Biomedical subjects

A Dodge

Publications and source records attributed to A Dodge.

13 recordsLinked to original sources

PubMed2001

Electrokinetically driven microfluidic chips with surface-modified chambers for heterogeneous immunoassays.

This article presents the first example of a microfluidic chip for heterogeneous bioassays using a locally immobilized biospecific layer and operated electrokinetically. The reaction chamber has picoliter dimensions and is integrated into a network of microchannels etched in glass. The high affinity of protein A (PA) for rabbit immunoglobulin G (rIgG) was exploited for chip testing, with PA being immobilized on microchannel walls and fluorescently labeled (Cy5) rIgG serving as sample. It was possible to operate the chip in an immunoaffinity chromatographic manner, using electrokinetically pumped solutions. Concentration of antibody from dilute solution onto the solid phase was demonstrated, with signal gains of approximately 30 possible. A dose-response curve for Cy5-rIgG was obtained for concentrations down to 50 nM, for an incubation time of 200 s. The flexibility of chip layout was demonstrated for competitive immunoassay of rIgG, using both a combined sample/tracer incubation and sequential addition of these solutions. With assay times generally below 5 min for this unoptimized device, the microfluidic approach described shows great potential for many high-throughput screening applications.

Carbocyanines↗

PubMed1998

Direct repair of right atrial rupture after blunt chest trauma without cardiopulmonary bypass.

Tamponade from free wall rupture of the cardiac chambers following blunt thoracic trauma is relatively frequent. Diagnosis requires a high index of suspicion and is rapidly confirmed by echocardiography. Emergent surgery is always mandatory despite apparent stable vital signs. We report a successful repair of a lacerated right atrium without cardiopulmonary bypass (CPB), saved in extremis after undue in-hospital delay.

Adult↗

PubMed1998

How to do it: aortic and mitral valve replacement through aortotomy.

Combined replacement of the aortic and mitral values is a relatively common operation. Occasionally it is feasible to replace the mitral value through the aortic root. This remarkable approach eliminates the need for a second atrial incision, and in reoperation it avoids extensive dissection and release of adhesions. Injury to the heart is minimized and the incidence of perioperative bleeding is reduced. The exposure is excellent and the operation is performed safely and expeditiously.

Aged↗

PubMed1997

Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease.

Huntington disease (HD) is associated with abnormal expansions of a CAG repeat close to the 5' end of the IT15 gene. We have assembled a set of 293 HD subjects whose ages of onset were known and sized their HD CAG repeats. These repeats accounted for 69% of the variance of age of onset when we used the most parsimonious model, which relates the logarithm of age of onset to a function of CAG repeat number. Since other familial factors have been proposed to influence the age of onset of HD, we have examined a number of candidate loci. The CAG repeat number on normal chromosomes, the delta2642 polymorphism in the HD gene, and apolipoprotein E genotypes did not affect the age of onset of HD. Although mitochondrial energy production defects in HD have led to suggestions that variants in the mitochondrial genome may be associated with clinical variability in HD, this suggestion was not supported by our preliminary experiments that examined the DdeI mitochondrial restriction fragment length polymorphism at position 10,394. Excitotoxicity has been a favored mechanism to explain the cell death in HD, particularly since intrastriatal injection of excitatory amino acids in animals creates HD-like pathology. Accordingly, we investigated the GluR6 kainate receptor. Of the variance in the age of onset of HD that was not accounted for by the CAG repeats, 13% could be attributed to GluR6 genotype variation. These data implicate GluR6-mediated excitotoxicity in the pathogenesis of HD and highlight the potential importance of this process in other polyglutamine repeat expansion diseases.

Adult↗

PubMed1997

Clinical presentation and patterns of regional cerebral atrophy related to the length of trinucleotide repeat expansion in patients with adult onset Huntington's disease.

We correlated trinucleotide CAG repeat numbers in the huntingtin gene with the regional brain atrophy and clinical phenotype in 23 adult autopsy cases of Huntington's disease (HD). CAG repeat number (39-56, mean 45.4 +/- 4.6) correlated inversely (P < 0.0001) with age at onset and death, but not with disease duration or initial symptoms. Cross-sectional areas of the striatum, pallidum, thalamus, amygdala, hippocampus, and the cortical grey and white matter within the frontal, temporal and parietal lobes at four levels (genu of the corpus callosum, amygdala, accumbens, hippocampus) were measured morphometrically from the coronal brain slices using image analysis. None of these morphometric variables correlated with number of CAG repeats. Thus, tissue atrophy in advanced HD is unrelated to the underlying genetic defect.

Adolescent↗

PubMed1997

Analysis of spinocerebellar ataxia types 1, 2, 3, and 6, dentatorubral-pallidoluysian atrophy, and Friedreich's ataxia genes in spinocerebellar ataxia patients in the UK.

Accurate clinical diagnosis of the spinocerebellar ataxias (SCAs) can be difficult because of overlap in phenotype with other disorders and variation in clinical manifestations. Six SCA loci have been mapped and four disease causing genes identified, in addition to the causative gene for Friedreich's ataxia (FA). All of the identified mutations are expansions of trinucleotide repeat tracts. The SCA2 and SCA6 genes were published recently. The extent of the normal CAG size ranges at these loci and the relative frequencies of the known causes of SCA in the UK are not known. This study first investigated the normal size ranges of the SCA2 and SCA6 loci by genotyping control populations of West African and South African subjects, since African populations generally show the greatest allelic diversity. We found one allele larger than the previously determined normal range for SCA2, and our results at the SCA6 locus agreed with the previously reported normal range. The second component of the study assessed the relative frequencies of the SCA1, 2, 3, and 6, DRPLA, and FA trinucleotide repeat mutations in 146 patients presenting with SCA-like symptoms referred to genetic diagnostic laboratories in the UK. We detected mutations in 14% of patients referred with a diagnosis of autosomal dominant SCA, and in 15% of patients referred with spinocerebellar ataxia where we did not have sufficient family history data available to allow categorisation as familial or sporadic cases. Friedreich's ataxia accounted for 3% of the latter category of cases in our sample, but the most common causes of SCA were SCA2 and SCA6.

Adolescent↗

PubMed1997

Homozygotes and heterozygotes for ciliary neurotrophic factor null alleles do not show earlier onset of Huntington's disease.

The CAG repeat number on Huntington's disease (HD) chromosomes accounts for about 60% of the variance in the age at onset of HD. However, distinct familial factors may also influence the age at onset. HD is associated with loss of medium-sized GABA-ergic striatal output neurons. Intracerebral administration of human ciliary neurotrophic factor (CNTF) protects striatal output neurons in excitotoxic rodent and primate models of HD induced by intrastriatal quinolinic acid injection. We have examined the effect of a common null mutation in the human CNTF gene on the age of onset of HD using a multiple regression approach that takes into account the CAG repeat number on HD chromosomes. We failed to detect an earlier onset of HD in nine homozygotes and 71 heterozygotes with this CNTF mutation compared with 203 homozygotes with wild-type alleles.

Age of Onset↗

PubMed1996

Phenotypic characterization of individuals with 30-40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats.

Abnormal CAG expansions in the IT-15 gene are associated with Huntington disease (HD). In the diagnostic setting it is necessary to define the limits of the CAG size ranges on normal and HD-associated chromosomes. Most large analyses that defined the limits of the normal and pathological size ranges employed PCR assays, which included the CAG repeats and a CCG repeat tract that was thought to be invariant. Many of these experiments found an overlap between the normal and disease size ranges. Subsequent findings that the CCG repeats vary by 8 trinucleotide lengths suggested that the limits of the normal and disease size ranges should be reevaluated with assays that exclude the CCG polymorphism. Since patients with between 30 and 40 repeats are rare, a consortium was assembled to collect such individuals. All 178 samples were reanalyzed in Cambridge by using assays specific for the CAG repeats. We have optimized methods for reliable sizing of CAG repeats and show cases that demonstrate the dangers of using PCR assays that include both the CAG and CCG polymorphisms. Seven HD patients had 36 repeats, which confirms that this allele is associated with disease. Individuals without apparent symptoms or signs of HD were found at 36 repeats (aged 74, 78, 79, and 87 years), 37 repeats (aged 69 years), 38 repeats (aged 69 and 90 years), and 39 repeats (aged 67, 90, and 95 years). The detailed case histories of an exceptional case from this series will be presented: a 95-year-old man with 39 repeats who did not have classical features of HD. The apparently healthy survival into old age of some individuals with 36-39 repeats suggests that the HD mutation may not always be fully penetrant.

Adult↗

PubMed1995

Surgery in native valve endocarditis: indications, results and risk factors.

Seventy-nine patients (mean age 49 years) underwent valve replacement or repair for active (58.2%) or healed (41.8%) native valve endocarditis between 1976 and 1992. The most common indication for surgery was congestive heart failure (73.4%), followed by multiple systemic emboli (21.5%). Emergency operation was necessary in 27.8% of the cases. Operative mortality was 3.8% (3 patients) and late mortality 15.1% (12 patients). Streptococci were the most common infecting agents (41.8%), followed by Staphylococcus aureus (11.4%). No organisms were isolated in 27 cases (34.2%). Follow-up spanned 379.8 patient-years with a maximum of 15.8 years. Fifteen late valve-related events (periprosthetic leak, recurrent endocarditis, thrombo-embolic events and hemolysis) and 20 other late complications (anticoagulant-related hemorrhage, arrhythmias or congestive heart failure) occurred in 22 patients. The linearized rate for all late complications is 5.8% per patient-year. The influence of eight preoperative variables on overall mortality and late valve-related complications was assessed: age, valve(s) affected, active or healed infection, bacteriology, annular abscess, emergency or elective surgery, preoperative renal function and NYHA class. Only Staphylococcus aureus (P = 0.0012) was a significant predictor of late valve-related complications. Furthermore, no difference in survival or in valve-related complications was found between the active and healed infections.

Actuarial Analysis↗

PubMed1993

Mutation size and age at onset in Huntington's disease.

The mutation responsible for Huntington's disease is a polymorphic (CAG)n repeat sequence which is expanded on affected chromosomes. The number of repeat units observed on 229 affected chromosomes varied from 27 to 102, while the control chromosomes showed a range of 7 to 34 repeats. There was a highly significant relationship between the size of the expanded region and age at onset, larger mutations being associated with earlier onset. This association was strongest in those with onset before 25 years of age but less clear cut with later onset, and is therefore unlikely to be useful for predicting age at onset in the context of presymptomatic testing.

Adult↗

PubMed1989

Uptake of presymptomatic predictive testing for Huntington's disease.

Predictive testing by means of gene probes was offered to 110 adults at risk of Huntington's disease (HD). A further 91 individuals spontaneously sought predictive testing. Acceptance rates were highest (85.1%) amongst 47 individuals who spontaneously sought testing and were referred from outside the region, and lowest (15.5%) among the 110 invited to consider predictive testing. Many expressed an interest in predictive testing, then withdrew. Fetal exclusion testing was rarely requested, and then only by individuals who lacked the necessary pedigree structure for predictive testing for themselves.

Adult↗

PubMed1989

Molecular genetics in the National Health Service in Britain.

A recent report from the Departments of Health draws attention to the value of DNA diagnosis for inherited diseases and the need for planning these services in the National Health Service. There is great potential for preventive medicine, but a major immediate benefit is the newfound ability to exclude the carrier state in many people at risk and to protect fetuses from abortion when, as in most cases, they are shown to be normal by DNA tests. However, the widespread application of these new techniques requires prior evaluation and general acceptance. This will only be obtained after public debate, education of professionals and the population, and the establishment of adequate non-directive genetic counselling services. Some of the points to be considered in setting up molecular genetics laboratories are described.

Cystic Fibrosis↗

PubMed1987

Wolf-Hirschhorn locus is distal to D4S10 on short arm of chromosome 4.

We report a family in which Wolf-Hirschhorn syndrome in two children with partial monosomy of the short arm of chromosome 4 is the result of unbalanced segregation of a reciprocal 4;12 translocation in the mother. Studies with the DNA probe G8 show that the translocation breakpoint in this family is distal to the D4S10 locus. Previously reported cases of Wolf-Hirschhorn syndrome have involved the deletion of D4S10. These observations may prove helpful in the search for better genetic markers for Huntington's chorea, which maps close to D4S10.

Abnormalities, Multiple↗