Pathology and experimental prophylaxis of avian poxvirus in red-legged partridges (Alectoris rufa).
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Animals↗
Biomedical subjects
R March
Publications and source records attributed to R March.
Genetic analysis of multicase families of visceral leishmaniasis in northeastern Brazil: no major role for class II or class III regions of HLA.
Familial aggregation, high relative risk to siblings, and segregation analysis, suggest genetic control of visceral leishmaniasis in Brazil. Class II gene effects in mice, and high circulating tumour necrosis factor alpha in humans, provide reasons to target HLA. Fifteen polymorphic markers across 1.03 Mb (DQB1 to TNFa) were genotyped (87 multicase families; 638 individuals). Model-based parametric analyses using single-point combined segregation and linkage in COMDS, or multi-point linkage in ALLEGRO, failed to detect linkage. Model-free nonparametric affected sibling pair (SPLINK) or NPL(all) score (ALLEGRO) analyses also failed to detect linkage. Information content mapping confirmed sufficient marker information to detect linkage. Analysis of simulated data sets demonstrated that these families had 100% power to detect NPL(all) scores of 5 to 6 (>LOD4; P < 0.00001) over the range (7% to 61%) of age-related penetrances for a disease susceptibility gene. The extended transmission disequilibrium test (TDT) showed no consistent allelic associations between disease and the 15 loci. TDT also failed to detect significant associations between extended haplotypes and disease, consistent with failure to detect significant linkage disequilibrium across the region. Linkage disequilibrium between adjacent groups of markers (HLADQ/DR; 82-1/82-3/-238bpTNFA; LTA/62/TNFa) was not accompanied by significant global haplotype TDT associations with disease. The data suggest that class II/III regions of HLA do not contain major disease gene(s) for visceral leishmaniasis in Brazil.
Animals↗
Pharmacogenetics--legal, ethical and regulatory considerations.
The overall objective of pharmacogenetics is to determine the genetic basis of variability in drug efficacy and safety, and to use this information to benefit the patient. Genetics can be used to develop drugs that are suitable for the majority of patients and to help identify those patients for whom a certain drug may not be the most appropriate. This review will cover some background to pharmacogenetics and various issues including confidentiality, data protection, coding of samples and genetic data, informed consent, and drug development guidelines. International, national and regional variation in the legal and regulatory basis for pharmacogenetics presents challenges for researchers attempting to increase scientific understanding in the field. Examples of national and international regulations and guidelines will be given. It is clear that pharmacogenetics today is a long way from the 'personalised medicine' advocated by some individuals in recent years. The aim of pharmacogenetic research should always be to make sure that patients have the best treatment available and that patients are not exposed to drugs to which they are genetically unable to respond. This vision must continue to inspire researchers and regulators who are working together to make it a widespread reality.
Clinical Trials as Topic↗
Evaluation of fine mapping strategies for a multifactorial disease locus: systematic linkage and association analysis of IDDM1 in the HLA region on chromosome 6p21.
The positional cloning of multifactorial disease genes is a major challenge in human genetics. We have therefore empirically tested the utility of the available polymorphic microsatellite map to locate the already identified type 1 diabetes locus IDDM1 (sibling risk/population prevalence ratio lambda(s)= 2.7) within a 14 Mb region of chromosome 6p21 linked to disease. In a two-stage approach to fine mapping, linkage was evaluated in 385 affected sib-pair families using 13 evenly spaced polymorphic microsatellite markers. The whole 14 Mb showed strong linkage. Then, each marker was analysed for evidence of allelic association, revealing evidence of disease association at one marker located within the 95% confidence interval of 1.7 cM obtained by linkage. Analysis of an additional 12 markers flanking this marker revealed a highly specific region of 570 kb associated with disease ( P = 7.5 x 10(-35)), which included the HLA class II genes, known to be the primary determinants of IDDM1. The peak of association was as close as 85 kb centromeric of the disease-predisposing class II gene HLA-DQB1. We investigated the importance of the underlying inter-marker linkage disequilibrium, marker informativity and recombination for fine mapping and demonstrate that the majority of disease association in the region can be explained by linkage disequilibrium with the class II susceptibility genes. Recombination within the major histocompatibility complex was rare and nearly absent in the class III region. We demonstrate that fine mapping of a multifactorial disease gene is possible with high accuracy even in a region with extraordinary linkage disequilibrium across distances of several Mb. The results will be applicable to association studies of disease loci with lambda(s)values <2.7 except that much larger data sets will be required.
Adolescent↗
Pharmacogenomics: the genomics of drug response.
Pharmacogenomics is defined as the study of the association between genetics and drug response. This is a rapidly expanding field with the hope that, within a few years, prospective genotyping will lead to patients being prescribed drugs which are both safer and more effective ('the right drug for the right patient', or personalized medicine). There are many existing examples in the literature of strong associations between genetic variation and drug response, and some of these even form the basis of accepted clinical tests. The molecular basis for some of these associations is described, and includes examples of variation in genes responsible for absorption and metabolism of the drug, and in target and disease genes. However, there are many issues surrounding the legal, regulatory and ethical framework to these studies that remain unanswered, and a huge amount of education both for the public and healthcare professionals will be needed before the results of this new medicine can be widely accepted.
Drug Therapy↗
Isolation of an attenuated myxoma virus field strain that can confer protection against myxomatosis on contacts of vaccinates.
Twenty MV strains obtained from a survey of field strains currently circulating throughout Spain were analyzed for their virulence and horizontal spreading among rabbits by contact transmission. A virus strain with suitable characteristics to be used as a potential vaccine against myxomatosis in wild rabbit populations was selected. Following inoculation, the selected MV strain elicited high levels of MV specific antibodies and induced protection of rabbits against a virulent MV challenge. Furthermore, the attenuated MV was transmitted to 9 out of 16 uninoculated rabbits by contact, inducing protection against myxomatosis.
Animals↗
Conditional ETDT analysis of the human leukocyte antigen region in type 1 diabetes.
Several studies have indicated that additional genes in the major histocompatibility complex (MHC) region, other than the class II genes HLA-DQB1 and -DRB1 (the IDDM1 locus), may contribute to susceptibility and resistance to type 1 diabetes. The relative magnitude of these non- DR/DQ effects is uncertain and their map location is unknown owing to the extraordinary linkage disequilibrium that extends over the 3.5 Mb of the MHC. The homozygous parent test has been proposed as a method for detection of additional risk factors conditional on HLA-DQB1 and -DRB1. However, this method is inefficient since it uses only parents homozygous for the primary disease locus, the DQB1-DRB1 haplotype. To overcome this limitation, Conditional ETDT was used in the present report to test for association conditional on the DQB1-DRB1 haplotype, thereby allowing all parents to be included in the analysis. First, we confirm in UK and Sardinian type 1 diabetic families that allelic variation at HLA-DRB1 has a very significant effect on the association of DQB1 and vice versa. The Conditional ETDT was then applied to the HLA TNF (tumour necrosis factor) region and microsatellite marker D6S273 region, both of which have been reported to contribute to IDDM1 independent of the HLA-DQB1-DRB1 genes. We found no evidence for a major role for either of these two regions in IDDM1.
Adolescent↗
A genome-wide screen for susceptibility loci in ankylosing spondylitis.
OBJECTIVE: To localize the regions containing genes that determine susceptibility to ankylosing spondylitis (AS). METHODS: One hundred five white British families with 121 affected sibling pairs with AS were recruited, largely from the Royal National Hospital for Rheumatic Diseases AS database. A genome-wide linkage screen was undertaken using 254 highly polymorphic microsatellite markers from the Medical Research Council (UK) (MRC) set. The major histocompatibility complex (MHC) region was studied more intensively using 5 microsatellites lying within the HLA class III region and HLA-DRB1 typing. The Analyze package was used for 2-point analysis, and GeneHunter for multipoint analysis. RESULTS: When only the MRC set was considered, 11 markers in 7 regions achieved a P value of < or =0.01. The maximum logarithm of odds score obtained was 3.8 (P = 1.4 x 10(-5)) using marker D6S273, which lies in the HLA class III region. A further marker used in mapping of the MHC class III region achieved a LOD score of 8.1 (P = 1 x 10(-9)). Nine of 118 affected sibling pairs (7.6%) did not share parental haplotypes identical by descent across the MHC, suggesting that only 31% of the susceptibility to AS is coded by genes linked to the MHC. The maximum non-MHC LOD score obtained was 2.6 (P = 0.0003) for marker D16S422. CONCLUSION: The results of this study confirm the strong linkage of the MHC with AS, and provide suggestive evidence regarding the presence and location of non-MHC genes influencing susceptibility to the disease.
Chromosome Mapping↗
Transmyocardial laser revascularization: results of a multicenter trial with transmyocardial laser revascularization used as sole therapy for end-stage coronary artery disease.
BACKGROUND: Transmyocardial laser revascularization was used as the sole therapy for patients with ischemic heart disease not amenable to percutaneous transluminal coronary angioplasty or coronary artery bypass grafting. This technique uses a carbon dioxide laser to create transmyocardial channels for direct perfusion of the ischemic heart. METHODS: Since 1992, 200 patients, at eight hospitals in the United States, have undergone transmyocardial laser revascularization. The patients have a combined 1560 months of follow-up for an average of 10 +/- 3 months per patient. Their age was 63 +/- 10 years and their ejection fraction was 47% +/- 12%. Eighty-two percent had at least one previous bypass graft operation and 38% had a prior angioplasty. Preoperatively, the patients underwent nuclear single photon emission computed tomography perfusion scans to identify the extent and severity of their ischemia. These scans were repeated at 3, 6, and 12 months. Angina class, admissions for angina, and medications were recorded. RESULTS: The perioperative mortality was 9%. Angina class decreased significantly from before treatment to 3, 6, and 12 months (p < 0.001). Likewise, there was a significant decrease in the number of perfusion defects in the treated left ventricular free wall. Concomitantly, there was a significant decrease in the number of admissions for angina in the year after the procedure when compared with the year before treatment (2.5 vs 0.5 admissions per patient-year). CONCLUSION: These combined results indicate that transmyocardial laser revascularization provides angina relief, decreases hospital admissions, and improves perfusion in patients with severe coronary artery disease.
Adult↗
Prediction of in-hospital cardiac events using dipyridamole-thallium scintigraphy performed very early after acute myocardial infarction.
BACKGROUND AND HYPOTHESIS: Ischemic complications occur frequently during hospitalization after acute myocardial infarction. Dipyridamole-thallium scintigraphy performed early after admission can detect residual ischemia, may have additional prognostic value and be useful in the management of these patients. METHODS: Dipyridamole infusion and 201thallium imaging were performed on the third day of infarction in 114 consecutive patients. Coronary angiography was performed before hospital discharge in 90% of patients and exercise testing was performed at the time of discharge in patients without contraindications. RESULTS: Side effects occurred in 28 patients, but they were mild and transient or rapidly reversed with intravenous aminophylline. During hospitalization, three patients died and four had a nonfatal reinfarction. Patients with these major cardiac events had previously shown a higher prevalence of reversible perfusion defects during testing (71 vs. 31%, p < 0.05). In addition, 19 patients had early recurrent ischemia requiring early in-hospital revascularization. Overall, cardiac events defined as death, reinfarction, or early myocardial revascularization occurred in 22 patients. Of the patients with these events, 68% had thallium redistribution on initial myocardial scanning compared with 25% of patients without events (p = 0.0001). Patients with cardiac events also showed a higher number of myocardial segments with reversible perfusion defects (1.8 +/- 2.2 vs. 0.6 +/- 1.3, p = 0.001). Logistic regression analysis revealed that among all the other clinical, scintigraphic, and angiographic variables, the presence of thallium redistribution on the dipyridamole-thallium scan was the only independent predictor of cardiac events, increasing the risk by sixfold. Furthermore, during a 1-year follow-up, 14 other patients had ischemic events. Of these, 64% had previously shown thallium redistribution during early dipyridamole testing compared with 19% of patients without cardiac events (p < 0.001). CONCLUSIONS: Intravenous dipyridamole-thallium-scintigraphy performed very early after myocardial infarction is safe and useful to predict in-hospital ischemic events.
Aged↗
An unusual cardiac mass shown by intraoperative transesophageal echocardiography.
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Coronary Aneurysm↗
Endogenous nitric oxide influences acetylcholine-induced bronchovascular dilation in sheep.
To test whether endogenous endothelial nitric oxide (NO) influences baseline bronchial vascular tone and mediates acetylcholine (ACh)-induced bronchial vascular dilation and/or modulates bronchoconstriction in ovine airways, we studied anesthetized ventilated open-chest sheep and measured bronchial blood flow (Qbr) and pulmonary resistance (RL). In six sheep we measured the response of Qbr and RL to the dose of ACh required to produce 50% of the maximal increase in Qbr at baseline during infusion of the NO synthase inhibitor NG-nitro-L-arginine (L-NNA; 10(-2) M). Infusion of L-NNA decreased both the baseline Qbr (28 +/- 13 to 8 +/- 2 ml/min, P < 0.01) and the change in Qbr (delta Qbr) from the baseline value (84 +/- 42 to 33 +/- 18 ml/min, P < 0.05). There was no difference in baseline RL or in the response of RL to ACh at any time. In another six sheep, phenylephrine (5 x 10(-6) to 5 x 10(-7) M) decreased baseline Qbr (22 +/- 6 to 10 +/- 3 ml/min, P < 0.05) but not delta Qbr (62 +/- 13 to 66 +/- 21 ml/min, not significant). Infusion of L-NNA in these sheep decreased the baseline Qbr to a similar extent (11 +/- 5 ml/min) and also decreased delta Qbr (42 +/- 16 ml/min, P < 0.05). We conclude that endogenous endothelial NO influences baseline vascular tone and ACh-induced vasodilation of the ovine bronchial vasculature but has no effect on baseline RL or ACh-induced bronchoconstriction.
Acetylcholine↗
Isolation and transcriptional competence of three tRNA(Trp) genes from Arabidopsis thaliana L.
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Base Composition↗
Cosmic-ray muons in the deep ocean.
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Journal Article↗
Hyperglycemia after trauma increases with age.
The metabolic responses to trauma and surgery have been well described and are observed most typically in otherwise healthy young and middle-aged individuals. To investigate the effect of age on blood glucose, insulin, and cortisol responses after mild to moderate trauma, we studied 33 patients (Injury Severity Scores, 5-38, and ages 16 to 81 years) before resuscitation and 24-96 hours postinjury. Age was associated with an increase in serum glucose during both "ebb" and "flow" phases of the injury response, but not with serum insulin. Serum glucose also increased with the degree of injury as reflected in Glasgow Coma Scale on admission and Injury Severity Score subsequently. Serum cortisol responses were increased in older patients and tended to decrease with time following injury. A more detailed knowledge of how age may alter the ability of elderly patients to respond to trauma and critical illness is essential to allow the continued development of rational therapies for such patients.
Adolescent↗
Effect of sulindac on angiotensin converting enzyme inhibitor-induced cough: randomised placebo-controlled double-blind cross-over study.
The effect of sulindac on ACE inhibitor-induced cough was studied in eight hypertensive subjects in a randomised placebo-controlled double blind cross-over trial. There was no significant improvement in cough or sense of well-being. Blood pressure, renal function, plasma renin and ACE activity were unchanged. Sulindac however, appears to be effective in some individuals in reducing ACE inhibitor-induced cough with acceptable tolerance and few side effects. Further work is needed to elucidate the mechanism of sulindac's interaction with ACE inhibitors.
Adult↗
Effects of potassium and chloride on the membrane potentials of P815 mastocytoma tumor cells.
The steady-state transmembrane potentials of P815 mastocytoma cells were recorded when the cells were bathed in salines of different compositions. In the normal growth medium (RPMI 1640 with added fetal calf serum) the mean membrane potential was -8.7 mV (SEM +/- 0.4, n = 22). A family of Tris-buffered salines (TBS), modeled from Dulbecco's modified PBS (289 mosmol, 169 milliionic strength units, pH 7.5), having different K+ and different C1- concentrations, were designed and used to bathe the tumor cells. All of the TBS solutions had constant, but reduced levels of ionized Ca2+. In the absence of external C1-, an increase of external K+ from 2 to 20 mM results in a 5.7 mV depolarization. In the presence of external C1- the same increase in external K+ results in a 2.1 mV depolarization. The presence of 145 mM C1- resulted in a steady-state depolarization (for either level of K) of about 50%. One explanation for these results would be the presence of an inward-going active C1- transport.
Cell Line↗