George C. Roush

The effects of hydrogen peroxide on DNA repair activities

Oxygen free radicals generated by H2O2 are involved in the multistage carcinogenic process; mechanisms include carcinogen activation, oxidative DNA damage, and tumor promotion. In this study, we have evaluated another potential mechanism of H2O2 in carcinogenesis--modulation of DNA repair activities. Preexposure of human peripheral mononuclear leukocytes to H2O2 significantly inhibited DNA repair activities in response to damage induced by N-methyl-N-nitro-N-nitrosoguanidine, measured as unscheduled DNA synthesis. The responses to H2O2 were compared in four healthy human subjects with two sample preparations on different days. Results from multivariate general linear models showed that H2O2 significantly inhibited DNA repair in a dose-dependent manner after adjustment for between- and within-subject variabilities. There was an estimate of 5.0 units (dpm/5 x 10(5) cells) decrease in induced unscheduled DNA synthesis per unit (microM) increase of H2O2 treatment. Furthermore, there was substantial variability in DNA repair activities for the same individual sampled on different days regardless of H2O2 dose level. Results from this study suggest that H2O2 not only can induce DNA damage, but also have suppressive effects on DNA repair.

A reversal in the long-term increase in deaths attributable to malignant melanoma.

For a few years in the 1980s, United States mortality rates suggested a plateau in the long‐term increase for malignant melanoma. However, temporary plateaus in the increase of the age‐adjusted rate by year of death have occurred in previous decades, only to be followed by a continued upward increase, with a long‐term rise of about 2% per year. To determine whether a cessation in the long‐term increase might be in progress, death rates were analyzed by year of birth, age at death, and year of death: (1) the long‐term patterns of change are best described by birth cohort rather than by time period of death, indicating that analyses by a year of birth are key to a better understanding of the long‐term trends; (2) in both men and women, evidence for a change in slope begins among those born in the early 1930s; (3) the decline in the rates begins among women born since the early 1930s and among men born since the early 1950s: the slope for men is ‐0.2661 (95% confidence limits [CL] = −0.380 to −0.152), and, for women, the slope is ‐0.02354 (95% CL = ‐0.041 to ‐0.005); (4) long‐term Connecticut and US mortality trends were similar in pattern and direction, and long‐term Connecticut incidence rates showed a persistent increase through the 1955 to 1965 birth cohorts. These analyses suggest a persistent cessation in the long‐term increase and a downward trend in death rates from this cancer.

Poly(ADP-ribose) polymerase in human breast cancer : a case-control analysis

The importance of a genetic polymorphism (A/B allele) of poly(ADP-ribose) polymerase (PARP) pseudogene on chromosome 13q34-qter, and PARP enzyme activities in the development of human breast cancer were evaluated in a cancer case-control study. A total of 309 Caucasian women (> or = 50 years old) were evaluated for the PARP genotype, 70 of whom had histologically confirmed breast cancer, 128 women with benign breast diseases as study controls, and 111 reference controls. Age was significantly associated with case-control status (p < 0.0001), but family history of breast cancer, age at menarche, age at first live birth and parity were not. The frequency of the PARP B allele was similar in breast cancer cases (0.14), study controls (0.13), and reference controls (0.15). In a subset of 14 breast cancer cases and 32 study controls, the mean PARP enzyme activities (induced by H2O2 or oligonucleotide) were observed to be lower in cancer cases; an age-adjusted odds ratio of 3.40 (95% confidence interval = 0.70-19.54) for the below-median oligonucleotide-induced PARP was suggestive of an association. In subjects with the AB or BB genotype, the mean H2O2-induced PARP enzyme activity was significantly higher (p = 0.02, adjusted for case-control status and age) compared with that in subjects with the AA genotype. These findings indicate that: (a) the genetic polymorphism of the PARP pseudogene on chromosome 13 is not associated with the development of breast cancer in our study population; (b) oligonucleotide-induced PARP activity may be useful for identifying postmenopausal women at increased risk for breast cancer; and (c) there is a possible functional link between the genotype of the PARP pseudogene and enzyme activation.

DNA Repair as A Susceptibility Factor in Chronic Diseases in Human Populations

Three case-control studies of DNA repair in the general population were conducted with: i. 88 primary basal cell carcinoma (BCC) cases and 135 cancer-free controls, ii 304 study subjects including 57 arsenical cancer patients and 247 noncancerous controls in Taiwan and iii 41 breast cancer patients and 73 controls. The host reactivation assay was used to measure cellular DRC capacity with cryopreserved peripheral lymphocytes from both the cases and their controls. In study i. reduced repair of UV-induced DNA damage contributed to the risk of sunlight-induced BCC. A family history of BCC is a predictor of low DNA repair. Repair of UV damaged DNA declines at a rate of about 0.6 per annum in in non-cancerous controls. In addition, reduced DNA repair is more likely seen in young BCC cases, indicating that BCC is a premature aging disease of the skin. The persistence of photochemical damage because of reduced repair, results in point mutations in the p53 gene and allelic loss of the nevoid BCC (Gorlin’s syndrome) gene located on chromosome 9q. Xeroderma pigmentosum appears to be a valid paradigm for the role of DNA repair in BCC in the general population. An extension of these studies led to conclusions from Black Foot Disease (BDF) studies that DRC by itself is not a risk factor for arsenical skin cancer, but those individuals with low DRC,are at much greater risk when exposed to high levels of arsenic in their drinking water or when they are on poor diets. DRC, therefore, appears to be a susceptibility factor in this disease. Further DRC is consistently lower in breast cancer cases than in controls and appears to be a susceptibility factor in breast cancer and DRC in lymphocytes may be employed as a biomarker for human breast cancer risk.

Prognostic impact of sex-ambulatory blood pressure interactions in 10 cohorts of 17 312 patients diagnosed with hypertension: systematic review and meta-analysis.

Background: Whether ambulatory blood pressure (BP) among hypertensive patients better predicts cardiovascular events (CVEs) in women relative to men is unclear. Methods: We searched PUBMED and OVID databases. Cohorts were required to have hypertension, 1+ years of follow-up, with stroke and coronary artery disease as outcomes. Lead investigators for these cohorts provided ad hoc analyses. Random-effect meta-analyses gave hazard ratios for CVEs from a 1 standard deviation (SD) mmHg increase and a 10u200ammHg increase in SBP. Subgroup and meta-regression analyses quantified the relative increase in risk in women versus men. Results: Patients were from Europe, Brazil, and Japan (10 cohorts, nu200a=u200a17u200a312, CVEsu200a=u200a1892). One cohort lacked sex-specific hazard ratios from 24u200ah and clinic SBP. Compared with men, women tended to have greater SDs and coefficients of variation of SBP. Subgroup analyses showed higher hazard ratios in women than in men from increases in ambulatory but not clinic SBPs. For women relative to men, a 1 SD increase in night-time, daytime, 24u200ah, and clinic SBP gave hazard ratios (95% confidence limits) of 1.17 (1.06–1.30), 1.24 (1.10–1.39), 1.21 (1.08–1.36), and 0.94 (0.84–1.05), respectively, whereas a 10u200ammHg increase in SBP, gave hazard ratios of 1.06 (0.99–1.14), 1.13 (1.03–1.23), 1.10 (1.01–1.21), and 0.96 (0.89–1.03), respectively. Conclusion: In patients with hypertension, increases in ambulatory, but not clinic, SBP predict higher risks for CVEs in women than in men. Although women tended to have greater variability in SBP, this did not entirely explain the sex–ambulatory BP interactions.

Modulation of the cancer susceptibility measure, adenosine diphosphate ribosyl transferase (ADPRT), by differences in low‐dose n‐3 and n‐6 fatty acids

Adenosine diphosphate ribosyl transferase (ADPRT) is related to oxidants, and lower values for ADPRT in white cells suggest increased cancer susceptibility. Ordinarily, oxidants are generated intracellularly via metabolism of n-6 fatty acids common in western diets. However, n-3 fatty acids in fish oils might limit oxidants via competitive inhibition of key enzymes, elevate ADPRT, and lower cancer risk. In this controlled trial, 47 women were assigned either lecithin (an n-6 fatty acid, 7.2 g daily) or eicosapentaenoic acid-docosahexaenoic acid (n-3 fatty acids, 1.5 g daily) for six weeks, and 45 women completed all four visits. After six weeks, ADPRT increased by 9.3 +/- 10.8% (SD) for the n-3 fatty acid group relative to the n-6 fatty acid group. For the subset of 39 women with good compliance, ADPRT increased by 20.9 +/- 11.1% (nonparametric p = 0.039). This increase persisted after adjustment for regression to the mean. The trial suggests a normalizing effect of low-dose n-3 fatty acids on the ADPRT measure.

Hydrochlorothiazide vs chlorthalidone, indapamide, and potassium-sparing/hydrochlorothiazide diuretics for reducing left ventricular hypertrophy: A systematic review and meta-analysis

Left ventricular hypertrophy develops in 36%‐41% of hypertensive patients and independently predicts cardiovascular events and total mortality. Moreover, drug‐induced reduction in left ventricular mass (LVM) correlates with improved prognosis. The optimal thiazide‐type diuretic for reducing LVM is unknown. Evidence regarding potency, cardiovascular events, sodium, and potassium suggested the hypothesis that “CHIP” diuretics (CHlorthalidone, Indapamide, and Potassium‐sparing diuretic/hydrochlorothiazide [PSD/HCTZ]) would reduce LVM more than HCTZ. Systematic searches of five databases were conducted. Among the 38 randomized trials, a 1% reduction in systolic blood pressure (SBP) predicted a 1% reduction in LVM, P = 0.00001. CHIP‐HCTZ differences in reducing LVM differed across trials (ie, heterogeneity), making interpretation uncertain. However, among the 28 double‐blind trials, heterogeneity was undetectable, and HCTZ reduced LVM (percent reduction [95% CI]) by −7.3 (−10.4, −4.2), P < 0.0001. CHIP diuretics surpassed HCTZ in reducing LVM: chlorthalidone −8.2 (−14.7, −1.6), P = 0.015; indapamide −7.5 (−12.7, −2.3), P = 0.005; and all CHIP diuretics combined −7.7 (−12.2, −3.1), P < 0.001. The comparison of PSD/HCTZ with HCTZ had low statistical power but favored PSD/HCTZ: −6.0 (−14.1, +2.1), P = 0.149. Thus, compared to HCTZ, CHIP diuretics had twice the effect on LVM. CHIP diuretics did not surpass HCTZ in reducing systolic or diastolic blood pressure: −0.3 (−5.0, +4.3) and −1.6 (−5.6, +2.4), respectively. The strength of evidence that CHIP diuretics surpass HCTZ for reducing LVM was high (GRADE criteria). In conclusion, these novel results have demonstrated that CHIP diuretics reduce LVM 2‐fold more than HCTZ among hypertensive patients. Although generally related to LVM, blood pressure fails to explain the superiority of CHIP diuretics for reducing LVM.

Quality of Meta-Analyses for Randomized Trials in the Field of Hypertension: an Updated and Improved Systematic Review

Publications of hypertension-related meta-analyses (MAs) have increased exponentially in the past 25xa0years and now average 8/month. Theoretically, this is facilitating evidence-based management of patients. However, some practitioners and authors of guidelines have questioned the quality of published MAs. By extending a prior review, we have assessed the quality of 212 hypertension-related meta-analyses over 5xa0years based on systematically searching three computerized libraries. Seventeen criteria grouped into four domains of quality yielded the following results: (1) Assessment of trial quality was accomplished in 89% of MAs, and 38% analyzed trials in subgroups of trial quality where appropriate. (2) All three measures of heterogeneity (I2, tau, and P for heterogeneity) were reported in 36%, reflecting the failure to report tau, the standard deviation of the main effect. (3) Publication bias was assessed in 75%, and 43% of MAs used a statistical test for publication bias. (4) Regarding transparency, 9 to 31% of MAs reported problems in the previous three domains in the article’s abstract. Journal impact factor reporting the MAs declined significantly over 5xa0years. The percent with criteria of quality in a MA was modestly correlated with journal impact factor (R2xa0=xa00.05, Pxa0=xa00.001). False-positive results from inappropriate application of the DerSimonian-Laird model affected 25% of articles, which reported these false positives in the article’s abstract in 72%. No more than 25% of MAs had 67% or more of the criteria of quality. In conclusion, skepticism of hypertension-related MAs is justified, but their quality can be readily corrected.