Finance managers--figure heads. Interview by Ann Dix.
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Administrative Personnel↗
Biomedical subjects
N Chapman
Publications and source records attributed to N Chapman.
The polypeptide backbone of recombinant human zona pellucida glycoprotein-3 initiates acrosomal exocytosis in human spermatozoa in vitro.
Human gamete interaction is of fundamental biological importance, yet the molecular interactions between spermatozoa and the zona pellucida are poorly understood. Surprisingly, the role of the polypeptide backbone of zona pellucida glycoprotein 3 (ZP3), the putative ligand for spermatozoa activation, has been largely overlooked. Purified recombinant human ZP3 was expressed in Escherichia coli as a C-terminal fusion to the dimeric glutathione S-transferase (GST) from Schistosoma japonicum and was shown to induce acrosomal exocytosis in live, capacitated human spermatozoa. The level of exocytosis is comparable with that obtained using purified, glycosylated, recombinant human ZP3 [van Duin, M., Polman, J.E.M., DeBreet, I.T.M., Van Ginneken, K., Bunschoten, H., Grootenhuis, A., Brindle, J. and Aitken, R.J. (1994). Biol Reprod. 51, 607-617]. These data imply that the polypeptide chain of human ZP3 contributes to recognition of spermatozoa during acrosomal exocytosis in vitro.
Acrosome↗
Evaluation of locus heterogeneity and EXT1 mutations in 34 families with hereditary multiple exostoses.
Hereditary multiple exostoses (EXT) is an autosomal dominant disorder characterized by growth of benign bone tumors. Three chromosomal loci have been implicated in this genetically heterogeneous disease: EXT1 at 8q24, EXT2 at 11p13, and EXT3 on 19p. EXT1 and EXT2 were recently cloned. We evaluated 34 families with EXT to estimate the proportion of disease attributable to EXT1, EXT2, and EXT3 and to investigate the spectrum of EXT1 mutations. Linkage analyses combined with heterogeneity testing provides strong evidence in favor of linkage of disease to both chromosomes 8 and 11, but does not support evidence of linkage to chromosome 19 in this data set. The 11 EXT1 exons were PCR-amplified and sequenced in all 11 isolated cases and in 20 of the 23 familial cases. Twelve different novel EXT1 mutations were detected, including 5 frame-shift deletions or insertions, 1 codon deletion, and 6 single base-pair substitutions distributed across 8 of the exons. Only 2 of the mutations were detected in more than one family. Three mutations affect sites in which alterations were previously reported. Nonchain-terminating missense mutations were identified in codons 280 and 340, both coding for conserved arginine residues. These residues may be crucial to the function of this protein. Although the prevalence of EXT has been estimated to be approximately 1/50,000 individuals, the disease has been reported to occur much more frequently in the Chamorro natives on Guam. Our detection of an EXT1 mutation in one Chamorro subject will allow investigation of a possible founder effect in this population. Combined mutational and heterogeneity analyses in this set of families with multiple exostoses suggest that 66% of our total sample, including 45% of isolated and 77% of familial cases, are attributable to abnormalities in EXT1.
Chromosomes, Human, Pair 11↗
Gunshot wound traversing the ventricular septum with peripheral embolization presenting as complete heart block.
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Adult↗
Ethnic differences in the hypertensive heart and 24-hour blood pressure profile.
Black hypertensive persons have been observed to have a greater degree of left ventricular hypertrophy than white hypertensives. However, previous studies have matched groups for blood pressure (BP) measured in the clinic, and it has been demonstrated that black hypertensives have an attenuated nocturnal BP dip. Clinic BPs may thus underestimate mean 24-hour BP in this group. To investigate whether the differences in left ventricular hypertrophy can be accounted for by the greater mean 24-hour BP in black hypertensives, 92 previously untreated hypertensives were studied with 24-hour ambulatory BP monitoring and echocardiography. The 46 black hypertensives (24 men and 22 women) were matched with the 46 white hypertensives for age, gender, and mean 24-hour BP. Despite similar mean 24-hour BPs (blacks, 142/93 mm Hg; whites, 145/92 mm Hg; P=.53/.66), the black group had a smaller mean nocturnal dip than the white group (blacks, 8/8 mm Hg; whites, 16/13 mm Hg; P<.01). In addition, mean left ventricular mass index (LVMI) was greater (blacks, 130 g/m2; whites, 107 g/m2; P<.001). Mean 24-hour systolic BP was significantly related to LVMI in both groups (blacks, r=.45, P<.01; whites, r=.56, P<.01). However, systolic BP dip correlated inversely with LVMI only in the black group (blacks, r=-.30, P<.04; whites, r=.05, P=.76). In a multiple regression model, LVMI was independently related to both mean daytime BP and mean nocturnal BP dip in black subjects but only to mean daytime BP in white subjects. In conclusion, the increased left ventricular hypertrophy observed in black hypertensives compared with white hypertensives is not accounted for by differences in mean 24-hour BP. However, LVMI in black hypertensives appears to be more dependent on nocturnal BP than that in white hypertensives; this, coupled with the attenuated BP dip in black hypertensives, suggests that the BP profile rather than 24-hour BP may be important in determining the differences in left ventricular hypertrophy.
Adult↗
Coxsackieviruses and diabetes.
Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease whose etiology is complex. Both genetic susceptibility, which is polygenic, and environmental factors, including virus infections, appear to be involved in the development of IDDM. In this review, we have tried to balance the discussion of diabetes by examining both immunological and virological perspectives. Several mouse models, including viral and non-viral models, have been used to study diabetes. For this review, we include lessons gleaned from the non-obese diabetic (NOD) mouse and from mouse models of coxsackievirus- and encephalomyocarditis-virus-induced diabetes. Finally, we present a multi-stage model in which several viral infections, including the coxsackieviruses, are postulated to play a role in the autoimmune destruction of pancreatic beta cells.
Animals↗
Generation of an infectious cDNA of a highly cardiovirulent coxsackievirus B3(CVB3m) and comparison to other infectious CVB3 cDNAs.
An infectious cDNA of a highly myocarditic coxsackievirus B3 (CVB3m; Nancy strain) was cloned. Sequence data revealed 43 extra non-viral nucleotides upstream of the initial 5' sequence. However, the authentic 5' end sequence was maintained during replication of viral RNA transfected into HeLa cells, suggesting the RNA synthesizing complex edits the picornaviral 5' terminus sequence. Nucleotide sequences of the 5' nontranslated region and the capsid protein gene sequence of CVB3m were compared with the published sequences of five other CVB3 Nancy strains and two main lineages were found. In comparative assays for cardiovirulence, three of four CVB3 tested were cardiovirulent in adolescent male CD-1 mice. Only one of the three available CVB3 strains was neutralized with several anti-CVB3m monoclonal antibodies, suggesting that mutations in the surface epitopes of the capsid polypeptides contribute to antigenic drift within the serotype, perhaps in part through immunoselective pressures. Thus, phenotypic diversity of CVB3 within the prototype Nancy strain is an example of RNA viruses adapting to changing environments (cells, mice and humans) through mutations and selective pressure.
Animals↗
The effects on cardiac arrhythmias of antihypertensive therapy causing regression of left ventricular hypertrophy.
To examine the effects of antihypertensive therapy causing regression of left ventricular hypertrophy on cardiac arrhythmias, 26 hypertensive subjects were treated with ramipril with felodipine if required, and followed for 6 months after blood pressure control. Compared with baseline, left ventricular mass index (LVMI) was significantly reduced both at blood pressure control and after a further 6 months of treatment (baseline, blood pressure control, 6 months after blood pressure control; LVMI 142 +/- 3.6, 131 +/- 3.4, 123 +/- 3.8* g/m2, *P < .01 compared with baseline). There was a significant relationship between the decrease in systolic blood pressure and the decrease in LVMI after 6 months of blood pressure control compared with baseline (r = 0.41, P = .05). Compared with baseline, the average total number of ventricular ectopics decreased after blood pressure was controlled (88 +/- 59 and 21 +/- 12 respectively); however this reduction was not maintained after 6 months of further treatment, either before (78 +/- 50) or after drug washout (86 +/- 40). Compared with baseline (639 +/- 590) supraventricular ectopic total was not initially reduced after blood pressure control (650 +/- 604), but was reduced after a further 6 months of treatment (294 +/- 261). This reduction was maintained after drug washout (267 +/- 254), although this did not reach statistical significance. Radionuclide scanning at baseline was not a predictor of patients with the highest risk of arrhythmia and there was no correlation between improvement or worsening of a defect with changes in ventricular ectopic total. In conclusion, antihypertensive therapy with ramipril and felodipine, although causing regression of left ventricular hypertrophy did not lead to a sustained reduction in ventricular ectopic total.
Adult↗
Retinal vascular network architecture in low-birth-weight men.
BACKGROUND: Low birth weight is associated with hypertension and increased cardiovascular mortality, but the mechanism of this association is not known. Hypertension is accompanied by abnormalities of the microvasculature including rarefaction. OBJECTIVE: To test the hypothesis that low birth weight is associated with an alteration in microvascular architecture. DESIGN: A stratified random sample of 100 men aged 64-74 years was selected from a cohort of men whose birth weights were known. They were of relatively high or low birth weight ('high' > or = 3700 g, 'low' < or = 3200 g) and high or low systolic blood pressure (high > or = 160 mmHg, low < or = 140 mmHg). METHODS: Retinal arteriolar geometry was defined in terms of arteriolar bifurcation angles and junction exponents (a measure of the relative diameters of parent and daughter vessels), measured from photographic diapositives using operator-directed image analysis. RESULTS: Members of low-birth-weight groups had significantly narrower bifurcation angles than did members of high-birth-weight groups (74 +/- 1 degree versus 78 +/- 1 degree, P= 0.017 by analysis of variance). There was no significant difference between angles in members of groups with high and low blood pressures. Neither birth weight nor blood pressure grouping affected junction exponents. CONCLUSIONS: Narrower bifurcation angles are associated with increased circulatory energy costs and may be related to a lower than normal microvascular density. Our finding of differences in retinal microvascular architecture might reflect a persistent alteration in vascular architecture as a result of an impairment of foetal development and could provide a mechanistic link between low birth weight and subsequently increased cardiovascular risk.
Aged↗
Genomic regions of coxsackievirus B3 associated with cardiovirulence.
The molecular basis for cardiovirulence in the coxsackievirus B3 (CVB3) genome was examined in a murine model of acute myocarditis. Infectious cDNAs representing a highly cardiovirulent coxsackievirus B3 (CVB3m) and a noncardiovirulent (CVB30) virus were used to construct infectious chimeric cDNAs. Assays of the resulting recombinant viruses for cardiovirulence in adolescent male CD-1 mice showed that the 5' nontranslated region (5' NTR) of the CVB3m genome plays the major role in determining cardiovirulence and that the genomic region encoding the capsid proteins has a minor additive effect in increasing cardiovirulence. Nucleotide sequences in the 5' NTR of CVB3m and CVB30 differ at 23 positions; 14 are located in four stemloop motifs of the secondary structure and may influence the cardiovirulent phenotype by regulating RNA or protein synthesis. A comparison of predicted amino acid sequences of capsid proteins in CVB3m and CVB30 identified two amino acids as potential candidate contributors to cardiovirulence, i.e., amino acids at positions A207 (Asn-Asp) in the puff structure of the E-F loop of VP2 and A566 (Gln-Glu) in the C terminal of VP3 at the external surface. The data from this study and published literature support the conclusion that cardiovirulence of a CVB3 can depend on several regions of the genome.
Animals↗
Factors affecting the fat content of National School Lunch Program lunches.
An analysis of a week's menus from a nationally representative sample of 515 National School Lunch Program schools found that < 5% of schools offer lunches that provide a 5-d average close to the Dietary Guidelines recommendation for fat. This paper examines the factors associated with schools offering meals that, on average, provided different amounts of fat: low (< 32% of food energy from fat), moderate (32-35% fat), high (35-40% fat), and very high (> 40% fat). Schools in which NSLP lunches come close, on average, to meeting the Dietary Guidelines' goal for total fat follow several menu-planning, food-purchasing, and food-preparation practices to reduce the fat content of the school lunches.
Adolescent↗
Genetics of coxsackievirus B3 cardiovirulence.
The human enteroviruses, especially the coxsackie B viruses, have been established as aetiologic agents of human inflammatory heart disease, a condition which may lead to dilated cardiomyopathy and heart failure. It is clear from murine models of coxsackievirus B3-induced inflammatory heart disease that not all strains of the virus are cardiovirulent (able to cause disease). Here, we present preliminary data mapping the site in a coxsackievirus B3 genome which determines a cardiovirulent phenotype.
Animals↗
A non-cardiovirulent strain of coxsackievirus B3 causes myocarditis in mice with severe combined immunodeficiency syndrome.
The most extensively studied animal model of coxsackievirus B3 (CVB3)-induced inflammatory heart muscle disease is the murine model. In the acute and chronic phase of the disease, it has been suggested that autoimmune mechanisms play a major role in the pathogenesis of the disease. In this study, C3H mice without functional T- and B-lymphocytes (C3H SCID) were inoculated either with a cardiovirulent (CVB3/20) or a non-cardiovirulent (CVB3/0) strain of coxsackievirus B3. Both viruses caused myocarditis in SCID mice. Furthermore, it could be demonstrated, that CVB3/0 had mutated to a cardiovirulent phenotype, able to cause myocarditis in immunocompetent mice.
Animals↗
Coxsackievirus-induced chronic myocarditis in murine models.
Challenge of several murine strains with two highly myocarditic variants of coxsackievirus B3 (CVB3) induced acute and chronic myocarditis, detectable at 21 and 45 days post-inoculation (p.i.). In-situ hybridization of coronal heart sections showing chronic inflammation with a radiolabelled CVB3 probe detected viral genomic RNA at day 7 p.i. but rarely at 21 or 45 days p.i., suggesting few murine heart cells actively replicate virus during chronic myocardial inflammation. Data will be presented that favour an alternative hypothesis, i.e. autoimmune responses to shared epitopes among CVB3 proteins, cardiac myosin and myocardial cell surface proteins (molecular mimicry) can affect the severity of chronic inflammation. Mice inoculated with human cardiac myosin (HM) prior to a CVB3m challenge develop less myocarditis than mice inoculated with virus only, suggesting that antibodies stimulated by HM bind virus, reduce the virus burden and provide protection. Mice inoculated with HM only develop non-neutralizing antibodies against purified CVB3m particles. Several strains of mice inoculated with specific synthetic peptides of HM produce antibodies against CVB3m and/or develop cardiomyopathy. Thus antigen-challenged mice can produce antibodies which cross-react among CVB3m HM or cardiac cells to protect or exacerbate heart disease.
Animals↗
Toxoplasma gondii--an unusual cause of myocarditis in old age.
We report the case of an 86-year-old man who was admitted with congestive cardiac failure and chronic renal failure. He was previously known to have a thoracic aortic aneurysm and chronic bronchitis. There was no history of myocardial infarction but his heart failure was assumed to be due to ischaemic heart disease. Despite treatment of the heart failure the patient died. At post-mortem he was found to have Toxoplasma gondii myocarditis.
Aged↗
Interesting problems in enteroviral inflammatory heart disease.
Enteroviral inflammatory heart disease is an established entity. Based upon the accumulated work from many laboratories, specific and definitive questions can be posed regarding the pathogenic nature of the viruses involved and how the host immune systems respond to the insult of enterovirus replication in the myocardium. The answers to these questions may well lead to efficient intervention therapies such as vaccination or effective anti-viral compounds, thus eradicating enterovirus-induced heart disease. Understanding the nature of the acute disease is the first requirement toward a complete understanding of the mechanisms at work in chronic inflammatory heart disease.
Animals↗
Survey of farm wells for nutrients and minerals, Ontario, Canada, 1986 and 1987.
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Calcium↗
Degradation of parent compounds of nine organophosphorus insecticides in Ontario surface and ground waters under controlled conditions.
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Chromatography, Gas↗