Publications

Mutations in beta-globin, glucose-6-phosphate dehydrogenase, and promoters for tumor necrosis factor-alpha and inducible nitric oxide synthase (iNOS) were examined for associations with the incidence of symptomatic malaria in a cohort of 307 Ugandan children. After adjustment of incidence rates for age, water source, use of preventative measures, and proximity to mosquito breeding sites, glucose-6-phosphate dehydrogenase A- heterozygous females had a significantly higher incidence of malaria (incidence rate ratio [IRR] = 1.63, P = 0.03) and a trend towards higher parasite densities (37,100 versus 26,200 parasites/microL; P = 0.18) compared with wild-type children. Male hemizygotes had trends in the same direction. Heterozygotes for sickle hemoglobin had trends toward a lower incidence of malaria and lower parasite density at presentation. Heterozygotes for the iNOS promoter G954C polymorphism, but not other promoter polymorphisms, had a significantly lower incidence of malaria compared with wild-type children (IRR = 0.69, P = 0.05). Host polymorphisms appear to impact upon the incidence of uncomplicated malaria in Ugandan children.

Since the introduction of HIV protease inhibitors (PIs), disorders of glucose and lipid metabolism have emerged. In dissecting out the direct effect on lipid and glucose metabolism, it has become apparent that individual PIs have different effects on metabolism. Some PIs such as indinavir acutely induce insulin resistance. PIs have also been shown to cause other disorders of glucose metabolism, including impairment of insulin secretion and increased endogenous glucose production. Individual PIs also have different effects on lipid metabolism. Ritonavir predominantly increases triglyceride and very low-density lipoprotein cholesterol levels. Limited studies in HIV-negative volunteers suggest that several of the PIs do not increase low-density lipoprotein cholesterol levels. This review examines the direct effects of PIs on glucose and lipid metabolism by assessing prospective studies of HIV-infected and healthy normal volunteers, and in vitro studies.

Aire (autoimmune regulator), the gene responsible for the clinical disorder autoimmune polyendocrinopathy syndrome type I, has recently been identified as an important mediator of central tolerance. Aire upregulates the transcription of certain organ-specific self-antigens in medullary thymic epithelial cells, and has a role in the negative selection of organ-specific thymocytes. However, the molecular mechanisms by which Aire functions in these processes are still not well understood. Structural characteristics and biochemical data suggest that Aire might have a direct role in nuclear transcription and that it can function as an ubiquitin ligase. Although these molecular details await further characterization, the association of Aire with the prevention of autoimmunity highlights the importance of thymic mechanisms in the maintenance of tolerance.

The kidney adjusts net acid excretion to match production with exquisite precision, despite little or no change in the plasma bicarbonate concentration. The acid-sensing pathway that signals the kidney to increase acid secretion involves activation of the proto-oncogene c-Src. A new study in this issue shows that proline-rich tyrosine kinase 2 (Pyk2) is responsible for acid-induced activation of c-Src and is essential for acid sensing in renal epithelial cells. The findings implicate a broader role for Pyk2 in acid-base homeostasis in bone and other tissues beyond the kidney.

BACKGROUND

The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the effect of daily beta-carotene (30 mg) and retinyl palmitate (25,000 IU) on the incidence of lung cancer, other cancers, and death in 18,314 participants who were at high risk for lung cancer because of a history of smoking or asbestos exposure. CARET was stopped ahead of schedule in January 1996 because participants who were randomly assigned to receive the active intervention were found to have a 28% increase in incidence of lung cancer, a 17% increase in incidence of death and a higher rate of cardiovascular disease mortality compared with participants in the placebo group.

METHODS

After the intervention ended, CARET participants returned the study vitamins to their study center and provided a final blood sample. They continue to be followed annually by telephone and mail self-report. Self-reported cancer endpoints were confirmed by review of pathology reports, and death endpoints were confirmed by review of death certificates. All statistical tests were two-sided.

RESULTS

With follow-up through December 31, 2001, the post-intervention relative risks of lung cancer and all-cause mortality for the active intervention group compared with the placebo group were 1.12 (95% confidence interval [CI] = 0.97 to 1.31) and 1.08 (95% CI = 0.99 to 1.17), respectively. Smoothed relative risk curves for lung cancer incidence and all-cause mortality indicated that relative risks remained above 1.0 throughout the post-intervention follow-up. By contrast, the relative risk of cardiovascular disease mortality decreased rapidly to 1.0 after the intervention was stopped. During the post-intervention phase, females had larger relative risks of lung cancer mortality (1.33 versus 1.14; P = .36), cardiovascular disease mortality (1.44 versus 0.93; P = .03), and all-cause mortality (1.37 versus 0.98; P = .001) than males.

CONCLUSIONS

The previously reported adverse effects of beta-carotene and retinyl palmitate on lung cancer incidence and all-cause mortality in cigarette smokers and individuals with occupational exposure to asbestos persisted after drug administration was stopped although they are no longer statistically significant. Planned subgroup analyses suggest that the excess risks of lung cancer were restricted primarily to females, and cardiovascular disease mortality primarily to females and to former smokers.

BACKGROUND

Seasonal allergic rhinitic (SAR) subjects are more physiologically reactive to airborne irritants than non-rhinitic (NR) subjects; however the mechanism underlying this difference is unclear.

OBJECTIVE

We sought to determine whether irritant-induced nasal airflow limitation involves neuropeptide release into nasal lining fluid, and if so, whether such release occurs differentially by rhinitic status.

METHODS

Eight SAR and 8 NR subjects were exposed to 1.0 ppm chlorine and filtered air in random order during separate visits; exposures were via nasal mask and lasted 15 min. Rhinomanometry was performed before, immediately post-, and 15 min post-exposure. Following a minimum of 2 weeks' time, exposures and symptom reporting were repeated with nasal lavage pre- and post-exposure. Neuropeptides (substance P, cacitonin gene-related protein, vasoactive intestinal peptide, and neuropeptide Y) as well as markers of plasma leakage (albumin and urea) and glandular secretion (lysozyme and 7F10-mucin) were measured using standard methods.

RESULTS

Cl(2) provocation significantly increased nasal airway resistance in SAR but not NR subjects (p<0.05). Neuropeptide levels in nasal lavage fluid, on the other hand, were unaffected, with the exception of a paradoxical increase in vasoactive intestinal peptide in non-rhinitic controls post-Cl(2) provocation.

CONCLUSIONS

Irritant-induced nasal airflow limitation is more pronounced among SAR than NR subjects. We could not, however, demonstrate a role for neuropeptide release in the nasal congestive response of SAR subjects.

Whereas small-fibre sensory neuropathies might ultimately lead to cell death and loss of sensation, they first progress through a phase, which might last for years, characterized by the presence of analgesia-resistant neuropathic dysesthesias and pain. Much previous research has addressed these two phases as separate phenomena mediated by presumably discrete biochemical mechanisms. We hypothesized that activity in signalling pathways that ultimately lead to apoptosis plays a critical role in the generation of neuropathic pain, before death of sensory neurons becomes apparent. We have tested the hypothesis that activator and effector caspases, defining components of programmed cell death (apoptosis) signalling pathways, also contribute to pain-related behaviour in animals with small-fibre peripheral neuropathies and that the death receptor ligand, tumour necrosis factor-alpha, and its downstream second messenger, ceramide, also produce pain-related behaviour via this mechanism. In two models of painful peripheral neuropathy, HIV/AIDS therapy (induced by the nucleoside reverse transcriptase inhibitor, dideoxycytidine), and cancer chemotherapy (induced by vincristine) peripheral neuropathy, and for pain-related behaviour induced by tumour necrosis factor-alpha and its second messenger, ceramide, inhibition of both activator (1, 2, 8 and 9) and effector (3) caspases attenuates neuropathic pain-related behaviour, although has no effect in streptozotocin-diabetic neuropathy and control rats. We conclude that during a latent phase, before apoptotic cell death is manifest, the caspase signalling pathway can contribute to pain in small-fibre peripheral neuropathies, and that inflammatory/immune mediators also activate these pathways. This suggests that these pathways are potential targets for novel pharmacological agents for the treatment of inflammatory as well as neuropathic pain.

Many of the genes that affect aging and longevity in model organisms, such as mice, fruit flies, and worms, have human homologs. This article reviews several genetic pathways that may extend lifespan through effects on aging, rather than through effects on diseases such as atherosclerosis or cancer. These include some of the genes involved in the regulation of DNA repair and nuclear structure, which cause the progeroid syndromes when mutated, as well as those that may affect telomere length, since shorter telomeres have been associated with shorter survival. Other potential longevity genes, such as sirtuins, are involved in regulating the response to cellular stress, including caloric restriction. The best-studied pathway involves insulin and insulin-like growth factor 1 signaling; mutations in homologs of these genes have extended lifespan up to sixfold in model organisms. Other potential candidates include mitochondrial DNA and the genes that regulate the inflammatory response. Despite the challenges in study design and analysis that face investigators in this area, the identification of genetic pathways that regulate longevity may suggest potential targets for therapy.

BACKGROUND

The density of breast tissue on a mammogram is a strong predictor of breast cancer risk and may reflect cumulative estrogen effect on breast tissue. Endogenous and exogenous estrogen exposure increases the risk of estrogen receptor (ER)-positive breast cancer. We determined if mammographic density is associated more strongly with ER-positive breast cancer than with ER-negative breast cancer.

METHODS

We analyzed data from 44,811 participants in the San Francisco Mammography Registry of whom 701 developed invasive breast cancer. Mammographic density was measured using the Breast Imaging Reporting and Data System (BI-RADS) classification system (1 = almost entirely fat, 2 = scattered fibroglandular, 3 = heterogeneously dense, 4 = extremely dense). We tested for associations between mammographic density and ER-positive and ER-negative breast cancer separately. Analyses were adjusted for age, body mass index, postmenopausal hormone use, family history of breast cancer, menopausal status, parity, and race/ethnicity.

RESULTS

Mammographic density was strongly associated with both ER-positive and ER-negative breast cancers. Compared with women with BI-RADS 2, women with BI-RADS 1 (lowest density) had a lower risk of ER-positive cancer [adjusted hazard ratio (HR), 0.28; 95% confidence interval (95% CI), 0.16-0.50] and ER-negative cancer (adjusted HR, 0.17; 95% CI, 0.04-0.70). Women with BI-RADS 4 (highest density) had an increased risk of ER-positive breast cancer (adjusted HR, 2.21; 95% CI, 1.64-3.04) and an increased risk of ER-negative breast cancer (adjusted HR, 2.21; 95% CI, 1.16-4.18).

CONCLUSION

Surprisingly, women with high mammographic density have an increased risk of both ER-positive and ER-negative breast cancers. The association between mammographic density and breast cancer may be due to factors besides estrogen exposure.

OBJECTIVE

Managed care may have widespread impacts on health care delivery for all patients in the areas where they operate. We examine the relationship between area managed care activity and screening for breast, cervical, and prostate cancer among patients enrolled in more managed care plans and patients who are enrolled in less managed plans.

DATA AND METHODS

Data on cancer screening from the 1996 Medical Expenditure Panel Survey (MEPS) were linked to data on health maintenance organization (HMO) and preferred provider organization (PPO) market share and HMO competition at the metropolitan statistical area (MSA) level. Logistic regression analysis was used to examine the relationship between area managed care prevalence and the use of mammography, clinical breast examination, Pap smear, and prostate cancer screening in the past two years, controlling for important covariates.

RESULTS

Among all patients, increases in area-level HMO market share are associated with increases in the appropriate use of mammography, clinical breast exam, and Pap smear (OR for high relative to low managed care areas are 1.75, p < .01, for mammography, 1.58, p < .05, for clinical breast exam, and 1.71, p < .01, for Pap smear). In analyses of subgroups, the relationship is significant only for individuals who are enrolled in the nonmanaged plans; there is no relationship for individuals in more managed plans. No relationship is observed between area HMO market share and prostate cancer screening in any analysis. Neither the level of competition between area HMOs nor area PPO market share is associated with screening rates.

CONCLUSIONS

Area-level managed care activity can influence preventive care treatment patterns.