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Biomedical subjects

J M Manson

Publications and source records attributed to J M Manson.

At least 55 records · Page 3Linked to original sources
PubMed1986

Indications for and results of operation in inflammatory bowel disease.

Of 363 patients with inflammatory bowel disease presenting between 1972 and 1983, 166 required definitive operation. A classification by histological type distinguishes Crohn's disease (CD) from ulcerative colitis (UC) and indeterminate inflammatory bowel disease. CD is divided into predominantly ileal disease (81), total or subtotal colonic disease (74) and distal disease (22), whilst UC is classified into colonic (95) or distal disease (63). Most patients with ileal disease required operation for chronic persistent symptoms. In patients with total colonic involvement a greater proportion of patients with CD than those with UC came to surgery. Very few patients with distal disease required surgery. After resection for ileal disease there was a low incidence of anastomotic leakage (3%) and no operative mortality. There was an overall operative mortality of 8% after colonic resection. This was much lower in the non-urgent cases but rose to 12% in urgent cases.

Colitis, Ulcerative↗
PubMed1986

Mechanism of nitrofen teratogenesis.

Nitrofen (2,4-dichloro-4'-nitrodiphenyl ether) is an herbicide with potent teratogenic activity in rats. When administered at doses as low as 0.15 mg/kg/day during organogenesis, abnormal development of the heart, kidneys, diaphragm, and lung occurs. The specific pattern of visceral malformations produced in the absence of overt maternal toxicity or embryolethality/cytotoxicity suggest that the compound perturbs processes unique or highly selective for embryonic differentiation. Despite findings of metabolic activation to mutagenic intermediates and carcinogenic activity in adult rodents, several lines of evidence indicate that teratogenicity is not based on mutagenic insult to the embryo. Rather, evidence is accumulating that nitrofen exerts a teratogenic effect via alterations in thyroid hormone status. The premature and pharmacologic exposure of the embryo to a nitrofen-derived thyromimetic challenge is believed to be the cause of abnormal morphogenesis of the heart, lungs, kidneys, and diaphragm. The parent compound itself could directly bind to embryonic nuclear receptors for T3, leading to altered differentiation of target organs. Alternatively, increased availability and placental transport of free thyroid hormones in the maternal compartment could be the source of thyromimetic challenge to the embryo. Overall, these studies indicate that, in the case of nitrofen, the mode of teratogenic activity is uniquely different from the mode of adult toxicity.

Abnormalities, Drug-Induced↗
PubMed1986

Positive nitrogen balance with human growth hormone and hypocaloric intravenous feeding.

Nitrogen equilibrium cannot be achieved in surgical patients without adequate nitrogen and calorie intake, frequently requiring central venous feedings. To investigate the hormonal environment under which nitrogen retention might be achieved during hypocaloric feedings, we administered peripheral vein nutrition with growth hormone (GH) to four healthy male patients. The intravenous diets provided 50% of estimated energy requirements (mean 566 kcal/m2/day) and adequate nitrogen (6 gm/m2/day). Each subject was studied for two 7-day periods; 10 mg of GH was given daily during one period and placebo during the other. Administration of GH decreased weight loss, caused retention of nitrogen, potassium, and phosphorus in amounts closely matching their proportions in skeletal muscle, and stimulated insulin production. GH also raised serum levels of free fatty acids and glycerol, increased urinary excretion of ketones, and favored fat oxidation in the postabsorptive state. Hyperinsulinemia and increased lipolysis and ketogenesis may augment the primary effects of GH. Further studies at adequate and approximately 30% of adequate calorie intake confirmed these findings. Maintenance of body protein with GH may allow improved nutritional care of catabolic patients that was previously unrecognized.

Adult↗
PubMed1986

Strain-dependent differences in the metabolism of 3-methylcholanthrene by maternal, placental, and fetal tissues of C57BL/6J and DBA/2J mice.

C57BL/6J (B6) and DBA/2J (D2) mice have different susceptibilities to developmental toxicity and transplacental carcinogenesis induced by in utero exposure to polycyclic aromatic hydrocarbons, which has been associated with polycyclic aromatic hydrocarbon metabolism and inducibility at the Ah locus. The distribution of total 3-methylcholanthrene (3-MC)-associated radioactivity in maternal, placental, and fetal tissues of beta-naphthoflavone-pretreated pregnant B6 and D2 mice was determined up to 12 h after p.o. exposure to [6-14C]-3-MC (63 mg/kg, 20 mu Ci) on gestational day 17. 3-MC-associated radioactivity in maternal plasma was not significantly different in the two strains. However, D2 tissue homogenates had consistently higher levels of 3-MC-associated radioactivity, which included both bound and free parent compound and metabolites. Increased metabolism of 3-MC by B6 maternal liver was suggested by the induced levels of aryl hydrocarbon hydroxylase activity in that tissue and by the observation that levels of total radioactivity decreased more rapidly in B6 tissues than in D2 tissues. The D2 fetal lung, the target tissue for 3-MC-induced transplacental carcinogenesis, appeared to accumulate 3-MC-associated radioactivity for a longer period of time than either the D2 fetal liver or the B6 fetal tissues. This study suggests that the genetic differences in fetal susceptibility to the developmental toxicity and transplacental carcinogenesis of 3-MC may be related to the presystemic elimination of the compound from both maternal and fetal tissues.

Animals↗
PubMed1984

Effects of oral exposure to trichloroethylene on female reproductive function.

The present study was conducted to determine if subchronic oral exposure to trichloroethylene (TCE) influenced female reproductive performance, and if TCE or major metabolites trichloroacetic acid (TCA) and trichloroethanol (TCOH) preferentially accumulated in female reproductive organs or neonatal tissues. Female Long-Evans hooded rats were exposed to vehicle (corn-oil), 10, 100 or 1000 mg/kg/day by gavage for 2 weeks before mating and throughout mating to day 21 of pregnancy. Gas chromatography analysis of tissues from females at the end of premating exposure indicated that TCE levels were uniformly high in fat, adrenals and ovaries across treatment groups, while uterine tissue had relatively high levels of TCA. Female fertility, however, was not influenced in any treatment group. In the 1000 mg/kg/day group, 5 out of 23 females died and weight gain was significantly depressed throughout the treatment period. Neonatal survival was significantly depressed in this group alone, with the majority of deaths occurring among female offspring at the time of birth. TCA levels in blood, liver, and milk contents of the stomach in female but not male neonates increased across treatment groups. These results indicate that oral exposure to TCE at levels below those causing limiting maternal toxicity had no influence on pregnancy outcome, and that the accumulation of TCE and TCA in ovaries, adrenals and uteri had no influence on mating success.

Administration, Oral↗
PubMed1984

Neonatal toxicity in mice associated with the Ahb allele following transplacental exposure to 3-methylcholanthrene.

This study was conducted to determine if the Ah genotype in mice could influence the incidence of neonatal mortality following maternal exposure to 3-methylcholanthrene (3-MC). Male F1 hybrids (Ahb/Ahd) produced from a cross of C57BL/6J and DBA/2J were backcrossed to DBA/2J females. This backcross mating resulted in noninducible pregnant mice (Ahd/Ahd) containing litters with a 1:1 ratio of AHH-inducible (Ahb/Ahd) and noninducible (Ahd/Ahd) fetuses. Dams were exposed by the oral route to 3-MC in corn oil at doses of 7, 21, or 63 mg/kg/day on Days 15, 16, and 17 of pregnancy, or to the positive control agent urethane at 1 mg/g ip on Day 17. The phenotype of surviving offspring was determined by zoxazolamine paralysis time and hepatic aryl hydrocarbon hydroxylase (AHH) activity measurements. Dose-related responses in all 3-MC treatment groups were obtained in measures of neonatal toxicity, i.e., number of litters surviving to term, litter size at birth, survival to weaning, and weight gain to 13 weeks of age. Correlation of the Ah phenotype with the neonatal toxicity data indicated that genetically responsive offspring had higher levels of neonatal toxicity than nonresponsive offspring within the same exposure groups. Thus, when fetuses are exposed in the same maternal environment to 3-MC, genetic differences in Ah genotype may influence the susceptibility to neonatal toxicity.

Administration, Oral↗
PubMed1984

Lung tumorigenesis and hyperplasia in offspring associated with the Ahd allele following in utero exposure to 3-methylcholanthrene.

This study was conducted to determine if the Ah genotype could influence the incidence of tumorigenesis in offspring exposed to 3-methylcholanthrene (3-MC) during the fetal period. Male F1 hybrids (Ahb/Ahd) were backcrossed to Ahd/Ahd females, resulting in pregnant mice containing litters with a 1:1 ratio of Ahb/Ahd (AHH-inducible) and Ahd/Ahd (AHH-noninducible) fetuses. Dams were exposed by gavage to corn oil or to 3-MC at 7, 21, or 63 mg/kg on Days 15, 16, and 17 of gestation, or to the positive control urethane at 1 mg/g ip on Day 17. The phenotype of surviving offspring was determined by hepatic aryl hydrocarbon hydroxylase (AHH) activity. The lung was the major site of neoplastic involvement in adult offspring 6 months after in utero exposure to 3-MC. Dose-related responses in all 3-MC treatment groups were obtained for percent nodule-bearing animals, percentage adenoma-bearing animals, mean number of nodules per animal, mean nodular size per animal, and diffuse bronchiolar hyperplasia. Correlation of Ah phenotype with adult tumorigenesis indicated that genetically nonresponsive (Ahd/Ahd) offspring had a higher incidence of nodules, adenomas, and diffuse bronchiolar hyperplasia than responsive offspring within the same treatment group. Thus, when fetuses are exposed in the same maternal environment to 3-MC, genetic differences in Ah genotype may influence susceptibility to transplacental carcinogenesis.

Alleles↗
PubMed1984

Teratogenicity of nitrofen (2,4-dichloro-4'-nitrodiphenyl ether) and its effects on thyroid function in the rat.

Nitrofen is a herbicide with potent teratogenic activity in rodent species. Previous studies have indicated that this agent has a stereochemical structure similar to thyroid hormone, and that exposure of adult mice results in depression of thryoxine (T4) levels. The present study was undertaken to determine if teratogenic exposure to nitrofen alters pituitary-thyroid function in nonpregnant, pregnant, and fetal rats, and if these potential alterations could be related to induction of birth defects. In adult thyroparathyroidectomized (TPTX) female rats, nitrofen exposure for 2 weeks resulted in a significant suppression of thyrotropin-stimulating hormone (TSH) levels. When a single dose of nitrofen was administered to euthyroid female rats, a trend toward reduction (p = 0.058) in the release of TSH after a thyrotropin-releasing hormone (TRH) challenge was observed 4 and 5 hr after exposure. Pregnant euthryoid rats given a single dose of nitrofen on Day 11 of gestation had significantly depressed TSH and T4 levels, and fetal T4 levels were markedly depressed at term. Administration of T4 on Day 2 through 22 of pregnancy plus nitrofen on Day 9 through 11 to TPTX dams resulted in a 70% reduction in the frequency of malformed fetuses, especially in regard to the frequency of heart anomalies, compared to nitrofen exposure alone. Competitive displacement studies in radioimmunoassays for T4 and T3 indicated that a nitrofen metabolite (4-hydroxy-2,5-dichloro-4'-aminodiphenyl ether) competed with [125I]T3 for antibody binding, while the parent compound and six isolated metabolites failed to compete with [125I]T4 for antibody binding. These results have been interpreted to indicate that nitrofen teratogenicity is mediated at least in part by alterations in maternal and/or fetal thyroid hormone status, and may be due to a premature and pharmacologic exposure to the embryo to a nitrofen-derived, T3-active metabolite.

Animals↗
PubMed1983

Contribution of mesenchymal cell death and mitotic alteration to asymmetric limb malformations induced by MNNG.

N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) induces fetal asymmetric limb malformations with exposure of pregnant mice to 50 mg/kg on day 11 of gestation. Hindlimbs were more frequently malformed than forelimbs, and a fourfold greater incidence of postaxial ectrodactyly was found in left forelimbs than in right forelimbs, and a two fold excess in left hindlimbs compared to right hindlimbs. The level of cell death and mitotic index were measured in forelimbs and hindlimbs from treated and control embryos at 1, 4, 18, 24, 48, and 72 hr after exposure to ascertain if these parameters could be correlated with the differential teratogenic susceptibility of the limbs. An increase in necrotic index was first detected in treated limbs at 4 hr, increased at 18 hr, peaked at 24 hr, and began declining at 48 hr to reach the control baseline at 72 hr. At 24 hr, the correlation between the level of cell death and susceptibility of malformation was the strongest, with the left hindlimb having a necrotic index of 58%, the right hindlimb 47%, the left forelimb 30% and the right forelimb 12%. In both forelimbs and hindlimbs, MNNG treatment initially depressed mitotic activity followed by an elevation at 48 hr relative to controls. The magnitude of the depression, extent of the elevation, and overall pattern of mitotic activity could not be uniformly related to limb defects. These results indicate that the amount of cell death in limb buds at 24 hr after MNNG exposure may predict target organ susceptibility. Depressions in mitotic activity and alterations in the pattern of mitosis were also observed which were not as clearly correlated with the incidence of malformations as was the amount of cell death.

Animals↗
PubMed1983

Distribution and metabolism of the teratogen nitrofen (2,4-dichloro-4'-nitro diphenyl ether) in pregnant rats.

Oral exposure of pregnant Long-Evans rats on day 11 of gestation to the teratogen, nitrofen (2,4-dichloro-4'-nitro diphenyl ether), which was uniformly labeled with 14C in the nitrophenyl ring, resulted in the accumulation of radioactivity in maternal fat with lesser amounts found in liver, kidney, other tissues, and in the embryonic compartment. The peak concentration of radioactivity occurred 7-9 h after dosing and the half-life of the label in maternal blood was approximately 8 days. In the embryonic compartment, radioactivity was first detected at 2 h after dosing, peaked at 4-6 h, and declined to half of that initially seen by 24 h. High performance liquid chromatography of embryo-placental extracts revealed 4 metabolites in addition to the parent compound: 4'-amino and 4'-acetylamino derivatives plus 2 hydroxylated derivatives. A similar metabolic profile was observed in maternal blood and liver. In another experiment, purified 4'-amino metabolite was found to have no adverse effect on neonatal survival when administered orally on day 11 of gestation at doses up to 215 mg/kg. These results suggest that the teratogenicity of nitrofen cannot be readily explained by preferential distribution of the compound in the embryo or by a unique profile of stable, extractable metabolites in the embryonic compartment.

Animals↗
PubMed1983

The pharmacokinetics of cefotetan excretion in the unobstructed biliary tree.

Cefotetan excretion was studied in 17 patients undergoing biliary or pancreatic surgery. The antibiotic was detected in bile taken from the common bile duct within 15 min of a 1 g iv bolus and therapeutic plasma levels were found up to 10 h after administration. Even higher concentrations of cefotetan were measured in the bile from functioning gall bladders, despite the presence of gall stones. Concentrations of cefotetan in bile from the common bile ducts and functioning gall bladders were greater than the plasma concentrations at all times. These concentrations exceed the in-vitro minimum inhibitory concentrations (MIC) for most common biliary tract pathogens.

Anti-Bacterial Agents↗
PubMed1982

Studies of DNA damage and cell death in embryonic limb buds induced by teratogenic exposure to cyclophosphamide.

Many teratologic investigations have shown that certain types of chemical insults to the embryo (those altering replication, transcription, and translation) can cause excessive cell death in tissues destined to become malformed. Chemical carcinogens also induce cell death in target tissues, but the critical event is believed to be heritable alteration in the DNA of surviving cells. In the present study, an attempt was made to study the interaction between cell death and DNA damage in the initiation of birth defects. The pattern of DNA damage induced by cyclophosphamide was examined at time intervals before, during, and after the necrotic episode in mouse embryo limb buds. The alkaline elution assay was used to measure alkali-labile sites in single-strand DNA due to its adaptability to small tissue samples. An ip dose of 20 mg/kg of cyclophosphamide induced forelimb malformations in 85% of surviving mouse fetuses and 30% embryolethality when administered at 9 am on Day 11. As early as 5 hr after exposure, a slight excess of necrosis was observed in treated limbs by light microscopy, while at 24 hr, massive necrosis was evident. By 48 and 72 hr, excess necrosis was not observed in treated limbs. When alkaline elution analysis was conducted at prenecrotic (1-, and 5-hr), necrotic (24-hr), and postnecrotic (48-, and 72-hr) intervals, a trend toward increasing DNA damage in treated limbs with time was observed. The greatest differences in elution values occurred during the postnecrotic period. Although mean retention values were not significantly different, significantly increased variance was obtained in retention values of treated limbs at all time intervals other than 1 hr. This may reflect the actual in vivo situation where relatively few cells within a heterogeneous population of cells carry sublethal DNA damage into the postnecrotic period. These results suggest that not all limb bud cells affected by teratogenic exposure to cyclophosphamide die, but that some persist to the postnecrotic period carrying heritable alterations in their DNA.

Abnormalities, Drug-Induced↗
PubMed1981

The heart and diaphragm: target organs in the neonatal death induced by nitrofen (2,4-dichlorophenyl-p-nitrophenyl ether).

This paper examines the effects of in utero exposure to 2,4-dichlorophenyl-p-nitrophenyl ether (nitrofen) on the viability of neonatal Long-Evans rats. Oral administration of this herbicide on days 8-18 of gestation reduced neonatal survival and birth weight. Day 11 of gestation was the most sensitive day for induction of neonatal mortality; 116 mg/kg to the dam on this day was the LD50 for the neonate. An increased incidence of hydronephrosis was observed in 35-day survivors. This increase was dose-related in animals exposed on day 11 of gestation. Fetuses exposed on day 11 and examined at term had reduced weights, delayed skeletal ossification, and an increased frequency of hydronephrosis and diaphragmatic hernias. While nitrofen did cause a high incidence of hydronephrosis, BUN or creatinine levels in 4-h neonates were not elevated. Detailed examination of the hearts of term fetuses revealed cardiac malformations classified as ventricular septal defect, double outlet right ventricle, and transposition of the great vessels. We conclude from these studies that the heart and the diaphragm are the target organs in nitrofen-induced neonatal death.

Abnormalities, Drug-Induced↗