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D Ross

Publications and source records attributed to D Ross.

At least 37 records · Page 2Linked to original sources
PubMed2000

NAD(P)H:quinone oxidoreductase 1 (NQO1): chemoprotection, bioactivation, gene regulation and genetic polymorphisms.

NAD(P)H:quinone oxidoreductase 1 (NQO1) is an obligate two-electron reductase that is involved in chemoprotection and can also bioactivate certain antitumor quinones. This review focuses on detoxification reactions catalyzed by NQO1 and its role in antioxidant defense via the generation of antioxidant forms of ubiquinone and vitamin E. Bioactivation reactions catalyzed by NQO1 are also summarized and the development of new antitumor agents for the therapy of solid tumors with marked NQO1 content is reviewed. NQO1 gene regulation and the role of the antioxidant response element and the xenobiotic response element in transcriptional regulation is summarized. An overview of genetic polymorphisms in NQO1 is presented and biological significance for chemoprotection, cancer susceptibility and antitumor drug action is discussed.

Animals↗
PubMed2000

Charged-particle multiplicity near midrapidity in central Au+Au collisions at sqrt[SNN]=56 and 130 GeV.

We present the first measurement of pseudorapidity densities of primary charged particles near midrapidity in Au+Au collisions at sqrt[s(NN)] = 56 and 130 GeV. For the most central collisions, we find the charged-particle pseudorapidity density to be dN/deta|(|eta|<1) = 408+/-12(stat)+/-30(syst) at 56 GeV and 555+/-12(stat)+/-35(syst) at 130 GeV, values that are higher than any previously observed in nuclear collisions. Compared to proton-antiproton collisions, our data show an increase in the pseudorapidity density per participant by more than 40% at the higher energy.

Journal Article↗
PubMed2000

Caspase-dependent and -independent mechanisms in apoptosis induced by hydroquinone and catechol metabolites of remoxipride in HL-60 cells.

The hydroquinone and catechol like metabolites, NCQ344 and NCQ436 respectively, of the antipsychotic remoxipride have recently been demonstrated to induce apoptosis in myeloperoxidase (MPO)-rich human bone marrow progenitor and HL-60 cells [S.M. McGuinness, R. Johansson, J. Lundstrom, D. Ross, Induction of apoptosis by remoxipride metabolites in HL-60 and CD34+/CD19- human bone marrow progenitor cells: potential relevance to remoxipride-induced aplastic anemia, Chem. Biol. Interact. 121 (1999) 253-265]. In the present study, we determined the molecular mechanisms of apoptosis induced by these remoxipride metabolites in HL-60 cells. Our results show that apoptosis was accompanied by phosphatidylserine (PS) exposure, activation of caspases-9, -3, -7 and DNA cleavage. In HL-60 cells treated with the hydroquinone NCQ344 and catechol NCQ436, the general caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp. fluoromethyl ketone (Z-VAD.FMK) blocked DNA cleavage and activation of caspases-9, -3/-7. In addition, PS exposure was significantly but not completely inhibited by Z-VAD.FMK. These results demonstrate that although Z-VAD.FMK inhibitable caspases are necessary for maximal apoptosis induced by NCQ344 and NCQ436, additional caspase-independent processes may orchestrate changes leading to PS exposure during apoptosis induced by the remoxipride polyphenolic metabolites.

Amino Acid Chloromethyl Ketones↗
PubMed2000

Syndromic treatment of sexually transmitted diseases reduces the proportion of incident HIV infections attributable to these diseases in rural Tanzania.

OBJECTIVES: To compare the proportion of HIV seroconversions attributable to other sexually transmitted diseases in the intervention and comparison arms of the Mwanza sexually transmitted diseases (STD) intervention trial. DESIGN: Case-control study of 96 cases of HIV seroconversion and 974 HIV-negative controls, nested within the Mwanza trial cohort. METHODS: Data on reported STD symptoms during 2 years of follow-up, and serological evidence of recent syphilis, were used to obtain odds ratios (ORs) for HIV seroconversion, adjusted for community, age, marital status, sex partners and travel. Population-attributable fractions (PAF) of HIV seroconversions associated with these STD exposures were calculated separately for the intervention and comparison arms, and for men and women. RESULTS: In men in the comparison arm, adjusted ORs for ulcers (14.8), discharge (3.3), any symptom (4.1) and any STD (4.0) were highly significant. There were no significant associations between HIV incidence and STD exposures in the intervention arm. The PAF were consistently higher in the comparison arm than the intervention arm. In men, the PAF for any STD was 39.6% [95% confidence interval (CI), 12.4-58.3)] in the comparison arm but only 12.0% (CI, 0.0-35.9) in the intervention arm. The PAF for women were lower than for men. CONCLUSIONS: These are minimal PAF estimates and they do not account for STD effects on HIV infectiousness. Nevertheless, a substantial proportion of new HIV infections in men in the comparison arm were attributable to STD. Lower PAF in the intervention arm than in the comparison arm for men provide further evidence of the role of STD cofactors in HIV transmission, supporting the hypothesis that the Mwanza intervention reduced the duration of symptomatic STD, thus reducing the HIV risk associated with such STD.

Adolescent↗
PubMed2000

Structures of recombinant human and mouse NAD(P)H:quinone oxidoreductases: species comparison and structural changes with substrate binding and release.

NAD(P)H/quinone acceptor oxidoreductase (QR1, NQO1, formerly DT-diaphorase; EC ) protects animal cells from the deleterious and carcinogenic effects of quinones and other electrophiles. In this paper we report the apoenzyme structures of human (at 1.7-A resolution) and mouse (2.8 A) QR1 and the complex of the human enzyme with the substrate duroquinone (2.5 A) (2,3,5, 6-tetramethyl-p-benzoquinone). In addition to providing a description and rationale of the structural and catalytic differences among several species, these structures reveal the changes that accompany substrate or cofactor (NAD) binding and release. Tyrosine-128 and the loop spanning residues 232-236 close the binding site, partially occupying the space left vacant by the departing molecule (substrate or cofactor). These changes highlight the exquisite control of access to the catalytic site that is required by the ping-pong mechanism in which, after reducing the flavin, NAD(P)(+) leaves the catalytic site and allows substrate to bind at the vacated position. In the human QR1-duroquinone structure one ring carbon is significantly closer to the flavin N5, suggesting a direct hydride transfer to this atom.

Amino Acid Sequence↗
PubMed2000

Relationship of temporal lobe seizures to sleep and arousal: a combined scalp-intracranial electrode study.

STUDY OBJECTIVES: The role of arousal from sleep in promoting epileptic seizures is controversial. To examine the question of whether seizures precede or follow arousals from sleep, we defined the timing of temporal lobe seizures in relation to sleep and arousal using combined scalp-intracranial electrodes. DESIGN: Retrospective review of 67 sleep-related mesial temporal lobe seizures in 14 subjects. SETTING: Inpatient epilepsy monitoring laboratory. PATIENTS: Subjects with medically refractory mesial temporal lobe seizures undergoing epilepsy surgery evaluations. INTERVENTIONS: None MEASUREMENTS AND RESULTS: Electroencephalographic (EEG) and/or polygraphic recordings and videotapes were independently reviewed to determine intracranial electrode seizure onset times and time of initial arousal from sleep. In 60 seizures in 13 subjects, intracranial ictal onsets always preceded clinical arousals from sleep. Electrographic signs of arousal in the scalp EEG, defined by the presence of sustained alpha or theta activity, either coincided with or followed, but never preceded, intracranial ictal onsets. In seven seizures in one subject with known seizures upon awakening, intracranial ictal onsets always followed clinical arousals and electrographic signs of arousal from sleep. Seven of the 14 subjects had electrooculogram and chin electromyogram monitoring; in these subjects, no seizures occurred during REM sleep with the majority occurring during NREM stage 2 sleep. CONCLUSIONS: Most sleep-related temporal lobe seizures occurred during NREM sleep and preceded arousals, supporting the premise that processes involved in the initiation and maintenance of NREM sleep play a greater role in facilitating temporal seizures than those involved in promoting REM sleep and arousal. However, arousal from sleep may provoke seizures in exceptional cases.

Electrodes↗
PubMed2000

Mouse genetics/genomics: an effective approach for drug target discovery and validation.

The mouse has become the premier mammalian system for the identification of the genetic basis of both mono- and oligogenic disorders, as well as the understanding of complex diseases with gene-gene and gene-environment interactions. The similarity between human and mouse genetic disease is sometimes striking, while in other cases the phenotypes are less similar. The ability to genetically map and then clone single gene disorders rapidly, and the emerging technologies that will allow the economical identification of the polygenes controlling quantitative traits further demonstrate the utility of the mouse as a model for gene discovery. Additionally, the ability to genetically manipulate the mouse through transgenesis and gene targeting allows for the testing of hypotheses regarding specific gene function and their role in disease. The utility of the mouse extends beyond being just a gene discovery tool to provide prevalidated targets. It can also be used for the development of animal models, and the testing of compounds in specifically constructed transgenic and knockout strains to further define the target and pathway of a therapeutic compound.

Amino Acid Sequence↗
PubMed2000

Using discrete choice modelling in priority setting: an application to clinical service developments.

Limited resources for health care means that techniques are required to aid the process of priority setting. This paper represents one of the first attempts to use discrete choice modelling (DCM) within the area of priority setting. It is shown how the technique can be used to estimate cost per unit of benefit ratios for competing clinical service developments. Integer programming is proposed as a method to be used, alongside DCM, to help policy makers select the optimal combination of clinical service developments within a given budget. The technique is also shown to be internally valid and internally consistent. It is argued that DCM is a potentially useful technique to be used within the area of priority setting more generally. However, further work is required to address methodological issues around the technique.

Adult↗
PubMed2000

Immunodetection of NAD(P)H:quinone oxidoreductase 1 (NQO1) in human tissues.

Despite the extensive interest in NADPH:quinone oxidoreductase (NQO1, DT-diaphorase), there is little immunohistochemical information regarding its distribution in either normal human tissues or in human tumors. Using immunohistochemistry (IHC), we have examined cell-specific expression of NQO1 in many normal tissues and tumors as a step toward defining the distribution of NQO1 in humans. NQO1 was detected by IHC in respiratory, breast duct, thyroid follicle, and colonic epithelium, as well as in the corneal and lens epithelium of the eye. NQO1 was also detected by IHC in vascular endothelium in all tissues examined. NQO1 could also readily be detected in the endothelial lining of the aorta but was not detected using immunoblot analysis in the myocardium. Adipocytes stained positive for NQO1, and the enzyme was also detected by both IHC and immunoblot analysis in parasympathetic ganglia in the small intestine and in the optic nerve and nerve fibers. NQO1 was not highly expressed in five different human liver samples using immunoblot analysis, whereas studies using IHC demonstrated only trace NQO1 staining in isolated bile duct epithelium. NQO1 expresion was also examined by IHC in a variety of solid tumors. Marked NQO1 staining was detected in solid tumors from thyroid, adrenal, breast, ovarian, colon, and cornea and in non-small cell lung cancers. The NQO1 content of many solid tumors supports the use of NQO1-directed anticancer agents for therapeutic purposes, but the distribution of NQO1 in normal tissues suggests that potential adverse effects of such agents need to be carefully monitored in preclinical studies.

Antibodies, Monoclonal↗
PubMed2000

Prospective validation of a standardized questionnaire for estimating childhood mortality and morbidity due to pneumonia and diarrhoea.

This paper reports the validation of a 'best-judgement' standardised questionnaire using guidelines and algorithms developed by an expert working group conducted in Nicaragua between 1995 and 1997. Prospective hospital data, including standardised medical recording of selected signs and symptoms, laboratory and radiographic test results and physician diagnoses were collected for children < 5 years admitted with any serious life-threatening condition in 3 study hospitals. The mothers or caregivers of the children were later traced and interviewed using the 'best-judgement' questionnaire. Interviews were completed 1-22 months after admission to hospital for 1115 children (400 who died during the stay in hospital and 715 who were discharged alive). The cause of death or admission to hospital was determined by an expert algorithm applied to hospital data. A similar procedure was used to derive the cause using the answers to questions from interviews. Hospital causes were compared with interview causes and sensitivity and specificity calculated, together with the estimated cause-specific fraction for diarrhoea and pneumonia. Multiple diagnoses were allowed; 378 children in the sample (104 deaths, 274 survivors) had a reference diagnosis of diarrhoeal illness, and 506 (168 deaths, 338 survivors) a reference diagnosis of pneumonia. When results for deaths and survivors in all age groups were combined, the expert algorithms had sensitivity between 86% and 88% and specificity between 81% and 83% for any diarrhoeal illness; and sensitivity between 74% and 87% and specificity between 37% and 72% for pneumonia. Algorithms tested in previous validation studies were also applied to data obtained in this study, and the results are compared. Despite less than perfect sensitivity and specificity, reasonably accurate estimates of the cause-specific mortality and morbidity fractions for diarrhoea were obtained, although the accuracy of estimates in other settings using the same instrument will depend on the true cause-specific fraction in those settings. The algorithms tested for pneumonia did not produce accurate estimates of the cause-specific fraction, and are not recommended for use in community settings.

Algorithms↗
PubMed2000

Effects of oral and transdermal 17beta-estradiol with cyclical oral norethindrone acetate on insulin sensitivity, secretion, and elimination in postmenopausal women.

Few studies have examined the effects of 17beta-estradiol on parameters of insulin and glucose metabolism. We studied 42 healthy, untreated postmenopausal women seeking relief from menopausal symptoms. They were randomized to receive either oral 17beta-estradiol 2 mg daily combined with sequential oral norethindrone acetate (NETA) 1 mg daily from days 12 to 22, or transdermal 17beta-estradiol 0.05 mg daily combined with sequential oral NETA 1 mg daily from days 17 to 28. Intravenous glucose tolerance tests (IVGTTs) were performed at baseline and after 46 weeks (estrogen-alone phase) and 48 weeks (combined phase) of completed therapy. Mathematical modeling analysis of plasma glucose, insulin, and C-peptide concentration profiles provided measures of insulin resistance, secretion, and elimination. Both types of therapy were associated with a decrease in fasting insulin and glucose levels. Insulin sensitivity was increased by oral estradiol during the estrogen-alone phase but was reversed by the addition of NETA. Transdermal estradiol did not affect insulin sensitivity. Hepatic insulin uptake and insulin secretion were increased with both types of treatment. The oral regimen of estradiol therapy was favorable to both insulin elimination and sensitivity. Transdermal estradiol therapy had relatively few effects on insulin metabolism.

Administration, Cutaneous↗
PubMed2000

Sinonasal undifferentiated carcinoma: case series and review of the literature.

OBJECTIVE AND IMPORTANCE: We report on four cases of sinonasal undifferentiated carcinoma (SNUC), a relatively newly described clinicopathological entity of the nasal cavity and paranasal sinuses. SNUC tends to present with advanced-stage disease, often with intracranial invasion, and requires an aggressive treatment approach that includes surgical resection. A review of the literature identified several reports of SNUC in pathology and otolaryngology journals since its initial description in 1986, but no report has yet appeared in the neurosurgery literature. CLINICAL PRESENTATION: Four patients presented with various symptoms related to the nose and/or orbit, including one or more of the following: obstruction, epistaxis, decreased visual acuity, diplopia, and pain. All patients were noted to have masses in the nasal cavity or paranasal sinuses, with or without intracranial extension. INTERVENTION: All four patients underwent multimodal treatment with chemotherapy, radiotherapy (60-65 Gy), and aggressive surgical resection via a combined bifrontal craniotomy and a subcranial approach to the anterior cranial fossa. Three of four patients died as a result of their disease, an average of 15 months after diagnosis. Only one patient remains alive, although with metastatic intracranial disease, at 24 months after diagnosis. CONCLUSION: SNUC is a rare neoplasm with a poor prognosis despite an aggressive multimodal approach to treatment. On the basis of our experience, we advocate radical resection as part of the initial combined therapy for patients who present with locally advanced, nonmetastatic disease but we suggest reserving surgery for patients with early brain invasion until there has been a radiographically proven central nervous system response to adjuvant therapy.

Adult↗
PubMed2000

Sequence analysis of the ank gene of granulocytic ehrlichiae.

The ank gene of the agent of human granulocytic ehrlichiosis (HGE) codes for a protein with a predicted molecular size of 131.2 kDa that is recognized by serum from both dogs and humans infected with granulocytic ehrlichiae. As part of an effort to assess the phylogenetic relatedness of granulocytic ehrlichiae from different geographic regions and in different host species, the ank gene was PCR amplified and sequenced from a variety of sources. These included 10 blood specimens from patients with confirmed human granulocytic ehrlichiosis (three from New York, four from Wisconsin, two from Slovenia, and one from Sweden). Also examined was a canine granulocytic ehrlichia sample obtained from Minnesota, Ehrlichia equi from California, Ehrlichia phagocytophila from Sweden, and the granulocytic ehrlichia isolate USG3. The sequences showed a high level of homology (>95.5% identity), with the lowest homology occurring between a New York HGE agent and the Swedish E. phagocytophila. Several 3-bp deletions and a variable number of 51- and 81-bp direct repeats were noted. Although the North American HGE sequences showed the highest conservation (>98.1% identity), phylogenetic analyses indicated that these samples represent two separate clades, one including the three New York HGE samples and the USG3 strain and another with the Wisconsin HGE and Minnesota canine sequences. Two of the New York samples and the USG3 strain showed 100% identity over the entire 3,696-bp product. Likewise, three of the Wisconsin human samples and the Minnesota dog sample were identical (3,693 bp). Whereas phylogenetic analysis showed that the E. equi sequence was most closely related to the Upper Midwest samples, analysis of the repeat structures showed it to be more similar to the European samples. Overall, the genetic analysis based on the ank gene showed that the granulocytic ehrlichiae are closely related, appear to infect multiple species, and can be grouped into at least three different clades, two North American and one European.

Adult↗
PubMed2000

Effect of a low calcium dialysate on parathyroid hormone secretion in diabetic patients on maintenance hemodialysis.

Diabetic patients on maintenance dialysis often are characterized by a relative parathyroid hormone (PTH) deficiency and a form of renal osteodystrophy with low bone turnover known as adynamic bone. The goal of the present study was to determine whether a reduction in the dialysate calcium concentration would increase the predialysis (basal) PTH and maximal PTH level. Thirty-three diabetic maintenance hemodialysis patients with basal PTH values less than 300 pg/ml were randomized to be dialyzed with either a regular (3.0 mEq/liter or 3.5 mEq/liter, group I) or low (2.25 mEq/liter or 2.5 mEq/liter, group II) calcium dialysate for 1 year. At baseline and after 6 months and 12 months of study, low (1 mEq/liter) and high (4 mEq/liter) calcium dialysis studies were performed to determine parathyroid function. At baseline, basal (I, 126+/-20 vs. II, 108+/-19 pg/ml) and maximal (I, 269 pg/ml+/-40 pg/ml vs. II, 342 pg/ml+/-65 pg/ml) PTH levels were not different. By 6 months, basal (I, 98+/-18 vs. II, 200+/-34 pg/ml, p = 0.02) and maximal (I, 276 pg/ml+/-37 pg/ml vs. II, 529 pg/ml+/-115 pg/ml; p = 0.05) PTH levels were greater in group II. Repeated measures analysis of variance (ANOVA) of the 20 patients who completed the entire 12-month study showed that only in group II patients were basal PTH (p = 0.01), maximal PTH (p = 0.01), and the basal/maximal PTH ratio (p = 0.03) different; by post hoc test, each was greater (p < 0.05) at 6 months and 12 months than at baseline. When study values at 0, 6, and 12 months in all patients were combined, an inverse correlation was present between basal calcium and both the basal/maximal PTH ratio (r = -0.59; p < 0.001) and the basal PTH (r = -0.60; p < 0.001). In conclusion, in diabetic hemodialysis patients with a relative PTH deficiency (1) the use of a low calcium dialysate increases basal and maximal PTH levels, (2) the increased secretory capacity (maximal PTH) during treatment with a low calcium dialysate suggests the possibility of enhanced parathyroid gland growth, and (3) the inverse correlation between basal calcium and both the basal/maximal PTH ratio and the basal PTH suggests that the steady-state PTH level is largely determined by the prevailing serum calcium concentration.

Calcium↗
PubMed2000

Immunohistochemical localization of NQO1 in epithelial dysplasia and neoplasia and in donor eyes.

PURPOSE: To examine the expression of NAD(P)H:quinone oxidoreductase 1 (NQO1, DT-diaphorase), a potential bioactivating enzyme for mitomycin C in corneal and conjunctival epithelial dysplasia and neoplasia and in normal tissues from human donor eyes, by immunohistochemistry. METHODS: Formalin-fixed, paraffin-embedded sections of human donor eyes and tissue sections with histologic diagnoses of corneal and conjunctival epithelial dysplasia and neoplasia from the Eye Pathology Laboratory, University of Colorado Health Sciences Center were analyzed. Detection of NQO1 in tissues was performed using standard immunohistochemical techniques with monoclonal antibodies against NQO1 and immunoperoxidase staining. RESULTS: All 20 tumors stained positive for NQO1. In seven eyes from four donors, positive staining for NQO1 was detected in all epithelial and endothelial layers, in fibroblasts, in all retinal layers except the photoreceptor outer segments, and in the fascicles and arachnoid of the optic nerve. Only minimal staining was detected in the photoreceptor outer segments and the optic nerve pia and dura. Immunostaining was markedly reduced in all tissues in both eyes from donor 5. Genetic analysis confirmed that this individual was homozygous for a polymorphism in NQO1 (NQO1*2). CONCLUSIONS: NQO1 was detected by immunohistochemistry in every examined section of corneal and conjunctival epithelial dysplasia and neoplasia, suggesting that NQO1 may play a role in the bioactivation of mitomycin C in these tumors. However, the presence of NQO1 in the corneal, conjunctival, and ciliary epithelium; the retinas; and the optic nerves of donor eyes may indicate the potential for mitomycin C toxicity, particularly at higher doses.

Antibodies, Monoclonal↗
PubMed2000

Resource allocation and budgetary mechanisms for decentralized health systems: experiences from Balochistan, Pakistan.

This paper identifies key political and technical issues involved in the development of an appropriate resource allocation and budgetary system for the public health sector, using experience gained in the Province of Balochistan, Pakistan. The resource allocation and budgetary system is a critical, yet often neglected, component of any decentralization policy. Current systems are often based on historical incrementalism that is neither efficient nor equitable. This article describes technical work carried out in Balochistan to develop a system of resource allocation and budgeting that is needs-based, in line with policies of decentralization, and implementable within existing technical constraints. However, the development of technical systems, while necessary, is not a sufficient condition for the implementation of a resource allocation and decentralized budgeting system. This is illustrated by analysing the constraints that have been encountered in the development of such a system in Balochistan.

Budgets↗