Two-stage Study of Familial Prostate Cancer by Whole-exome Sequencing and Custom Capture Identifies 10 Novel Genes Associated with the Risk of Prostate Cancer

BackgroundFamily history of prostate cancer (PCa) is a well-known risk factor, and both common and rare genetic variants are associated with the disease.ObjectiveTo detect new genetic variants associated with PCa, capitalizing on the role of family history and more aggressive PCa.Design, setting, and participantsA two-stage design was used. In stage one, whole-exome sequencing was used to identify potential risk alleles among affected men with a strong family history of disease or with more aggressive disease (491 cases and 429 controls). Aggressive disease was based on a sum of scores for Gleason score, node status, metastasis, tumor stage, prostate-specific antigen at diagnosis, systemic recurrence, and time to PCa death. Genes identified in stage one were screened in stage two using a custom-capture design in an independent set of 2917 cases and 1899 controls.Outcome measurements and statistical analysisFrequencies of genetic variants (singly or jointly in a gene) were compared between cases and controls.Results and limitationsEleven genes previously reported to be associated with PCa were detected (ATM, BRCA2, HOXB13, FAM111A, EMSY, HNF1B, KLK3, MSMB, PCAT1, PRSS3, and TERT), as well as an additional 10 novel genes (PABPC1, QK1, FAM114A1, MUC6, MYCBP2, RAPGEF4, RNASEH2B, ULK4, XPO7, and THAP3). Of these 10 novel genes, all but PABPC1 and ULK4 were primarily associated with the risk of aggressive PCa.ConclusionsOur approach demonstrates the advantage of gene sequencing in the search for genetic variants associated with PCa and the benefits of sampling patients with a strong family history of disease or an aggressive form of disease.Patient summaryMultiple genes are associated with prostate cancer (PCa) among men with a strong family history of this disease or among men with an aggressive form of PCa.     

Acute and custodial care among impaired aged

The authors surveyed a community-based population of 628 persons who were 65 and over and who lived either in a rural Maryland county or in Baltimore. For each subject, the number of different medical problems, the subject's capacity to perform physical tasks, and the ability to function were assessed. The number and type of medical problems tended to be the best predictors of whether or not hospital or physician's office care were used, and of the volume of physician's office visits for subjects who sought outpatient care. The subject's ability to function was the best predictor of whether or not the subject used a paid home aide and the volume of family caregiving. Implications for research on association between need and use of long-term care are discussed.     

Pulmonary function, airway responsiveness, and respiratory symptoms in asthmatics following exercise in NO2

Two experiments were conducted to determine respiratory responses of persons with asthma performing intermittent moderate exercise while exposed to low concentrations of NO2. In the first, preliminary experiment, 13 male subjects, aged 19-35, with mild asthma were exposed on separate days in a chamber (natural breathing, 20 degrees C, 40% RH) to 0.30 ppm NO2 and to a control or "clean air" exposure (0.0 ppm NO2). Exposure included three 10-min periods of moderate treadmill exercise (VE = 44.5 liter/min), each followed by symptom measurement and pulmonary function testing. The average decrease in FEV1 following the initial 10 min exercise in 0.30 ppm was 11% which was significantly greater (p less than 0.05) than that observed in clean air (7%). Differences in FVC and SRaw were not significantly different at this time. Slight cough and dry mouth and throat were apparent only after the first exercise in NO2. After the second and third exercises, decreases in FEV1 and FVC and increases in SRaw were significantly greater in 0.30 than in 0.0 ppm NO2. Individual subject responses were variable. These results suggested that some asthmatics who perform moderate exercise while exposed to 0.30 ppm NO2 may experience bronchoconstriction and reduction in spirometric performance. Because of these preliminary findings, a more comprehensive, concentration-response experiment was conducted. Twenty-one male volunteers with mild asthma were exposed for 75 min with natural breathing to 0.0, 0.15, 0.30, and 0.60 ppm NO2. Exposure included three 10-min periods of moderate treadmill exercise (VE = 43 liter/min), each exercise followed by symptoms measurement and pulmonary function testing. In addition, airway responsiveness was measured two hr after each exposure by methacholine bronchial challenge testing. In the control exposures (0.0 ppm NO2), the exercise alone caused substantial decrements in pulmonary function. These decrements (as measured by decreases in FEV1 and FVC, and increases in SRaw) were not increased relative to the control exposure after any exercise session in any concentration of NO2. Furthermore, there was no overall group-averaged indication of a concentration-related effect of the NO2 on pulmonary function. Likewise, symptoms reported after NO2 exposure were not significantly different from those reported in clean air. Group-averaged airway responsiveness after exercise in NO2 was also not different from responsiveness after exercise in clean air. For only two subjects was there any indication of a concentration-related increase in airway responsiveness due to exposure to NO2.(ABSTRACT TRUNCATED AT 400 WORDS)     

Assessing and planning home-based care for persons with AIDS

The HIV/AIDS pandemic continues to gather momentum in many developing countries, increasing the already heavy burden on health care facilities. As a result, donors, implementing partners and communities are beginning to create home-based care programmes to provide care for persons with HIV/AIDS. This paper recommends reorienting this home care provision as a service founded in, and coming from, the community rather than the health system. A methodology, in the form of an assessment matrix, is provided to facilitate the assessment of a community's capacity to provide care for people with AIDS. The focus is on rapid assessment methods using, where possible, readily available information to clearly and systematically define current circumstances. The matrix created for a specific community is then used in the development of an action plan with interventions prioritized and tailored to local needs. A case study from a hypothetical developing country, where HIV/AIDS is a significant problem, is used to illustrate the process.     

Mechanical methods in refractive corneal surgery

Over the past decade, keratorefractive surgery has moved into the mainstream of ophthalmology as improved instrumentation and newer techniques have evolved. These new aspects increase the safety and effectiveness of the various keratorefractive procedures. The introduction of new techniques and knife designs has led to improved results with radial keratotomy. The newly developed arcuate keratome purportedly offers the possibility of improving the predictability of arcuate keratotomy. Keratomileusis and epikeratoplasty have been successful for some difficult refractive states, such as aphakia and high myopia. Intracorneal lenses are showing promise in correcting high refractive errors and may offer an alternative to the more technically challenging lamellar procedures performed for correcting these conditions. Intrastromal ring implants are early in their clinical testing, but may provide an alternative to radial keratotomy for correcting myopia. The predictability, effectiveness, safety, and stability are far from perfect for current procedures, but recent results are encouraging.     

Facial Nerve Monitoring under Neuromuscular Blockade

The characteristics of facial nerve electromyography at various levels of neuromuscular blockade are unclear. Partial blockade is well known to facilitate anesthetic safety and management. However, the use of neuromuscular blockage in many skull base procedures is avoided to allow intraoperative facial nerve monitoring.We studied the influence of various levels of neuromuscular blockade on facial nerve stimulation in the New Zealand white rabbit. The facial nerve was exposed in the middle ear of six rabbits. Using electromyographic-type facial nerve monitor, we recorded the facial electromyography signals in these rabbits at increasing levels of vecuronium-induced neuromuscular blockade. All animals demonstrated reliable facial electromyography response at all levels of partial neuromuscular blockade (P < .02). Five of the six animals could be monitored throughout complete blockade. These results clearly demonstrate that rabbit facial electromyography monitoring is possible under neuromuscular blockade. The effect of neuromuscular blockers on facial electromyography monitoring deserves further study, as partial blockade would greatly facilitate the management of anesthesia in otologic, neurotologic, and skull base surgery.     

Air pollution and infant mortality in Mexico City

Historic air pollution episodes of the 1950s led to acute increases in infant mortality, and some recent epidemiologic studies suggest that infant or child mortality may still result from air pollution at current levels. To investigate the evidence for such an association, we conducted a time-series study of infant mortality in the southwestern part of Mexico City in the years 1993 to 1995 using mortality data from death registrations and air pollution measurements from a monitoring station we operated. Excess infant mortality was associated with the level of fine particles in the days before death, with the strongest association observed for the average concentration of fine particles during the period 3 to 5 days previously: a 10-microg m(-3) increase in the mean level of fine particles during these 3 days was associated with a 6.9% excess of infant deaths (95% confidence interval 2.5-11.3%). Infant mortality was also associated with the levels of nitrogen dioxide and ozone 3 to 5 days before death, but not as consistently as with particles.     

National health expenditures, 1998

In 1998, national health care expenditures reached $1.1 trillion, an increase of 5.6 percent from the previous year. This marked the fifth consecutive year of spending growth under 6 percent. Underlying the stability of the overall growth, major changes began taking place within the Nation's health care system. Public payers felt the initial effects of the Balanced Budget Act of 1997 (BBA), and private payers experienced increased health care costs and increased premium growth.     

Business, households, and government: health spending, 1994

During the 1990s, growth in health care costs slowed considerably, helping to lessen the spending strain on business, government, and households. Although cost growth has slowed, the Federal Government continues to pay an ever-increasing share of the total health care bill. This article reviews important health care spending trends, and for the first time, provides separate estimates of the employer and employee share of the premium costs for employer-sponsored private health insurance. This article also highlights some of the emerging trends in the employer-sponsored insurance market, including managed care, cost-sharing, and employment shifts.