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Biomedical subjects

A Richter

Publications and source records attributed to A Richter.

At least 271 records · Page 15Linked to original sources
PubMed1994

The use of transcutaneous photodynamic therapy in the prevention of adjuvant-enhanced arthritis in MRL/lpr mice.

The use of transcutaneous photodynamic therapy (PDT) has been investigated in the prevention of adjuvant enhanced arthritis in MRL/lpr mice. Mice receiving adjuvant were treated with PDT at 10-day intervals starting on the day of adjuvant administration. PDT was carried out by intravenous injection of the photosensitizer, benzoporphyrin derivative-monoacid ring A, followed by its transcutaneous activation with light. Adjuvant-injected animals displayed a delayed onset and reduced incidence and severity of arthritis when compared to untreated animals. Most importantly, inflammatory structural damage to cartilage and bone tissues was prevented by PDT. PDT was found to have no adverse effects on animals as assessed by mitogen responses, hematopoiesis, and serum enzyme levels. As mitogen-activated MRL/lpr splenocytes were shown to be more susceptible to in vitro photodynamic treatment, it is postulated that the observed effects were the result of selective destruction of adjuvant-activated lymphocytes in the circulation and/or joints.

Administration, Cutaneous↗
PubMed1994

Lack of prophylactic or therapeutic efficacy of 5-HT2A receptor antagonists in halothane-induced porcine malignant hyperthermia.

During halothane-induced malignant hyperthermia (MH), plasma levels of serotonin (5-hydroxytryptamine, 5-HT) increase in pigs. Administration of 5-HT agonists which stimulate the 5-HT2A subreceptor triggers MH in susceptible pigs. A possible link between MH induced by 5-HT2A receptor agonists and halothane could be an increase of second messengers such as phosphoinositides (inositol polyphosphates), which have recently been implicated in the abnormal regulation of skeletal muscle calcium release in MH. If so, antagonists of 5-HT2A receptors which are linked to phosphoinositide turnover should be capable of preventing, retarding or attenuating halothane-induced MH. This possibility was investigated in the present study in MH susceptible pigs, using dantrolene for comparison, Development of MH triggered by a halothane challenge (inhalation of 3% halothane for 15 min) was completely prevented by dantrolene, 3.5 mg/i.v., whereas the 5-HT2A receptor antagonists ritanserin (0.5-10 mg/kg i.v.) or ketanserin (0.5-10 mg/kg i.v.) exerted no prophylactic effect. In pigs in which dantrolene, ritanserin or ketanserin where given in combination with hyperventilation after development of MH, dantrolene exerted therapeutic efficacy, whereas neither ritanserin nor ketanserin were effective treatments. The data indicate that 5-HT is not critically involved in the mechanisms of halothane-induced MH, at least under the conditions of the present experimental study.

Animals↗
PubMed1994

Mouse genes encoding DNA topoisomerase I.

We have initiated a genetic analysis of the physiologically important enzyme type I DNA topoisomerase in mouse. The exon-intron structures of the 5' part and the 3' part of the active gene, Top-1, were determined and shown to be quite similar to those of the previously determined human gene TOP1. The active mouse gene was mapped to the distal Chromosome (Chr) 2. In addition, the mouse genome contains one truncated processed topoisomerase-I-related pseudogene (retroposon), Top-1ps, on Chr 16. The Top-1ps locus, together with the immunoglobulin-lambda-light-chain locus, defines an additional conserved linkage group common to murine Chr 16 and human Chr 22, the site of the human pseudogene TOP1P2. The mapping data suggest that the pseudogene was established before mammalian radiation. Structural features, shared by the mouse and the human pseudogene, support this possibility.

Animals↗
PubMed1994

Plasma concentration of elastase-alpha 1-proteinase inhibitor complex in surfactant-treated preterm neonates with respiratory distress syndrome.

Although exogenous surfactant replacement improves respiratory distress syndrome (RDS) of immature neonates, it may not prevent subsequent lung damage and development of bronchopulmonary dysplasia associated with polymorphonuclear neutrophil (PMN)-activation. We therefore wanted to assess whether surfactant administration would be associated with activation of circulating PMNs. Since elastase-alpha 1-proteinase inhibitor (E-alpha 1-PI) has proved to be a sensitive indicator of intravascular PMN activation, we studied E-alpha 1-PI plasma concentration in preterm neonates during the treatment of RDS with a bovine surfactant preparation (group I: n = 23). Results were compared with those from a retrospective control group treated by ventilation alone (group II: n = 13), and with a reference group of 92 newborns (group III). Following surfactant administration, median E-alpha 1-PI concentration increased significantly (day 1 80.5 vs Day 2,234 micrograms.l-1), and exceeded the upper limit of the reference range of 274 micrograms.l-1 in seven patients, with a maximal value of 1,881 micrograms.l-1 after multiple surfactant administrations. In contrast, 12 infants from Group II showed no increase in median E-alpha 1-PI levels (Day 1,107 vs Day 2,107 micrograms.l-1), and remained within the reference range (Day 1,125 micrograms.l-1; Day 2,107 micrograms.l-1) of the 92 newborns without respiratory impairment, infection, birth-trauma or asphyxia. From these results, it is concluded that surfactant may trigger a transient, mainly local, inflammatory response, reflected by increased levels of E-alpha 1-PI, and may exert a dose-related pathogenic influence on the course and prognosis of RDS.(ABSTRACT TRUNCATED AT 250 WORDS)

Bronchopulmonary Dysplasia↗
PubMed1994

Forms of physiological aliasing within the heart rate fluctuations by higher frequent respiratory movements.

In adult conscious rabbits, the respiratory frequency (RF) is almost always higher than half the heart rate (HR) Thus, no "classical" respiratory sinus arrhythmia occurred. But now, slow HR fluctuations, which were not synchronous to the respiratory rhythm but effected by it, occurred systematically. By cholinergic blockade, these slow HR fluctuations could be essentially reduced but not completely abolished. Up to now, this phenomenon was not be taken into account in the analysis of HR fluctuations. Thus misinterpretations are inevitable. During general anaesthesia, the RF decrease up to 2 RF < HR, and now classical respiratory sinus arrhythmia occurred which also could be essentially reduced but not completely abolished by vagal blockade. The possibilities of calculation of such slow HR fluctuations were shown, as those during 1/2 HR < RF < 3/2 HR and RF > 3/2 HR.

Acid-Base Equilibrium↗
PubMed1994

Antagonistic effects of deoxycholic acid and butyrate on epithelial cell proliferation in the proximal and distal human colon.

Colon cancer is a major malignant disease in Western countries where--for unknown reasons--it occurs predominantly in the distal colon. Fecal secondary bile acids are an important risk factor whereas butyrate may be a protective agent. In this in-vitro study biopsies from the normal ascending and sigmoid colon of 24 subjects were incubated with 5 microM DCA (proximal vs. sigmoid colon) or DCA and DCA plus 10 mM butyrate (DCA vs. DCA/BUT, only sigmoid colon) and cell proliferation measured by bromodeoxyuridine immunohistochemistry. Whole crypt labeling index (LI) after DCA-incubation was similar in the ascending (15.4%) and sigmoid colon (15.4%) indicating an equal mucosal response of the two colonic subsites to DCA. Compared to DCA/BUT, incubation with DCA alone resulted in a significantly higher LI for the whole crypt (16.8 vs. 11.4%, p < 0.01) and for the upper 40% of the crypt (4.5 vs. 0.8%, p < 0.01). This may indicate a butyrate-related decrease in the susceptibility for colon cancer. Since luminal concentrations of DCA and butyrate are influenced by dietary interventions the findings of this study may be of particular interest with regard to colon cancer development and prevention.

Butyrates↗
PubMed1993

Morphological and morphometric measurements in colorectal mucosa of subjects at increased risk for colonic neoplasia.

Measurements of intermediate biomarkers have recently increased, attempting to provide useful information about cancer risk. We report morphological findings in rectal mucosal biopsies from patients at low risk and at high risk for colorectal cancer. Rectal biopsies were analyzed from fourteen Seventh-Day Adventist (SDA) subjects at low risk and from twenty-seven members of families with hereditary nonpolyposis colonic cancer (HNPCC) at higher risk. The following measurements were made on rectal crypts: length of crypts, numbers of cells, diameter of the surface, middle and base of the crypts and infiltration of inflammatory cells into the lamina propria. Findings indicated morphological differences in normal-appearing rectal mucosa of individuals in the HNPCC group compared with SDA subjects (P < 0.05). They included shorter crypts with fewer epithelial cells and increased cellular infiltration in the mucosa of HNPCC subjects compared with SDA subjects, suggesting minimal inflammation, and an early stage of crypt atrophy in the rectal mucosa of subjects at higher risk for colonic neoplasia.

Colonic Neoplasms↗
PubMed1993

The atypical neuroleptic, clozapine, exerts antidystonic activity in a mutant hamster model. Comparison with haloperidol.

The effects of the atypical neuroleptic clozapine were studied in an inbred line of Syrian golden hamsters with generalized dystonia, i.e. a frequent movement disorder in humans. The effects of clozapine were compared with those of the classical neuroleptic, haloperidol. Clozapine, 7.5-20 mg/kg i.p., potently reduced the severity of dystonic attacks in the mutant hamster model, but induced marked sedation at these doses. Lower doses were ineffective. Haloperidol, 0.5 mg/kg i.p., significantly reduced the severity of dystonia without marked sedation. The finding that clozapine possesses antidystonic potency similar to that of haloperidol in a genetic model of dystonia might suggest that this atypical neuroleptic is an effective alternative in the treatment of dystonic patients who respond to neuroleptics, particularly because of the clinical evidence that clozapine is almost devoid of extrapyramidal adverse effects.

Animals↗
PubMed1993

The glycine/NMDA receptor ligand (+)-HA-966 but not D-cycloserine has potent antidystonic efficacy in a genetic animal model of dystonia.

The effects of R-(+)-HA-966 ((+)-3-amino-1-hydroxypyrrolid-2-one), a low-efficacy partial agonist of the glycine modulatory site of the NMDA receptor complex, were studied in an inbred line of Syrian golden hamsters with generalized dystonia, a frequent movement disorder in humans. The effects of R-(+)-HA-966 were compared with those of D-cycloserine, a glycine/NMDA receptor ligand with higher intrinsic activity. R-(+)-HA-966, 30-60 mg/kg i.p., potently reduced the severity of dystonic attacks in the mutant hamster model of dystonia without inducing any behavioural adverse effects. D-Cycloserine did not exert antidystonic activity at i.p. doses of 10-40 mg/kg, which might be due to its much higher intrinsic activity at the glycine site. The data indicate that the antidystonic effect of (+)-HA-966 is related to antagonism of NMDA receptor-mediated excitatory neurotransmission.

Animals↗
PubMed1993

Proliferation of human colonic mucosa as an intermediate biomarker of carcinogenesis: effects of butyrate, deoxycholate, calcium, ammonia, and pH.

A high-fat/high-protein diet has been reported to promote colon cancer by increasing luminal bile acid and ammonia concentrations, whereas butyrate, calcium, and low colonic pH may have protective effects. In this study, bromodeoxyuridine labeling of colonic epithelium was investigated after incubating biopsies from the ascending colon of 70 patients with HCl (20 mM, pH 6.0), butyric acid (H-BUT, 20 mM, pH 6.0), sodium butyrate (Na-BUT, 10 mM, pH 8.0), CaCl2 (10 mM), calcium butyrate (Ca-BUT, 10 mM), ammonium butyrate (NH4-BUT, 10 mM), deoxycholic acid (DCA, 5 microM), and a combination of DCA and Na-BUT (DCA/Na-BUT, 5 microM/10 mM). Compared to NaCl, H-BUT and Na-BUT increased the whole crypt-labeling index significantly, whereas HCl and CaCl2 had no effect. Reduced labeling, however, occurred with Ca-BUT in comparison to equimolar Na-BUT. No differences in the labeling indexes were found for NH4-BUT compared to Na-BUT, but increased labeling with expansion of the proliferative zone to the upper 40% of the crypt was seen with DCA compared to NaCl. DCA-induced hyperproliferation was abolished by coincubation with DCA/Na-BUT. These data suggest that butyrate, calcium, and DCA have complex influences on mucosal proliferation. Since luminal concentrations of these compounds are influenced by dietary interventions, the findings of this study may be of particular interest with regard to colon cancer development and prevention.

Adult↗
PubMed1993

The kappa-opioid receptor agonist, U50,488H, exerts antidystonic activity in a mutant hamster model of generalized dystonia.

The kappa-opioid receptor agonist, U50,488H (trans-(+-)-3,4-dichloro-N-methyl-[2-(1-pyrrolidinyl)-cyclohexyl]- benzeneacetamide), has recently been reported to induce dystonia after s.c. administration of 5-10 mg/kg in guinea pigs. The dystonic movements observed in response to U50,488H resembled those previously reported to occur spontaneously or in response to mild environmental stimuli in a mutant hamster model of paroxysmal generalized dystonia. This prompted us to study the effects of opioid receptor antagonists and of U50,488H in the mutant hamster model. Naloxone and naltrexone, 1 and 10 mg/kg i.p., were either ineffective or tended to induce prodystonic effects in the mutant hamsters. In contrast, U50,488H markedly reduced the severity of dystonic movements at doses of 1-10 mg/kg s.c. In non-dystonic hamsters, U50,488H reduced locomotor activity but did not produce dystonic-like symptoms. The data from mutant hamsters demonstrate that stimulation of kappa-opioid receptors is a powerful means of attenuating dystonic movements in a genetic animal model of idiopathic dystonia. The antidystonic effects of U50,488H might relate to interactions between kappa-opioid receptors and dopaminergic and glutamatergic neurotransmission.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1993

The AMPA receptor antagonist NBQX exerts antidystonic effects in an animal model of idiopathic dystonia.

The effects of the AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline) were studied in an inbred line of Syrian golden hamsters with paroxysmal dystonia. The severity of dystonia in these mutant hamsters was significantly reduced by NBQX at doses of 10-20 mg/kg i.p. Coadministration of the transport inhibitor probenecid prolonged the antidystonic action of NBQX, indicating that NBQX may be rapidly eliminated by a process sensitive to probenecid. A similar potent and long-lasting antidystonic effect was obtained when NBQX was administered as an aqueous suspension rather than an aqueous solution, which may be explained by retarded absorption of NBQX after its injection as a suspension. The antidystonic activity of the AMPA antagonist NBQX may indicate that an overactivity of excitatory acidergic neurotransmission is involved in the pathophysiology of dystonia in genetically dystonic hamsters.

Animals↗
PubMed1993

Dye-mediated photolysis is capable of eliminating drug-resistant (MDR+) tumor cells.

We evaluated the potential role of photoradiation therapy with a benzoporphyrin derivative, monoacid ring A (BPD-MA), and dihematoporphyrin ether (DHE), for the ex vivo purging of residual tumor cells from autologous bone marrow (BM) grafts. BPD-MA and DHE photosensitizing activity was tested against two human large-cell lymphoma cell lines and colony-forming unit-leukemia (CFU-L) derived from patients with acute myelogenous leukemia (AML). In mixing experiments, 4-log elimination of tumor cell lines was observed after 1 hour of incubation with 75 ng/mL of BPD-MA or 30 minutes of treatment with 12.5 micrograms/mL of DHE followed by white light exposure. By comparison, using the same concentration of BPD-MA, the mean recovery of normal BM progenitors was 4% +/- 0.8% (mean +/- SD) for granulocyte-macrophage colony-forming unit (CFU-GM) and 5% +/- 0.8% for burst-forming unit-erythroid (BFU-E). Similarly, DHE treatment resulted in the recovery of 5.2% +/- 2% and 9.8% +/- 3% of CFU-GM and BFU-E, respectively. Furthermore, equivalently cytotoxic concentrations of both DHE and BPD-MA and light were found not to kill normal pluripotent stem cells in BM, as demonstrated by their survival in two-step long-term marrow culture at levels equal to untreated controls. The T-lymphoblastic leukemia cell line CEM and its vinblastine (VBL)-resistant subline CEM/VBL, along with the acute promyelocyte leukemia cell line HL-60 and its vincristine (VCR)-resistant subline HL-60/VCR, were also tested. BPD-MA at 75 ng/mL was able to provide a greater than 4-log elimination of the drug-sensitive cell lines, but only a 34% and 55% decrease of the drug-resistant HL-60/VCR and CEM/VBL cell lines, respectively. On the contrary, 12.5 micrograms/mL of DHE reduced the clonogenic growth of all the cell lines by more than 4 logs. Further experiments demonstrated decreased uptake of both BPD-MA and DHE by the resistant cell lines. However, all the cell lines took up more DHE than BPD-MA under similar experimental conditions. Our results demonstrate the preferential cytotoxicity of BPD-MA and DHE toward neoplastic cell lines and CFU-L from AML patients. In addition, DHE was slightly more effective in purging tumor cells expressing the p-170 glycoprotein. These results suggest that photoradiation with DHE would be useful for in vitro purging of residual drug-resistant leukemia and lymphoma cells.

Bone Marrow↗
PubMed1993

Alterations in pharmacological sensitivity of GABAergic but not dopaminergic and glutamatergic systems during ontogenesis in dystonic mutant hamsters.

Attacks of sustained dystonia of the limbs and trunk can be initiated by handling or mild environmental stimuli (e.g. new cage) in mutant (gene symbol dtsz) Syrian golden hamsters. The severity of the dystonic syndrome in these mutant hamsters is age-dependent, with a peak at weaning (21 days of age) and a second peak at about 30-40 days of age. Spontaneous remission occurs at an age of about 70 days. The syndrome in hamsters is thus similar to transient paroxysmal dystonia in children. In the present experiments, it was examined whether dystonic hamsters exhibit age-dependent differences in susceptibility to drugs which affect GABA (gamma-aminobutyrate)ergic, glutamatergic or dopaminergic functions. After acute administration, the GABA-elevating drug aminooxyacetic acid was significantly less potent in attenuating the severity of dystonic attacks at 21 days than at 31 days of age. Similar but less marked age-dependent differences in antidystonic activity were found for phenobarbital and diazepam. In contrast to these GABAmimetic drugs, the NMDA receptor antagonist CGP 37849 (DL-[E]-2-amino-4-methyl-5-phosphono-3-pentenoic acid) or the dopamine receptor antagonist haloperidol had about the same antidystonic potency at both 21 and 31 days of age. Chronic treatment of dystonic hamsters with aminooxyacetic acid, starting at 21 days of age, did not alter the time course or the severity of dystonia.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗