin in the right atrium, in the second case an atrial tachycardia with AV-block originating in the right atrium too. The pathogenetic mechanism is discussed. In both cases after treatment with amiodarone a complete cessation of the tachycardias was reached.
Amiodarone↗
[Non-invasive morphologic and functional assessment of arteriovenous fistula in dialysis patients with duplex sonography].
In 61 patients with end-stage renal disease the results of 89 consecutive Duplex examinations of the arteriovenous fistulas used for haemodialysis were evaluated. The examinations were performed because of various problems concerning the vascular access or before the first puncture. Using 7.5 and 10.0 MHz probes (pulsed Doppler 3.0 and 4.5 MHz) the morphology and the function of the fistulas were evaluated. In 35 cases the results were normal, in a further 27 cases minor anomalies were seen without influencing the function. Complete thrombosis was observed in 7, partial thrombosis and severe stenosis in 4 cases each. Large aneurysms were documented in 6 examinations and in the remaining 6 the fistulas had not matured sufficiently within 4 weeks. The ultrasound results correlated well with consecutive angiography or surgery. The mean flow in normal fistulas was 514 +/- 223 ml/min. It was higher in PTFE shunts (614 +/- 242 ml/min) than in Cimino-Brescia fistulas (464 +/- 199 ml/min). Complications were observed more often in the PTFE group (63.9% vs. 58.5%). We think that Duplex sonography offers an accurate, non-invasive way to evaluate the morphology and the function of arteriovenous fistulas of patients on haemodialysis. This should therefore be performed as the first imaging method whenever problems concerning the fistula occur.
Adult↗
Evolution of the vacuolar H+-ATPase: implications for the origin of eukaryotes.
Active transport across the vacuolar components of the eukaryotic endomembrane system is energized by a specific vacuolar H+-ATPase. The amino acid sequences of the 70- and 60-kDa subunits of the vacuolar H+-ATPase are approximately equal to 25% identical to the beta and alpha subunits, respectively, of the eubacterial-type F0F1-ATPases. We now report that the same vacuolar H+-ATPase subunits are approximately equal to 50% identical to the alpha and beta subunits, respectively, of the sulfur-metabolizing Sulfolobus acidocaldarius, an archaebacterium (Archaeobacterium). Moreover, the homologue of an 88-amino acid stretch near the amino-terminal end of the 70-kDa subunit is absent from the F0F1-ATPase beta subunit but is present in the alpha subunit of Sulfolobus. Since the two types of subunits (alpha and beta subunits; 60- and 70-kDa subunits) are homologous to each other, they must have arisen by a gene duplication that occurred prior to the last common ancestor of the eubacteria, eukaryotes, and Sulfolobus. Thus, the phylogenetic tree of the subunits can be rooted at the site where the gene duplication occurred. The inferred evolutionary tree contains two main branches: a eubacterial branch and an eocyte branch that gave rise to Sulfolobus and the eukaryotic host cell. The implication is that the vacuolar H+-ATPase of eukaryotes arose by the internalization of the plasma membrane H+-ATPase of an archaebacterial-like ancestral cell.
Amino Acid Sequence↗
Increase in Hb-O2-affinity at moderate altitude (2000 m) in patients on maintenance hemodialysis.
Oxygen transport by erythrocytes was studied in eight patients on maintenance hemodialysis before, during and after a 2-week stay at an altitude of 2000 m. Dialysis was continued at that altitude. In all tests, blood samples were collected one or two days following hemodialysis. Pre-altitude tests: The patients exhibited anemia (hemoglobin concentration, Hb = 97.4 +/- 17 g/l). Due to an elevated red cell 2,3-diphosphoglycerate concentration (2,3-DPG) and mild metabolic acidosis, elevated standard and in vivo P50 values (pO2 at 50% oxygen saturation of hemoglobin, sO2) were measured. Altitude: Upon ascent, arterial pO2 decreased from 82 +/- 4 torr to about 60 torr, sO2 was lowered by 5%. After 2 weeks sojourn, pO2 and sO2 increased towards normal values. In contrast to healthy subjects, dialysis patients developed respiratory alkalosis (blood pH: +0.074) upon ascent. This caused a significant shift to the left of the oxygen dissociation curve (ODC), indicated by lowered in vivo P50-values (P50,vv,-2 torr). Red cell 2,3-DPG, P50,st (P50 at a blood pH = 7.4 and pCO2 = 40 torr), hemoglobin concentration and hematocrit showed a high day-to-day variability and did not change because of the altitude exposure. We interpret the increase of the oxygen affinity of hemoglobin in patients with renal anemia as beneficial, as it favors oxygen loading of hemoglobin in the lung during exposure to a hypoxic environment.
2,3-Diphosphoglycerate↗