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Biomedical subjects

J Flint

Publications and source records attributed to J Flint.

At least 109 records · Page 6Linked to original sources
PubMed1993

The population genetics of the haemoglobinopathies.

The haemoglobinopathies are the commonest single gene disorders known, and are so common in some regions of the world that the majority of the population carries at least one genetic abnormality affecting the structure or synthesis of the haemoglobin molecule. The prevalence of the common haemoglobinopathies (the alpha- and beta-thalassaemias, HbS, HbC and HbE) is almost certainly a result of the protection they provide against malaria, as the epidemiological evidence reviewed in this chapter shows. World-wide, the distributions of malaria and the common haemoglobinopathies largely overlap, and micro-epidemiological surveys have confirmed the close relationship between the disorders. However, there are complications to this picture which appear to undermine the malaria hypothesis. First, in some areas, malaria and haemoglobinopathies are not coincident. Second, the malaria hypothesis does not easily explain why no two regions of the world have the same haemoglobinopathy or combination of haemoglobinopathies. The majority of mutations have arisen only once and are regionally specific. By using molecular characterization of mutations and the analysis of haplotypes on haemoglobinopathy-bearing chromosomes it is possible to show how a combination of selection by malaria, genetic drift and population movements can explain the first complication. In order to explain the second, we have argued that malaria selection has operated relatively recently on human populations (within the last 5000 years). The present distribution is then seen as the result of selection elevating sporadic mutations in local populations. In the absence of sufficient gene flow to spread all mutations to all populations, the consequence is a patchwork distribution of haemoglobinopathies. Given time, we would expect the mutations that protect and do not compromise the health of their carriers to become widely disseminated, but it is likely that human intervention will alter this process of natural selection.

Africa↗
PubMed1993

A computer simulation study of VNTR population genetics: constrained recombination rules out the infinite alleles model.

Extensive allelic diversity in variable numbers of tandem repeats (VNTRs) has been discovered in the human genome. For population genetic studies of VNTRs, such as forensic applications, it is important to know whether a neutral mutation-drift balance of VNTR polymorphism can be represented by the infinite alleles model. The assumption of the infinite alleles model that each new mutant is unique is very likely to be violated by unequal sister chromatid exchange (USCE), the primary process believed to generate VNTR mutants. We show that increasing both mutation rates and misalignment constraint for intrachromosomal recombination in a computer simulation model reduces simulated VNTR diversity below the expectations of the infinite alleles model. Maximal constraint, represented as slippage of single repeats, reduces simulated VNTR diversity to levels expected from the stepwise mutation model. Although misalignment rule is the more important variable, mutation rate also has an effect. At moderate rates of USCE, simulated VNTR diversity fluctuates around infinite alleles expectation. However, if rates of USCE are high, as for hypervariable VNTRs, simulated VNTR diversity is consistently lower than predicted by the infinite alleles model. This has been observed for many VNTRs and accounted for by technical problems in distinguishing alleles of neighboring size classes. We use sampling theory to confirm the intrinsically poor fit to the infinite alleles model of both simulated VNTR diversity and observed VNTR polymorphisms sampled from two Papua New Guinean populations.

Alleles↗
PubMed1993

Migraine madness: recurrent psychosis after migraine.

A 69 year old man with longstanding migraine with aura had four episodes of psychosis lasting 7-28 days during a 17 year period. During attacks he had formed visual hallucination and delusions, including reduplicative paramnesia. His mother was similarly affected. His EEG showed symmetrical frontal delta waves. The time course and EEG changes are similar to acute confusional migraine. The reduplicative paramnesia suggests a focal non-dominant hemisphere dysfunction.

Aged↗
PubMed1992

Familial calcification of the basal ganglia: a case report and review of the literature.

Although calcification of the basal ganglia is a relatively common and asymptomatic finding on cranial computed tomography, familial idiopathic calcification of the basal ganglia (ICBG) is a rare disorder with neurological and behavioral manifestations. Attention has recently been drawn to the frequency with which cases are diagnosed as schizophrenic (Cummings et al. 1983; Lowenthal, 1986; Davison, 1987). We report a family in which a mother and son have ICBG, but while the son has a paranoid schizophrenia and intellectual deterioration, the mother shows no psychiatric illness. A review of the relevant literature suggests that psychosis is not as common as usually supposed, and may only be coincidentally associated with familial ICBG. Moreover, we find little convincing evidence that familial ICBG is an independent entity; instead, and in agreement with earlier authorities (Bruyn et al. 1964), we argue that published accounts and our own cases provide evidence that the condition is related to pseudo-hypoparathyroidism (PHP) and, therefore, may be due to a defect in a guanine nucleotide binding protein.

Adult↗
PubMed1992

Factor structure of the Wechsler Adult Intelligence Scale-revised (WAIS-R): a clinical sample.

Factor analysis was performed on a heterogeneous clinical sample of neurological patients. Both a two- and a three-factor model were extracted. The two-factor solution corresponded to Wechsler's categorization of verbal and performance subtests. The three-factor solution suggested a verbal comprehension factor, a perceptual organization and a third factor with highest loadings on digit span, arithmetic and digit symbol. Both models were consistent with factor models obtained from the standardization sample. As has previously been reported in neurologically impaired samples, the third factor was relatively more prominent than in the standardization sample. This study provides further evidence for the robustness of the WAIS-R factor structure across different populations and gives good support for the use of the WAIS-R in British clinical samples.

Adult↗
PubMed1992

A survey of nuclear cardiological practice in Great Britain. The British Nuclear Cardiology Group.

There is little information on the practice of nuclear cardiology in Great Britain. On behalf of the British Nuclear Cardiology Group in October 1988 we sent a postal questionnaire to 143 hospitals with nuclear medicine facilities (at least 70% of such hospitals). Sixty nine replies were received (48%), of which 23 (33%) were from teaching hospitals and 46 (39%) non-teaching. In these hospitals 147,904 isotope investigations were performed annually (mean 2311 per centre) of which 17,298 (12%) (mean 254 per centre) were cardiac studies. Of these, 59% were equilibrium radionuclide ventriculograms, 14% first pass ventriculograms, and 27% thallium-201 scans. Rest studies were performed more commonly by radiographers or technicians (63%) than by doctors (20%), but doctors were more commonly involved in stress studies (48%). Radiologists reported the studies more often (28%) than they performed them (6%). Methods of acquisition and analysis were varied and, for instance, the lower limit of normal left ventricular ejection fraction ranged from 35% to 75% (mean 49%). For thallium imaging 42% of centres used dipyridamole in some patients and 24% used tomography. These data show that nuclear cardiology techniques are used much less frequently in Great Britain than in countries such as the United States and Germany, that the ratio of blood pool to myocardial perfusion imaging is much higher than elsewhere, and that methods are poorly standardised. They may provide the impetus to improve the service and serve as a baseline for future surveys.

Cardiology↗
PubMed1990

A TATA-like sequence located downstream of the transcription initiation site is required for expression of an RNA polymerase II transcribed gene.

TFIID, the TATA-binding protein, was found to stimulate transcription from the adenovirus IVa2 promoter, a promoter considered to lack the TATA motif. Remarkably, a TATA-like sequence element located downstream of the transcription start site binds TFIID and is required for TFIID-dependent transcription from the IVa2 promoter. Transcription from the IVa2 and the adjacent adenovirus major late promoter (Ad-MLP) is divergent, and the cap sites are separated by 212 nucleotides. Nevertheless, the TATA motifs of the IVa2 promoter and Ad-MLP were found to be oriented in the same direction. An initiator motif around the transcription start site is located in the IVa2 promoter, and in contrast to the TATA motifs, the IVa2-initiator is in the opposite orientation with respect to the initiator of the Ad-MLP. A model is presented in which the polar nature of the initiator governs the direction of transcription. We propose that RNA polymerase II and accessory factors recognize the initiator in an orientation-dependent fashion. The recognition of the IVa2 initiator by RNA polymerase is enhanced by the binding of TFIID to the downstream TATA motif.

Adenoviridae↗
PubMed1989

Non-invasive investigation in ischaemic heart disease.

Non-invasive assessment of a patient who has had a recent myocardial infarction can identify those at high risk for subsequent events. High-risk patients can be offered further investigation to assess the benefit of revascularisation.

Coronary Disease↗
PubMed1989

Population bottlenecks in Polynesia revealed by minisatellites.

Tandem-repetitive highly variable loci in the human genome (minisatellites) have been used in gene mapping and as DNA "fingerprints", but they have not yet found much application in population genetics. We have investigate the capacity of six minisatellites to discriminate between four populations in Oceania. We find that in comparison to Melanesians, Polynesians have a significant loss of heterozygosity (or gene diversity), not noted using more traditional markers. We show also that the number of alleles, the allele distribution and the mutation rates at the Polynesian minisatellite loci do not deviate from those predicted by the neutral mutation/infinite allele model. The low gene diversity is therefore likely to be a result of the maintenance of small population sizes and bottleneck effects during the colonization of the Pacific.

Alleles↗
PubMed1988

Genetic factors as determinants of infectious disease transmission in human communities.

Genetic factors may play an important role in individual susceptibility to infection. Hitherto this problem has been investigated by attempting to relate the distribution of genetic polymorphisms in populations to present or past infection, or by analysing specific infections by classical twin studies or group comparisons. There is reasonable evidence that the common red-cell polymorphisms involving haemoglobin, enzymes or membrane have been maintained by relative resistance to malaria. Blood-group heterogeneity, including secretor status, may reflect varying susceptibility to bacterial, virus and yeast infection. There is increasing evidence that the HLA-DR system may be involved in modifying the clinical course of bacterial, virus and parasitic infection. So far no specific resistance or susceptibility loci similar to those found in murine models have been found in man. DNA analysis, particularly involving restriction fragment length polymorphism associations with candidate genes, offers a valuable new approach to this problem.

Communicable Diseases↗
PubMed1988

Structure and evolution of the horse zeta globin locus.

The equine zeta globin gene locus consists of an intact 5' gene and a truncated 3' pseudogene (psi zeta) that has only 5' control sequences and a first exon and intron. Nevertheless, the psi zeta gene has retained almost perfect homology with its neighbour, presumably by gene conversion. The first introns of both zeta and psi zeta genes contain a number of degenerate tandem repeats of a 14 base-pair sequence that has been found in the zeta genes of goats and humans and that is related to a family of human minisatellite sequences. Comparisons of sequences flanking the zeta and psi zeta genes reveal areas of considerable interspecies homology, which can be explained by a zeta gene duplication that pre-dated the mammalian radiation.

Animals↗
PubMed1988

Novel alpha haemoglobin haplotypes in horses.

Four minor haplotypes that produce abnormal haemoglobin phenotypes in horses have been characterized. Two of them, AIIb and V, are copy number variants with, respectively, one and three alpha genes instead of the normal complement of two. The AIIa and C haplotypes, on the other hand, each have two alpha genes but, as a result of probable gene conversions, they now encode identical, though haplotype specific, globins. Two out of 60 unrelated and phenotypically normal horses studied had an unusual triplicated rearrangement in the embryonic zeta-gene locus. Each of these variants appears to have been produced by aberrant recombination events.

Animals↗