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Biomedical subjects

J B Walsh

Publications and source records attributed to J B Walsh.

At least 55 records · Page 3Linked to original sources

How often do duplicated genes evolve new functions?

A recently duplicated gene can either fix a null allele (becoming a pseudogene) or fix an (advantageous) allele giving a slightly different function, starting it on the road to evolving a new function. Here we examine the relative probabilities of these two events under a simple model. Null alleles are assumed to be neutral; linkage effects are ignored, as are unequal crossing over and gene conversion. These assumptions likely make our results underestimates for the probability that an advantageous allele is fixed first. When new advantageous mutations are additive with selection coefficient s and the ratio of advantageous to null mutations is rho, the probability an advantageous allele is fixed first is ([1 - e-s]/[rho S] + 1)-1, where S = 4Nes with Ne the effective population size. The probability that a duplicate locus becomes a pseudogene, as opposed to evolving a new gene function, is high unless rhoS >> 1. However, even if advantageous mutations are very rare relative to null mutations, for sufficiently large populations rhoS >> 1 and new gene function, rather than pseudogene formation, is the expected fate of most duplicated genes.

Biological Evolution↗

Small intestinal bacterial overgrowth--an incidental finding?

OBJECTIVES: To assess the prevalence of typical clinical features and need for treatment of small intestinal bacterial overgrowth (SIBO) in the elderly. DESIGN: Random selection of patients, regardless of their nutritional status. SETTING: Acute admissions ward in the Dept. of Medicine for the Elderly. PATIENTS: Thirty elderly patients between 68 and 90 years of age. MEASUREMENTS: Active clinical problems, including the presence of recent weight loss and diarrhea, were recorded. Routine blood tests, including serum vitamin B12, red cell folate, albumin and calcium, and qualitative small bowel bacteriology results, were analyzed. The effect of age on all variables was studied. RESULTS: Twenty of the 30 small bowel aspirates had proven SIBO, and strict anaerobes were isolated in 15. The mean blood test values did not differ significantly between culture-positive and culture-negative patients. There was no significant correlation between those variables and the total bacterial counts. Of the 20 proven SIBO cases, eight had anemia, five had hypoalbuminemia, five had diarrhea, four complained of recent weight loss, and none had B12 deficiency. Alternative causes other than SIBO were identified for many of these abnormalities. Advancing age correlated significantly with rising counts of small bowel strict anaerobes. CONCLUSIONS: These data suggest that age may be a predisposing factor in the development of anaerobic overgrowth but that SIBO is a benign entity in the elderly. Contrary to previous recommendations, treatment of this condition is not routinely indicated.

Age Factors↗

Differential diagnosis of dementia: a prospective evaluation of the DAT Inventory.

OBJECTIVE: To compare prospectively the concordance between the diagnosis of dementia based on clinical criteria and using the DAT Inventory. DESIGN, SETTING, AND PARTICIPANTS: A prospective study of 81 consecutive patients referred to a Memory Clinic. Only patients for whom a definitive diagnosis of dementia was established after 8 to 20 months follow-up were retained in the study (n = 76). MEASUREMENTS: The sensitivity, specificity, positive and negative predictive values, and overall diagnostic accuracy of the DAT Inventory were calculated. Kappa values were also computed. RESULTS: Based on all patients (n = 76), sensitivity and specificity were 71% and 95%, respectively, with 98% positive prediction, 56% negative prediction, 78% overall accuracy, and kappa of 0.54. Of 21 cases not meeting NINCDS/ADRDA criteria for DAT, one patient with multi-infarct dementia was misclassified as DAT on the DAT Inventory. Of 55 DAT cases (NINCDS/ADRDA criteria), 16 patients, predominantly very mild or mixed cases, were classified as non-DAT on the DAT Inventory. When mixed, very mild, and borderline cases were excluded (remaining n = 54), DAT Inventory sensitivity increased to 94%, and specificity remained unchanged at 95%, with 97% positive and 91% negative prediction, 94% overall accuracy, and kappa of 0.88. CONCLUSIONS: In general, scores above the designated cutoff point (> 14/20) on the DAT Inventory are consistent with a clinical diagnosis of DAT (NINCDS/ADRDA criteria). Concordance is best in cases of mild to moderate dementia (Clinical Dementia Rating 1-2). The Inventory is less discriminating as a differential diagnostic instrument in cases of very mild dementia, atypical presentations of DAT, or in cases of mixed pathology.

Aged↗

Primary auditory pathway and reticular activating system dysfunction in Alzheimer's disease.

Patients with Alzheimer's disease (AD) have pathologic involvement of several important components of the primary auditory pathway, including the inferior colliculus, medial geniculate body, primary auditory cortex, and secondary auditory cortex. The main components of the brainstem auditory evoked response (BAER) and middle latency response (MLR) reflect the function of portions of the primary auditory pathway, including those affected pathologically in AD. The amplitude of the P1 component of the MLR reflects the degree of neuronal activity of midbrain portions of the ascending reticular activating system (ARAS) with cortical cholinergic projections. To determine whether there is dysfunction of the primary auditory pathway and ARAS in AD, we compared simultaneous BAER and MLR component latency and amplitude measurements in patients with mild-moderate AD (n = 35) and age-matched healthy elderly controls (n = 34). There were significant latency delays in brainstem transmission time (BAER I-V interpeak latency; p < 0.05) and in primary auditory cortex evoked potential generation (MLR Pa latency; p < 0.05) in the AD group compared with controls. In addition, there was a significant reduction in the P1 component amplitude of the MLR in the AD group (p < 0.01). These results indicate dysfunction of the primary auditory pathway and ARAS in patients with mild-moderate AD and support the hypothesis that impairment of auditory function and of arousal are intrinsic features of AD.

Aged↗

The discriminant value of semiquantitative SPECT data in mild Alzheimer's disease.

UNLABELLED: In most semiquantitative SPECT studies, overlap between groups of patients with Alzheimer's disease (AD) and age-matched elderly controls is such that single posterior cortical perfusion measurements lack sensitivity. In the present study, the value of a combination of semiquantitative temporoparietal SPECT parameters was examined. METHODS: Supratentorial transaxial perfusion measurements were obtained in frontal, anterior temporal, posterior temporoparietal and occipital cortical areas in both hemispheres, in a baseline population of 10 healthy elderly controls and 30 mild to moderately impaired AD patients, as well as in a prospective group of 15 patients with mild cognitive impairment, 12 patients with a diagnosis of probable AD and individual cases of multi-infarct dementia, dementia-frontal type and paranoid psychosis. A linear discriminant function (LDF) was calculated from the baseline subjects' data to classify control and AD subjects individually. RESULTS: Highly significant hypoperfusion was noted in both the anterior temporal and posterior temporoparietal regions of interest in the AD group compared with controls, but with significant overlap. Using an LDF incorporating these perfusion measurements in both hemispheres, 10/10 (100%) controls and 26/30 (87%) AD baseline subjects were correctly classified. Using the baseline LDF in the prospective 15 mildly impaired cases, 11/12 new mild AD cases and none of the 3 non-AD cases were classified in the AD group. CONCLUSION: These results support the use of a combination of semiquantitative SPECT perfusion estimates from cortical areas with predictable pathological involvement in AD in a linear discriminant format in the clinical assessment of patients with suspected AD.

Aged↗

Observing the brachial artery through a pressure cuff.

A technique is described which enables ultrasonic imaging of the brachial artery whilst pressure is applied via a pressure cuff. This involves a new instrument--a sphygmomanometer, which uses water as opposed to air as the pressure medium, in order to permit ultrasonic imaging through the cuff. The technique was found to be acceptable in the clinical setting, and gave a measurement of the systolic blood pressure which correlated with the conventional cuff measurement in eleven elderly subjects (r = 0.89, p < 0.001). The technique should have an important role to play in studying the origin of differences which occur between direct and indirect blood pressure measurements.

Blood Pressure Determination↗

Measurement of arterial closing pressure.

It has been suggested that certain artifacts in blood pressure measurement by auscultation stem from stiffness of the tissues underneath the pressure cuff, resulting in a component of cuff pressure being required to overcome resistance to brachial artery collapse. This paper describes a technique for measuring the pressure required to collapse a segment of the brachial artery which has been isolated from central arterial pressure. This measurement is termed the arterial closing pressure. In a study of eleven elderly subjects, the artery collapsed spontaneously (zero closing pressure) after being isolated from central pressure in seven subjects. The remaining four required external pressures ranging from 4.6 to 10.7 kPa (35 to 81 mmHg) in order to collapse the artery. Thus arterial closing pressure may frequently be a significant fraction of arterial blood pressure in the elderly population, and may contribute to error in the measurement of blood pressure by auscultation. Arterial closing pressure may be a useful tool for investigating the origin of differences between indirect and direct blood pressure measurements, and also in the investigation of spontaneous arterial closure.

Aged↗

Parkinson's dementia and Alzheimer's dementia: an evoked potential comparison.

Auditory endogenous event-related potentials (ERPs) and flash visual evoked potentials (VEPs) were recorded in 26 elderly patients with idiopathic Parkinson's disease (PD), 14 with dementia and 12 non-demented, 16 elderly patients with Alzheimer dementia (AD) and 15 cognitively intact controls. ERP P3 and flash-VEP N2, P2 and delta (P2-P1) latency measures were significantly increased in the demented PD group compared with controls. The ERP P3 latency was also significantly delayed in the AD group compared with controls, but the differences in the flash-VEP measures from controls were not significant. No significant differences were noted between the PD groups, except for a significantly shorter flash-VEP N1 latency in the demented PD group; this was also the only significant evoked potential difference between the AD and PD dementia groups, which were otherwise electrophysiologically similar.

Aged↗

Suitable screening tests for cognitive impairment and depression in the terminally ill--a prospective prevalence study.

Although confusional states and depression are common accompaniments of advanced cancer, few objective data are available concerning the prevalence of these clinical states or what methods are most suitable for their accurate detection. We decided that a 10-question Abbreviated Mental Test Score (AMTS) and a semistructured application of modified DSMIII-R (Diagnostic and Statistical Manual of Mental Disorder, third edition-revised) criteria for a major depressive illness were the most suitable screening tests for a terminally ill population. Thirty of 87 patients (34%) displayed significant cognitive impairment. The AMTS rating declined with approaching death and also correlated negatively with age. Of 81 patients, 21 (26%) were depressed when screened using DSMIII-R criteria for depression. One-third of patients with impaired AMTS scores also satisfied DSMIII-R criteria for depression. Of cognitively impaired patients, 90% had at least two possible causes for their confused state. We have found that both the AMTS and semistructured interview using DSMIII-R criteria for depression are useful routine screening tests in the terminally ill.

Adult↗

Lattice degeneration of the retina and the pigment dispersion syndrome.

Retinal detachment occurs more frequently in patients with pigment dispersion syndrome. We evaluated the incidence of peripheral retinal abnormalities known to predispose to rhegmatogenous retinal detachment in a consecutive series of 60 patients with pigment dispersion syndrome with or without glaucoma. Lattice degeneration was present in at least one eye of 12 patients (20%). Seven patients had bilateral lesions. Full-thickness retinal breaks were found in seven patients (11.7%) and two patients (3.3%) had asymptomatic rhegmatogenous retinal detachments that required scleral buckle procedures. The incidence of lattice degeneration and full-thickness retinal breaks appears to be increased in this group of patients, and may be responsible for the increased risk of rhegmatogenous detachment.

Adult↗

Biased gene conversion, copy number, and apparent mutation rate differences within chloroplast and bacterial genomes.

We investigate the possibility that differences between synonymous substitution rates of organelle and bacterial genes differing only in copy number may be due to conversion bias. We find that the rather large observed difference in the synonymous rates between genes in the single copy and inverted-repeat regions of chloroplasts can be accounted for by a very small bias against new mutants. More generally, differences in the within-organelle fixation probability result in different apparent mutation rates as measured by the expected rate of appearance of cells homoplasmic for new mutants. Thus, differences in intracellular population parameters rather than molecular mechanisms can account for some variation in the apparent mutation rates of organelle genes, and possibly in other systems with variable numbers of gene copies. On the other hand, our analysis suggests that conversion bias is not a likely explanation for relatively low mutation rates observed near the replication origin of bacterial chromosomes.

Chloroplasts↗

Intracellular selection, conversion bias, and the expected substitution rate of organelle genes.

A key step in the substitution of a new organelle mutant throughout a population is the generation of germ-line cells homoplasmic for that mutant. Given that each cell typically contains multiple copies of organelles, each of which in turn contains multiple copies of the organelle genome, processes akin to drift and selection in a population are responsible for producing homoplasmic cells. This paper examines the expected substitution rate of new mutants by obtaining the probability that a new mutant is fixed throughout a cell, allowing for arbitrary rates of genome turnover within an organelle and organelle turnover within the cell, as well as (possibly biased) gene conversion and genetic differences in genome and/or organelle replication rates. Analysis is based on a variation of Moran's model for drift in a haploid population. One interesting result is that if the rate of unbiased conversion is sufficiently strong, it creates enough intracellular drift to overcome even strong differences in the replication rates of wild-type and mutant genomes. Thus, organelles with very high conversion rates are more resistant to intracellular selection based on differences in genome replication and/or degradation rates. It is found that the amount of genetic exchange between organelles within the cell greatly influences the probability of fixation. In the absence of exchange, biased gene conversion and/or differences in genome replication rates do not influence the probability of fixation beyond the initial fixation within a single organelle. With exchange, both these processes influence the probability of fixation throughout the entire cell. Generally speaking, exchange between organelles accentuates the effects of directional intracellular forces.(ABSTRACT TRUNCATED AT 250 WORDS)

DNA Replication↗

Ocular hazards of nebulized bronchodilators.

Three cases of pupillary dilatation associated with the development of acute glaucoma, precipitated by the use of nebulized bronchodilators are described. We suggest measures to reduce the risk of this complication.

Adult↗

'Pseudo-Alzheimer's' and primary brain tumour.

Primary brain tumour may present in the elderly purely as a dementing illness before the onset or detection of sensorimotor neurological symptoms or signs. Although neurological examination may indicate no definite signs, close attention to accepted DSM-IIIR and NINCDS-ADRDA diagnostic criteria for primary degenerative dementia and 'probable' Alzheimer's disease respectively will suggest a process other than a degenerative one. This was the case in two patients with primary brain tumour presenting clinically with dementing illness similar to but distinct from Alzheimer's disease.

Aged↗

Vitamin-D-fortified liquid milk--a highly effective method of vitamin D administration for house-bound and institutionalised elderly.

The aim of the study was to assess the efficacy and acceptability of vitamin-D-fortified liquid milk in the management of hypovitaminosis D in an elderly institutionalised population. The design was a single-blind randomised controlled study. In phase I, patients were encouraged to drink an increased quantity of either fortified or unsupplemented milk for 3 months. In phase II, patients were continued on either fortified or on unsupplemented milk which was given as part of the everyday diet for a further 6 months with no extra encouragement of any patient to take additional amounts. Ninety-eight patients (mean age 84 years) from extended care wards at the Department of Medicine for the Elderly, St. James's Hospital, Dublin, Ireland, participated in the study. Seventy-eight patients completed phase I, and 62 completed phase II. A general biochemical screen and 25-hydroxy vitamin D measurements were performed at entry and repeated 3 and 9 months later. The average milk intake per patient in phase I was 454 ml/day in the unsupplemented group and 359 ml/day in the fortified milk group. In phase II, the average daily milk intake per patient was 235 ml in the unsupplemented milk group and 140 ml in the fortified milk group. Seventy-four patients (94%) of the total who completed phase I had serum vitamin D baseline levels below the normal range. In the fortified milk group, mean vitamin D levels rose from 2.4 to 14.80 ng/ml (p < 0.001) at the end of phase I and remained significantly elevated at 10.2 ng/ml (p < 0.001) at the end of phase II.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

Role of diabetes mellitus on the natural history of central retinal vein occlusion.

In order to elucidate the role of diabetes mellitus on the natural history of central retinal vein occlusion, we compared two groups of central retinal vein occlusion, one with diabetes mellitus (32 patients) and one without diabetes mellitus (113 patients). The two groups were quite similar with respect to age, sex, systemic hypertension and glaucoma. No fellow eye had proliferative diabetic retinopathy. The diabetic group had angiographically a more ischemic type of central retinal vein occlusion (72%) than the nondiabetic group (39%; p less than 0.002). Diabetics with central retinal vein occlusion should be closely monitored.

Adolescent↗