PubMed Health⌕ Search

Biomedical subjects

R Mueller

Publications and source records attributed to R Mueller.

At least 55 records · Page 3Linked to original sources
PubMed1997

30-day oral toxicity study of domoic acid in cynomolgus monkeys: lack of overt toxicity at doses approaching the acute toxic dose.

Domoic acid was orally administered to 3 cynomolgus monkeys at doses of 0.5 mg/kg for 15 days and then at 0.75 mg/kg for another 15 days. After the 30-day dosing period, the treated monkeys were killed. Parameters monitored as markers for toxicity included body weight, food and water consumption, clinical observations, hematology, serum chemistry, light microscopy of all major organs (including brain and retina), and glial fibrillary acid protein immunohistochemistry. Domoic acid in serum and 24-hour urine samples was measured at several time points. All parameters measured remained unremarkable. Domoic acid concentrations measured in the 24-hour urine samples indicated that gastrointestinal absorption in the monkey was approximately 4-7 percent of the administered dose, which is at least twice that previously reported for the rat.

Administration, Oral↗
PubMed1997

Interindividual variation in the enzymatic 15-keto-reduction of 13,14-dihydro-15-keto-prostaglandin E1 in human liver and in human erythrocytes.

OBJECTIVE: The therapeutic response to PGE1 is highly variable, and a contribution by variable formation of its active tertiary metabolite PGE0 is in question. Hence, the objective of this study was to assess the person-to-person variation of the reduction of the inactive intermediate metabolite 15-KD PGE1 by human liver and human erythrocytes in forming the active metabolite PGE0. METHODS: Source of enzyme was lysed erythrocytes from 29 donors, and a bank of 37 donor livers including specimens from 15 children. Tritium-labelled 13,14-dihydro-15-keto-prostaglandin E1 (15-KD PGE1) was used at low nanomolar concentrations and found to be converted almost exclusively to the more polar compound 13,14-dihydro-prostaglandin E1 (PGE0) by an NADPH-dependent carbonyl reductase. The identity of the product PGE0 was established by comparison of its chromatographic and mass spectral characteristics with authentic PGE0. RESULTS: Lysed erythrocytes had readily measurable enzymatic activity; differences between the preparations from 29 subjects were very small with only a twofold range of variation. In contrast to lysed erythrocytes, intact erythrocytes did not catalyse the reaction so that the erythrocyte activity should be medically immaterial. 15-KD PGE1 15-ketoreductase activity of liver cytosol averaged 61.1 fmol.min-1.mg-1 protein in preparations from 37 human livers. Individual activities varied over an almost tenfold range, with indications of a non-normal distribution. Kinetic studies of selected specimens showed substantially different Vmax values but indistinguishable kM values, suggesting that the individual variation in 15-KD PGE1 15-ketoreduction is the result of differences in enzyme concentration rather than of structural enzyme variations. The activity in 15 livers from children was significantly lower than in those from adults. Inhibition data suggest that both the liver and the erythrocyte enzymes belong to the class of carbonyl reductases. CONCLUSIONS: The variations in hepatic enzyme activity may be expected to affect the transformation of 15-KD PGE1 to the active metabolite PGE0 in vivo. The clinical significance remains to be explored.

Adolescent↗
PubMed1997

Subchronic oral toxicity of di-n-octyl phthalate and di(2-Ethylhexyl) phthalate in the rat.

The subchronic oral toxicity of di(2-ethylhexyl) phthalate (DEHP) and di-n-octyl phthalate (DNOP) was studied. Groups of 10 male and 10 female Sprague-Dawley rats were administered DEHP in the diet at 0, 5, 50, 500 or 5000 ppm for 13 wk. In a separate study, groups of 10 male and 10 female Sprague-Dawley rats were given DNOP (5, 50, 500 and 5000 ppm) in the diet while control groups received basal diet containing 4% corn oil and positive control groups were fed a diet containing 5000 ppm DEHP. Growth rate and food consumption were not affected by treatment with either compound. Hepatomegaly was observed in the highest dose groups of both sexes administered DEHP but not in the DNOP-treated animals. At the highest dose, DNOP caused threefold (females) and 12-fold (males) increases in liver ethoxyresorufin-O-deethylase activity while DEHP did not. Mild changes in serum biochemistries were mostly confined to rats in the highest dose group of DEHP, and included increased serum albumin and albumin/globulin ratio in both sexes and decreased cholesterol in female rats. Mild vacuolations in the Sertoli cells were observed in male rats exposed to 500 ppm DEHP. At 5000 ppm DEHP, there was mild to moderate seminiferous tubule atrophy and Sertoli cell vacuolation in males, and rats of both sexes showed hepatic peroxisome proliferation. Both DEHP and DNOP at 5000 ppm caused mild histological changes in the thyroid consisting of reduced follicle size and colloid density, and the liver consisting of endothelial nuclear prominence, nuclear hyperchromicity and anisokaryosis. There was accentuation of zonation of the hepatic lobules and increased perivenous cytoplasmic vacuolation in DNOP-treated rats. Trace quantities (3-5 ppm) of DEHP and DNOP were detected in the liver, and 15-31 ppm were found in adipose tissue of the highest dose groups. The no observed-effect-level was judged to be 50 ppm in the diet or 3.7 mg/kg body weight/day for DEHP, and 500 ppm or 36.8 mg/kg body weight/day for DNOP.

Administration, Oral↗
PubMed1997

Mechanism underlying counterregulation of autoimmune diabetes by IL-4.

Diabetes in nonobese diabetic (NOD) mice is an autoimmune disease characterized by the destruction of the beta cells in the pancreas. We have previously reported that transgenic expression of interleukin-4 (IL-4) counterregulates the disease process, completely protecting NOD mice from insulitis and diabetes. Here we demonstrate the presence of autoreactivity but lack of pathogenicity of the IL-4-regulated lymphocytes. The importance of T cell diversity for the protective effect of IL-4 is demonstrated through breeding with transgenic BDC2.5 mice, which have an almost exclusively monoclonal T cell repertoire. Limitation of T cell diversity abrogated the protection by IL-4. We suggest that "immune deviation" in NOD-IL-4 mice is mediated by the pancreatic tissue itself, which causes activation of distinct, nonpathogenic T cell specificities.

Animals↗
PubMed1997

The prevalence of fragile-X syndrome in an institution for people with learning disability.

The prevalence of Fragile-X syndrome in those with learning disability has been reported. There is little agreement regarding the prevalence rate which varies between 0% and 16%. We report a study investigating the prevalence of Fragile-X syndrome in two institutions for those with learning disability, using DNA testing. We found a rate of 0.7%, which is one of the lowest record rates. We also found that physical signs could be used as a reliable discriminator to determine those likely to have the disorder. We conclude that indiscriminate mass screening of those with learning disability for the Fragile-X syndrome is probably not useful because, in adults, physical signs and a family history of learning disability can predict those likely to have the disorder.

Adult↗
PubMed1997

A sector-integration method for calculating the output factors of irregularly shaped electron fields.

An empirical model is presented that uses a sector-integration method for calculating the output factors of irregularly shaped electron fields. The sector-integration method accounts for changes in electron fluence, lateral scatter equilibrium, and scatter from the edge of a cutout shield. This method is tested for elliptical and rectangular fields with a ratio of the long-to-short axis as great as 4 to 1. Differences between measured and calculated values for output factors were less than +/- 1%. Comparisons were also carried out for a large number of cutout shields that were used in the clinic and similar levels of accuracy were obtained.

Biophysical Phenomena↗
PubMed1997

A report of a child with a deletion (9)(q34.3): a recognisable phenotype?

We report a case of a male infant who presented with congenital anomalies and was found to have a de novo deletion in the terminal region of the long arm of chromosome 9. He died at the age of 17 weeks of cardiorespiratory failure owing to RSV positive bronchiolitis. A review of previously published reports documented one previous report of a patient with a deletion of (9)(q34.3) and multiple congenital anomalies. Comparison with the previously reported case suggests that the phenotype observed constitutes a clinically recognisable pattern of malformations.

Abnormalities, Multiple↗
PubMed1997

Tissue-specific expression of interleukin-4 induces extracellular matrix accumulation and extravasation of B cells.

We have assessed the consequences of tissue-specific production of IL-4 by generating transgenic mice that express IL-4 under the control of the human insulin promoter in the Langerhans' islets of the pancreas. In these transgenic mice, designated Ins-IL-4 mice, we observed the deposition of extracellular matrix (ECM) around the islets beginning at an early age. This matrix was interspersed with eosinophils, macrophages, and fibroblasts; T cells were notably absent. As the mice aged, the exocrine tissue was steadily replaced by ECM and adipose tissue, and the pancreatic islets were disrupted by ECM deposition and newly formed pancreatic ducts. Most striking was the preferential accumulation of B lymphocytes around the blood vessels close to the islets. Vascular changes included induction of MadCAM (mucosal addressin cell adhesion molecule)-1, von Willebrand factor, and intercellular adhesion molecule-1 on endothelial cells in pancreata of Ins-IL-4 mice. Overall, tissue-specific expression of IL-4 induced a complex, localized host response that resulted in the excessive generation of ECM and the selective recruitment of inflammatory cells. These findings suggest that IL-4 has a role in (a) the regulation of potentially pathologic fibrotic events associated with chronic inflammatory lesions and (b) the recruitment of inflammatory cells in Th2 cell-dependent diseases such as allergic disorders.

Animals↗
PubMed1997

Association between preoperative acute phase response and postoperative complications.

OBJECTIVE: To find out if there is an association between the acute phase response preoperatively and the development of postoperative infective complications. DESIGN: Prospective open study. SETTING: Teaching hospital Germany. SUBJECTS: 229 patients who were to undergo major abdominal operations. INTERVENTIONS: Measurements of serum concentrations of interleukin 6 (IL-6), alpha-1-antitrypsin, C-reactive protein (CRP), albumin, and prealbumin. MAIN OUTCOME MEASURES: Abnormal values of substances measured. RESULTS: Serum concentrations of IL-6, alpha-1-antitrypsin and CRP were raised, and those of albumin and prealbumin were reduced in 5% to 14% of patients. 25 (11%) developed major complications, of whom 9 (4%) died. 9 Patients (4%) had a severe systemic inflammatory response caused by infective complications that did not result from technical failure of the operative technique. Of these 9 patients, 7 (78%) already had signs of an increased acute phase response before operation that was significantly different from the incidence among patients who recovered without complications (21/204. p < 0.001) CONCLUSION: These data suggest that if there are signs of an acute phase response preoperatively the patient's response to operation and infection during the postoperative period may be adversely affected.

Acute-Phase Reaction↗
PubMed1996

Pancreatic expression of interleukin-4 abrogates insulitis and autoimmune diabetes in nonobese diabetic (NOD) mice.

Diabetes in nonobese diabetic (NOD) mice is a T cell-dependent autoimmune disease. The destructive activities of autoreactive T cells have been shown to be tightly regulated by effector molecules. In particular, T helper (Th) 1 cytokines have been linked to diabetes pathogenesis, whereas Th2 cytokines and the cells that release them have been postulated to be protective from disease. To test this hypothesis, we generated transgenic NOD mice that express interleukin (IL) 4 in their pancreatic beta cells under the control of the human insulin promoter. We found that transgenic NOD-IL-4 mice, both females and males, were completely protected from insulitis and diabetes. Induction of functional tolerance to islet antigens in these mice was indicated by their inability to reject syngeneic pancreatic islets and the failure of diabetogenic spleen cells to induce diabetes in transgenic NOD-IL-4 recipients. Interestingly, however, islet expression of IL-4 was incapable of preventing islet rejection in overtly diabetic NOD recipient mice. These results demonstrate that the Th2 cytokine IL-4 can prevent the development of autoimmunity and destructive autoreactivity in the NOD mouse. Its ability to regulate the disease process in the periphery also indicates that autoimmune diabetes in NOD mice is not a systemic disease, and it can be modulated from the islet compartment.

Animals↗
PubMed1996

IL-10 is necessary and sufficient for autoimmune diabetes in conjunction with NOD MHC homozygosity.

Contrary to expectations based on in vitro experiments, we previously found that pancreatic IL-10 did not inhibit autoimmune diabetes but accelerated it in an MHC-dependent manner. Therefore, the ability of IL-10 to overcome the absence of all non-MHC diabetes susceptibility (Idd) alleles was studied in transgenic mice expressing pancreatic IL-10 backcrossed to B10.H2g7 congenic mice, which have no Idd alleles other than NOD MHC (H2g7). IL-10 transgenic backcross 1 (BC1) mice with H2g7/g7 haplotype developed clear-cut insulitis and diabetes, but neither transgenic mice with the H2g/b haplotype nor nontransgenic BC1 mice did so. Further implicating IL-10 in autoimmune diabetes, anti-IL-10 antibody treatment inhibited the development of insulitis in NOD mice. These results suggest that IL-10 may be necessary and sufficient for producing autoimmune diabetes in conjunction with NOD MHC homozygosity and that some Idd genes may be related to the regulation of IL-10.

Alleles↗
PubMed1996

Transgenic expression of interleukin 10 in the pancreas renders resistant mice susceptible to low dose streptozotocin-induced diabetes.

Transgenic mice expressing interleukin 10 (IL-10) within the beta cells of the pancreas were used to assess the role of this cytokine in the development of diabetes following low-dose streptozotocin treatment. Nontransgenic mice injected with low doses of streptozotocin were largely resistant to the induction of hyperglycaemia; that is, average blood glucose values, although above mean blood glucose levels of buffer-injected controls, did not exceed 14 mmol/l. In sharp contrast, IL-10 transgenic mice exhibited significant sensitivity to the diabetogenic actions of streptozotocin resulting in a mean blood glucose level of 21.6 mmol/l at the end of the 56-day study period. Histological analysis of pancreata from streptozotocin-injected transgenic mice revealed severe insulitis and destruction of pancreatic beta cells, whereas their streptozotocin-injected nontransgenic littermates remained completely insulitis-free. According to immunocytochemical analysis, the pancreatic inflammatory infiltrates of streptozotocin-injected transgenic mice contained CD4+ and CD8+ T lymphocytes, B lymphocytes and macrophages. Furthermore, various adhesion molecules, the co-stimulatory molecule B7-1 and the Ia antigen could be detected. Splenocytes from streptozotocin-injected transgenic mice did not transfer disease to irradiated syngeneic nontransgenic recipients, suggesting that the presence of IL-10 in streptozotocin-injected mice had a general immunostimulatory effect but did not lead to the activation of beta cell-specific T cells. Our data suggest a critical role for IL-10 in the development of diabetes in vivo despite its established immunosuppressive activities in vitro.

Animals↗
PubMed1996

Fumonisin B1 toxicity in male Sprague-Dawley rats.

Male rats were gavaged with fumonisin B1 (FB1) once daily for 11 consecutive days at doses of 0, 1, 5, 15, 35, and 75 mg FB1/kg body weight. Urine osmolality (at 5-75 mg FB1/kg) and organic ion transport in kidney slices (at 5-75 mg FB1/kg) were reduced. Urinary excretion of protein (at 15-75 mg FB1/kg) and of the enzymes LDH (at 5-75 mg FB1/kg), NAG (at 5-75 mg FB1/kg) and GGT (at 15-75 mg FB1/kg) were increased. These findings were indicative of glomerular and tubular toxicity. Histopathologic changes in the kidney consisted of necrosis of tubular epithelia of variable extent accentuated in the inner cortex. These changes were present at 1 and 5 mg FB1/kg and were more pronounced at 15-75 mg FB1/kg. Serum enzymes indicative of hepatotoxicity (ALT, GGT) were elevated compared to controls at 75 mg FB1/kg only. There were noticeable increases in mitotic figures in hepatocytes at 35-75 mg FB1/kg, while single cell necroses were increasingly numerous from 15-75 mg FB1/kg. The kidneys were considered to be the primary target organs in this study.

Acetylglucosaminidase↗
PubMed1996

Subchronic toxicity study of domoic acid in the rat.

Male and female Sprague-Dawley rats were dosed by gavage for 64 days with 0, 0.1 or 5 mg/kg/day domoic acid. Treated animals showed no clinical abnormalities. Terminal values in haematology and clinical chemistry did not reveal differences between treated and control groups. Findings in histopathology and immunohistochemistry were unremarkable. The 24-hr urinary excretion rate for domoic acid determined at three time points was approximately 1.8% of the dose and remained unchanged during the study.

Administration, Oral↗
PubMed1996

Different cytokine patterns in bronchial biopsies in asthma and chronic bronchitis.

Bronchial biopsies have made possible the detailed study of the pathology of the airways of humans with respiratory disease. Much data has been accumulated on asthmatics or normal controls but much less is known about chronic bronchitics. The aim of this study was to characterize the cellular and cytokine pattern seen in chronic bronchitics and to compare these with control and asthmatic subjects. The patients were also characterized clinically. In this study, immunocytochemistry on cryostat sections from bronchial biopsies were used to determine the level of inflammatory cells and cells of the immune system as well as the pattern of cytokines. This study revealed a distinct cellular and cytokine pattern for each of the three different patient groups, although the diversity of the cytokines analysed was limited by the size of the biopsies. In the inflammatory infiltrate of patients with asthma, CD4+ T-cells and eosinophils were the most prominent cell types discerned. All of the expected cytokines such as IL-1, TNF-alpha, IL-4, IL-5 and IFN-gamma were found. In contrast, the emphasis in chronic bronchitic patients was quite different. The predominant cell types were macrophages, neutrophils, mast cells and CD8+ T-cells, but eosinophils were also abundant. In addition, IL-4 and TNF-alpha were the only cytokines present of those tested.

Adult↗