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Biomedical subjects

R Hardy

Publications and source records attributed to R Hardy.

At least 19 recordsLinked to original sources
PubMed2000

Aberrant P-cadherin expression is a feature of clonal expansion in the gastrointestinal tract associated with repair and neoplasia.

The recognition of key roles for cadherins in the determination of epithelial cell phenotype, migration, differentiation, and tumour dissemination have stimulated much interest in this family of adhesion molecules. In the gastrointestinal tract, alteration of the expression of classical cadherins with aberrant P-cadherin up-regulation, associated with co-expression or loss of E-cadherin expression, is seen in neoplastic transformation of oral and oesophageal squamous mucosa and in lesions representing early neoplastic transformation of glandular mucosa, such as aberrant crypt foci and metaplastic and adenomatous polyps. This same phenotype is seen in enterocytes adjacent to foci of ulceration in the intestine in colitis, including inflammatory bowel disease, and in colitis-associated dysplasia. In coeliac disease, reversible E-cadherin down-regulation correlates with the degree of villous atrophy, but in contrast with colitis, aberrant P-cadherin expression is not a feature. Aberrant epithelial P-cadherin expression is thus associated with a proliferative phenotype related to ulceration and neoplastic transformation in the gastrointestinal tract, which may confer a survival advantage on these cells, but the relative functional roles of P-cadherin and E-cadherin and the molecular mechanisms underlyingP-cadherin/catenin interactions have yet to be elucidated.

Cadherins↗
PubMed2000

The bulk of the phosphorylation of human respiratory syncytial virus phosphoprotein is not essential but modulates viral RNA transcription and replication.

The ability of variants of the human respiratory syncytial virus (HRSV) phosphoprotein (P protein) to support RNA transcription and replication has been studied by using HRSV-based subgenomic replicons. The serine residues normally phosphorylated in P during HRSV infection have been replaced by other residues. The results indicate that the bulk of phosphorylation of P (98%) is not essential for viral RNA transcription or replication but that phosphorylation can modulate these processes.

HN Protein↗
PubMed1999

Mouse oligospheres: from pre-progenitors to functional oligodendrocytes.

To study the biology and repair capacities of mouse oligodendroglial cells, we established cultures of cells purified from neonatal wild-type and 9.6-kb MBP-LacZ transgenic newborn mice cerebral hemispheres as free-floating aggregates in the continuous presence of neuroblastoma conditioned medium (N1-B104). In vitro analysis indicated that the initial cell preparations were enriched in oligodendrocyte pre-progenitors that expressed PSA-NCAM and GAP-43 but not GD3, O4, NF68 or glial fibrillary acidic protein (GFAP) markers. These pre-progenitors required increased concentrations of insulin and progesterone to allow their survival in vitro. With time in culture, spheres composed of oligodendrocyte pre-progenitors became oligospheres enriched in oligodendrocyte progenitors expressing GAP-43 and GD3. As well as conserving bipotentiality in vitro, these spheres were able to form myelin in vivo after transplantation into the neonatal shiverer mouse brain. Thus, the oligosphere strategy is a powerful method for generating large populations of mouse oligodendrocyte pre-progenitors and progenitors. The ability to generate oligospheres from transgenic mice will be instrumental in the further dissection of the molecular and cellular mechanisms of myelination and remyelination of the central nervous system.

Animals↗
PubMed1999

Lifetime cognitive function and timing of the natural menopause.

BACKGROUND: There is evidence that ovarian steroids influence both reproductive aging and neural development. OBJECTIVE: We investigated the relationship between menopause and lifetime cognitive function in a prospective birth cohort study. METHODS: Participants were 1,572 women enrolled in the Medical Research Council National Survey of Health and Development (the British 1946 birth cohort). By age 50, 245 women were postmenopausal, 724 were pre- or perimenopausal, 288 had had a hysterectomy or bilateral oophorectomy, and 291 women had started taking hormone replacement therapy (HRT) before their menopause. The remaining 24 women, for various reasons, could not be classified into any of these groups. We investigated the association between cognitive function at ages 8, 11, 15, 26, and 43 years and menopause timing using Cox proportional hazard models, censoring for hysterectomy and bilateral oophorectomy, and initially for HRT use. The effect of including HRT use before menopause as an additional outcome was investigated using a competing risks analysis. RESULTS: Higher cognitive scores were associated with later menopause. The effect was strongest in childhood. This finding could not be explained by a variety of potential confounders, including early social background, physical development, education, adult social class, parity, smoking, and alcohol consumption. CONCLUSIONS: Childhood cognitive function is related to timing of the natural menopause. Both may be influenced by ovarian steroids across the life-span.

Adolescent↗
PubMed1999

Reproductive characteristics and the age at inception of the perimenopause in a British National Cohort.

Data from a British national cohort of women born in 1946 were used to investigate the hypothesis that the rate of depletion of oocyte numbers is associated with the age at which a woman reaches the inception of the perimenopause. Menopausal status was obtained using an annual questionnaire, sent to the cohort since the age of 47 years, and risk factor information from contacts with the survey throughout earlier life. Parous women entered the perimenopause later than nulliparous women. Those with the most children had the latest perimenopause, where the estimated hazard ratio for women having four or more children compared with those having none was 0.56 (95% confidence interval 0.39-0.81). Women who had a unilateral oophorectomy reached perimenopause earlier then those who had not (hazard ratio = 1.96, 95% confidence interval 1.15-3.35). There was some evidence that early age at menarche and short menstrual cycles were associated with an earlier perimenopause. No relation was observed with oral contraceptive pill use. Results provided some support for the hypothesis under consideration, while estimates of the median age at inception of the perimenopause due to these factors ranged from 46 to 50 years, which is an important variation with respect to later health.

Adult↗
PubMed1999

The relationship of serum androgens and ovulatory status to blood pressure in reproductive-age women.

The objective of this cross-sectional study was to determine the relationship between hyperandrogenemia and blood pressure in women with menstrual irregularities seen at an endocrinology clinic. Women with serum testosterone levels (T) > or = 30 ng/dL were more likely to have general obesity (odds ratio [OR] = 6.8, 95% confidence intervals [CI] = 2.2-27.2) and central obesity (OR = 14.5, 95% CI = 6.1-38.7) than euandrogenemic women. Hyperandrogenemic women (HA) had an OR of 2.4 (95% CI = 1.0-6.2) for elevated SBP and an OR of 2.7 (95% CI = 0.8-8.8) for elevated DBP, independent of age and ovulatory status. Obese HA had an OR of 4.7 (95% CI = 2.3-10.4) for elevated SBP and an OR of 2.9 (95% CI = 1.9-9.9) for elevated DBP. In conclusion, T is associated with an increased risk for obesity and central adiposity. T predicts BP elevation independent of age and ovulatory status. There was a synergistic relationship between obesity and androgens in their affect on BP.

Abdomen↗
PubMed1999

Urinary incontinence in middle aged women: childhood enuresis and other lifetime risk factors in a British prospective cohort.

STUDY OBJECTIVE: To investigate the prevalence and lifetime risk factors for urinary incontinence in middle aged women. DESIGN: Nationally representative birth cohort study with prospective data on childhood enuresis, measured adult height and weight, childbearing histories and measures of socioeconomic status updated at regular contacts, and measures of menopausal status, symptomatology and health care in midlife. SETTING: England, Scotland and Wales. PARTICIPANTS: General population sample of 1333 women aged 48 years. MAIN RESULTS: Fifty per cent reported symptoms of stress incontinence and 22% reported symptoms of urge incontinence in the previous year. Eight per cent had severe symptoms. Women who at age 6 years had wet in the day or several nights a week were more likely to suffer severe incontinence and report urge symptoms but occasional bedwetting was not associated with an increased risk in adult life. Those who were older at the birth of their children and who had vaginal deliveries had an excess risk of stress symptoms. Heavier adult body weight was also a risk factor for these symptoms and for severe incontinence. Postmenopausal women were less likely to report stress symptoms. These risk factors remained significant after taking account of the increased reporting of incontinence among women with high levels of general symptomatology and general practitioner visits, and of stress symptoms among better educated women. CONCLUSIONS: Urinary incontinence is a common problem among middle aged women. This is the first prospective study of a general population sample to support the postulated link between childhood enuresis and adult incontinence. Child-bearing has long term adverse effects, particularly for older mothers. Overweight is a common risk factor.

Child↗
PubMed1999

Cadherin adhesion in the intestinal crypt regulates morphogenesis, mitogenesis, motogenesis, and metaplasia formation.

The topographical organisation of the epithelium lining mucous membranes has been an intense point of research. One of the fundamental biological issues underpinning this and associated issues relates to the role and regulation of epithelial adhesion molecules. Adhesion between individual cells allows an intact layer to be formed, which is selectively permeable. In addition, the orchestrated regulation of multiple adhesion molecules allows the gradual transition from basal secretory cells to apical absorptive cells in the crypt-villus gradient. Moreover, it is becoming clear that no one class of adhesion molecule can sufficiently govern crypt architecture; however, the main cell-cell adhesion molecules are the cadherins and the related desmosomal cadherins. These latter molecules interact with the catenins, which bind directly or indirectly with cytoskeletal molecules such as Rho and Rac. In addition, other complex glycoproteins, such as the carcinoembryonic antigens, might contribute to adhesion, although their mechanisms of function are distinctly different. Integrins on the basal aspect of the cells also signal important morphoregulatory signals as a result of their binding to the extracellular maxtrix. The disruption of these physiological processes also provides a necessary and, in some cases, sufficient molecular mechanism for cancer invasion and metastasis, such as occurs in E-cadherin mutation positive familial gastric cancer.

Cadherins↗
PubMed1999

A colorectal cell line with alterations in E-cadherin and epithelial biology may be an in vitro model of colitis.

BACKGROUND: It has been shown previously in ulcerative colitis tissue that E-cadherin can occasionally be mutated in the extracellular domain early in neoplastic progression. E-cadherin is known to maintain differentiation and inhibits invasion in vivo. AIMS: To assess the mechanisms by which such dysfunction occurs. METHODS: Four human colorectal cancer cell lines, HCA-7 colonies 1, 3, 6, and 30, derived from a single heterogeneous colorectal cancer were studied. The HCA-7 cell line has p53 mutations and a random errors of replication "positive" phenotype, as is seen in early colitis associated cancers or hereditary nonpolyposis coli cancer (HNPCC). RESULTS: Cell lines 6 and 30 expressed E-cadherin abundantly and this correlated positively with their degree of differentiation and organisation; however, both cell lines had loss of heterozygosity of E-cadherin. Interestingly, E-cadherin production was downregulated in the poorly differentiated cell line 1, and this was associated with major chromosomal rearrangements of 16q. This cell line also had a mutation in the homophilic binding domain of exon 4, which was associated with disaggregation by low titres of a function blocking antibody, and an invasive phenotype. CONCLUSIONS: These multiple biological alterations further characterise the complex association that E-cadherin has with tumour heterogeneity and suggest that this series of cell lines may be a useful model of colitis associated or HNPCC associated tumorigenesis.

Agar↗
PubMed1998

Evaluating the relative status of health and safety programs for minority academic and research institutions.

The health and safety programs that support academic and research institutions face many challenges because of the wide variety of potential hazards present and the possibility of simultaneous exposures to several agents. This study investigated whether differences in health and safety programs exist between minority and nonminority state-funded academic and research institutions. A cross-sectional mail survey was conducted that included 24 minority and 51 nonminority schools. Questionnaires solicited information on descriptive institutional parameters, health and safety staffing, the hazards present, programs in place to address hazards, and medical surveillance services. The hazard types identified as present on both campus types were found to be very similar. The mean number of health and safety staff serving minority institutions was lower (1.14 versus 3.12), with the difference reliably predicted by the number of institutional employees, not minority status or regulatory environment. Other targeted parameters were found to be similar, with a consistent lack of awareness of specific medical evaluations noted for both groups. Since on average a single person is charged with controlling a diverse set of potential hazards on the minority campuses studied, the need for a comprehensive awareness of a variety of health and safety issues is discussed.

Accident Prevention↗
PubMed1998

Meta-analysis of trials comparing antidepressants with active placebos.

BACKGROUND: Unblinding effects may introduce bias into clinical trials. The use of active placebos to mimic side-effects of medication may therefore produce more rigorous evidence on the efficacy of antidepressants. METHOD: Trials comparing antidepressants with active placebos were located. A standard measure of effect was calculated for each trial and weighted pooled estimates obtained. Heterogeneity was examined and sensitivity analyses performed. A subgroup analysis of in-patient and out-patient trials was conducted. RESULTS: Only two of the nine studies examined produced effect sizes which showed a consistent significant difference in favour of the active drug. Combining all studies produced pooled effect size estimates of between 0.41 (0.27-0.56) and 0.46 (0.31-0.60) with high heterogeneity due to one strongly positive trial. Sensitivity analyses excluding this and one other trial reduced the pooled effect to between 0.21 (0.03-0.38) and 0.27 (0.10-0.45). CONCLUSIONS: Meta-analysis is very sensitive to decisions about exclusions. Previous general meta-analyses have found combined effect sizes in the range 0.4-0.8. The more conservative estimates produced here suggest that unblinding effects may inflate the efficacy of antidepressants in trials using inert placebos.

Adolescent↗
PubMed1998

Infant nutrition and cognitive development in the first offspring of a national UK birth cohort.

Several studies show a modest beneficial effect of breastfeeding on cognitive development after controlling for sociodemographic confounders. It is still unclear, however, to what extent this is due to the nutritional advantage of breast milk or to environmental influences associated with breastfeeding. We compared verbal ability scores at age 8 years in 511 first-born offspring of the National Survey of Health and Development who were ever or never breastfed, adjusting for paternal occupation, maternal education, maternal cognitive performance, attendance at nursery school, and maternal age at birth of the participant. A positive association between breastfeeding and cognitive performance was found but this was no longer the case after adjusting for either paternal occupation, maternal education, or maternal cognitive performance in turn. In contrast, an association between breastfeeding and cognitive function was not found for mothers of these offspring. Breastfeeding was increasingly associated with a non-manual social class across the generations although it remains unclear how this might mediate the effect of breastfeeding on cognitive performance.

Adult↗
PubMed1997

Oligodendroglial progenitors labeled with the O4 antibody persist in the adult rat cerebral cortex in vivo.

The monoclonal antibody O4 has been used to define a biologically distinct stage of the oligodendroglial lineage in vitro. Furthermore, O4+ oligodendroglial progenitors have been found in cell cultures derived from mature tissue, leading to speculation about the presence of oligodendroglial progenitors in the adult central nervous system (CNS). However, the existence of adult oligodendroglial progenitors has yet to be conclusively demonstrated in the intact animal. We have investigated the expression of O4 immunoreactivity in the developing and mature rat forebrain and the relationship of these cells to cells expressing the early oligodendroglial progenitor markers GD3 ganglioside and NG2 chondroitin sulfate proteoglycan, and to differentiated galactocerebroside expressing oligodendroglia. By the day of birth O4+ cells were already widely distributed throughout the formative corpus callosum and increased in number in the white matter and cortical gray matter over the first 2 postnatal weeks. In contrast to cell culture observations, most O4+ cells seen over this period failed to express GD3, although the majority did express NG2. Beginning at postnatal day 4, NG2+/O4-progenitors in the corpus callosum and cerebral cortical gray matter underwent a wave of differentiation into NG2+/O4+ cells and then into galactocerebroside-positive oligodendroglia. Interestingly, not all cells underwent this progression: a population remained as O4+/NG2+ progenitors. Furthermore, this O4+/NG2+ population persisted into adulthood and failed to express their GD3, galactocerebroside, RIP, or myelin basic protein (MBP). They were also distinguishable from glial fibrillary acidic protein+ and glutamine synthetase+ astrocytes and OX-42+ microglia. We therefore propose that these O4+/NG2+ cells represent adult oligodendroglial progenitors hitherto only described in cell culture.

Animals↗
PubMed1997

The effects of divorce and separation on mental health in a national UK birth cohort.

BACKGROUND: Many studies have reported a negative impact of divorce and separation on health although it is still unclear to what extent this is due to early vulnerability, the material and social consequences of divorce or to its direct emotional effects. METHOD: Measures of anxiety and depression and potential alcohol abuse at age 43 were compared in 2085 participants from the MRC National Survey of Health and Development who were either married and never divorced or separated, or who had divorced or separated at least once. Analyses were adjusted for sociodemographic features, early vulnerability factors and current stressors. RESULTS: Divorce and separation were associated with increased anxiety and depression, and increased risk of alcohol abuse. This was the case after adjusting for educational attainment, age at first marriage, parental divorce, childhood aggression and neuroticism, and current financial hardship, lack of a confidante and frequency of social contact with friends or family. The association between divorce and risk of alcohol abuse became non-significant when the latter variable was controlled for. Associations between divorce and psychopathology were observed even though half of those separated or divorced were re-married or reunited with their spouses at the time of the analysis. There was, furthermore, no association between these mental health measures and time since first separation or divorce.

Adult↗
PubMed1997

Recombinant vaccinia viruses expressing the F, G or N, but not the M2, protein of bovine respiratory syncytial virus (BRSV) induce resistance to BRSV challenge in the calf and protect against the development of pneumonic lesions.

The immunogenicity and protective efficacy of recombinant vaccinia viruses (rVV) encoding the F, G, N or M2 (22K) proteins of bovine respiratory syncytial virus (BRSV) were evaluated in calves, the natural host for BRSV. Calves were vaccinated either by scarification or intratracheally with rVV and challenged 6 to 7 weeks later with BRSV. Although replication of rVV expressing the F protein in the respiratory tract was limited after intratracheal vaccination, the levels of serum and pulmonary antibody were similar to those induced following scarification. The serum antibody response induced by the F protein was biased in favour of IgG1 antibody, whereas the G and the N proteins induced similar levels of IgG1:IgG2, and antibody was undetectable in calves primed with the M2 protein. The F protein induced neutralizing antibodies, but only low levels of complement-dependent neutralizing antibodies were induced by the G protein, and antibody induced by the N protein was not neutralizing. The F and N proteins primed calves for BRSV-specific lymphocyte proliferative responses, whereas proliferative responses were detected in calves primed with the G protein only after BRSV challenge. The M2 protein primed lymphocytes in only one out of five calves. Although there were differences in the immune responses induced by the rVVs, the F, G and N, but not the M2, proteins induced significant protection against BRSV infection and, in contrast with the enhanced lung pathology seen in mice vaccinated with rVV expressing individual proteins of human (H)RSV, there was a reduction in lung pathology in calves.

Animals↗
PubMed1997

Women's health in midlife: the influence of the menopause, social factors and health in earlier life.

OBJECTIVE: To describe the health symptoms of a large representative sample of British women at age 47 years, and to examine the influence of the menopause allowing for social factors and health in earlier adult life. DESIGN: A national prospective birth cohort study. Information on health problems, menstrual cycle, use of hormone replacement therapy and life stress at 47 years was collected using a postal questionnaire. Information on health, smoking behaviour and educational attainment earlier in life had been collected at previous home visits. SETTING: England, Scotland and Wales. POPULATION: A general population sample of 1498 women, 84% of those sent a questionnaire. MAIN OUTCOME MEASURE: Twenty self-reported health symptoms over the previous 12 months. RESULTS: Women who had experienced an early natural menopause had a strongly raised risk of vasomotor symptoms (hot flushes or night sweats), sexual difficulties (vaginal dryness or difficulties with intercourse) and trouble sleeping. However, there was little or no excess risk of other somatic or psychological symptoms. In contrast, all types of symptoms were more common among women who had had a hysterectomy or were users of hormone replacement therapy. Women with the least education, stressful lives, or a previous history of poor physical and psychological health at age 36 also reported more symptoms at 47 years compared with other women, but adjustment for these factors in a logistic regression model did not affect the relations between symptoms and current menopausal status. For vasomotor symptoms, postmenopausal women had an adjusted odds ratio of 4.7 (95% CI 2.6-8.5) and perimenopausal women had an adjusted odds ratio of 2.6 (95% CI 1.9-3.5) compared with premenopausal women. Corresponding adjusted odds ratios for sexual difficulties were 3.9 (95% CI 2.1-7.1) and 2.2 (95% CI 1.4-3.2), and for trouble sleeping were 3.4 (95% CI 1.9-6.2) and 1.5 (95% CI 1.1-2.0). CONCLUSIONS: Specific symptoms were clearly associated with the natural menopause. More general health concerns were common among women in middle life, particularly among those with stressful lives, or those who had had a hysterectomy or started taking hormone replacement therapy before they were postmenopausal. Appropriate advice and support needs to be easily accessible.

Adult↗