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Biomedical subjects

A Richter

Publications and source records attributed to A Richter.

At least 199 records · Page 11Linked to original sources
PubMed1997

Synthesis and in vitro trypanocidal activity of some novel iron chelating agents.

This report describes the syntheses and in vitro trypanocidal activity of a number of iron (III) chelators against epimastigotes of Trypanosoma cruzi. The compounds examined included a number of lipophilic N-alkyl derivatives of 2-ethyl- and 2-methyl-3-hydroxypyrid-4-ones, N,N'-bis(o-hydroxybenzyl)-(+/-)-trans-1,2-diaminocyclohexane, cyclotetrachromotropylene and four commercially available carboxy derivatives of pyridine, pyrazine, and pyarazole. Benznidazole, the drug clinically used in the treatment of Chagas' disease in humans, served as standard. All compounds were screened in vitro against Trypanosoma cruzi epimastigotes at 50 and 100 micrograms/ml for 72 h of exposure. At 100 micrograms/ml dosage, at least 4 compounds exhibited high epimastigote growth inhibition (65-69%) comparable to benznidazole (72%), whereas 9 compounds showed moderate to fair activity (53-64%) in the in vitro assay. At the lower concentration (50 micrograms/ml), the inhibitory activity of the best of these compounds was reduced significantly (39-48%) compared to the standard drug (59%). The activity of all the carboxylic acids remained in the lower range (4-25%). It is hypothesized that the enhanced activity of some of the compounds is due to their increased lipophilicity which enables them to successfully pass through the cellular membrane of Trypanosoma cruzi epimastigotes. The trypanocidal activities of the most effective compounds were significantly reduced when tested in the presence of added ferric ion.

Animals↗
PubMed1997

The in vitro biological activities of synthetic 18-O-methyl mycalamide B, 10-epi-18-O-methyl mycalamide B and pederin.

Mycalamides A and B, which were originally isolated from a marine sponge, show close structural similarity to the insect toxin pederin, and exhibit potent cytotoxicity and antitumour activity. Detailed investigation of the clinical potential of these compounds has been hampered because they are available in only minute quantities from natural sources. We now describe the biological activities of 18-O-methyl mycalamide B, 10-epi-18-O-methyl mycalamide and pederin, all prepared by total synthesis. The activities of 18-O-methyl mycalamide B and pederin were virtually indistinguishable when evaluated in DNA or protein synthesis assays, and in cytotoxicity assays using human carcinoma cell lines (IC50s 0.2-0.6 nM). In all assays, 10-epi-18-O-methyl mycalamide B was 10(3) times less toxic than its diastereoisomer, demonstrating that the cytotoxicity of 18-O-methyl mycalamide B is inseparable from its ability to inhibit protein synthesis. Short-term exposure of squamous carcinoma cells to 18-O-methyl mycalamide B or pederin caused an irreversible inhibition of cellular proliferation and induced cellular necrosis. In contrast, the antiproliferative effects of the compounds on human fibroblasts were reversible and there was no evidence of necrosis. Demonstration that 18-O-methyl mycalamide B and the synthetically less complex molecule, pederin, show some tumour cell toxicity indicates that this novel class of compounds should be subjected to preclinical evaluation.

Animals↗
PubMed1997

[Results and experiences of a two-year investigation in the use of sonographic pregnancy control in sows at different stages of gestation].

This paper presents the results of 16,592 pregnancy diagnoses in 4086 gilts and 12,506 sows. The animals were scanned transcutaneously between days 20 and 110 after mating or insemination (m/i). Animals being obviously pregnant or nonpregnant were scanned once, whereas sows which could not be recognized definitely as pregnant or not were characterized as animals with equivocal status and examined once again seven to 14 days later. Between days 20 to 23 after m/i pregnant sows were obviously identified to 99.5% (3336/3352). Nonpregnant sows were clearly recognized to 97% (3145/3243) between days 20 and 28 after m/i. Beginning on days 26 and 32, respectively, and later in gestation, pregnant and nonpregnant sows could be diagnosed to 100%. Confirmed through the re-examination, altogether nine (of 16 ambiguous pregnant sows) and 19 (of 97 ambiguous nonpregnant sows) animals were diagnosed false pregnant and nonpregnant, respectively. To avoid incorrect diagnoses or assessments, numerous phenomena should be attended. On days 20 to 23 after m/i, sows which did not establish pregnancy often show middle- or nonechogenic areas in the uterus and/or between the uterus loops. Since this can hardly be distinguished from pregnant uterine structures, it is recommended to examine the ovaries as well. Pregnant animals with signs of embryonic death should be grouped separately and examined twice, because it is unpredictable whether the pregnancy will stay intact or not. In conclusion, the ultrasonography is well suitable to detect pregnant and nonpregnant sows and can be applied very early in gestation.

Age Factors↗
PubMed1997

[Incidence, diagnosis, therapy and subsequent fertility in goats with hydrometra].

The hydrometra is a comparatively common disease in dairy goats. The etiology and pathophysiology of this pathological uterine condition has not been completely clarified yet. In the present study 143 cases of hydrometra were found in 2434 goats which had been subjected to pregnancy diagnosis with transrectal ultrasonography for three years. The mean incidence was 5.78%. The uterus of the goats was filled with a clear or slightly turbid fluid which contained small blobs to a certain extent. The amount of the aseptic fluid in the uterus varied from 0.25 to 8.3 l. Hydrometra occurred in goats which had been mated as well as in those which had not been mated. Hydrometra may also be accompanied by embryonic/fetal mortality. The incidence of hydrometra was significantly increased in older does and in does which had been mated after estrus synchronisation with gestagens and PMSG. Out of the breeding season the incidence was higher than during the breeding season. The breed of the does and the milk yield did not influence the incidence of hydrometra. The application of prostaglandin analoques performed a luteolysis and the cloudburst in the goats with high efficiency. After therapy the performance in breeding was significantly decreased. The performances improved when does were mated in a longer distance to the disease. The goats showed a high risk of developing hydrometra again.

Animals↗
PubMed1996

Friedreich ataxia in Acadian families from eastern Canada: clinical diversity with conserved haplotypes.

The gene for Friedreich ataxia (FRDA), an autosomal-recessive neurodegenerative disease, remains elusive. The current candidate region of about 150 kb lies between loci FR2 and F8101 near the D9S15/D9S5 linkage group at 9q13-21.1. Linkage homogeneity between classical FRDA and a milder, slowly progressive Acadian variant (FRDA-Acad) has been demonstrated. An extended D9S15-D9S5 haplotype (C6) predominates in FRDA-Acad chromosomes from Louisiana. We studied 10 Acadian families from New Brunswick, Canada. In eight families, affected individuals conformed to the clinical description of FRDA-Acad; in one, 2 sibs presented with spastic ataxia (SPA-Acad). In the last family, 2 sibs had FRDA-Acad, and one had SPA-Acad. We found that SPA-Acad is linked to the FRDA gene region. The C6 haplotype and a second major haplotype (B7) were identified. The same ataxia-linked haplotypes segregated with both FRDA-Acad and SPA-Acad in two unrelated families. The parental origins of these haplotypes were different. Our observation of different phenotypes associated with the same combination of haplotypes may point to the influence of the parent of origin on gene expression, indicate the effect of modifier genes, or reflect the presence of different mutations on the same haplotypes. Our findings underline the need to investigate families with autosomal-recessive ataxias for linkage to the FRDA region, despite lack of key diagnostic manifestations such as cardiomyopathy or absent deep-tendon reflexes.

Canada↗
PubMed1996

Abnormal c-fos expression in the lateral habenula during dystonic attacks in a hamster model of idiopathic dystonia.

The genetically dystonic hamster (dtsz), an animal model of idiopathic dystonia, displays sustained twisting movements and postures either spontaneously or in response to mild stress. In the present study the expression of c-fos immunoreactive neurons (Fos-ir), used as an indicator of neuronal activity, was investigated within various brain regions in dtsz hamsters and non-dystonic control hamsters. Under baseline condition, i.e. in the absence of dystonia, the expression of Fos-ir did not reveal any differences between dtsz hamsters and controls. However, in response to mild stress several brain regions, particularly the lateral habenula (LHb), exhibited differences in c-fos induction in dtsz hamsters and controls. Whereas in the LHb the expression of Fos-ir was markedly enhanced in controls, it showed almost no increase in dystonic hamsters, indicating impaired neuronal activity. Since the lateral habenula receives major input from the basal ganglia via the entopeduncular nucleus, the present data might indicate that basal ganglia are involved in the dystonic syndrome in mutant hamsters.

Animals↗
PubMed1996

The significance of valine 33 as a ligand-specific epitope of transforming growth factor alpha.

Although binding of epidermal growth factor (EGF) and transforming growth factor alpha (TGFalpha) to the EGF receptor (EGFR) is mutually competitive, their binding is not identical, and their biological activities are not always equivalent. To probe for ligand-specific interactions, we have synthesized analogues of TGFalpha with modifications to the residue lying between the fourth and fifth cysteines (the "hinge"). Although this residue lies in a structurally conserved region of the protein, it is not conserved within the EGFR ligand family. Our results show that in TGFalpha there is a preference for a bulky hydrophobic hinge residue; this contrasts with EGF, for which a hydrogen bond donor functionality is preferred. Sequence analysis of the human EGFR ligands revealed that the nature of the hinge residue correlated with the sequence in the B-loop beta-sheet. As this region is an important determinant in recognition of TGFalpha by the chicken EGFR, we assessed the mitogenicity of the TGFalpha hinge mutants, as well as the other EGFR ligands, using chicken embryo fibroblasts. The preference of the chicken EGFR for TGFalpha hinge mutants with hydrophobic side chains paralleled that of the human EGFR. Betacellulin and heparin-binding EGF-like growth factor also possess an hydrophobic hinge; both were at least as potent as TGFalpha for chicken embryo fibroblasts. EGF and amphiregulin, both with hydrogen bond donor functionalities at their hinge, displayed markedly decreased in potency by comparison with TGFalpha. We propose that EGFR ligands can be subclassified into TGFalpha-like and EGF-like and that this is of functional significance, identifying a potential mechanism whereby EGFR can discriminate between its ligands.

Amino Acid Sequence↗
PubMed1996

Alt et al. reply.

Explore the source record for details and available documents.

Journal Article↗
PubMed1996

Antidystonic effects of L-type Ca2+ channel antagonists in a hamster model of idiopathic dystonia.

The effects of selective L-type Ca2+ channel antagonists on severity of dystonia were investigated in a mutant hamster model of idiopathic generalized dystonia. Nimodipine and diltiazem significantly decreased the severity of dystonia. Nimodipine was more potent in this respect and did not cause any behavioral side effects. The present data therefore suggest that Ca2+ channel antagonists could be useful in the treatment of idiopathic dystonia. The antidystonic effect of diltiazem and nimodipine may be based on their antidopaminergic action. However, the lack of significant effects of the L-type channel agonist (+/-)-BAY k-8644 (1-5 mg/kg; methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoro-methylphenyl) -pyridine-5-carboxylate)) on severity of dystonia may indicate that voltage-gated Ca2+ channels are not critically involved in the pathophysiology of dystonia in mutant hamsters.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1996

Increased levels of kynurenic acid in brains of genetically dystonic hamsters.

Recent pharmacological studies have shown antidystonic effects of NMDA and non-NMDA receptor antagonists in an inbred line of Syrian hamsters (dt(sz)) with primary generalized dystonia, i.e. a neurological syndrome of sustained muscle contractions which occurs in the absence of any pathomorphological alterations. This prompted us to examine the levels of kynurenic acid (KYNA), the endogenous broad spectrum antagonist of the excitatory amino acid receptors. The concentrations of KYNA were determined by HPLC in forebrain, cerebellum, brainstem and plasma in dystonic hamsters and age-matched non-dystonic controls. Dystonia in mutant hamsters is transient and disappears completely at the age of 70 days. In order to examine if neurochemical changes are associated with dystonia, KYNA was determined at the age of maximum severity (30 days) and after remission (70 days). The levels of KYNA were significantly increased in forebrain, cerebellum and brainstem (37-130 percent) in dystonic hamsters at the age of maximum severity of dystonia (30 days of life) compared to both a genetically related non-dystonic inbred line and a non-related outbred line of hamsters. The increase of KYNA in brain regions was accompanied by enhanced plasma levels. However, there was no correlation between brain and plasma levels. Since the changes in KYNA levels disappeared in parallel with dystonia (70 days), the present data provide further evidence that abnormal activity of excitatory amino acids may be pathogenetically involved in dystonia in mutant hamsters. With regard to the recent finding of antidystonic effects of glutamate receptor antagonists the increased levels of kynurenic acid may be interpreted as a counteracting process to an overactivity of the glutamatergic system.

Aging↗
PubMed1996

Properties of the human nuclear protein p85Mcm. Expression, nuclear localization and interaction with other Mcm proteins.

Recently we identified a cDNA fragment encoding a conserved part of a new human minichromosome maintenance (Mcm) protein, provisionally termed P1.1Mcm3. Here, we report that the protein is most highly related to a yeast cell-division-cycle protein, Cdc47, encoded by the open reading frame YBR1441 on chromosome 11 of Saccharomyces cerevisiae. The human protein migrates on a polyacrylamide gel with an apparent molecular mass of 85 kDa and shares areas of significant similarity with the Mcm family of replication proteins. It is, therefore, designated as p85Mcm. Microscopic immuno-fluorescence studies revealed that protein p85Mcm is located in the nuclei of interphase cells, but is evenly distributed throughout the cell during mitosis. The amounts of p85Mcm do not significantly change during the cell cycle, but mRNA levels rise with the beginning of the S phase. However, in vitro differentiation of HL60 cells results in a striking decrease of both p85Mcm mRNA and protein levels, suggesting a role for p85Mcm in proliferating, but not in differentiated cells. Under physiological salt conditions, p85Mcm is a component of a high molecular-mass complex including other Mcm proteins. The complex dissociates at high ionic strength giving rise to stable subcomplexes, one of which contains protein p85Mcm together with Mcm proteins hCdc21 and p1O5Mcm.

Amino Acid Sequence↗
PubMed1996

Effects of the 5-HT2 receptor antagonist ritanserin on halothane-induced increase of inositol phosphates in porcine malignant hyperthermia.

Recent studies have shown a significant increase of inositol phosphates (IPs) in skeletal muscle during episodes of halothane-induced malignant hyperthermia (MH) in pigs. After treatment with dantrolene and disappearance of MH crisis the IP concentrations returned to basal levels. In order to examine if the increase of IPs during halothane-induced MH may be related to an enhanced IP synthesis in response to activation of 5-HT2 (5-hydroxytryptamine) receptors, the effects of ritanserin, a selective 5-HT2 receptor antagonist, on IP levels were investigated. Biopsies of skeletal muscle of the hindlimbs were obtained in random order and IPs were determined in homozygous MH-susceptible (MHS) and MH-non-susceptible (MHN) swine in the following order: (1) basal, (2) after treatment with ritanserin (2.0 mg/kg), (3) after halothane challenge (3 vol% for 20 min). Basal concentrations of all IPs were higher in MHS than in MHN swine. Ritanserin did not cause any significant changes of IP levels compared to the basal concentrations in MHS and MHN pigs. In MHS pigs, ritanserin did not prevent a halothane-induced MH-crisis. After halothane challenge, 1,3,4-IP3, 1,3,4,6-IP4 and 1,3,4,5-IP4 levels were increased in MHS (during MH crisis) vs. basal concentrations, whereas no changes were found in MHN pigs. Since the increases of IP levels in MHS pigs during MH crisis found in the present study were comparable to those without pretreatment with ritanserin, shown by recent studies, it may be concluded that ritanserin does not prevent the increase of IPs during a halothane-induced MH. Thus, the present data indicate that increases of IP levels during halothane-induced MH in swine are due to other mechanisms than 5-HT mediated enhancement of IP synthesis.

Anesthetics, Inhalation↗
PubMed1996

[Immune paralysis in acute pancreatitis--HLA-DR antigen expression on CD14+DR+ monocytes].

UNLABELLED: Determination of the prognosis in acute cases of pancreatitis, particularly in its serious and necrotizing form, still presents problems. Patients require intensive care and suffer from severe septic complications that do not correlate with pancreatic enzyme levels (amylase lipase). METHOD: Thirty-one patients with acute pancreatitis were examined: group 1 -- necrotizing pancreatitis (lethal outcome n = 7); group 2 -- necrotizing pancreatitis (surviving n = 12); group 3 edematous pancreatitis (surviving n = 12). For 11 consecutive days after admission to a clinical ward, flow cytometric check-ups were carried out daily on all patients. The antigen-presenting system HLA-DR antigen expression on monocytes and C-reactive protein were examined. RESULTS: When groups 1 and 2 were compared with group 3, HLA-DR values on monocytes were significantly different following the third day after admission (P < 0.01). Comparison of groups 1 and 2 were significant from the third day of observation (P < 0.001). During all 11 days of observation, patients in group 1 remained in immune paralysis (HLA-DR expression on monocytes CD14+DR+20% antigen density). All of these patients had infected necroses. Patients in group 2 overcame their immune paralysis. HLA-DR depression of monocytes and a long-standing high C-reactive protein level are almost certain predictors of a fatal outcome in cases with severe pancreatitis. A routine passage cytometric check/FACS to determine the activity of monocytes (HLA-DR) is of prognostic significance.

Adult↗
PubMed1996

Octreotide treatment in patients with necrotizing pancreatitis and pulmonary failure.

OBJECTIVE: To determine the efficiency of intravenous infusion of octreotide in the treatment of patients with severe pancreatitis and pulmonary failure. DESIGN: Prospective, case-control study. SETTING: Intensive care unit of a university hospital. PATIENTS: Treatment group: 39 patients with necrotizing pancreatitis were selected for the study. In all, pulmonary failure developed under conservative treatment and surgical intervention had been necessary because of local (abscess, necrosis) or systemic (systemic inflammatory response syndrome) complications. The outcome was prospectively followed up until death or discharge from the hospital. CONTROL GROUP: 54 case-control matched patients with acute necrotizing pancreatitis and pulmonary failure, who had not been treated with octreotide. INTERVENTION: Each patient in the treatment group received 100 micrograms intravenous octreotide three times daily for 10 days, in addition to the standard intensive care therapy. RESULTS: The groups (octreotide group, control group) were highly comparable with regard to age (mean age: 54, 51 years), sex, severity of illness (Acute Physiology and Chronic Health Evaluation II score: 27, 27), etiology of pancreatitis, and pretreatment at the time of admission to the intensive care unit. There was no difference in the development of renal, hepatic, gastrointestinal, hemostatic, neurologic, or local complications. But the frequency of the adult respiratory distress syndrome (18 vs 40%; p < 0.05) and circulatory shock (51 vs 87%; p < 0.05) was significantly lower in the treatment group. Furthermore, mortality was 26% (10 of 39 patients) in the octreotide group and 61% (33 of 54 patients) in the control group (p < 0.01). CONCLUSION: The results of our case-control study showed a beneficial effect of octreotide in patients with severe necrotizing pancreatitis and pulmonary failure. Based on these data, a prospective, double-blind, placebo-controlled study should be performed to evaluate these results.

APACHE↗
PubMed1996

Quantitative autoradiography reveals regionally selective changes in dopamine D1 and D2 receptor binding in the genetically dystonic hamster.

Dystonia has been proposed to be caused by abnormal input from thalamus to premotor cortex due to altered activity of the striatum projecting by way of the globus pallidus and substantia nigra pars reticulata to the thalamus. However, in the case of idiopathic dystonia, i.e. the most common form of dystonia in humans, there is only limited evidence to support such a neuroanatomic concept. In view of the problems of studying the pathophysiology of idiopathic dystonia in patients, genetically determined animal models of idiopathic dystonia may be used as a practical means of studying brain dysfunctions involved in this movement disorder. The genetically dystonic hamster is an animal model of idiopathic dystonia that displays sustained abnormal movements and postures either spontaneously or in response to mild environmental stimuli. Autoradiographic analysis of dopamine D1 receptor density, using the ligand [3H]SCH 23390, revealed significant decreases of D1 binding in several parts of the striatum and substantia nigra pars reticulata of dystonic hamsters. Binding of the D2 ligand [3H]YM-09151-2 was decreased in the dorsomedial caudate-putamen, but increased in nucleus accumbens. In most other sites studied, no significant changes were found in either [3H]SCH 23390 or [3H]YM-09151-2 binding. By studying groups of dystonic hamsters in the absence and presence of dystonic attacks, it was shown that most changes in D1 and D2 binding were not secondary to abnormal movement but rather due to the dystonic condition of the animals. The study provides evidence of altered dopamine receptor binding in dystonia and confirms the concept that basal ganglia dysfunction may be a primary component of dystonia.

Animals↗