Body weight and mortality among adults who never smoked.
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In a 12-year prospective study, the authors examined the relation between body mass index (BMI) and mortality among the 20,346 middle-aged (25-54 years) and older (55-84 years) non-Hispanic white cohort members of the Adventist Health Study (California, 1976-1988) who had never smoked cigarettes and had no history of coronary heart disease, cancer, or stroke. In analyses that accounted for putative indicators (weight change relative to 17 years before baseline, death during early follow-up) of pre-existing illness, the authors found a direct positive relation between BMI and all-cause mortality among middle-aged men (minimum risk at BMI (kg/m2) 15-22.3, older men (minimum risk at BMI 13.5-22.3), middle-aged women (minimum risk at BMI 13.9-20.6), and older women who had undergone postmenopausal hormone replacement (minimum risk at BMI 13.4-20.6). Among older women who had not undergone postmenopausal hormone replacement, the authors found a J-shaped relation (minimum risk at BMI 20.7-27.4) in which BMI <20.7 was associated with a twofold increase in mortality risk (hazard ratio (HR) = 2.2, 95% confidence interval (CI) 1.3, 3.5) that was primarily due to cardiovascular and respiratory disease. These findings not only identify adiposity as a risk factor among adults, but also raise the possibility that very lean older women can experience an increased mortality risk that may be due to their lower levels of adipose tissue-derived estrogen. (+info)
A naturally occurring mutation near the amino terminus of alphaIIb defines a new region involved in ligand binding to alphaIIbbeta3.
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Decreased expression of functional alphaIIbbeta3 complexes on the platelet surface produces Glanzmann thrombasthenia. We have identified mutations of alphaIIb(P145) in 3 ethnically distinct families affected by Glanzmann thrombasthenia. Affected Mennonite and Dutch patients were homozygous and doubly heterozygous, respectively, for a P(145)A substitution, whereas a Chinese patient was doubly heterozygous for a P(145)L substitution. The mutations affect expression levels of surface alphaIIbbeta3 receptors on their platelets, which was confirmed by co-transfection of alphaIIb(P145A) and beta3 cDNA constructs in COS-1 cells. Each mutation also impaired the ability of alphaIIbbeta3 on affected platelets to interact with ligands. Moreover, when alphaIIb(P145A) and beta3 were stably coexpressed in Chinese hamster ovary cells, alphaIIbbeta3 was readily detected on the cell surface, but the cells were unable to adhere to immobilized fibrinogen or to bind soluble fluorescein isothiocyanate-fibrinogen after alphaIIbbeta3 activation by the activating monoclonal antibody PT25-2. Nonetheless, incubating affected platelets with the peptide LSARLAF, which binds to alphaIIb, induced PF4 secretion, indicating that the mutant alphaIIbbeta3 retained the ability to mediate outside-in signaling. These studies indicate that mutations involving alphaIIb(P145 )impair surface expression of alphaIIbbeta3 and that the alphaIIb(P145A) mutation abrogates ligand binding to the activated integrin. A comparative analysis of other alphaIIb mutations with a similar phenotype suggests that these mutations may cluster into a single region on the surface of the alphaIIb and may define a domain influencing ligand binding. (Blood. 2000;95:180188) (+info)
Bioethics of the refusal of blood by Jehovah's Witnesses: Part 3. A proposal for a don't-ask-don't-tell policy.
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Of growing concern over Jehovah's Witnesses' (JWs) refusal of blood is the intrusion of the religious organisation into its members' personal decision making about medical care. The organisation currently may apply severe religious sanctions to JWs who opt for certain forms of blood-based treatment. While the doctrine may be maintained as the unchangeable "law of God", the autonomy of individual JW patients could still be protected by the organisation modifying its current policy so that it strictly adheres to the right of privacy regarding personal medical information. The author proposes that the controlling religious organisation adopt a "don't-ask-don't-tell" policy, which assures JWs that they would neither be asked nor compelled to reveal personal medical information, either to one another or to the church organisation. This would relieve patients of the fear of breach of medical confidentiality and ensure a truly autonomous decision on blood-based treatments without fear of organisational control or sanction. (+info)
Jehovah's Witnesses' refusal of blood: obedience to scripture and religious conscience.
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Jehovah's Witnesses are students of the Bible. They refuse transfusions out of obedience to the scriptural directive to abstain and keep from blood. Dr Muramoto disagrees with the Witnesses' religious beliefs in this regard. Despite this basic disagreement over the meaning of Biblical texts, Muramoto flouts the religious basis for the Witnesses' position. His proposed policy change about accepting transfusions in private not only conflicts with the Witnesses' fundamental beliefs but it promotes hypocrisy. In addition, Muramoto's arguments about pressure to conform and coerced disclosure of private information misrepresent the beliefs and practices of Jehovah's Witnesses and ignore the element of individual conscience. In short, Muramoto resorts to distortion and uncorroborated assertions in his effort to portray a matter of religious faith as a matter of medical ethical debate. (+info)
Variation in the interleukin 4-receptor alpha gene confers susceptibility to asthma and atopy in ethnically diverse populations.
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After a genomewide screen in the Hutterites was completed, the IL4RA gene was examined as the 16p-linked susceptibility locus for asthma and atopy. Seven known variants and one novel variant, representing all nonsynonymous substitutions in the mature protein, were examined in the Hutterites; on the basis of studies in the Hutterites, outbred white, black, and Hispanic families were genotyped for selected markers. All population samples showed evidence of association to atopy or to asthma (P values.039-.0044 for atopy and. 029-.0000061 for asthma), but the alleles or haplotypes showing the strongest evidence differed between the groups. Overall, these data suggest that the IL4RA gene is an atopy- and asthma-susceptibility locus but that variation outside the coding region of the gene influences susceptibility. (+info)
Estimation of variance components of quantitative traits in inbred populations.
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Use of variance-component estimation for mapping of quantitative-trait loci in humans is a subject of great current interest. When only trait values, not genotypic information, are considered, variance-component estimation can also be used to estimate heritability of a quantitative trait. Inbred pedigrees present special challenges for variance-component estimation. First, there are more variance components to be estimated in the inbred case, even for a relatively simple model including additive, dominance, and environmental effects. Second, more identity coefficients need to be calculated from an inbred pedigree in order to perform the estimation, and these are computationally more difficult to obtain in the inbred than in the outbred case. As a result, inbreeding effects have generally been ignored in practice. We describe here the calculation of identity coefficients and estimation of variance components of quantitative traits in large inbred pedigrees, using the example of HDL in the Hutterites. We use a multivariate normal model for the genetic effects, extending the central-limit theorem of Lange to allow for both inbreeding and dominance under the assumptions of our variance-component model. We use simulated examples to give an indication of under what conditions one has the power to detect the additional variance components and to examine their impact on variance-component estimation. We discuss the implications for mapping and heritability estimation by use of variance components in inbred populations. (+info)
An unstable trinucleotide-repeat region on chromosome 13 implicated in spinocerebellar ataxia: a common expansion locus.
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Larger CAG/CTG trinucleotide-repeat tracts in individuals affected with schizophrenia (SCZ) and bipolar affective disorder (BPAD) in comparison with control individuals have previously been reported, implying a possible etiological role for trinucleotide repeats in these diseases. Two unstable CAG/CTG repeats, SEF2-1B and ERDA1, have recently been cloned, and studies indicate that the majority of individuals with large repeats as detected by repeat-expansion detection (RED) have large repeat alleles at these loci. These repeats do not show association of large alleles with either BPAD or SCZ. Using RED, we have identified a BPAD individual with a very large CAG/CTG repeat that is not due to expansion at SEF2-1B or ERDA1. From this individual's DNA, we have cloned a highly polymorphic trinucleotide repeat consisting of (CTA)n (CTG)n, which is very long ( approximately 1,800 bp) in this patient. The repeat region localizes to chromosome 13q21, within 1.2 cM of fragile site FRA13C. Repeat alleles in our sample were unstable in 13 (5.6%) of 231 meioses. Large alleles (>100 repeats) were observed in 14 (1. 25%) of 1,120 patients with psychosis, borderline personality disorder, or juvenile-onset depression and in 5 (.7%) of 710 healthy controls. Very large alleles were also detected for Centre d'Etude Polymorphisme Humaine (CEPH) reference family 1334. This triplet expansion has recently been reported to be the cause of spinocerebellar ataxia type 8 (SCA8); however, none of our large alleles above the disease threshold occurred in individuals either affected by SCA or with known family history of SCA. The high frequency of large alleles at this locus is inconsistent with the much rarer occurrence of SCA8. Thus, it seems unlikely that expansion alone causes SCA8; other genetic mechanisms may be necessary to explain SCA8 etiology. (+info)
Molecular characterisation of congenital glaucoma in a consanguineous Canadian community: a step towards preventing glaucoma related blindness.
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Glaucoma is a leading cause of irreversible blindness in Canada. Congenital glaucoma usually manifests during the first years of life and is characterised by severe visual loss and autosomal recessive inheritance. Two disease loci, on chromosomes 1p36 and 2p21, have been associated with various forms of congenital glaucoma. A branch of a large six generation family from a consanguineous Amish community in south western Ontario was affected with congenital glaucoma and was studied by linkage and mutational analysis to identify the glaucoma related genetic defects. Linkage analysis using the MLINK component of the LINKAGE package (v 5.1) showed evidence of linkage to the 2p21 region (Zmax=3.34, theta=0, D2S1348 and D2S1346). Mutational analysis of the primary candidate gene, CYP1B1, was done by direct cycle sequencing, dideoxy fingerprinting analysis, and fragment analysis. Two different disease causing mutations in exon 3, 1410del13 and 1505G-->A, both segregated with the disease phenotype. The two different combinations of these alleles appeared to result in a variable expressivity of the phenotype. The compound heterozygote appeared to have a milder phenotype when compared to the homozygotes for the 13 bp deletion. The congenital glaucoma phenotype for this large inbred Amish family is the result of mutations in CYP1B1 (2p21). The molecular information derived from this study will be used to help identify carriers of the CYP1B1 mutation in this community and optimise the management of those at risk of developing glaucoma. (+info)