Interactions among antiviral drugs acting late in the replication cycle of human cytomegalovirus

This study describes the extent of cross-resistance and interactions for selected inhibitors of human cytomegalovirus (HCMV) DNA synthesis and DNA processing. HCMV isolates resistant to the benzimidazole D-ribonucleoside viral DNA processing inhibitors TCRB and BDCRB were sensitive to BAY 38-4766, a non-nucleoside inhibitor of viral DNA processing. This indicates that these two drug types have distinct interactions with the products of HCMV genes UL56 and UL89 required for viral DNA cleavage and packaging. These virus isolates also were sensitive to ganciclovir (GCV) but slightly resistant to the L-benzimidazole ribonucleoside viral DNA synthesis inhibitor 1263W94. Virus resistant to 1263W94 remained sensitive to BDCRB, GCV, and BAY 38-4766. Examination of drug-drug interactions in cell culture assays measuring inhibition of HCMV replication revealed strong synergism for the combination of BDCRB with 1263W94, and for combinations of 1263W94 with cidofovir (CDV) and foscarnet (PFA), but not with GCV. Combinations of GCV with CDV and PFA were synergistic as well. The combination of GCV with 1263W94 showed additive antiviral interactions, whereas, a combination of BAY 38-4766 with GCV showed antagonism. Interaction of BDCRB with BAY 38-4766 showed a mixed pattern of synergy and antagonism. The antiviral synergy observed between GCV and PFA or CDV serves to validate clinical combination therapies for these drugs. Antagonism seen for BAY 38-4766 with GCV indicates that these two drugs are unlikely to be useful for combination therapies. Notably, 1263W94 demonstrated greater synergy in combination with PFA or CDV than did GCV, suggesting some promise for this benzimidazole L-riboside in such combination therapies.     

Phase II trial of pyrazoloacridine in advanced non-small cell carcinoma of the lung--a Kansas Cancer Institute and Thompson Cancer Survival Center Study

Background: More active agents areneeded in the treatment of metastaticnon-small cell lung cancer. Pyrazoloacridine (PZA) is a 9-methoxyacridine compound containing a reducible5-nitro substituent. Although themechanism of action of PZA is unknown, theacridine compounds are known to causecytotoxicity by interaction with DNA andRNA. Methods: Eighteen patients withmetastatic non-small cell lung carcinomawere treated with pyrazoloacridine.Pyrazoloacridine was administered as athree-hour infusion at 750 mg/M² every21 days. Results: There were no objectiveresponses. One patient maintained stabledisease for 20 months. Median survival was4.8 months. The primary toxicity wasgranulocytopenia with 5 patientsexperiencing severe infections. Conclusions: Pyrazoloacridine has nodemonstrable activity in patients withmetastatic non-small cell carcinoma of thelung when given at this dose andschedule.     

What determines the use of home care services by elderly people?

The objective of the present study was to investigate the determinants of use of statutory and private home care services by older people living in the community. A questionnaire was distributed to a stratified random sample of 2,000 elderly people living in the community registered with 11 general practices in a British city (equal numbers of men and women, aged 65-74 years, and 75 years or over). The outcome measures were the use of statutory or private home care services in the previous 3 months. Logistic regression was used to explore potential determinants of the use of these services. The response rate was 79%. Increasing age, not owning a car and being a widow(er) were associated with greater use of both statutory and private home care services, as was worse self-reported overall health. Worse physical functioning, worse emotional health, problems with cognition, foot problems and a greater number of falls were determinants of use of statutory and private services. Older age on leaving full-time education was associated with increased use of private home care services. Problems with eyesight were determinants for both types of home care services for women, but only private services for men. For women, leakage of urine was associated with greater use of private services. Social networks and social support were not generally associated with use of these services after controlling for demographic factors. Understanding the determinants for the use of both statutory and private home care services is important because of the increasing numbers of elderly people in the population and the policy to maintain older people in their own homes. Purchasers and providers should be able to address at least some of the modifiable predictors.     

Obesity in South Africa: the South African demographic and health survey

OBJECTIVES: To ascertain the anthropometric profile and determinants of obesity in South Africans who participated in the Demographic and Health Survey in 1998. RESEARCH METHODS AND PROCEDURES: A sample of 13,089 men and women (age, > or =15 years) were randomly selected and then stratified by province and urban and nonurban areas. Height, weight, mid-upper arm circumference, and waist and hip circumference were measured. Body mass index (BMI) was used as an indicator of obesity, and the waist/hip ratio (WHR) was used as an indicator of abdominal obesity. Multivariate regression identified sociodemographic predictors of BMI and waist circumference in the data. RESULTS: Mean BMI values for men and women were 22.9 kg/m(2) and 27.1 kg/m(2), respectively. For men, 29.2% were overweight or obese (> or =25 kg/m(2)) and 9.2% had abdominal obesity (WHR > or =1.0), whereas 56.6% of women were overweight or obese and 42% had abdominal obesity (WHR >0.85). Underweight (BMI <18.5 kg/m(2)) was found in 12.2% of men and 5.6% of women. For men, 19% of the variation of BMI and 34% of the variation in waist circumference could be explained by age, level of education, population group, and area of residence. For women, these variables explained 16% of the variation of BMI and 24% of the variation in waist circumference. Obesity increased with age, and higher levels of obesity were found in urban African women. DISCUSSION: Overnutrition is prevalent among adult South Africans, particularly women. Determinants of overnutrition include age, level of education, ethnicity, and area of residence.     

The development of a simulation model of the treatment of coronary heart disease

A discrete event simulation models the progress of patients who have had a coronary event, through their treatment pathways and subsequent coronary events. The main risk factors in the model are age, sex, history of previous events and the extent of the coronary vessel disease. The model parameters are based on data collected from epidemiological studies of incidence and prognosis, efficacy studies, national surveys and treatment audits. The simulation results were validated against different sources of data. The initial results show that increasing revascularisation has considerable implications for resource use but has little impact on patient mortality.     

Comparison of the expression of calcitonin receptor-like receptor (CRLR) and receptor activity modifying proteins (RAMPs) with CGRP and adrenomedullin binding in cell lines

1. The calcitonin receptor-like receptor (CRLR) and specific receptor activity modifying proteins (RAMPs) together form receptors for calcitonin gene-related peptide (CGRP) and/or adrenomedullin in transfected cells. 2. There is less evidence that innate CGRP and adrenomedullin receptors are formed by CRLR/RAMP combinations. We therefore examined whether CGRP and/or adrenomedullin binding correlated with CRLR and RAMP mRNA expression in human and rat cell lines known to express these receptors. Specific human or rat CRLR antibodies were used to examine the presence of CRLR in these cells. 3. We confirmed CGRP subtype 1 receptor (CGRP(1)) pharmacology in SK-N-MC neuroblastoma cells. L6 myoblast cells expressed both CGRP(1) and adrenomedullin receptors whereas Rat-2 fibroblasts expressed only adrenomedullin receptors. In contrast we could not confirm CGRP(2) receptor pharmacology for Col-29 colonic epithelial cells, which, instead were CGRP(1)-like in this study. 4. L6, SK-N-MC and Col-29 cells expressed mRNA for RAMP1 and RAMP2 but Rat-2 fibroblasts had only RAMP2. No cell line had detectable RAMP3 mRNA. 5. SK-N-MC, Col-29 and Rat-2 fibroblast cells expressed CRLR mRNA. By contrast, CRLR mRNA was undetectable by Northern analysis in one source of L6 cells. Conversely, a different source of L6 cells had mRNA for CRLR. All of the cell lines expressed CRLR protein. Thus, circumstances where CRLR mRNA is apparently absent by Northern analysis do not exclude the presence of this receptor. 6. These data strongly support CRLR, together with appropriate RAMPs as binding sites for CGRP and adrenomedullin in cultured cells.     

The relationship of FcgammaRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus

OBJECTIVE: Despite wide use of the anti-CD20 monoclonal antibody rituximab in the treatment of B cell lymphomas, the mechanism by which it causes B cell depletion remains a subject of controversy. As part of an ongoing phase I/II trial of rituximab in the treatment of systemic lupus erythematosus (SLE), we sought to determine whether the effectiveness of B cell depletion was influenced by polymorphisms of Fc receptors (FcR) on effector cells. METHODS: During rituximab treatment of 12 SLE patients, B cell depletion was monitored as a function of the serum rituximab level and FcgammaRIIa and FcgammaRIIIa genotypes at baseline and at 1 month and 2 months after treatment. FcR genotypes were determined by polymerase chain reaction. Serum levels of rituximab were measured by enzyme-linked immunosorbent assay (ELISA). B lymphocyte percentages were assessed by flow cytometry. RESULTS: B cell depletion was highly variable in this patient cohort, with B cell percentages at the 1-2-month posttreatment nadir ranging from undetectable (<0.1 cell/microl) to 16% ( approximately 30 cells/microl) of the total peripheral blood lymphocytes. At 2 months posttreatment, B cell percentages were highly correlated with both the serum rituximab level and the FcgammaRIIIa genotype (R(2) = 0.75, P = 0.002). The FcgammaRIIIa genotype was a significant independent predictor of the efficacy of B cell depletion (P = 0.019). CONCLUSION: These results highlight the potential variability of B cell depletion by rituximab in the treatment of autoimmune disease and indicate that Fc receptors are an important determinant of that variability. The findings further suggest the importance of antibody-dependent cell-mediated cytotoxicity and/or apoptosis induction via FcgammaRIIIa-expressing effector cells in the mechanism of B cell depletion by this widely used monoclonal antibody.     

Childhood cancer and agricultural pesticide use: an ecologic study in California

We analyzed population-based childhood cancer incidence rates throughout California in relation to agricultural pesticide use. During 1988-1994, a total of 7,143 cases of invasive cancer were diagnosed among children under 15 years of age in California. Building on the availability of high-quality population-based cancer incidence information from the California Cancer Registry, population data from the U.S. Census, and uniquely comprehensive agricultural pesticide use information from California's Department of Pesticide Regulation, we used a geographic information system to assign summary population, exposure, and outcome attributes at the block group level. We used Poisson regression to estimate rate ratios (RRs) by pesticide use density adjusted for race/ethnicity, age, and sex for all types of childhood cancer combined and separately for the leukemias and central nervous system cancers. We generally found no association between pesticide use density and childhood cancer incidence rates. The RR for all cancers was 0.95 [95% confidence interval (CI), 0.80-1.13] for block groups in the 90th percentile and above for use of pesticides classified as probable carcinogens, compared to the block groups with use of < 1 lb/mi(2). The RRs were similar for leukemia and central nervous system cancers. Childhood leukemia rates were significantly elevated (RR = 1.48; 95% CI, 1.03-2.13) in block groups with the highest use of propargite, although we saw no dose-response trend with increasing exposure categories. Results were unchanged by further adjustment for socioeconomic status and urbanization.     

Influenza vaccination among minority populations in the United States

BACKGROUND: A large portion of the elderly population of the United States fails to receive an annual influenza vaccination. Minorities may receive disproportionately fewer vaccinations. The objectives of this study were to (a) estimate the levels of influenza vaccination among noninstitutionalized, U.S. citizens, 65 years and older, (b) examine the immunization levels among minority racial and ethnic groups relative to various majority groupings, and (c) explore potential factors that may contribute to disparities in vaccination levels. METHODS: We analyzed data from the 1996 Medical Expenditure Panel Survey to compare influenza vaccination levels of different racial and ethnic groups among 2,309 persons aged 65 years and older. RESULTS: Whites had 68.0% (+/- SE 1.5%) current influenza vaccination, Hispanics 61.7% (+/- SE 4.1%), and blacks 47.3% (+/- SE 4.3%). Blacks differed significantly compared to whites. Adjustment for potential confounders such as increased health risk, age distribution, perceived health status, family size, poverty level, and the number of ambulatory visits to a health care provider failed to change this difference substantially. CONCLUSIONS: In 1996, among elderly noninstitutionalized, U.S. citizens, blacks relative to whites were less likely to have current influenza vaccinations. This relationship remained significant even after adjustments for potential confounding variables.