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Biomedical subjects

D Ross

Publications and source records attributed to D Ross.

At least 307 records · Page 17Linked to original sources
PubMed1984

Duration of antidepressant drug treatment. What is an adequate trial?

Data from three six-week placebo-controlled randomized antidepressant trials were pooled to test the hypothesis that a four-week trial is insufficient to reach a determination of drug failure in depressed patients. We compared global clinical ratings at weekly intervals for patients receiving drug and patients receiving placebo and calculated the proportion of patients whose clinical status changed over time. We predicted, and found, that a significant proportion of patients who showed no clear-cut response at four weeks would show much improvement at six weeks in drug but not placebo conditions. Baseline Research Diagnostic Criteria diagnosis, baseline illness severity, and drug dose adjustments after four weeks did not predict either late clinical improvement or relapse between four and six weeks. Additional placebo-controlled studies are needed to replicate our findings concerning the advantage of extending trials to five or six weeks in samples of patients of various depressive subtypes.

Actuarial Analysis↗
PubMed1984

Identification of true drug response to antidepressants. Use of pattern analysis.

The purpose of this study was to develop a method for differentiating specific ("true") and nonspecific antidepressant drug response for the individual patient. Patterns of clinical response, based on weekly global ratings of clinical status, were generated for each of 185 patients participating in six-week placebo-controlled drug trials. We hypothesized and found that substantially more patients receiving active than placebo medication displayed treatment response patterns characterized both by two-week or greater delay in onset of initial improvement and nonfluctuating persistence of improvement once achieved. Identification of a distinctive pattern of clinical response to an active drug has both research and clinical applications. Pattern analysis may contribute to understanding the nature of drug mechanisms of action, may clarify some ambiguous treatment study outcomes, and in the individual case, may facilitate clinical management.

Ambulatory Care↗
PubMed1984

Alterations in intracellular thiol homeostasis during the metabolism of menadione by isolated rat hepatocytes.

The effects of menadione (2-methyl-1,4-naphthoquinone) metabolism on intracellular soluble and protein-bound thiols were investigated in freshly isolated rat hepatocytes. Menadione was found to cause a dose-dependent decrease in intracellular glutathione (GSH) level by three different mechanisms: (a) Oxidation of GSH to glutathione disulfide (GSSG) accounted for 75% of the total GSH loss; (b) About 15% of the cellular GSH reacted directly with menadione to produce a GSH-menadione conjugate which, once formed, was excreted by the cells into the medium; (c) A small amount of GSH (approximately 10%) was recovered by reductive treatment of cell protein with NaBH4, indicating that GSH-protein mixed disulfides were also formed as a result of menadione metabolism. Incubation of hepatocytes with high concentrations of menadione (greater than 200 microM) also induced a marked decrease in protein sulfhydryl groups; this was due to arylation as well as oxidation. Binding of menadione represented, however, a relatively small fraction of the total loss of cellular sulfhydryl groups, since it was possible to recover about 80% of the protein thiols by reductive treatments which did not affect protein binding. This suggests that the loss of protein sulfhydryl groups, like that of GSH, was mainly a result of oxidative processes occurring within the cell during the metabolism of menadione.

Animals↗
PubMed1984

Reactive products formed by peroxidase catalyzed oxidation of p-phenetidine.

The nature of the reactive metabolites formed during HRP/H2O2 catalyzed oxidation of p-phenetidine was investigated. Interaction with DNA measured as the induction of DNA single strand breaks and DNA binding resulted in a time-dependent decrease in the interaction and could be related to the primary oxidation of p-phenetidine. Oxygen uptake observed during p-phenetidine metabolism in the presence of GSH also exhibited such a correlation. GSH-conjugate formation and protein binding on the other hand exhibited an initial increase and did not appear to be directly related to primary p-phenetidine oxidation since maximal interaction was obtained when p-phenetidine had been completely metabolized. The GSH-conjugate and protein binding ratio of ring labelled to ethyl labelled p-phenetidine of approx. 2:1 indicated that these reactive metabolites(s) may be dimer(s) whose formation presumably involved loss of one ethoxy group of p-phenetidine. Accordingly formation of ethanol, indicative of ethoxy group elimination, could be observed during p-phenetidine metabolism. Only one metabolite generated from p-phenetidine oxidation exhibited a concentration dependent binding to protein. This metabolite also reacted with GSH to form water-soluble conjugates. Prior reduction of the metabolite by ascorbic acid prevented this conjugate formation. The mass spectral fragmentation pattern of the reactive protein- and GSH-binding metabolite was compatible with the structure N(4-ethoxyphenyl)-p-benzoquinoneimine.

Aminophenols↗
PubMed1984

Laboratory basis for the medical management of necrotizing enterocolitis (NEC).

Necrotizing enterocolitis (NEC) is a serious condition affecting the neonate that may be responsive to medical management. This study evaluates the efficacy of supplemental oxygen (FiO2 40% and 50%), systemic antibiotics (ampicillin and gentamicin, cephamandole) and oral antibiotics (trimethoprim-sulfamethoxazole, neomycin and gentamicin) in a weanling rat bowel ischemia model induced by a transient (one minute) occlusion of the superior mesenteric artery. Animals were evaluated for overall survival, duration of survival, presence of bowel necrosis or perforation at seven days. Mortality in ischemic controls was 83.8%. This was reduced to 52% by FiO2 of 50%, and 40% with systemic ampicillin and gentamicin (with or without FiO2 50%) (P less than .001). Length of survival was 3.4 days in controls and increased from 5.4 to 5.9 days in rats given FiO2 50% and/or ampicillin and gentamicin (P less than .001). The incidence of bowel necrosis in controls was 60% and was reduced to 25% in rats given systemic ampicillin and gentamicin and 23.3% with 50% FiO2 and the same antibiotics (P less than .001). Systemic cephamandole and oral antibiotics had no beneficial effects.

Animals↗
PubMed1984

Impaired bacterial clearance and trapping in obstructive jaundice.

Sepsis is a major cause of mortality in patients with common bile duct obstruction. To define possible contributing factors to this phenomenon, this study evaluates the effect of biliary obstruction on the intravascular clearance and organ trapping of viable Escherichia coli using a rat model. Adult male Sprague-Dawley rats were placed in three groups: Group I controls had sham operation, Group II had division and ligation of common bile duct (CDL), and Group III underwent splenectomy. At 21 days following operation 10(9) radiolabeled E. coli were injected intravenously. At varying intervals after infusion, blood samples were obtained for clearance study. At 10 minutes, bacterial distribution in the liver, spleen, kidneys, and lungs was determined (expressed as the mean percentage of injected viable E. coli). Intravascular clearance was similar in all groups. There was a significant decrease in the trapping of bacteria by the liver of CDL rats 14.5% +/- 4.95 (vs. control = 70.0% +/- 13.3) (p less than 0.005). A significant increase of bacterial trapping by the lung was observed in the CDL animals: 63.1% +/- 7.06 (vs. controls 1.4% +/- 0.82) (p less than 0.005). There was no significant change in bacterial localization in splenectomized rats. These data suggest that biliary obstruction decreases hepatic phagocytosis and increases pulmonary localization of viable E. coli. As the Kupffer cells of the liver are usually effective in removal of blood borne bacteria, this phagocytic dysfunction may contribute to the increased susceptibility to infection noted in instances of biliary obstruction.

Animals↗
PubMed1984

Left ventricular size, output, and structure during guinea pig pregnancy.

We investigated left ventricular (LV) hemodynamics, pressure-volume relations, and morphometry to determine what cardiac changes characterize pregnancy in the guinea pig. Time-bred virgin guinea pigs were paired by weight with unbred controls. Hemodynamic studies and LV pressure-volume relations were obtained on days 59-68 of the 68-day gestation. Weight of control sows increased from 817 to 902 g (P less than 0.01) and pregnant sows from 810 to 1,251 g (P less than 0.01). LV weights were not different. When indexed for maternal weight minus uterus and contents, pregnancy produced increases in O2 consumption, +48% (P less than 0.01); cardiac output, +32% (P less than 0.05); and stroke volume, +46% (P less than 0.025). Passive LV pressure-volume curves (dP/dV) were shifted to the right (P less than 0.025), but dP/dV at constant pressure was unchanged. Using a thin-walled spherical model, elastic modulus at constant stress was not different. The percent LV inter- and intracellular volumes and myocyte myofibril and organelle volumes were unchanged during pregnancy. In the guinea pig, pregnancy increases LV output, stroke volume, and size without changes in LV mass, morphometry, or elastic modulus.

Animals↗
PubMed1984

Specific active immunotherapy with butanol-extracted, tumor-associated antigens incorporated into liposomes.

With the use of whole tumor cell vaccines in a rat colon cancer minimal residual disease model, we have recently demonstrated that although tissue type-specific tumor immunogens protect against recurrence in the absence of histocompatibility differences, these immunogens offer no predictable tumor-specific protection in the presence of such differences. We have therefore begun to test whether syngeneic and allogeneic rat colon cancer tumor-associated antigens (TAAs), when incorporated into the bilayers of liposomes, could function as effective immunogens in immunotherapy and immunoprotection models. Male Wistar/Furth (W/Fu) rats were inoculated with 5 X 10(6) DMH-W163 colon cancer cells. All nonimmunized animals died of widespread metastases within 2 weeks of complete local tumor resection. In experimental groups, four methods of immunotherapy were used after resection: (1) irradiated whole tumor cells, (2) butanol-solubilized membrane extracts containing TAA only, (3) liposomes only, and (4) liposomes containing TAA. Only animals receiving TAA incorporated into liposomes had a significant increase in survival (p = 0.026). Thirty percent remain disease-free 6 months later. In additional experiments, Buffalo rats were challenged with 1 X 10(6) Buffalo rat colon adenocarcinoma cells after immunization by irradiated whole tumor cells or liposomes and butanol-extracted colon cancer TAAs. Only animals in the group immunized with TAA incorporated into liposomes were significantly protected from subsequent tumor isograft challenge. These data provide evidence of a way to present solubilized colon cancer-associated immunogens that may be applicable in a more clinically relevant, allogeneic setting.

1-Butanol↗
PubMed1983

The formation and metabolism of N-hydroxymethyl compounds--III. The metabolic conversion of N-methyl and N,N,-dimethylbenzamides to N-hydroxymethyl compounds.

The stability of metabolically-generated N-(hydroxymethyl) compounds was investigated using a series of N-methylbenzamides as model substrates. N-(Hydroxymethyl)-benzamide was characterized as a major metabolite of N-methylbenzamide in vitro, and was also identified as a urinary metabolite of N-methylbenzamide. N-(Hydroxymethyl) compounds were also found as metabolites of 4-chloro-N-methylbenzamide and 4-t-butyl-N-methylbenzamide in vitro. Thus substitution in the 4-position of the phenyl ring of derivatives of N-(hydroxymethyl)-benzamide did not affect their stability sufficiently to cause degradation to formaldehyde under the conditions used. N-(Hydroxymethyl)-N-methylbenzamide was identified as a metabolite of N,N-dimethylbenzamide in vitro. However, N-(hydroxymethyl)-N-methylbenzamide was less stable than N-(hydroxymethyl)-benzamide under alkaline conditions. Furthermore, N-(hydroxymethyl)-N-methylbenzamide, unlike N-(hydroxymethyl)-benzamide and its 4-substituted derivatives, was positive in the colorimetric assay for formaldehyde, presumably because of its degradation to produce formaldehyde. Thus substitution on the nitrogen atom which bears the methyl group in N-methylbenzamide markedly affected the stability of the N-methylol produced during oxidative metabolism. N-Formylbenzamide was identified as a metabolite of N-methylbenzamide in suspensions of mouse hepatocytes and also in vivo. The mechanism for its production probably involves the generation of N-(hydroxymethyl)-benzamide.

Animals↗
PubMed1983

The metabolism of a stable N-hydroxymethyl derivative of a N-methylamide.

N-Formylbenzamide and benzamide were characterised by high pressure liquid chromatography and mass spectrometry as products of the metabolism of N-hydroxymethylbenzamide in incubation mixtures with mouse liver preparations and isolated hepatocytes. This biotransformation occurred predominantly in 9000g and microsomal supernatant fractions and was also catalyzed by horse liver alcohol dehydrogenase fortified with NAD and could be inhibited by pyrazole. Unlike N-hydroxymethylbenzamide, which is very stable, N-formylbenzamide degraded rapidly to benzamide in buffer at pH 7.4 with a half-life of 7.8 min. The instability of N-formylbenzamide and the time course of its metabolic generation together with benzamide suggest that benzamide is a chemical breakdown product of N-formylbenzamide. N-Formylbenzamide was also tentatively identified as a urinary metabolite of N-hydroxymethylbenzamide. This is the first time that an N-hydroxymethyl compound has been shown to undergo metabolism either in vitro or in vivo.

Animals↗
PubMed1983

Circulating immune complexes in patients with colorectal cancer.

We have attempted to better define host humoral immune response in neoplasia by quantitating serial circulating immune complex values before and after surgery in patients with primary or metastatic colorectal cancer. Circulating immune complex levels were correlated with serial carcinoembryonic antigen values and tumor courses in patients with primary resectable colorectal cancer (four patients), resectable liver metastases (three patients), diffuse liver metastases treated with regional chemotherapy (three patients), and untreated intrahepatic (one patient) and extrahepatic metastases (one patient). Circulating immune complex levels, as measured by an antigen-nonspecific assay, which utilized 4 percent polyethylene glycol insolubilization, were increased in all patients at presentation (734 delta OD450 +/- 381) when compared with normal human control sera (202 +/- 4, p less than 0.05). No particular relation was found between presenting circulating immune complex levels and tumor burden. Progressive circulating immune complex increases were demonstrated only in patients whose tumors were either completely removed or dramatically responded to regional therapy (that is, when the tumor antigen load, as reflected by the carcinoembryonic antigen value, rapidly diminished). Serum samples obtained at times of presumed antibody excess in the patients with gastrointestinal cancers were found to contain unexpectedly high concentrations of IgA. We believe these data demonstrate the kinetics of circulating immune complex change during tumor course and they have allowed us to begin to identify circulating immune complex components in patients with colorectal cancer. The results confirm our earlier findings in patients with gestational tumors and differ from accepted relations between immune complexes and tumor growth.

Antigen-Antibody Complex↗
PubMed1983

Clastogenic effects of heroin in pregnant monkeys and their offspring.

Heroin was administered daily i.v. to pregnant Macaca mulatta monkeys, for 3 months, and after birth of their babies, was continued for 3 months post-partum. The dose was gradually increased to as high as 1.5 mg/kg/day. Pregnant control animals were given saline injections following the same design. WBC cultures for analysis of sister-chromatid exchanges (SCEs) and chromosome aberrations were taken from all adult animals, prior to heroin or saline administration, and also after 6 months, at time of sacrifice. Cultures were also done for all babies, and bone marrow analyses of aberrations were done on all animals at sacrifice. Both heroin mothers and babies showed a doubling in SCE level over their respective controls, and the heroin mothers demonstrated an almost 3-fold increase over their initial cultures. Heroin babies had 10 times as many chromosome aberrations in their WBC cultures as did their controls, and an equivalent increase in their bone marrow cells. The heroin mothers' final WBC cultures showed an increase in chromosome aberrations both over that of their initial cultures and those of their controls. The heroin babies demonstrated greater sensitivity to heroin, compared with their mothers, as measured by chromosome aberrations, but a corresponding sensitivity to SCE induction. No correlation in SCE levels was detected between individual pairs of mothers and babies, but there was one between the groups of mothers and babies. The route(s) through which the chromosomal alterations were inflicted in the babies could be transplacental, through the mother's milk, or both. The results of this investigation correspond with those of several previous studies on addict populations, and demonstrate that under these conditions, heroin is a chromosomal mutagen.

Aneuploidy↗
PubMed1983

Comparative effects of indomethacin, prostaglandin E1, and ibuprofen on bowel ischemia.

This study evaluates the effects of Indomethacin (IND), Prostaglandin E1 (PGE1), and Ibuprofen (IBP) in a bowel ischemia model. Laparotomy was performed in 80-gram rats (n = 260). Transient ischemia was induced by a one minute occlusion of the superior mesenteric artery. Animals were placed in five experimental groups: (I) ischemic controls (n = 80), (II) PGE1, 80 micrograms/kg IV (n = 20), (III) IBP, 12.5 mg/kg IV (n = 60), (IV) IND 15 mg/kg IV (n = 80) and (V) PGE1 + IND (n = 20). All medications were given just prior to laparotomy. Animals were evaluated for survival, length of survival and the presence of bowel necrosis and/or perforation at seven days. Survival was 18% in controls and was reduced to 5% by IND (p less than .005). Improved survival was observed with PGE1 (35%), TBP (31%) and PGE1 + IND (35%). IND resulted in early death, while PGE1, IBP, and PGE1 + IND all increased the length of survival (p less than .05). IND-treated rats had a high incidence of bowel perforation (greater than 40%). PGE1 reversed this effect when given concomitantly with IND. IBP had a significantly lower incidence of intestinal necrosis. These data suggest that infants treated with IND who are at risk for NEC should be carefully monitored for evidence of bowel necrosis. PGE1 and IBP may have a cytoprotective role in subjects at risk for bowel ischemia.

Alprostadil↗
PubMed1983

Aorto-left ventricular communication after closure. Late postoperative problems.

The long-term follow-up of six patients operated on for aorto-left ventricular communication has been reviewed in detail. All had residual aortic regurgitation after the initial repair of the defect. It was severe in four and required repeated reoperation in three with ultimate aortic valve replacement. The failure of early repair to solve the haemodynamic problem has provoked a reconsideration of the basic anatomy, of the surgical approach, and of the postoperative physiology of this anomaly. The so called "tunnel" is not a tunnel with length but should be considered as a localised breach at the insertion of the right coronary cusp. The localised aortic root dilatation at the site is a weakness that remains after closure of the tunnel leaving a poorly supported aortic valve and a weak root. Thus, the initial repair of the aorto-left ventricular communication must not only close the communication but reinforce, strengthen, and support the right aortic sinus in order to maintain cusp competence.

Adult↗
PubMed1983

Isolated radial nerve lesion in the newborn.

Two newborn infants had isolated radial nerve lesion documented on electromygraphy. Fibrillation potentials present in one child at age 6 days suggest the possibility of an in utero onset. Skin necrosis present above the triceps muscle and radial nerve favors an entrapment mechanism, possibly from the umbilical cord. Because both patients had complete resolution in 4 months, it is important to differentiate this lesion form the more common but more serious medial brachial plexus lesion.

Electromyography↗