Biomedical subjects
Publications and source records attributed to M Burke.
A recent report shows that zerumbone (ZER) inhibits the proliferation of, and induces apoptosis in, colon cancer cells. We suggest a mechanism for these phenomena, based on our recently proposed redox model of cell proliferation which stresses the importance of intracellular redox potential E in the control of proliferation of normal and cancer cells.
There is current interest in the health benefits of dietary carotenoids and the possible deleterious effects on certain sub-populations such as smokers. Here we report in vivo protection of human lymphocytes, conferred by dietary supplementation of lycopene rich foods against the reactive oxygen species, NO(2)(*) radical (by electron transfer) and 1(O)(2) (by energy transfer). It was found that a lycopene rich diet, maintained for 14 days, increased the serum lycopene level 10 fold compared to serum obtained after the same period, where a typical western European diet had been consumed. Relative lymphocyte protection factors of 17.6 and 6.3 against NO(2)(*) radical and 1(O)(2), respectively, were obtained, which re-enforce epidemiological data, showing protection against several chronic diseases by tomato lycopene.
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A variety of chemical substances are known to stop cell proliferation, although the mechanisms are obscure. We suggest that many of these chemicals employ the braking power of the retinoblastoma (RB) protein to stop proliferation by raising the intracellular redox potential. The elevation of the redox potential above a threshold prevents the phosphorylation of RB protein, which in turn impedes the release of transcription factors necessary for the progression of the cell cycle. The redox potential of normal proliferating fibroblasts has been found to be below that of fibrosarcoma cells. The possibility thus exists that, for cells with this property, the dosage of a redox-raising agent can be adjusted to stop cancer-cell proliferation without affecting the proliferation of normal cells.
OBJECTIVE: To compare drug-resistant variants from untreated (naive) and treated patients infected with clade B or C virus. METHODS: Consecutive samples (165) from patients throughout Israel were analyzed. All those in the treated group were failing highly active antiretroviral therapy. RESULTS: There were 87 clade B (14 naive) and 78 clade C (20 naive) [corrected] with significant differences in the prevalence of known drug-resistance mutations between the clades: in naive patients in the protease region M36I 7% and 95% (P < 0.0001), K20R 0% and 27% (P = 0.063), A71V 18% and 0% (P = 0.063), M46I 0% and 13%, and V77I 18% and 0% (P = 0.063), respectively, and in the reverse transcriptase region A98G/S 0% and 20% (P = 0.12), respectively. Most clade C viruses also showed significant differences from clade B consensus sequence at additional protease sites: R41K 100%, H69K/Q 85%, L89M 95% and I93L 80% (P < 0.0001). There were also significant differences (P < 0.03 to < 0.0001) in treated patients in clades B and C: in the protease region L10I 40% and 12%, M36I 26% and 95%, L63P 67% and 40%, A71I 38% and 7%, G73I and V77I 18% and 0%, I84V 16% and 3%, and L90M 40% and 12%, respectively; in the reverse transcriptase M41L 41% and 17%, D67N 41% and12%, K70R 30% and 7%, T215Y 48% and 29%, K219Q 21% and 7%, and A98G/S 3% and 24%, respectively. CONCLUSION: Significantly differences between clade B and C viruses may be associated with development of differing resistance patterns during therapy and may affect drug utility in patients infected with clade C.
The tendency for patients with antiphospholipid syndrome (APLS) to thromboembolism and the criteria for its detection are well established, whereas the mechanism of this thrombophilic syndrome is still obscure. Using immunofluorescent techniques and a microscopic spontaneous platelet aggregation test (mSPAT), we have previously demonstrated platelet binding by antibody followed by aggregation in patients with lupus anticoagulant. In the present study, we investigated 18 anticardiolipin antibody-positive (ACLA pos.) patients, comprised of 12 primary APLS and 6 secondary APLS lupus patients. We demonstrated direct platelet microaggregate formation in 16/18 cases, whereas this finding was not present in 20 ACLA-negative (ACLA neg.) subjects (P<.001). Indirect testing revealed 10/12 cases of platelet microaggregation and none in the ACLA neg. subjects. In addition, immunofluorescent studies showed that platelet antibody complex binding occurred in 8/12 cases tested directly and in 11/12 cases in indirect testing, as compared to 1 out of 20 binding in ACLA neg. subjects (P<.001). Antibody complex binding was inhibited in two cases by prior extraction of phospholipids. Platelet aggregation could be demonstrated in two ACLA neg. individuals by the addition of exogenous ACLA to platelets in EDTA-plasma. We therefore propose a mechanism for immune-mediated thrombosis in APLS in which calcium-independent platelet aggregation, or thromboagglutination, is initiated by an ACLA-phospholipid complex present in the patients' plasma. Following the antibody complex-induced platelet agglutination, thrombosis proceeds by release, recruitment, and fibrin formation. The mechanism should have important implications in the diagnosis, management, and monitoring of APLS.
The one-electron reduction potentials of the radical cations of five dietary carotenoids (beta-carotene, canthaxanthin, zeaxanthin, astaxanthin and lycopene) in aqueous micellar environments have been obtained from a pulse radiolysis study of electron transfer between the carotenoids and tryptophan radical cations as a function of pH, and lie in the range of 980-1060 mV. These values are consistent with our observation that the carotenoid radical cations oxidise tyrosine and cysteine. The decays of the carotenoid radical cations in the absence of added reactants suggest a distribution of exponential lifetimes. The radicals persist for up to about 1 s, depending on the medium.
OBJECTIVE: To analyze V3 loop sequences of HIV-1 in three seropositive individuals who exhibited declines in viremia while receiving a V3-targeted vaccine. DESIGN: Retrospective analysis of case series at an HIV Clinic, University of Tel Aviv. PATIENTS: Three HIV-1-seropositive, PPD-DTHR-positive (PPD, Siebert purified protein derivative of tuberculin; DTHR, delayed type hypersensitivity reaction) individuals who had been inoculated with a mixture of PPD-cross-linked V3 peptides from five HIV strains and then exhibited declines in HIV-1 viremia during the course of vaccination in the absence of combination antiretroviral therapy and whose virus levels resurged once vaccine boosting was discontinued. RESULTS: Declines in viremia were observed even when the viral V3 sequences of the patients' HIV differed by at least one or two amino acid residues from those of the five peptides in the vaccine. Although viral mutants with amino acid substitutions within V3 appeared during vaccination, plasma virus loads remained at low levels for several months after these variants appeared. About a year after boosting was discontinued, anti-V3 peptide antibodies in the patients had declined and plasma virus returned to the prevaccination levels or higher. Compared with the isolates that predominated during the course of vaccination, the resurgent viruses contained zero to six amino acid residue differences in the V3 loop but few synonymous substitutions. CONCLUSIONS: Viruses with altered V3 sequences did emerge but did not result in increased viremia during the course of vaccination. In two individuals where V3 mutations were absent in the virus that re-emerged after vaccine boosting ceased, resurgence could not have been a consequence of V3 changes.
BACKGROUND: Coronary artery bypass surgery (CABG) may be life saving, but known side effects include neurological damage and cognitive impairment. The temperature used during cardiopulmonary bypass (CPB) may be important with regard to these adverse outcomes, where hypothermia is used as a means of neuroprotection. OBJECTIVES: To assess the effectiveness of hypothermia during CABG in reducing neurological damage and subsequent cognitive deficits. SEARCH STRATEGY: The Cochrane Controlled Trials Register was searched for randomised controlled trials (RCT) and this was updated by searching MEDLINE and EMBASE to December 1999 using database specific RCT filters. Reference lists of retrieved articles were searched and experts in the field were contacted. SELECTION CRITERIA: Only RCTs were considered. All patients undergoing CABG, either first time or revisions, elective or emergency procedures, were included. Any hypothermia protocol was considered. Only trials reporting neurological outcomes were included. DATA COLLECTION AND ANALYSIS: Studies were selected independently and data were extracted from the source papers independently by two reviewers. Authors were contacted for further information. Studies were combined with meta-analysis where appropriate, and meta-regression was used to explore heterogeneity. MAIN RESULTS: There was a trend towards a reduction in the incidence of non fatal strokes in the hypothermic group (OR 0.68 (0.43, 1.05)). Conversely, there was a trend for the number of non stroke related perioperative deaths to be higher in the hypothermic group (OR 1.46 (0.9, 2.37)). Hypothermia had no effect on the incidence of non fatal myocardial infarction (OR 1.05 (0.81, 1.37)), but the incidence of another marker of myocardial damage, low output syndrome, was higher in the hypothermic group (OR 1.21 (0.99, 1.48). When pooling all "bad" outcomes (stroke, perioperative death, myocardial infarction, low output syndrome, intra aortic balloon pump use) there was no significant advantage of either hypothermia or normothermia (OR 1.07 (0.92, 1.24)). Only 4 of 17 trials reported neuropsychological function as an outcome. REVIEWER'S CONCLUSIONS: This review could find no definite advantage of hypothermia over normothermia in the incidence of clinical events. Hypothermia was associated with a reduced stroke rate, but this is off set by a trend towards an increase in non stroke related perioperative mortality and myocardial damage. There is insufficient data to date to draw any conclusions about the use of mild hypothermia. Similarly, there is insufficient data to date to comment on the effect of temperature during CPB on subtle neurological deficits, and further trials are needed in these areas.
The objective of this study was to evaluate the clinical significance of anti-nuclear antibodies (ANA) detected in the early stages of rheumatoid arthritis (RA), by a retrospective comparison of the clinical, laboratory, and therapeutic characteristics of patients with or without ANA. The files of 99 longstanding seropositive RA patients were reviewed. Data relating to demographics, medical history, family history, physical findings, extra-articular complications, laboratory tests, drugs [dosage, duration. efficacy, combinations, adverse effects (AEs)], intra-articular injections, and surgery were recorded. Patients with or without ANA at presentation of their disease were compared using chi-square and t-tests. Fifty-two ANA positive (group 1) and 47 ANA negative (group 2) patients were enrolled in the study. All were comparable in terms of their mean age, age at diagnosis, follow-up duration (approximately 10.5 years), and male:female (M:F) ratio. On admission, pain complaints were more pronounced in group 1 (P = 0.004 in the feet), but the physical findings did not differ. Deformities and nodules developed in similar numbers. Extra-articular complications were evenly distributed; vasculitis, however, was significantly more prevalent in ANA positive (10/52) than in ANA negative (2/47) patients. Thyroid disease was more common in group 2 (10/47 vs 3/52). Laboratory tests (presentation and maximal values) were similar, with the exception of higher anti-DNA (but within normal ranges) and gamma-globulin% in group 1. Group 1 used more drugs prior to diagnosis. Corticosteroids and disease-modifying anti-rheumatic drugs (DMARDs) were evenly used. Combination therapy, joint injections, and surgery were more prevalent in group 2. AEs to various DMARDs were more common in group 1. Although similar in many aspects, RA patients with ANA tend to present with more pain complaints, a higher risk of vasculitis and AEs relating to use of DMARDs, while those without ANA needed more aggressive therapeutic modalities.
Pulse radiolysis was used to generate the radical cations of beta-carotene and two xanthophylls, zeaxanthin and lutein, in unilamellar vesicles of dipalmitoylphosphatidyl choline. The rate constants for the reaction (repair) of these carotenoid radical cations with the water-soluble vitamin C were found to be similar (approximately 1x10(7) M(-1) s(-1)) for beta-carotene and zeaxanthin and somewhat lower (approximately 0.5x10(7) M(-1) s(-1)) for lutein. The results are discussed in terms of the microenvironment of the carotenoids and suggest that for beta-carotene, a hydrocarbon carotenoid, the radical cation is able to interact with a water-soluble species even though the parent hydrocarbon carotenoid is probably entirely in the non-polar region of the liposome.
Pheochromocytoma may present with a clinical picture indistinguishable from that of idiopathic dilated cardiomyopathy. We report 2 such patients who underwent cardiac transplantation following which we diagnosed and successfully treated pheochromocytoma.
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There is a resurgence of interest in the role of electron transfer reactions involving beta-carotene in photosynthesis. There is also current debate on the health benefits of dietary carotenoids and the possible deleterious effects on certain sub-populations such as smokers. The impact of dietary carotenoids on health may well be also related to radical reactions. A key parameter in biological systems is therefore the one-electron reduction potential of the carotenoid radical cation, now reported for the first time in a model biological aqueous environment. The value obtained is 1.06+/-0. 01 V and is sufficiently high to oxidise cell membrane proteins, but is low enough to repair P(680).+ in the photosynthetic reaction centre.
OBJECTIVES: To test 2 interventions to improve adherence to isoniazid preventive therapy for tuberculosis in homeless adults. We compared (1) biweekly directly observed preventive therapy using a $5 monetary incentive and (2) biweekly directly observed preventive therapy using a peer health adviser, with (3) usual care at the tuberculosis clinic. METHODS: Randomized controlled trial in tuberculosis-infected homeless adults. Outcomes were completion of 6 months of isoniazid treatment and number of months of isoniazid dispensed. RESULTS: A total of 118 subjects were randomized to the 3 arms of the study. Completion in the monetary incentive arm was significantly better than in the peer health adviser arm (P = .01) and the usual care arm (P = .04), by log-rank test. Overall, 19 subjects (44%) in the monetary incentive arm completed preventive therapy compared with 7 (19%) in the peer health adviser arm (P = .02) and 10 (26%) in the usual care arm (P = .11). The median number of months of isoniazid dispensed was 5 in the monetary incentive arm vs 2 months in the peer health adviser arm (P = .005) and 2 months in the usual care arm (P = .04). In multivariate analysis, independent predictors of completion were being in the monetary incentive arm (odds ratio, 2.57; 95% CI, 1.11-5.94) and residence in a hotel or other stable housing at entry into the study vs residence on the street or in a shelter at entry (odds ratio, 2.33; 95% CI, 1.00-5.47). CONCLUSIONS: A $5 biweekly cash incentive improved adherence to tuberculosis preventive therapy compared with a peer intervention or usual care. Living in a hotel or apartment at the start of treatment also predicted the completion of therapy.
The influence of scanner acoustic noise on somatosensory activation pattern in rat cortex was investigated by functional magnetic resonance imaging (fMRI) using the blood oxygenation level-dependent (BOLD) contrast. This was achieved by two approaches. The first approach was to compare a conventional, loud fMRI sequence with a new sequence, in which the noise level was reduced by about 30 dB. In the second approach, the inner ear of the animal was destroyed, resulting in deafness. We compared the activation patterns obtained with both sequences before and after cochleotomy. The activated area was larger when data were sampled with background noise, and was also larger before cochleotomy than after. Thus, facilitation of somatosensory activation is induced by additional acoustic stimulation. Magn Reson Med 44:317-321, 2000.
Carotene and xanthophyll triplet lifetimes are found to depend on the concentration of the parent molecule. These results account for some of the variations in carotenoid triplet lifetimes reported previously. The rate constants obtained for ground state quenching correlate with the number of conjugated double bonds, the longer chain systems having higher quenching rate constants.