[Neurodermatitis: do not scratch!].
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Child↗
Biomedical subjects
W Schulz
Publications and source records attributed to W Schulz.
UV light selectively coinduces supply pathways from primary metabolism and flavonoid secondary product formation in parsley.
The UV light-induced synthesis of UV-protective flavonoids diverts substantial amounts of substrates from primary metabolism into secondary product formation and thus causes major perturbations of the cellular homeostasis. Results from this study show that the mRNAs encoding representative enzymes from various supply pathways are coinduced in UV-irradiated parsley cells (Petroselinum crispum) with two mRNAs of flavonoid glycoside biosynthesis, encoding phenylalanine ammonia-lyase and chalcone synthase. Strong induction was observed for mRNAs encoding glucose 6-phosphate dehydrogenase (carbohydrate metabolism, providing substrates for the shikimate pathway), 3-deoxyarabinoheptulosonate 7-phosphate synthase (shikimate pathway, yielding phenylalanine), and acyl-CoA oxidase (fatty acid degradation, yielding acetyl-CoA), and moderate induction for an mRNA encoding S-adenosyl-homocysteine hydrolase (activated methyl cycle, yielding S-adenosyl-methionine for B-ring methylation). Ten arbitrarily selected mRNAs representing various unrelated metabolic activities remained unaffected. Comparative analysis of acyl-CoA oxidase and chalcone synthase with respect to mRNA expression modes and gene promoter structure and function revealed close similarities. These results indicate a fine-tuned regulatory network integrating those functionally related pathways of primary and secondary metabolism that are specifically required for protective adaptation to UV irradiation. Although the response of parsley cells to UV light is considerably broader than previously assumed, it contrasts greatly with the extensive metabolic reprogramming observed previously in elicitor-treated or fungus-infected cells.
3-Deoxy-7-Phosphoheptulonate Synthase↗
Stimulatory effects of cartilage-derived morphogenetic proteins 1 and 2 on osteogenic differentiation of bone marrow stromal cells.
Cartilage-derived morphogenetic proteins 1 and 2 (CDMP-1 and CDMP-2) are members of the bone morphogenetic protein (BMP) family which play an important role in embryonic skeletal development. Throughout adult life, bone marrow-derived precursor cells maintain their ability to differentiate into osteoblasts in response to local growth factors. This study examines the osteogenic potential of CDMP-1, CDMP-2, BMP-6 and osteogenic protein 1 (OP-1) in bone marrow stromal cells (BMSC) and investigates the endogenous expression of CDMPs/BMPs and their respective activin receptor-like kinase (ALK) receptors. A 4-day exposure of BMSC to CDMP-1, CDMP-2, BMP-6, and OP-1 under serum-free conditions stimulated the progression of the osteogenic lineage in a dose-dependent manner as evaluated by alkaline phosphatase activity and osteocalcin synthesis. In contrast to the BMPs, CDMP-1 and especially CDMP-2 were significantly less osteogenic, as confirmed by Northern blot analysis. Moreover, BMSC were shown to express endogenously CDMP-2, BMP-2 to -6 and ALK-1, -2, -3, -5 and -6. Phenotypic characterization of BMSC by RT-PCR showed transcripts of the fat marker adipsin and the prechondrocytic marker procollagen type IIA; however, we were unable to detect the mature cartilage markers, procollagen type IIB and aggrecan, even after growth factor treatment. Our data indicate that CDMP-1, CDMP-2, BMP-6 and OP-1 enhance the osteogenic phenotype in BMSC, with CDMPs being clearly less osteogenic than BMPs. The endogenous expression of a variety of CDMPs/BMPs and their respective ALK receptors, suggests a possible involvement of these growth factors in the osteogenic differentiation of bone marrow progenitor cells.
Activin Receptors↗
Insulin-like growth factor system components in hyperparathyroidism and renal osteodystrophy.
BACKGROUND: The insulin-like growth factor (IGF) system plays a key role in regulation of bone formation. In patients with renal osteodystrophy, an elevation of some IGF binding proteins (IGFBPs) has been described, but there is no study measuring serum levels of both IGF-I and IGF-II as well as IGFBP-1 to -6 in different forms of renal osteodystrophy and hyperparathyroidism. METHODS: In a cross-sectional study, we investigated 319 patients with mild (N = 29), moderate (N = 48), preuremic (N = 37), and end-stage renal failure (ESRF; N = 205). The ESRF group was treated by hemodialysis (HD; N = 148), peritoneal dialysis (PD; N = 27), or renal transplantation (RTX; N = 30). As controls without renal failure, we recruited age-matched healthy subjects (N = 87) and patients with primary hyperparathyroidism (pHPT; N = 25). Serum levels of total and free IGF-I, IGF-II, IGFBP-1 to -6, and biochemical bone markers including intact parathyroid hormone (PTH), bone alkaline phosphatase (B-ALP), and osteocalcin (OSC) were measured by specific immunometric assays. IGF system components and bone markers were correlated with clinical and bone histologic findings. Mean values +/- SEM are given. RESULTS: With declining renal function a significant increase was measured for IGFBP-1 (range 7- to 14-fold), IGFBP-2 (3- to 8-fold), IGFBP-3 (1.5- to 3-fold), IGFBP-4 (3- to 19-fold), and IGFBP-6 (8- to 25-fold), whereas IGFBP-5 levels tended to decrease (1.3- to 1. 6-fold). In contrast, serum levels of IGF-I, free IGF-I, and IGF-II remained constant in most patients. Compared with renal failure patients, pHPT patients showed a similar decline in IGFBP-5 levels and less elevated levels of IGFBP-1 (3.5-fold), IGFBP-2 (2-fold), IGFBP-3 (1.2-fold), and IGFBP-6 (4-fold) but no elevation of IGFBP-4 levels. In all subjects, free and total IGF-I levels showed significant negative correlations with IGFBP-1, IGFBP-2, and IGFBP-4 (that is, inhibitory IGF system components) and significant positive correlations with IGFBP-3 and IGFBP-5 (that is, stimulatory IGF system components). A positive correlation was observed between IGF-II and IGFBP-6. ESRF patients with mixed uremic bone disease and histologic evidence for osteopenia revealed significantly (P < 0.05) higher levels of IGFBP-2 and IGFBP-4 but lower IGFBP-5 levels. Histologic parameters of bone formation showed significant positive correlations with serum levels of IGF-I, IGF-II, and IGFBP-5. In contrast, IGFBP-2 and IGFBP-4 correlated positively with indices of bone loss. Moreover, dialysis patients with low bone turnover (N = 24) showed significantly (P < 0.05) lower levels of IGFBP-5, PTH, B-ALP, and OSC than patients with high bone turnover. CONCLUSION: Patients with primary and secondary hyperparathyroidism showed lower levels of the putative stimulatory IGFBP-5 but higher levels of IGFBP-1, -2, -3, and -6, whereas total IGF-I and IGF-II levels were not or only moderately increased. The marked increase in serum levels of IGFBP-4 appeared to be characteristic for chronic renal failure. IGFBP-5 correlated with biochemical markers and histologic indices of bone formation in renal osteodystrophy patients and was not influenced by renal function. Therefore, IGFBP-5 may gain significance as a serological marker for osteopenia and low bone turnover in long-term dialysis patients.
Adult↗
[Fluoride treatment of osteoporosis].
The development of anti-resorptive agents like vitamin D-hormones, or bisphosphonates offers a new outlook for the fluorine salt therapy. Numerous clinical studies have demonstrated increased bone mineral density in subjects treated with fluoride, however, the results of these studies were controversial. Fluoride has attracted attention as a therapeutic agent for osteoporosis because it is an effective stimulator of osteoblasts. Therefore fluoride seems to be useful, if the therapy is started in the early stages of osteoporosis, and especially in patients with intact trabecular bone. The greatest therapeutic benefit is seen with a low dose of fluoride in combination with vitamin D and calcium. This treatment will also reduce the well known side effects of fluoride. The treatment of osteoporosis could be improved with both, anti-resorptive agents and osteoblasts-stimulating agents like fluoride, but further research is needed to substantiate this therapeutical concept.
Anabolic Agents↗
Identification of the physiological promoter for spinocerebellar ataxia 2 gene reveals a CpG island for promoter activity situated into the exon 1 of this gene and provides data about the origin of the nonmethylated state of these types of islands.
In order to further use the spinocerebellar ataxia 2 (SCA2) promoter for transgenic mice models of "CAG repeat" neurodegeneration, different fragments of this 5' end were ligated into pGL3-Luc plasmid to obtain the better promoter-activity of the physiological promoter for SCA2. Base-par composition of the SCA2-5' region, and promoter prediction algorithms such as TSSW and TSSG, together with the high firefly luciferase expression after 48 hours of transient transfection in mammalian cells lines, showed a typical CpG island for promoter-activity. The promoter activity was specifically localized into the exon 1 of the SCA2 gene. The higher expression of firefly luciferase in the embryonal F9 cells by the use of SCA2 promoter, rather than by the use of CMV promoter may be related with the origin of the nonmethylated CpG island during the early embryogenesis. Analysis of the 5' region from HD gene revealed to a CpG island, which could be containing the physiological promoter for this gene.
Algorithms↗
[Renal osteopathy (ROP)].
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Chronic Kidney Disease-Mineral and Bone Disorder↗
Short-term hemodynamic, anti-ischemic, and antianginal effects of pirsidomine, a new sydnonimine.
Pirsidomine is a new sydnonimine compound in clinical development. As a prodrug, it is transformed into a nitric oxide-releasing metabolite in vivo. In animal tests there were no signs of tolerance with repeated administration. The short-term effects of 10, 20, and 40 mg of the drug on pulmonary hemodynamics and ischemic parameters were examined at rest and during exercise in a double-blind, randomized, placebo-controlled study. The study included 48 patients with documented coronary artery disease and exercise-induced ST-segment depression. Compared with the baseline test, there was a reduction of diastolic pulmonary artery pressure with pirsidomine at rest (placebo: -0.4 +/- 0.5 mm Hg; 10 mg: - 1.5 +/- 2.4 mm Hg; 20 mg: - 1.4 +/- 1.1 mm Hg; 40 mg: - 2.3 +/- 1.3 mm Hg [p < 0.05 ]) and at the highest comparable workload (placebo: -2.8 +/- 1.9 mm Hg; 10 mg: -7.3 +/- 6.8 mm Hg; 20 mg: -8.4 +/- 7.9 mm Hg [p <0.05]; 40 mg: -13.8 +/- 7.1 mm Hg [p <0.05]). ST-segment depression decreased at the highest comparable workload (placebo: -0.33 +/- 0.49 mm; 10 mg: -1.33 +/- 1.37 mm [p <0.05]; 20 mg: -1.33 +/- 0.83 mm [p <0.05]; 40 mg: -1.96 +/- 0.86 mm [p <0.05]) and total exercise time increased (placebo: 15 +/- 48 s; 10 mg: 98 +/- 126 s; 20 mg: 165 +/- 251 s [p <0.05]; 40 mg: 155 +/- 174 s [p <0.05]). Of 40 patients who complained of angina pectoris symptoms in the baseline test, 15 became free of angina pectoris with pirsidomine. Compared with placebo, blood pressure, heart rate during exercise, and cardiac output during exercise showed no significant change. Plasma concentration response relations of the metabolite revealed concentrations that caused a half-maximum effect of 6 ng/ml, 13 ng/ml, 20 ng/ml, and 28 ng/ml in reduction of ST-segment depression, reduction of diastolic pulmonary artery pressure, relief of angina pectoris symptoms, and an increase in exercise duration, respectively. Thus, pirsidomine is an effective anti-ischemic and antianginal agent. A significant preload reduction was obtained with plasma metabolite concentrations lower than those necessary to achieve a satisfactory antianginal effect.
Aged↗
Combining structural analysis of DNA with search routines for the detection of transcription regulatory elements.
MOTIVATION: Analysis of unannotated genomic sequences for regulatory regions depends on a reliable recognition of individual cis-acting elements. Since some of them have a very low conserved sequence pattern, additional criteria are required. RESULTS: Using molecular modelling techniques, we have created a complete database for the conversion of base sequences into profiles of structural parameters of DNA. On this basis, search routines can be developed that scan for profile matches. They may be used instead of or, probably most appropriate in most cases, in combination with conventional sequence pattern searches.
Algorithms↗
Fixed dose combinations of ACE inhibitors.
First-line antihypertensive monotherapy is effective in reducing blood pressure to within the normal range in approximately 50% of patients. Normalisation in the remaining patients may require a combination of two or more drugs. This review considers the clinical efficacy and tolerability of combinations involving angiotensin-converting enzyme (ACE) inhibitors. The efficacy of combinations with diuretics or calcium antagonists, as initial therapy or in patients with inadequate responses to monotherapy, has been demonstrated in many trials. With combination therapy, normalisation rates approaching 80% can be achieved using submaximal doses of both components. Therapy with both combinations is well tolerated; with ACE inhibitors reducing the diuretic metabolic effects or counteracting some calcium antagonist-associated vasodilatory effects. Data on ACE inhibitors with beta-blockers are limited. When patients respond inadequately to first-line monotherapy, the increasing availability of drug combinations will allow individual selection of the most appropriate combination, taking account of additional risk factors and concomitant disease.
Adrenergic beta-Antagonists↗
Double-blind comparison of antihypertensive treatment with ramipril and piretanide, given alone or in combination.
In a double-blind, randomized, multicenter trial, we compared the efficacy and safety of the fixed combination of 5 mg ramipril and 6 mg piretanide and the respective component monotherapies in hypertensive patients [supine diastolic blood pressure (DBP) 100-114 mm Hg]. After a single-blind run-in period on placebo, 611 patients were randomized to ramipril (n = 209), piretanide (n = 201), or the combination therapy (n = 201). At randomization, the three groups had the same characteristics (51% men, age 55 +/- 10 years, BP 165 +/- 18/104 +/- 6 mm Hg). At 4 weeks, BP decreased more with combined therapy than with monotherapy. As compared with piretanide monotherapy, the gain in the antihypertensive effect in the supine position averaged 2.1 mm Hg [90% confidence interval (CI) -0.8-5.0 mm Hg; p = 0.07] systolic BP (SBP) and 1.9 mm Hg (CI 0.3-3.5 mm Hg, p = 0.02) DBP and, as compared with ramipril monotherapy, these differences were 4.2 mm Hg (CI 1.3-7.0 mm Hg, p = 0.008) and 2.0 mm Hg (CI 0.5-3.6 mm Hg, p = 0.009). The incidence of adverse events (AE) and the changes in biochemical measurements were similar in the three treatment groups with the exception of spontaneously reported polyuria and serum uric acid concentration. Polyuria was reported more frequently (p < 0.001) with piretanide therapy (n = 23) and combined therapy (n = 19) than with ramipril therapy (n = 1).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Pharmacokinetics and pharmacodynamics of ramipril and piretanide administered alone and in combination.
The pharmacokinetics and pharmacodynamics of single oral doses of 5 mg ramipril and 6 mg piretanide administered separately and in combination were determined in a single blind, randomised, 3-period cross-over study in 24 healthy male volunteers. The peak plasma concentrations of ramipril and ramiprilat increased slightly (from 11.9 to 14.8 ng/ml, and from 6.39 to 8.96 ng/ml, respectively) as did the area under the plasma concentration-time curve of ramipril (0-4 h) and ramiprilat (0-24 h) (from 15.8 to 19.8 ng.ml-1.h, and from 63.4 to 74.6 ng.ml-1.h, respectively). The urinary excretion of ramiprilat also rose (from 6.82 to 7.73% of dose) following simultaneous treatment with piretanide. These effects were probably due to reduced first-pass metabolism of ramipril/ramiprilat to inactive metabolites. The blood pressure lowering effect, the time course of inhibition of ACE activity in plasma and the concentration-response relationship for the inhibition of plasma ACE activity were not affected by piretanide. The peak plasma concentration of piretanide was somewhat reduced (from 285 to 244 ng/ml) following simultaneous treatment with ramipril. No other pharmacokinetic parameter was affected. Piretanide increased urine flow, and sodium, chloride and potassium excretion, especially during the first 2 hours following administration. These pharmacodynamic parameters were not affected by ramipril. Thus, simultaneous administration of single oral doses of ramipril and piretanide caused modest changes in the peak and average plasma concentrations of both drugs, which did not lead to detectable alterations in the pharmacodynamic parameters measured in healthy volunteers.
Adult↗
Treponema pallidum rare outer membrane proteins: analysis of mobility by freeze-fracture electron microscopy.
Freeze-fracture and deep-etch electron microscopy were used to investigate the molecular architecture of the Treponema pallidum outer membrane (OM). Freeze-fracture electron microscopy of treponemes freshly harvested from rabbit testes revealed that the intramembranous particles (IMPs) in both the concave and convex OM leaflets were distributed into alternating areas of relatively high and low particle density; in many OM fractures, IMPs formed rows that ran either parallel to or obliquely across the fracture faces. Statistical analysis (runs test) confirmed that the IMPs were nonrandomly distributed in both OM leaflets. Examination of deep-etched specimens revealed that the particles observed in freeze-fractured OMs also were surface exposed. Combined analysis of deep-etched and cross-fractured treponemes revealed that the OM particles were located in regions of the OM away from the endoflagella and closely apposed to the cytoplasmic membrane-peptidoglycan complex. When treponemes were incubated for extended periods with heat-inactivated immune rabbit syphilitic serum, no alteration in the distribution of OM IMPs was detected. In further experiments, approximately 1:1 mixtures of T. pallidum and Escherichia coli or separate suspensions of the nonpathogenic Treponema phagedenis biotype Reiter were fixed at 34 degrees C or after cooling to 0 degree C (to induce lateral phase separations that would aggregate IMPs). Only particles in the T. pallidum OM failed to aggregate in cells fixed at the lower temperature. The combined data suggest that the mobility of T. pallidum rare OM proteins is limited, perhaps as a result of interactions between their periplasmic domains and components of the peptidoglycan-cytoplasmic membrane complex.
Animals↗
Diagnostic and therapeutic approaches to aluminium overload in dialysed patients--representative study by questionnaire in West German dialysis units in 1989-1990.
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Aluminum↗
[Radioimmunoscintigraphy of colorectal tumors with 99m-Tc marked CEA antibodies. Indications and clinical value].
In Germany, radioimmunoscintigraphy (RIS) (scintigraphic, specific imaging of benign and malignant diseases by radioactively labelled monoclonal antibodies) has been employed since 1985 in clinical trials involving patients with colorectal cancer. After proving successful for identifying primary tumors, RIS is now increasingly being used for the early diagnosis of recurrent and metastatic lesions. In this prospective study involving 75 patients with colorectal tumors confirmed by endoscopy and biopsy, it was shown that RIS using the SPECT technique with 99m-Tc-labelled monoclonal CEA antibodies has a sensitivity of 78% in the detection of local recurrent disease in cases in which diagnostic work-up has been inconclusive.
Adult↗
[The size of the liver metastases in a low metastatic count. A quantitative study of postmortem livers].
In this postmortem study 34 livers with one or few "large" metastases (greater than 1 cm) were investigated for the presence of synchronous "small" metastases (less than 1 cm). A total of 671 metastases were investigated morphometrically. Of these, 134 were large and 537 were small according to the given definitions. The relation of large to small metastases was 1:4 and turned out to be relatively constant in most cancer types, except for colorectal cancers. The latter showed a relation of 1:1.6 which is more favourable for the detection of occult small secondaries. The results are discussed in the view of the preoperative diagnosis of liver metastases.
Autopsy↗
[Preventive tuberculosis vaccination--pro and contra].
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BCG Vaccine↗
Response of coronary arteries to nitrates, the EDRF-donor SIN-1, and calcium antagonists.
Intracoronary drug administration is an important tool to study coronary effects without interaction of systemic effects. The difficult methodological aspects and the results of clinical trials in which the effects of vasodilating drugs were evaluated with respect to coronary dilatation are reviewed. Major (coronary substrate, study design) and minor (measuring devices, methods of evaluation) methodological problems make it difficult to precisely evaluate pharmacological effects such as dose-response relationship, duration of action, and selective responses, and to compare the effects of different drugs. From a clinical point of view, knowledge of the maximal effect (EDmax) in coronary stenoses and the duration of action is essential. NO-donors tend to act stronger than CA-channel blockers which may be attributable to their different modes of action. Among those NO-donors investigated, SIN-1 showed stronger effects than nitroglycerin. Only with SIN-1 were maximal effects obviously achieved. The additional administration of nitroglycerin or nisoldipine never led to a more prominent dilatation. In coronary stenoses, the underlying morphology causes a wider range of responses than is seen in normal segments: deendothelialized stenoses with high coronary tone show a larger dilatation, while fully sclerotic stenoses may not react.
Calcium Channel Blockers↗