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Biomedical subjects

M J Daly

Publications and source records attributed to M J Daly.

At least 73 records · Page 4Linked to original sources
PubMed1997

The vibrator mutation causes neurodegeneration via reduced expression of PITP alpha: positional complementation cloning and extragenic suppression.

The mouse vibrator mutation causes an early-onset progressive action tremor, degeneration of brain stem and spinal cord neurons, and juvenile death. We cloned the vibrator mutation using an in vivo positional complementation approach and complete resequencing of the resulting 76 kb critical region from vibrator and its parental chromosome. The mutation is an intracisternal A particle retroposon insertion in intron 4 of the phosphatidylinositol transfer protein alpha gene, causing a 5-fold reduction in RNA and protein levels. Expression of neurofilament light chain is also reduced in vibrator, suggesting one signaling pathway that may underlie vibrator pathology. The vibrator phenotype is suppressed in one intercross. We performed a complete genome scan and mapped a major suppressor locus (Mvb-1) to proximal chromosome 19.

Alleles↗
PubMed1997

Genetic analysis of ozone-induced acute lung injury in sensitive and resistant strains of mice.

Epidemiological studies have found air pollution to be associated with excessive mortality, particularly death from respiratory and cardiovascular causes. Interpretation of these findings is controversial, however, because toxicological mechanisms controlling mortality are uncertain. Susceptibility to many air pollutants entails an oxidative stress response. Accordingly, the best-characterized oxidant air pollutant is ozone, which causes direct oxidative damage of lung biomolecules. An underlying characteristic derived from clinical and epidemiological studies of healthy and asthmatic individuals of all ages is marked variability in the respiratory effects of ozone. This susceptibility difference among humans suggests that genetic determinants may control predisposition to the harmful effects of ozone. Mice also vary considerably in their response to ozone. Moreover, ozone-induced differences in strain responses indicate that susceptibility in mice can be genetically determined. Therefore, we used inbred mice to investigate the genetic determinants of acute lung injury. Recombinant inbred (RI) strains derived from A/J (A) mice (sensitive) and C57BL/6J (B) mice (resistant) showed a continuous phenotypic pattern, suggesting a multigenic trait. Quantitative trait locus and RI analyses suggested three major loci linked to ozone susceptibility. Differences in phenotype ratios among the reciprocal back-crosses were consistent with parental imprinting. These findings implicate various genetic and epigenetic factors in individual susceptibility to air pollution.

Animals↗
PubMed1997

Clinical economics review: Helicobacter pylori-associated peptic ulcer disease.

The high prevalence and chronic nature of peptic ulcer disease have traditionally resulted in a major economic burden on health care systems. In 1991, for example, peptic ulcer disease was estimated to account for over one-third of all National Health Service expenditure on gastrointestinal diseases. It is now well established that elimination of Helicobacter pylori can lead to a dramatic reduction in gastroduodenal ulcer relapse, with obvious clinical benefits. This review considers the economic implications of the use of H. pylori eradication therapy in peptic ulcer disease.

Clinical Trials as Topic↗
PubMed1997

Genomewide scan of multiple sclerosis in Finnish multiplex families.

Multiple sclerosis (MS) is a neurological, demyelinating disorder with a putative autoimmune etiology. It is thought to be a multifactorial disease with a complex mode of inheritance. Here we report the results of a two-stage genomewide scan for loci predisposing to MS. The first stage of the screen, with a low-resolution map, was performed in a selection of 16 pedigrees collected from an isolated Finnish population. Multipoint, non-parametric linkage analysis of the 328 markers did not reveal statistically significant results. However, 10 slightly interesting regions (P = .1-.15) emerged, including our previous findings of the HLA complex on 6p21 and a putative locus on 5p14-p12. Eight of these novel regions were further analyzed by use of denser marker maps, in the second stage of the scan. For the chromosomal regions 4cen, 11tel, and 17q, the statistical significance increased, but not conclusively; for 2q32 and 10q21, the statistical significance did not change. Accordingly, genotyping of the high-density markers in these regions was performed, and the data were analyzed by use of two-point, parametric linkage analysis using the complete pedigree information of the 21 Finnish multiplex families. We detected suggestive evidence for a predisposing locus on chromosomal region 17q22-q24. Several markers on 17q22-q24 yielded positive LOD scores, with the maximum LOD score (Zmax) occurring with D17S807 (Zmax = 2.8, theta = .04; dominant model). Interestingly, a suggestive linkage between MS and the markers on 17q22-q24 was also revealed by a recent genomewide scan in MS families from the United Kingdom.

Autoimmune Diseases↗
PubMed1997

Genetic control of serum IgE levels and asthma: linkage and linkage disequilibrium studies in an isolated population.

Immunoglobulin E (IgE) concentration in serum is elevated in atopic diseases such as asthma. A large genomic region on chromosome 5 has previously been implicated in the control of IgE levels and bronchial hyperreactivity and may, therefore, harbor genes predisposing to asthma. In an effort to confirm this linkage and to delimit the critical region, we took advantage of an isolated founder subpopulation in Finland to study genetic linkage and haplotype associations. Sixteen polymorphic markers, including the Interleukin-4 and -9 genes (IL4, IL9), were physically ordered and genotyped in 157 nuclear families. Genetic linkage studies involving sib- and cousin-pair analyses found no evidence of genetic linkage between markers in 5q and either serum IgE levels or asthma. Haplotype association studies were also performed. Although initial inspection suggested the possibility of linkage disequilibrium in the region of IL9, we developed a rigorous permutation test for assessing association and determined that the association was no greater than would be expected by chance. Sequence analysis of the IL9 gene in three patients sharing a possibly conserved haplotype revealed a T113M coding polymorphism, but this variant showed no association with either serum IgE levels or asthma. We conclude that allelic variation at chromosome 5q31 is not likely to contribute to inheritance of serum IgE levels or the development of asthma in this Finnish subpopulation.

Adolescent↗
PubMed1996

Genetic mapping of a murine locus controlling development of T helper 1/T helper 2 type responses.

Genetic background of the T cell can influence T helper (Th) phenotype development, with some murine strains (e.g., B10.D2) favoring Th1 development and others (e.g., BALB/c) favoring Th2 development. Recently we found that B10.D2 exhibit an intrinsically greater capacity to maintain interleukin 12 (IL-12) responsiveness under neutral conditions in vitro compared with BALB/c T cells, allowing for prolonged capacity to undergo IL-12-induced Th1 development. To begin identification of the loci controlling this genetic effect, we used a T-cell antigen receptor-transgenic system for in vitro analysis of intercrosses between BALB/c and B10.D2 mice and have identified a locus on murine chromosome 11 that controls the maintenance of IL-12 responsiveness, and therefore the subsequent Th1/Th2 response. This chromosomal region is syntenic with a locus on human chromosome 5q31.1 shown to be associated with elevated serum IgE levels, suggesting that genetic control of Th1/Th2 differentiation in mouse, and of atopy development in humans, may be expressed through similar mechanisms.

Animals↗
PubMed1996

A comprehensive genetic map of the mouse genome.

The availability of dense genetic linkage maps of mammalian genomes makes feasible a wide range of studies, including positional cloning of monogenic traits, genetic dissection of polygenic traits, construction of genome-wide physical maps, rapid marker-assisted construction of congenic strains, and evolutionary comparisons. We have been engaged for the past five years in a concerted effort to produce a dense genetic map of the laboratory mouse. Here we present the final report of this project. The map contains 7,377 genetic markers, consisting of 6,580 highly informative simple sequence length polymorphisms integrated with 797 restriction fragment length polymorphisms in mouse genes. The average spacing between markers is about 0.2 centimorgans or 400 kilobases.

Animals↗
PubMed1996

Renal disease susceptibility and hypertension are under independent genetic control in the fawn-hooded rat.

Hypertension, diabetes and hyperlipidemia are risk factors for life-threatening complications such as end-stage renal disease, coronary artery disease and stroke. Why some patients develop complications is unclear, but only susceptibility genes may be involved. To test this notion, we studied crosses involving the fawn-hooded rat, an animal model of hypertension that develops chronic renal failure. Here, we report the localization of two genes, Rf-1 and Rf-2, responsible for about half of the genetic variation in key indices of renal impairment. In addition, we localize a gene, Bpfh-1, responsible for about 26% of the genetic variation in blood pressure. Rf-1 strongly affects the risk of renal impairment, but has no significant effect on blood pressure. Our results show that susceptibility to a complication of hypertension is under at least partially independent genetic control from susceptibility to hypertension itself.

Animals↗
PubMed1996

Prescribing patterns for dyspepsia in primary care: a prospective study of selected general practitioners.

AIM: To define prescribing patterns for symptomatic dyspeptic patients in a cross-section of general practitioners in Leeds, United Kingdom. METHODS: Nine general practitioners from a range of practices took part in a prospective observational study of prescribing patterns for dyspepsia. All consultations with symptomatic dyspeptic patients were recorded over a 4-month period. Symptoms were recorded as ulcer-like, reflux-like, or nonspecific, and details of recent therapy, previous investigations and any prescription issued were noted. RESULTS: 257 consecutive consultations were recorded (new patients 23%, consulted before but not investigated 33%, previously investigated 44%). 93% of consultations resulted in a prescription (antacids 24%, prokinetic/motility agent 8%, H2-receptor antagonist 36%, proton pump inhibitor 24%, Helicobacter pylori eradication therapy 8%). 42.5% of new patients received an acid-suppressing drug as first-line therapy, of which only 32% had tried over-the-counter remedies. Symptom-type (ulcer-like, reflux-like or nonspecific) significantly influenced choice of empiric therapy (P < 0.001), though prescribing was still variable. Although around 60% of patients with previously negative investigations or only minor disease received acid-suppressing drugs, such patients were six times more likely to receive 'less potent' treatments (no prescription, antacid or motility agent) than those with known acid-peptic disease (odds ratio 6.23, P < 0.01). Only 30% of patients with previously documented peptic ulcer received H. pylori eradication therapy, yet patients with a wide range of other diagnoses received this form of treatment. CONCLUSIONS: Management guidelines may help to promote a more consistent and selective use of newer treatments, and promote more cost-effective patient care.

Dyspepsia↗
PubMed1996

Clinical economics review: gastroenterology.

In the prevailing climate of cost containment, doctors are increasingly expected to consider the economic consequences of treatment choices. Clinical (or medical) economics attempts to apply economic principles to the description and analysis of the costs of medical interventions, so as to identify how best to spend scarce health care resources. Such economic evaluations may assess the overall financial burden of a disease to society as a whole (macro-economics), or attempt to compare alternative treatment strategies for a specific clinical situation (micro-economics). In addition to expenditure on drugs and investigations (direct medical costs), economic studies may consider a variety of other costs. These include direct costs borne by patients (e.g. prescription charges, travel, food), indirect costs to society owing to lost productivity (resulting from morbidity or premature mortality) and even intangible costs which assign a monetary value to outcomes of disease such as pain, distress and anxiety. Four main types of economic analysis are in current use. Cost-minimization analysis attempts to identify the least expensive option in situations where there are a range of equally effective treatments for a given clinical condition, whereas cost-effectiveness analysis allows management strategies differing both in cost and efficacy to be compared. The cost-effectiveness of health care programmes targeting different disease states may also be compared using cost-utility analysis, in which health benefits are translated into a common utility-based unit of outcome, such as the Quality Adjusted Life Year (QALY). Cost-benefit analysis attempts to quantify health outcomes in monetary terms, so that the net result provides an assessment of value-for-money of health interventions. Gastrointestinal disorders are amongst the commonest of complaints, and considerable health care resources are consumed in treatment. Issues of cost-effectiveness are likely to assume increasing importance in gastroenterology because of the ever expanding range of drug choice, the increasing number of high cost treatments and the development of new therapeutic interventions.

Cost of Illness↗
PubMed1996

Expression of recA in Deinococcus radiodurans.

Deinococcus (formerly Micrococcus) radiodurans is remarkable for its extraordinary resistance to ionizing and UV irradiation and many other agents that damage DNA. This organism can repair > 100 double-strand breaks per chromosome induced by ionizing radiation without lethality or mutagenesis. We have previously observed that expression of D. radiodurans recA in Escherichia coli appears lethal. We now find that the RecA protein of D. radiodurans is ot detectable in D. radiodurans except in the setting of DNA damage and that termination of its synthesis is associated with the onset of deinococcal growth. The synthesis of Shigella flexneri RecA (protein sequence identical to that of E. coli RecA) in recA-defective D. radiodurans is described. Despite a large accumulation of the S. flexneri RecA in D. radiodurans, there is no complementation of any D. radiodurans recA phenotype, including DNA damage sensitivity, inhibition of natural transformation, or inability to support a plasmid that requires RecA for replication. To ensure that the cloned S. flexneri recA gene was not inactivated, it was rescued from D. radiodurans and was shown to function normally in E. coli. We conclude that neither D. radiodurans nor S. flexneri RecA is functional in the other species, nor are the kinetics of induction and suppression similar to each other, indicating a difference between these two proteins in their modes of action.

DNA Damage↗
PubMed1996

An alternative pathway of recombination of chromosomal fragments precedes recA-dependent recombination in the radioresistant bacterium Deinococcus radiodurans.

Deinococcus radiodurans R1 and other members of this genus are able to repair and survive extreme DNA damage induced by ionizing radiation and many other DNA-damaging agents. The ability of R1 to repair completely > 100 double-strand breaks in its chromosome without lethality or mutagenesis is recA dependent. However, during the first 1.5 h after irradiation, recA+ and recA cells show similar increases in the average size of chromosomal fragments. In recA+ cells, DNA continues to enlarge to wild-type size within 29 h. However, in recA cells, no DNA repair is observed following the first 1.5 h postirradiation. This recA-independent effect was studied further, using two slightly different Escherichia coli plasmids forming adjacent duplication insertions in the chromosome, providing repetitive sequences suitable for circularization by non-recA-dependent pathways following irradiation. After exposure to 1.75 Mrad (17,500 Gy), circular derivatives of the integration units were detected in both recA+ and recA cells. These DNA circles were formed in the first 1.5 h postirradiation, several hours before the onset of detectable recA-dependent homologous recombination. By comparison, D. radiodurans strains containing the same E. coli plasmids as nonrepetitive direct insertions did not form circular derivatives of the integration units before or after irradiation in recA+ or recA cells. The circular derivatives of the tandemly integrated plasmids were formed before the onset of recA-dependent repair and have structures consistent with the hypothesis that DNA repair occurring immediately postirradiation is by a recA-independent single-strand annealing reaction and may be a preparatory step for further DNA repair in wild-type D. radiodurans.

Alleles↗
PubMed1996

Parametric and nonparametric linkage analysis: a unified multipoint approach.

In complex disease studies, it is crucial to perform multipoint linkage analysis with many markers and to use robust nonparametric methods that take account of all pedigree information. Currently available methods fall short in both regards. In this paper, we describe how to extract complete multipoint inheritance information from general pedigrees of moderate size. This information is captured in the multipoint inheritance distribution, which provides a framework for a unified approach to both parametric and nonparametric methods of linkage analysis. Specifically, the approach includes the following: (1) Rapid exact computation of multipoint LOD scores involving dozens of highly polymorphic markers, even in the presence of loops and missing data. (2) Non-parametric linkage (NPL) analysis, a powerful new approach to pedigree analysis. We show that NPL is robust to uncertainty about mode of inheritance, is much more powerful than commonly used nonparametric methods, and loses little power relative to parametric linkage analysis. NPL thus appears to be the method of choice for pedigree studies of complex traits. (3) Information-content mapping, which measures the fraction of the total inheritance information extracted by the available marker data and points out the regions in which typing additional markers is most useful. (4) Maximum-likelihood reconstruction of many-marker haplotypes, even in pedigrees with missing data. We have implemented NPL analysis, LOD-score computation, information-content mapping, and haplotype reconstruction in a new computer package, GENEHUNTER. The package allows efficient multipoint analysis of pedigree data to be performed rapidly in a single user-friendly environment.

Algorithms↗
PubMed1995

A model for repair of radiation-induced DNA double-strand breaks in the extreme radiophile Deinococcus radiodurans.

The bacterium Deinococcus (formerly Micrococcus) radiodurans and other members of the eubacterial family Deinococaceae are extremely resistant to ionizing radiation and many other agents that damage DNA. Stationary phase D. radiodurans exposed to 1.0-1.5 Mrad gamma-irradiation sustains > 120 DNA double-strand breaks (dsbs) per chromosome; these dsbs are mended over a period of hours with 100% survival and virtually no mutagenesis. This contrasts with nearly all other organisms in which just a few ionizing radiation induced-dsbs per chromosome are lethal. In this article we present an hypothesis that resistance of D. radiodurans to ionizing radiation and its ability to mend radiation-induced dsbs are due to a special form of redundancy wherein chromosomes exist in pairs, linked to each other by thousands of four-stranded (Holliday) junctions. Thus, a dsb is not a lethal event because the identical undamaged duplex is nearby, providing an accurate repair template. As addressed in this article, much of what is known about D. radiodurans suggests that it is particularly suited for this proposed novel form of DNA repair.

DNA Damage↗
PubMed1995

A genetic linkage map of the laboratory rat, Rattus norvegicus.

We report the construction of the first complete genetic linkage map of the laboratory rat. By testing 1171 simple sequence length polymorphisms (SSLPs), we have identified 432 markers that show polymorphisms between the SHR and BN rat strains and mapped them in a single (SHR x BN) F2 intercross. The loci define 21 large linkage groups corresponding to the 21 rat chromosomes, together with a pair of nearby markers on chromosome 9 that are not linked to the rest of the map. Because 99.5% of the markers fall into one of the 21 large linkage groups, the maps appear to cover the vast majority of the rat genome. The availability of the map should facilitate whole genome scans for genes underlying qualitative and quantitative traits relevant to mammalian physiology and pathobiology.

Animals↗