Activation of mitomycin C by NADPH:cytochrome P-450 reductase

Mitomycin C is an alkylating agent used in cancer chemotherapy that shows some specificity towards hypoxic cells. The therapeutic effects of this compound are thought to result from its metabolic activation by enzymes such as NADPH:cytochrome P-450 reductase. In a previous report we described a Chinese hamster ovary cell line resistant to mitomycin C, which had a decreased NADPH:cytochrome P-450 reductase activity coupled with a lower rate of mitomycin C metabolism. In order to provide further evidence that the lower reductase activity is a factor in the resistance mechanism, we incorporated NADPH:cytochrome P-450 reductase into cytotoxicity assays and showed that it significantly sensitizes cells to mitomycin C. Also, the difference in drug sensitivity between the wild-type and drug-resistant Chinese hamster ovary cells was no longer observed. In addition to these studies, we expressed a rat liver NADPH:cytochrome P-450 reductase cDNA in a Salmonella typhimurium strain, LR5000. The bacteria expressing the rat NADPH: cytochrome P-450 reductase showed increased sensitivity to mitomycin C when incubated with this compound under aerobic conditions. However, under hypoxic conditions increased sensitivity was not observed. This parallels the previous finding with mitomycin C-resistant Chinese hamster ovary cells. These data provide direct evidence for the role of NADPH:cytochrome P-450 reductase in the cytotoxic action of this mitomycin C under aerobic but not hypoxic conditions and suggest that reduced levels of this enzyme can lead to drug resistance. P-450 reductase expressed in S. typhimurium may provide a valuable tool for evaluating the role of this enzyme in the toxicity of drugs activated through a one electron reduction pathway.     

The effectiveness of targeted feeding assistance to improve the nutritional intake of elderly dysphagic patients in hospital

Background Dysphagic older patients are prescribed texture modified food or fluids as treatment. The present study aimed to determine whether targeted feeding assistance using trained volunteers increased oral intake in elderly dysphagic patients. Method Individualized feeding assistance was given to patients who were diagnosed with dysphagia by a speech and language therapist. Data were collected between 08.00 h and 16.00 h and compared with previously collected data from dysphagic patients who received no targeted feeding assistance. Results The group with targeted assistance (n = 16) had higher intakes of energy and protein from both meals and supplements combined compared to the controls (n = 30); mean difference = 2327 kJ (554 kcal) (95% CI = 1294–3360 kJ; P < 0.001) and 28 g protein (95% CI = 13–41 g; P = 0.01). The assisted group ate more from meals only; mean difference = 1336 kJ (318 kcal) (95% Cl = 517–2155 kJ; P = 0.002) and 6 g of protein (95% Cl = 2–26 g; P = 0.02); and from nutritional supplements only, median difference = 1205 kJ (287 kcal) (95% CI = 613–1273 kJ; P = 0.0002) and 15 g protein (95% CI 6.9–15 g; P < 0.0001). Conclusion Nutritional intake can be improved by targeted feeding assistance in hospitalized elderly dysphagic patients on texture modified diets.     

Hearing impairment affects older people's ability to drive in the presence of distracters

OBJECTIVES: To investigate the effects of hearing impairment and distractibility on older people's driving ability, assessed under real‐world conditions. DESIGN: Experimental cross‐sectional study. SETTING: University laboratory setting and an on‐road driving test. PARTICIPANTS: One hundred seven community‐living adults aged 62 to 88. Fifty‐five percent had normal hearing, 26% had a mild hearing impairment, and 19% had a moderate or greater impairment. MEASUREMENTS: Hearing was assessed using objective impairment measures (pure‐tone audiometry, speech perception testing) and a self‐report measure (Hearing Handicap Inventory for the Elderly). Driving was assessed on a closed road circuit under three conditions: no distracters, auditory distracters, and visual distracters. RESULTS: There was a significant interaction between hearing impairment and distracters, such that people with moderate to severe hearing impairment had significantly poorer driving performance in the presence of distracters than those with normal or mild hearing impairment. CONCLUSION: Older adults with poor hearing have greater difficulty with driving in the presence of distracters than older adults with good hearing.     

Evaluation of attendance and weight loss in an intensive weight management clinic compared to standard dietetic care

Background:  With increasing rates of obesity, the effectiveness of weight reduction programmes come under increasing scrutiny. This nonrandomized study aimed to review the effectiveness of two weight loss clinics in terms of percent and rate of weight loss, and attendance.
Methods:  Data were collected on consecutive obese patients, attending either an intensive weight management clinic (IWMC) or a general dietetic outpatient clinic. The IWMC had a structured approach with six once-a-month appointments, a signed agreement to attend, an initial screening of readiness to change and consistent advice from one dietitian. The general clinic was less structured, had more ad hoc follow up and did not guarantee one dietitian.
Results:  Seventy percent of patients referred were female [mean (SD) age 48 (14.2) years]. Thirty-three percent (103/313) of all patients referred did not book an appointment. Of those attending with a body mass index ≥ 32 kg m⁻², 55% were seen in the general and 45% in the intensive clinic, but only 19% and 53%, respectively, completed the programmes. The total amount and rate of weight loss did not differ significantly between clinics. However, analysis using the last recorded weight revealed a median weight reduction of 1.8% (interquartile range = −5.6–0) at the median rate of −0.4 kg month⁻¹(−1–0) in the intensive clinic, compared to no overall weight loss in the general clinic ( P  ≤ 0.001).
Conclusions:  A more structured approach and initial screening of readiness to change is likely to achieve better weight loss results and therefore will comprise a better use of dietetic time than including obese patients in general clinics.     

Gay men as victims of nonconsensual sex

Incidents of nonconsensual sexual activity among 930 homosexually active men living in England and Wales are analyzed. Of these men, 27.6% said they had been sexually assaulted or had sex against their will at some point in their lives; one third had been forced into sexual activity (usually anal intercourse) by men with whom they had previously had, or were currently having, consensual sexual activity. The contention that male rape is usually committed by heterosexually identified men, primarily as an expression of power and control, is not supported. Recognition that gay men rape other gay men is needed, both by the gay community and support services for victims.The work of Project SIGMA is funded by the Medical Research Council and the Department of Health. The views and opinions expressed herein are, however, those of the authors only.Who died from an AIDS-related illness during the period following submission.     

Repair of cisplatin-DNA adducts by protein extracts from human ovarian carcinoma

Human ovarian carcinoma exhibits a spectrum of responses to treatment with cisplatin, ranging from marked sensitivity to relative resistance. Variations in the efficiency with which cells repair cisplatin-DNA adducts may in part determine cisplatin sensitivity. We have investigated the use of a novel cell-free assay of nucleotide excision repair of platinated DNA to assess the DNA repair capacity of direct biopsies of untreated human ovarian carcinoma. In this pilot study, ovarian carcinoma extracts performed in vitro excision repair of platinated DNA. Moreover, tumors from different individuals varied as much as I O-fold in their repair capacity in this assay. © 1994 Wiley-Liss, Inc.     

Associations Between Neighborhood Characteristics,Social Cohesion,and Perceived Sex Partner Risk and Non-Monogamy Among HIV-Seropositive and HIV-Seronegative Women in the Southern U.S.

Neighborhood social and physical factors shape sexual network characteristics in HIV-seronegative adults in the U.S. This multilevel analysis evaluated whether these relationships also exist in a predominantly HIV-seropositive cohort of women. This cross-sectional multilevel analysis included data from 734 women enrolled in the Women’s Interagency HIV Study’s sites in the U.S. South. Census tract-level contextual data captured socioeconomic disadvantage (e.g., tract poverty), number of alcohol outlets, and number of non-profits in the census tracts where women lived; participant-level data, including perceived neighborhood cohesion, were gathered via survey. We used hierarchical generalized linear models to evaluate relationships between tract characteristics and two outcomes: perceived main sex partner risk level (e.g., partner substance use) and perceived main sex partner non-monogamy. We tested whether these relationships varied by women’s HIV status. Greater tract-level socioeconomic disadvantage was associated with greater sex partner risk (OR 1.29, 95% CI 1.06–1.58) among HIV-seropositive women and less partner non-monogamy among HIV-seronegative women (OR 0.69, 95% CI 0.51–0.92). Perceived neighborhood trust and cohesion was associated with lower partner risk (OR 0.83, 95% CI 0.69–1.00) for HIV-seropositive and HIV-seronegative women. The tract-level number of alcohol outlets and non-profits were not associated with partner risk characteristics. Neighborhood characteristics are associated with perceived sex partner risk and non-monogamy among women in the South; these relationships vary by HIV status. Future studies should examine causal relationships and explore the pathways through which neighborhoods influence partner selection and risk characteristics.     

Pedometer determined physical activity tracks in African American adults: The Jackson Heart Study

ABSTRACT: BACKGROUND: This study investigated the number of pedometer assessment occasions required to establish habitual physical activity in African American adults. METHODS: African American adults (mean age 59.9 +/- 0.60 years; 59 % female) enrolled in the Diet and Physical Activity Substudy of the Jackson Heart Study wore Yamax pedometers during 3-day monitoring periods, assessed on two to three distinct occasions, each separated by approximately one month. The stability of pedometer measured PA was described as differences in mean steps/day across time, as intraclass correlation coefficients (ICC) by sex, age, and body mass index (BMI) category, and as percent of participants changing steps/day quartiles across time. RESULTS: Valid data were obtained for 270 participants on either two or three different assessment occasions. Mean steps/day were not significantly different across assessment occasions (p values > 0.456). The overall ICCs for steps/day assessed on either two or three occasions were 0.57 and 0.76, respectively. In addition, 85 % (two assessment occasions) and 76 % (three assessment occasions) of all participants remained in the same steps/day quartile or changed one quartile over time. CONCLUSION: The current study shows that an overall mean steps/day estimate based on a 3-day monitoring period did not differ significantly over 4 - 6 months. The findings were robust to differences in sex, age, and BMI categories. A single 3-day monitoring period is sufficient to capture habitual physical activity in African American adults.     

Subjective social status and psychosocial and metabolic risk factors for cardiovascular disease among African Americans in the Jackson Heart Study

Subjective social status has been shown to be inversely associated with multiple cardiovascular risk factors, independent of objective social status. However, few studies have examined this association among African Americans and the results have been mixed. Additionally, the influence of discrimination on this relationship has not been explored. Using baseline data (2000-2004) from the Jackson Heart Study, an African American cohort from the U.S. South (N=5301), we quantified the association of subjective social status with selected cardiovascular risk factors: depressive symptoms, perceived stress, waist circumference, insulin resistance and prevalence of diabetes. We contrasted the strength of the associations of these outcomes with subjective versus objective social status and examined whether perceived discrimination confounded or modified these associations. Subjective social status was measured using two 10-rung "ladders," using the U.S. and the community as referent groups. Objective social status was measured using annual family income and years of schooling completed. Gender-specific multivariable linear and logistic regression models were fit to examine associations. Subjective and objective measures were weakly positively correlated. Independent of objective measures, subjective social status was significantly inversely associated with depressive symptoms (men and women) and insulin resistance (women). The associations of subjective social status with the outcomes were modest and generally similar to the objective measures. We did not find evidence that perceived racial discrimination strongly confounded or modified the association of subjective social status with the outcomes. Subjective social status was related to depressive symptoms but not consistently to stress or metabolic risk factors in African Americans.     

The Bloom's syndrome gene product promotes branch migration of holliday junctions

Bloom's syndrome (BS) is an autosomal recessive disorder associated with dwarfism, immunodeficiency, reduced fertility, and elevated levels of many types of cancer. BS cells show marked genomic instability; in particular, hyperrecombination between sister chromatids and homologous chromosomes. This instability is thought to result from defective processing of DNA replication intermediates. The gene mutated in BS, BLM, encodes a member of the RecQ family of DExH box DNA helicases, which also includes the Werner's syndrome gene product. We have investigated the mechanism by which BLM suppresses hyperrecombination. Here, we show that BLM selectively binds Holliday junctions in vitro and acts on recombination intermediates containing a Holliday junction to promote ATP-dependent branch migration. We present a model in which BLM disrupts potentially recombinogenic molecules that arise at sites of stalled replication forks. Our results have implications for the role of BLM as an anti-recombinase in the suppression of tumorigenesis.