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Biomedical subjects

D Ross

Publications and source records attributed to D Ross.

At least 181 records · Page 10Linked to original sources
PubMed1993

Safety and efficacy of preoperative donation of blood for autologous use by patients with end-stage heart or lung disease who are awaiting organ transplantation.

Many patients are, perhaps inappropriately, denied the benefits of autologous blood transfusion, because they are thought to be too ill to donate blood safely. The safety and efficacy of autologous blood donation by selected patients with end-stage heart or lung disease who are awaiting organ transplantation were studied to determine if even these critically ill patients could be suitable candidates for autologous blood donation. Seventy-two adults awaiting heart or lung transplantation were evaluated for autologous blood donation in a hospital-based blood collection facility. Phlebotomy was performed if the patient met the required medical eligibility protocol, and if he or she consented to participate. Units of blood were separated into packed red cells and plasma and stored in a frozen state. Of 48 heart transplant candidates, 31 (65%) were each able to donate 1 to 8 units of blood. The median number of exposures to allogeneic components was 1 for patients who donated and 7 for nondonors (p = 0.0141). Among patients who donated, 54 percent required allogeneic components, as compared to 88 percent of nondonors (p = 0.0968). Of 24 lung transplant candidates, 15 (63%) made 1 to 6 donations each. The median number of exposures to allogeneic components was 0 for donors and 2 for nondonors (p = 0.1871), but only 45 percent of donors required allogeneic components, as compared to 100 percent of nondonors (p = 0.0418). No serious complications during or following phlebotomy were observed. It is concluded that autologous blood donation by patients with end-stage heart or lung disease may be safe.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Age and physical activity effects on reaction time and digit symbol substitution performance in cognitively active adults.

University professors (N = 56), divided into two age groups (< 50 years and > 50 years) and two physical activity level groups (high and low), were tested on three tasks requiring increasingly complex cognitive processing--simple reaction time (SRT), choice reaction time (CRT), and on a digit symbol substitution test (DSST). A significant main effect for exercise, with high active subjects performing better than low active subjects, was found for SRT (p < .001) and CRT (p < .01) but not for DSST (p < .09). Significant main effects for age, with younger subjects performing better than older subjects, were found on DSST (p < .01) and CRT (p < .05) but not for SRT (p < .09). The observation that the effect of age was more pronounced with increasing task complexity is consistent with previous research. However, the tendency for exercise effects to decrease with increasing task complexity is not consistent with former findings, suggesting that perhaps the controlled high level of cognitive activity of subjects in this study may have offset the usual effects of exercise on information processing speed. No significant Age x Activity Level interactions were found on any of the dependent raw score data. However, compared to normative scores of the population at large, there was a slight increase in DSST percentile ranks with age for the older aerobically active professors, whereas a decrease occurred for the inactive subjects.

Adult↗
PubMed1993

Peroxidase activation of hydroquinone results in the formation of DNA adducts in HL-60 cells, mouse bone marrow macrophages and human bone marrow.

Metabolism of benzene results in the formation of multiple metabolites, including hydroquinone (HQ). HQ is a reducing co-substrate for peroxidase enzymes, and the resultant semiquinone and para-benzoquinone (p-BQ) may bind to DNA. The role of peroxidase activation in the formation of DNA adducts by benzene metabolites has not been established. In this study we investigated the role of peroxidase activation in the formation of DNA adducts by HQ and p-BQ in HL-60 cells, human bone marrow (HBM) cells, mouse bone marrow macrophages (MBMM) and the U-937 and Raji leukemia cell lines. Adduct formation was measured by P1-enhanced 32P-postlabeling; peroxidase activity was measured with a spectrophotometric assay. Treatment with p-BQ resulted in the formation of two DNA adducts in all of the cell lines. The DNA adducts were identical in all of the cells, however, the adduct level varied by 80-fold. Treatment with HQ produced one DNA adduct in HL-60 cells, HBM and MBMM; no adducts were detected in U-937 or Raji cells. The HQ-DNA adducts in the three cell lines were identical. The adduct level was highest in the HL-60 cells, followed by HBM and MBMM. There was a statistically significant correlation between peroxidase activity and the formation of HQ-DNA adducts. These results suggest that peroxidase-mediated metabolism is involved in the activation of HQ to form DNA adducts in mouse bone marrow and HBM.

Animals↗
PubMed1993

Loss of drug effects during continuation therapy.

OBJECTIVE: This study sought to determine what proportion of relapses during continuation therapy with antidepressants can be attributed to loss of nonspecific placebo effects while the patients are taking the drugs. METHOD: Depressed patients were studied over a 12-week period. One hundred sixty-four patients were randomly assigned to placebo, 174 to imipramine, and 169 to phenelzine. At 6 weeks 35 were judged to be responders to placebo, 70 to imipramine, and 96 to phenelzine. These patients continued their double-blind treatment for weeks 7-12. RESULTS: Thirty-one percent of the patients who were taking placebo, approximately 12% who were taking imipramine, and approximately 9% who were taking phenelzine relapsed in the 7- to 12-week phase. Two different methods of estimating relapses suggested that during the first 3 months of treatment, a large percentage of the relapses of patients taking drugs was attributable to the loss of nonspecific placebo effects rather than true drug effects. CONCLUSIONS: A considerable proportion of relapses in the first 3 months of treatment with antidepressants appears to be due to loss of placebo effects. These clinically relevant data may be used to encourage patients who relapse during this period, and who erroneously conclude that anti-depressant effects are temporary, to try another medication.

Antidepressive Agents↗
PubMed1993

pH-dependent inactivation of DT-diaphorase by mitomycin C and porfiromycin.

Mitomycin C and porfiromycin were found to inactivate rat hepatic DT-diaphorase. Inactivation was pH dependent; little inactivation was detected at pH 5.8, but inactivation increased as the pH was raised to 7.8. Inactivation was concentration and time dependent and displayed pseudo-first-order kinetics. Inactivation was NADH dependent, indicating that reductive metabolism was necessary for inhibition. [3H]Mitomycin C was covalently bound to DT-diaphorase during inhibition, and the stoichiometry for inactivation of DT-diaphorase by mitomycin C was approximately 0.8 nmol of mitomycin C bound/nmol of enzyme. A higher molecular mass product (60 kDa) was detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot analysis of DT-diaphorase preincubated with NADH and mitomycin C at pH 7.8, suggesting that mitomycin C is capable of cross-linking DT-diaphorase. The kinetics of inhibition, requirement for NADH for inhibition, covalent binding of [3H] mitomycin C to DT-diaphorase, and approximate 1:1 stoichiometry suggest that this inactivation process may be mechanism based. Inhibition of DT-diaphorase by mitomycin C and porfiromycin is not limited to a cell-free system and could also be observed in HT-29 cells in culture at pH 7.2. Bioactivation of mitomycin C or porfiromycin by DT-diaphorase is favored at lower pH, whereas at higher pH values enzyme alkylation and inactivation of DT-diaphorase occur. These data suggest that the success of attempts to exploit the elevated DT-diaphorase content of certain human tumors for improved chemotherapeutic response using mitomycin C or porfiromycin will depend on intracellular pH.

Animals↗
PubMed1993

Mitomycin C.

In conclusion, recent work has highlighted the fact that NSCLCs have elevated levels of NQO1 activity and that such an increase represents an excellent target for therapeutic exploitation. The 5-year survival rate seen with lung cancer is dismal and there is a high number of cancer deaths associated with this disease each year. This renders the design of molecules that can be activated by NQO1 (such as MeDZQ or CB 10-200) an extremely important and urgent issue.

Carcinoma, Non-Small-Cell Lung↗
PubMed1992

Bioreductive activation of mitomycin C by DT-diaphorase.

The role of DT-diaphorase (DTD, EC 1.6.99.2) in the bioreductive activation of mitomycin C was examined using purified rat hepatic DTD. The formation of adducts with reduced glutathione (GSH), binding of [3H]mitomycin C to DNA, and mitomycin C-induced DNA interstrand cross-linking were used as indicators of bioactivation. Mitomycin C was metabolized by DTD in a pH-dependent manner with increasing amounts of metabolism observed as the pH was decreased from 7.8 to 5.8. The major metabolite observed during DTD-mediated reduction of mitomycin C was 2,7-diaminomitosene. GSH adduct formation, binding of [3H]mitomycin C and mitomycin C-induced DNA interstrand cross-linking were observed during DTD-mediated metabolism. In agreement with the pH dependence of metabolism, increased bioactivation was observed at lower pH values. Temporal studies and experiments using authentic material showed that 2,7-diaminomitosene could be further metabolized by DTD resulting in the formation of mitosene adducts with GSH. DNA cross-linking during either chemical (sodium borohydride) or enzymatic (DTD) mediated reduction of mitomycin C could be observed at pH 7.4, but it increased as the pH was decreased to 5.8, showing the critical role of pH in the cross-linking process. These data provide unequivocal evidence that the obligate two-electron reductase DTD can bioactivate mitomycin C to reactive species which can form adducts with GSH and DNA and induce DNA cross-linking. The use of mitomycin C may be a viable approach to the therapy of tumors high in DTD activity, particularly when combined with strategies to lower tumor pH.

Animals↗
PubMed1992

Exercise tolerance in panic disorder patients.

Sixteen panic patients and fifteen normal controls performed submaximal exercise testing on a bicycle ergometer. Only one patient subject panicked. Biochemical, physiological, and psychological data showed similar exercise tolerance in both patients and controls. Exercise-induced distress and lactate increment do not appear to cause panic attacks.

Adult↗
PubMed1992

Alteration in DNA cross-linking and sequence selectivity of a series of aziridinylbenzoquinones after enzymatic reduction by DT-diaphorase.

DT-diaphorase (DTD) mediated reduction of a series of 2,5-bis-substituted-3,6-diaziridinyl-1,4-benzoquinones was found to increase the level of DNA interstrand cross-linking (ISC) formed at neutral pH with an enhancement observed as the pH was decreased to 5.8. The analogues used were symmetrically alkyl-substituted carbamoyl ester analogues of AZQ (D1-D7), 3,6-diaziridinyl-1,4-benzoquinone (DZQ), the 2,5-dimethyl derivative (MeDZQ), and a 2,5-bis[(2-hydroxyethyl)amino] analogue (BZQ). At pH 5.8, the level of DNA ISC induced by enzymatic reduction was as follows: DZQ greater than MeDZQ much greater than D1 (methyl) greater than D3 (n-propyl) greater than D2 (AZQ; ethyl) greater than D5 (n-butyl) greater than D7 (sec-butyl) greater than D4 (isopropyl) D6 greater than (isobutyl). A similar trend was observed at pH 7.2. The level of DNA ISC induced by BZQ, which is not a substrate for DTD, was not increased by enzymatic reduction. Dicumarol, a known inhibitor of DTD, was capable of inhibiting the DNA ISC induced by these quinones upon enzymatic reduction. MeDZQ and DZQ reacted with guanines, as measured by Maxam and Gilbert sequencing, with a sequence selectivity similar to that of the nitrogen mustard class of antitumor agents. Enzymatic reduction of DZQ and MeDZQ by DTD was found to alter their sequence-selective alkylation. Reduced DZQ showed enhanced guanine alkylation in 5'-GC-3' sequences and new sites of adenine alkylation in 5'-(A/T)AA-3' sequences. Reduced MeDZQ only showed new sites of adenine alkylation at 5'-(A/T)AA-3' sequences but no enhancement of guanine alkylation. The new sites of adenine alkylation were found to be inhibited in the presence of magnesium and rapidly converted into apurinic sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkylation↗
PubMed1992

NAD(P)H:quinone oxidoreductase gene expression in human colon carcinoma cells: characterization of a mutation which modulates DT-diaphorase activity and mitomycin sensitivity.

NAD(P)H:quinone oxidoreductase (DT-diaphorase; DTD) is an obligate two-electron reductase which may play a role in the bioactivation of antitumor quinones such as mitomycin C (MMC). We studied 10 colon carcinoma cell lines showing different levels of DTD activity (range, 0-3447 nmol/min/mg protein), as measured by the reduction of dichlorophenolindophenol. Expression of the NAD(P)H:quinone reductase gene (NQO1), which codes for the DTD enzyme, as measured by a polymerase chain reaction amplification technique was then correlated with enzymatic activity in all cell lines. HT-29 cells, which have intermediate DTD activity (769 +/- 144 nmol/min/mg protein, mean +/- SD) and are sensitive to MMC, showed high NQO1 expression relative to beta-actin (taken as 100% here for comparative purposes). BE cells which have no detectable DTD activity and are resistant to MMC showed moderate NQO1 expression (91% of HT-29). RNA single-strand conformational polymorphism analysis and subsequent sequencing of BE complementary DNA revealed a C to T mutation in the NQO1 complementary DNA. This confers a proline to serine substitution in the amino acid sequence of the protein. Additionally, HCT-116 cells showed both moderate DTD activity (390 +/- 41 nmol/min/mg protein) and NQO1 expression (41% of HT-29), while resistant subclones of these cells, exposed to MMC during 11 and 44 weeks, showed low gene expression (5 and 9% of HT-29 respectively) and enzymatic activity (11 +/- 6 and 36 +/- 16 nmol/min/mg protein). These results support the ideas that reductive activation of MMC by DTD may be important in the cytotoxicity of MMC and that polymerase chain reaction may be a useful technique for quantitating the relative expression of genes in human tumors.

Actins↗
PubMed1992

Neurotoxic components in normal serum.

Serum neurotoxicity was studied by adding whole or fractionated serum (adult human, adult horse, or newborn calf) to neuron-rich cultures prepared from various regions of embryonic (Days 14-15) rat brain, including spinal cord, ventral mesencephalon, cerebellum, septum, and striatum. Effects of serum were also tested on several types of embryonic non-neuronal cells (skeletal muscle myotubes, cardiac muscle myocytes, and fibroblasts from skin and lung). Serum concentrations of 50% or more killed more than 95% of all neurons within 3 days. Serum concentrations as low as 10% also killed some neurons, especially those from cerebellum. Septal, cerebellar, and spinal cord neurons were more sensitive than striatal or mesencephalic neurons. All the tested non-neuronal cells survived much better than neurons at serum concentrations of 20% or more. Neurotoxicity was present in both fresh (human) and previously frozen (human and animal) sera, and affected both young (4 days in vitro) and older (42 days in vitro) cultures. Neurotoxicity was greatly diminished by heating the serum to 56 degrees C for 30 min. Experiments indicated that serum toxicity was not due to lipoprotein, complement, or tumor necrosis factor. All serum neurotoxicity was retained by an ultrafilter with a nominal molecular weight cutoff of 10 kDa. The profile of neurotoxicity following gel filtration at neutral pH was variable, with high toxicity most consistently observed in fractions with apparent molecular weights exceeding 100 kDa, and variable degrees of toxicity at lower molecular weights.

Animals↗
PubMed1992

Metabolism of trans,trans-muconaldehyde by aldehyde and alcohol dehydrogenases: identification of a novel metabolite.

The metabolism of trans,trans-muconaldehyde (MA), a highly reactive alpha,beta-unsaturated dialdehyde, was examined in vitro using purified yeast alcohol and aldehyde dehydrogenases (ADH and ALDH, respectively). In the presence of NAD(+)-fortified ALDH, the mono-oxidation product (acid/aldehyde) was the primary metabolite formed with trace amounts of the dioxidation product (trans,trans-muconic acid). In NADH-fortified reactions with ADH, both the mono- and direduction products (hydroxy/aldehyde and dihydroxy, respectively) were readily detected. Oxidation and reduction products of MA were formed in incubates containing both dehydrogenases together with either NAD+ or NADH. Unexpectedly, an additional metabolite was detected, which was a major product in both NAD(+)- and NADH-fortified systems containing ALDH and ADH in combination and whose formation could be inhibited by pyrazole (an ADH inhibitor). ALDH-mediated oxidation of a synthetic standard of the hydroxy/aldehyde derivative of MA resulted in formation of this new metabolite, which was also a major product formed by rat hepatocytes incubated with MA. Using HPLC/photodiode array detection, the new metabolite was found to cochromatograph and have a uv spectrum identical to that of a synthetic standard of the hydroxy/acid derivative of MA. The metabolite was confirmed as the hydroxy/acid derivative of MA after preparative HPLC, TMS derivatization, and GC/MS analysis. The hydroxy/acid metabolite was not formed during ADH-mediated reduction of the mono-oxidation product of MA, suggesting that this metabolite was formed by yeast dehydrogenases via a primary reduction of MA and subsequent oxidation of the hydroxy/aldehyde to the hydroxy/acid. These data show that the hydroxy/acid derivative is a novel metabolite of MA, which arises from the interaction of both oxidative and reductive routes of metabolism.

Alcohol Dehydrogenase↗
PubMed1992

Fatigue syndrome due to localized radiation.

For cancer patients, fatigue is a disturbing symptom caused by many factors. Since fatigue is the most common side effect of localized radiation to the breast, this treatment provides a unique opportunity to follow patients prospectively as they develop one type of fatigue. We evaluated the effect of radiation treatment in 15 women with Stage I or II node-negative breast cancer who were otherwise healthy. Fatigue, contrary to our hypothesis, did not increase linearly with cumulative radiation dose over time. It dropped from the first to second week and rose in the third week. The cumulative effects reached a plateau in the fourth week (after an average of 17 fractions), which was maintained during the remaining weeks of treatment. Within 3 wk after treatment, fatigue had diminished. No patient had sustained depressive symptoms. Cardiopulmonary exercise capacity in 5 patients at 6 and 12 wk did not change from just before radiation. Other markers, including reverse triiodothyronine and pulse change with orthostatic stress, did not correlate with subjective fatigue nor cumulative radiation in 15 patients. The curve of the fatigue syndrome during treatment conforms to the adaptation of the organism to a continuing stress and begins to describe a mild fatigue syndrome associated with radiation.

Adult↗