Strategies to identify disease genes

The correlation between genes and disease began in earnest in the early 1900s with the identification of Mendelian-like inheritance of "inborn errors of metabolism." Since then, the ever-broadening field of genetics has been established as one of the most important and groundbreaking branches of science and medicine to date. With the announcement of a "working draft" sequence of the human genome in 2001, the vast array of both genomic and expressed sequence information available in the public databases alone has meant that the concept of hunting for genes is evolving. Nowadays, researchers can substitute many labor-intensive hours in the lab for less time searching on the World Wide Web. Specialization within genetics has been continuously providing subsets of the genre such as genomics, pharmacogenetics, chemogenomics, gene therapy, proteomics and functional genomics, all of which are based on the fundamental starting block, the gene. This review aims to summarize both traditional and current strategies for identifying susceptibility and monogenetic disease genes and describes how these strategies have evolved in tune with the ever-expanding wealth of information now available at our fingertips.     

Osteoporosis: A possible aetiological factor in the development of Scheuermann's disease

The aim of this study was to test the hypothesis that spinal osteoporosis is an aetiological factor in the development of Scheuermann's disease in adolescents. Clinical and radiological data was collected on 12 individuals with Scheuermann's disease (SD). Lumbar spine bone mineral density (L2-4) was measured using dual energy X-ray absorptiometry. Age and sex-matched adolescents were used as controls. The number of standard deviations from the mean of age and sex-matched controls were calculated. In regards to results, SD patients demonstrated high bone densities of between 1 and 1.5 standard deviations above the mean of age-matched controls. These results suggest that osteoporosis is not an aetiological factor in Scheuermann's disease and that bone density measurements may indeed be higher than aged-matched controls in the general population.     

The Long-term Benefits of a Single Scan for Abdominal Aortic Aneurysm (AAA) at Age 65

AIM: To investigate the efficacy of a single ultrasonic scan at age 65 to identify patients at risk from ruptured abdominal aortic aneurysm (AAA). METHOD: A total of 6058 men aged 64-81 were recruited to a randomised trial, and 3000 were invited to attend a single screening test. An additional population of 1011 men was offered screening as they reached age 65. If a normal aorta was identified in this sub-group, further scans were offered at two-yearly intervals. Follow up and treatment of those identified as having an aortic dilatation of 3 cm or greater was undertaken. All subject groups were monitored for deaths occurring over the study period, and date and cause of death were recorded. RESULTS: A total of 2212 men attended screening in the randomised trial; the overall compliance was 74%, and prevalence of AAA was 7.7%. Compliance decreased, and prevalence increased, with age. Mortality from ruptured AAA was reduced by 68% at 5 years (screened group compared to the age-matched control population), and by 42% in the study arm (screened and refusers) compared with controls. The benefit persisted at ten years (53% and 21% respectively). Of the uncontrolled sample of 1011 men offered a scan at age 65, 681 attended and 649 of these were found to have a normal aortic diameter; re-screening demonstrated new aneurysm development in 4% over ten years. The aortic diameters of the new AAAs were under 4 cm and would therefore have a low risk of rupture.1 Mortality from rupture in all those with an initially normal aortic diameter was low, at 1 case per 1000 scans over ten years. CONCLUSION: Screening once for AAA at age 65 can identify the majority of AAA that are of clinical significance and can identify a large population at low risk from rupture who do not require surveillance. This policy has been effective when combined with selective treatment in reducing the risk of rupture for ten years in those who attend the screening programme.     

Dose-response effect of fetal cocaine exposure on newborn neurologic function

BACKGROUND: Studies of fetal cocaine exposure and newborn neurologic function have obtained conflicting results. Although some studies identify abnormalities, others find no differences between cocaine-exposed and cocaine-unexposed infants. To determine the effects of prenatal cocaine exposure on intrauterine growth and neurologic function in infants, we prospectively evaluated 253 infants shortly after birth. METHODS: Women who delivered a live singleton >36 weeks by dates were eligible for enrollment. Maternal exclusionary criteria were known parenteral drug use, alcoholism, and acquired immunodeficiency syndrome; infant exclusionary criteria were Apgar scores 相似文献   

Subchronic hydrocortisone treatment alters auditory evoked potentials in normal subjects

RATIONALE: Abnormalities of cortical evoked potentials and background electroencephalographic (EEG) frequencies occur in several psychiatric disorders, some of which, especially depression, are associated with hypercortisolaemia. However, there have been few investigations of the effects of exogenously administered cortisol on waking EEG measures. OBJECTIVES: To examine the effects of subchronic hydrocortisone administration on auditory evoked potentials and background EEG activity. METHODS: Hydrocortisone, 20 mg twice daily, or placebo was administered to 30 normal male volunteers for 7 days in a between-subjects, double-blind trial. Auditory evoked potentials and EEG frequencies were measured on the last day. RESULTS: Hydrocortisone significantly increased the amplitudes of the N1P2 and P300 components of the auditory evoked response, but there was no change in background EEG. CONCLUSION: The results indicate that subchronic hydrocortisone treatment in normal subjects increases the amplitude of auditory evoked potentials, possibly reflecting a central alerting effect.     

Should intake of carbon monoxide be used as a guide to intake of other smoke constituents?

The relation between blood carboxyhaemoglobin (COHb) and plasma nicotine concentrations was studied in a group of 12 smokers smoking cigarettes of three levels of standard delivery. While the intake of carbon monoxide from a single cigarette was unrelated to the intake of nicotine, presmoking "trough" concentrations of the two substances (reflecting longer-term exposure) were highly correlated. Various other measures of nicotine exposure were at best only moderately correlated with blood nicotine concentrations. Thus trough COHb concentrations might be used to provide a reliable indication of the exposure to nicotine of individual smokers smoking the same type of cigarette, and of the relative exposure to nicotine of populations smoking cigarettes of different standard deliveries.     

The influence of brain lateralization of function on a manual skill

The present study considers the predictions of the brain lateralization of function hypothesis for the concurrent-task situation where the subject is required, to perform simultaneously a manual and a cognitive task. The manual task required the subject to successively press two keys with either the right or left hand, this being done concurrently with one of twelve different cognitive tasks. The cognitive tasks varied in terms of their verbal (left hemisphere) and non-verbal (right hemisphere) attributes. The results indicate that, for the concurrent verbal task conditions, only right-hand performance was disrupted while left-hand performance remained unchanged. For the non-verbal conditions both left and right hand performance was disrupted. These findings were interpreted in terms of brain lateralization of cognitive functions and possible hemispheric processes controlling manual performance.