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Biomedical subjects

R Hardy

Publications and source records attributed to R Hardy.

At least 19 recordsLinked to original sources
PubMed2006

Desmocollin switching in colorectal cancer.

The desmocollins are members of the desmosomal cadherin family of cell-cell adhesion molecules. They are essential constituents of desmosomes, intercellular junctions that play a critical role in the maintenance of tissue integrity in epithelia and cardiac muscle. In humans, three desmocollins (Dsc1, Dsc2 and Dsc3) have been described. The desmocollins exhibit tissue-specific patterns of expression; only Dsc2 is expressed in normal colonic epithelium. We have found switching between desmocollins in sporadic colorectal adenocarcinoma with a reduction in Dsc2 protein (in 8/16 samples analysed by immunohistochemistry) being accompanied by de novo expression of Dsc1 (16/16) and Dsc3 (7/16). Similar results were obtained by western blotting of a further 16 samples. No change was found in Dsc2 mRNA, but de novo expression of Dscs 1 and 3 was accompanied by increased message levels. Loss of Dsc2 (8/19) and de novo expression of Dsc1 (11/19) and Dsc3 (6/19) was also found in colorectal adenocarcinomas on a background of colitis. The data raise the possibility that switching of desmocollins could play an important role in the development of colorectal cancer.

Adenocarcinoma↗
PubMed2006

Breast cancer in relation to childhood parental divorce and early adult psychiatric disorder in a British birth cohort.

BACKGROUND: Jacobs and Bovasso reported (Psychological Medicine 2000, 30, 669-678) that maternal death in childhood and chronic severe depression in adulthood were associated with subsequent breast cancer. We have examined the effects of parental loss in childhood and psychiatric disorder in adult life on breast cancer risk using a national birth cohort study. METHOD: Eighty-three cases of breast cancer were diagnosed in a study of 2253 women followed from birth to age 59 years. Cox proportional hazards models were used to test whether breast cancer rates were higher in women who experienced parental death and divorce before age 16, psychiatric disorders between 15 and 32 years, symptoms of anxiety and depression at 36 years, or use of antidepressant medication at 31 or 36 years than in women who did not have these experiences. RESULTS: There was no overall association between parental death, parental divorce or psychiatric disorder and the incidence of breast cancer. There was some evidence that women with more severe psychiatric disorders between the ages of 15 and 32 years were more likely to develop breast cancer early. The interaction between parental divorce and severe psychiatric disorder was non-significant (p=0.1); however, the group who experienced both these events had an increased breast cancer risk compared with those who experienced neither [hazard ratio (HR) 2.64, 95% confidence interval (CI) 1.13-6.19]. CONCLUSIONS: Our study does not provide strong support for the hypothesis that early loss or adult psychiatric disorders are associated with breast cancer. A meta-analysis is needed that uses data from all available cohort studies and investigates possible interactive effects on breast cancer risk.

Adolescent↗
PubMed2006

Validity of age at menarche self-reported in adulthood.

OBJECTIVE: To test the validity of age at menarche self-reported in adulthood and examine whether socioeconomic position, education, experience of gynaecological events and psychological symptoms influence the accuracy of recall. DESIGN: Prospective birth cohort study. SETTING: England, Scotland and Wales. PARTICIPANTS: 1050 women from the Medical Research Council National Survey of Health and Development, with two measures of age at menarche, one recorded in adolescence and the other self-reported at age 48 years. RESULTS: By calculating the limits of agreement, kappa statistic and Pearson's correlation coefficients (r), we found that the validity of age at menarche self-reported in middle age compared with that recorded in adolescence was moderate (kappa = 0.35, r = 0.66, n = 1050). Validity was improved by categorising age at menarche into three groups: early, normal and late (kappa = 0.43). Agreement was influenced by educational level and having had a stillbirth or miscarriage. CONCLUSIONS: The level of validity shown in this study throws some doubt on whether it is justifiable to use age at menarche self-reported in middle age. It is likely to introduce error and bias, and researchers should be aware of these limitations and use such measures with caution.

Abortion, Spontaneous↗
PubMed2005

Early growth and type 2 diabetes: evidence from the 1946 British birth cohort.

AIMS/HYPOTHESIS: We assessed whether low birthweight or early adiposity rebound was more strongly associated with type 2 diabetes, and whether any effect of low birthweight or early adiposity rebound was explained by adult BMI, adult height, social class of subject or of his/her father, or maternal or paternal diabetes. METHODS: Cox's proportional hazard models were used on data from the National Birth Cohort Study (the MRC National Survey of Health and Development), which was begun in 1946 and had self-reported physician-diagnosed diabetes with age at onset ranging from 31 to 53 years (n=78 cases, and n=47 cases in the multivariate analysis) as the outcome. RESULTS: A U-shaped association between birthweight and type 2 diabetes rates was close to statistical significance (quadratic term p value=0.08). Younger age at adiposity rebound was associated with increased rates of type 2 diabetes (test for trend p=0.002), the association being robust to adjustment for each of sex, birthweight, weight at 2 years, father's social class, parental diabetes, and own social class. The effect of early adiposity rebound was very slightly reduced by adjustment for sex and adult height (p=0.003), but considerably reduced after adjustment for sex and adult BMI (test for trend p=0.1), and further reduced (p=0.4) after additional adjustment for birthweight, weight at 2 years, adult height, social class of subject and of his/her father, and parental diabetes. CONCLUSIONS/INTERPRETATION: Early adiposity rebound was associated with an increased rate of type 2 diabetes independently of birthweight, but its effect was mostly through high adult BMI. Parental diabetes and possibly low weight at 2 years were also risks.

Adiposity↗
PubMed2005

Social outcomes in adulthood of children with intellectual impairment: evidence from a birth cohort.

BACKGROUND: Social Policy for people with intellectual disabilities (ID) continues to evolve, but little is known about the lives to which such policies are applied. We aimed to use a prospective follow-up of a British birth cohort to identify children with mild and more severe intellectual impairment, and compare a range of social outcomes in adulthood with people in the rest of the cohort. METHOD: We used data from the MRC National Survey for Health and Development. Intellectual impairment was identified by intelligence tests and educational history. Adult outcome measures included employment and social class, education, marriage and children, home ownership, social networks and community use. RESULTS: We identified 111 people with mild intellectual impairment (2.7%) and 23 with severe intellectual impairment (0.6%) at age 15/16. By the age of 43, there were 52 people remaining in the mild impairment group and 14 in the severe impairment group. In adulthood those with intellectual impairment enjoyed contact with friends and family, and joined in informal social activities. Although the mild intellectual impairment group were less likely to attain the following social outcomes than people with normal intellectual functioning, 67% had jobs, 73% were married, 62% had children and 54% owned their own homes. 12% participated in adult education. People with more severe intellectual impairment were less likely to attain these outcomes. CONCLUSIONS: These outcomes highlight issues in current social policy and suggest efforts should be directed particularly towards promoting educational opportunities and developing social inclusion for people with ID.

Achievement↗
PubMed2005

Cardiovascular risk at age 53 years in relation to the menopause transition and use of hormone replacement therapy: a prospective British birth cohort study.

OBJECTIVES: To investigate cardiovascular risk factors and changes in risk factor levels in relation to menopausal stage, hysterectomy status and hormone replacement therapy use in a cohort of women aged 53 years with prospective data on smoking, lifetime socio-economic circumstances, and blood pressure and obesity at age 43 years. DESIGN: A prospective study. SETTING: England, Scotland and Wales. POPULATION: A cohort of women from the Medical Research Council Survey of Health and Development. METHODS: A total of 1303 women, aged 53 years, from a UK birth cohort study with measures of cardiovascular risk factors were classified by five menopausal status groups (premenopause, perimenopause, postmenopause, hysterectomy and hormone replacement therapy user). Body mass index, glycosolated haemoglobin, blood pressure, high density lipoprotein, low density lipoprotein and total cholesterol measurements were taken, and analysed within the groups taking confounding variables into account. Changes in body mass index and blood pressure measurement in the same women obtained when 43 years of age were also compared. MAIN OUTCOME MEASURES: Body mass index, glycosolated haemoglobin, blood pressure, high density lipoprotein, low density lipoprotein and total cholesterol. RESULTS: At 53 years, body mass index, waist circumference, total and low density lipoprotein cholesterol, and glycosolated haemoglobin (HbA1c) varied by menopausal status group, but blood pressure did not. Levels of total cholesterol and HbA1c increased across the natural menopause transition, before and after adjustment for body mass index, smoking and lifetime socio-economic circumstances. After adjustment for confounders, levels of risk factors for hysterectomised women were similar to those of naturally postmenopausal women. Women on hormone replacement therapy had lower levels of total and low density lipoprotein cholesterol, HbA1c, and were less obese than postmenopausal women. The lower obesity levels were partly due to these women already being less obese at age 43 years. CONCLUSIONS: This study showed that naturally postmenopausal or hysterectomised women had higher levels of metabolic risk factors compared with premenopausal or perimenopausal women of the same age. The long term stability of these differences and their translation into variations in incidence of cardiovascular disease remain to be seen. The lower levels of metabolic risk factors for women on hormone replacement therapy may protect against future cardiovascular disease or may be overwhelmed by other adverse, and as yet unknown, effects of hormone replacement therapy.

Blood Pressure↗
PubMed2004

Active placebos versus antidepressants for depression.

BACKGROUND: Although there is a consensus that antidepressants are effective in depression, placebo effects are also thought to be substantial. Side effects of antidepressants may reveal the identity of medication to participants or investigators and thus may bias the results of conventional trials using inert placebos. Using an 'active' placebo which mimics some of the side effects of antidepressants may help to counteract this potential bias. OBJECTIVES: To investigate the efficacy of antidepressants when compared with 'active' placebos. SEARCH STRATEGY: The Cochrane Collaboration Depression, Anxiety and Neurosis review groups's search strategy was used to search MEDLINE (1966-2000), PsychLIT (1980-2000) and EMBASE (1974-2000) and this was last done in July 2000. Reference lists from relevant articles and textbooks were searched and 12 specialist journals were handsearched up to 1996. SELECTION CRITERIA: Randomised and quasi randomised controlled trials comparing antidepressants with active placebos in people with depression. DATA COLLECTION AND ANALYSIS: Since many different outcome measures were used a standard measure of effect was calculated for each trial. A subgroup analysis of inpatient and outpatient trials was conducted. Two reviewers independently assessed whether each trial met inclusion criteria. MAIN RESULTS: Nine studies involving 751 participants were included. Two of them produced effect sizes which showed a consistent and statistically significant difference in favour of the active drug. Combining all studies produced a pooled estimate of effect of 0.39 standard deviations (confidence interval, 0.24 to 0.54) in favour of the antidepressant measured by improvement in mood. There was high heterogeneity due to one strongly positive trial. Sensitivity analysis omitting this trial reduced the pooled effect to 0.17 (0.00 to 0.34). The pooled effect for inpatient and outpatient trials was highly sensitive to decisions about which combination of data was included but inpatient trials produced the lowest effects. REVIEWER'S CONCLUSIONS: The more conservative estimates from the present analysis found that differences between antidepressants and active placebos were small. This suggests that unblinding effects may inflate the efficacy of antidepressants in trials using inert placebos. Further research into unblinding is warranted.

Antidepressive Agents↗
PubMed2004

[Chronic pain management: a multidisciplinary approach].

Assessment of chronic pain is one of medicine's most difficult challenges. A structured and flexible multidisciplinary approach allows full characterisation of the various components of the pain syndrome. This then allows the use of a rational combination of pharmacologic, physical, psychological, and surgical techniques. It is essential to gain the patient's confidence, collaboration, and compliance. Patients can better manage their situation when their needs are clarified and when care is oriented toward concrete therapeutic objectives.

Chronic Disease↗
PubMed2003

Life-course body size and perimenopausal mammographic parenchymal patterns in the MRC 1946 British birth cohort.

Dense mammographic parenchymal patterns are associated with an increased risk of breast cancer. Certain features of body size have been found to be associated with breast cancer risk, but less is known about their relation to breast density. We investigated the association of birth size, childhood growth and life-course changes in body size with Wolfe grade in 1298 perimenopausal women from a British cohort of women born in 1946. The cohort benefits from repeated measures of body size in childhood and adulthood. We obtained mammograms for 90% of women who at age 53 years reported having previously had a mammogram. We found no associations with birth weight or maximum attained height. Body mass index (BMI) at age 53 years and breast size were independently and inversely associated with Wolfe grade (P-value for trend <0.001 for both). Women who reached puberty later were at a greater odds of a higher Wolfe grade than women who had an earlier puberty (odds ratio associated with a 1 year delay in menarche 1.14, 95% CI: 1.01-1.27, adjusted for BMI and breast size at mammography). A higher BMI at any age during childhood or adult life was associated with a reduction in the odds of a higher Wolfe grade, after controlling for breast size and BMI at mammography, for example, standardised odds ratio for height at age 7 was 0.72 (95% CI: 0.64, 0.81). These findings reveal the importance of taking life-course changes in body size, and not just contemporaneous measures, into account when using mammographic density as an intermediate marker for risk of breast cancer.

Adolescent↗
PubMed2003

Weight from birth to 53 years: a longitudinal study of the influence on clinical hand osteoarthritis.

OBJECTIVE: To determine the influence of body weight throughout the life course on the development of clinical hand osteoarthritis (OA). METHODS: A British national survey was used to perform a prospective cohort study of 1,467 men and 1,519 women born in 1946. Weight was measured at birth and at subsequent followup visits through childhood and adulthood. The main outcome measure was the odds ratio for the presence of hand OA at the age of 53 years. RESULTS: Two hundred eighty men (19%) and 458 women (30%) had OA in at least 1 hand joint. Hand OA was significantly associated with increased weight at ages 26 years, 43 years, and 53 years and with decreased weight at birth in men. Birth weight and adult weight showed independent effects, such that men with the highest risk for OA represented those who had been heaviest at age 53 years and lightest at birth. These findings were not explained by grip strength. There was no significant relationship between weight and hand OA in women. CONCLUSION: The results of this study show that increased adult weight is associated with, and may precede, development of hand OA in men. An association between hand OA and weight was not observed in women. The relationship between hand OA and decreased birth weight is a new finding and may reflect the persisting influence of prenatal environmental factors on adult joint structure and function.

Adolescent↗
PubMed2003

The clinical effectiveness of counselling in primary care: a systematic review and meta-analysis.

BACKGROUND: Counselling is frequently used in the management of common mental disorders (such as anxiety and depression) in primary care. However, there are concerns over the clinical effectiveness of counselling, both in comparison with usual general practitioner care, and with other treatments such as alternative psychological therapies and antidepressant treatment. This study used systematic review methodology to assess the current evidence-base. METHOD: A systematic literature review located seven trials of relevance, comparing counselling with usual general practitioner care, cognitive-behaviour therapy and antidepressant medication. Data on internal and external validity were examined using a standardized quality rating scheme. Data concerning the impact of counselling on symptoms of anxiety and depression were pooled using meta-analytical procedures. RESULTS: The main analyses showed significantly greater clinical effectiveness of counselling compared with usual general practitioner care in the short-term (standardized mean difference -0.28, 95% CI -0.43 to -0.13, N=741, six trials) but not the long-term (standardized mean difference -0.07, 95% CI -0.26 to 0.12, N=447, four trials). Sensitivity analyses were undertaken to test the robustness of the results. CONCLUSION: Counselling is associated with modest improvement in short-term outcome compared with usual general practitioner care, and thus may be a useful addition to mental health services in primary care.

Cognitive Behavioral Therapy↗
PubMed2003

Microtibial embolectomy.

BACKGROUND: microtibial embolectomy is an important technique in cases of limb threatening acute arterial occlusion affecting native crural and pedal vessels. It is particularly useful when thrombolysis is contraindicated or ineffective as in "trash foot". METHODS: in order to evaluate the efficacy of this technique, a retrospective case note review was carried out for patients undergoing microtibial embolectomy from 1990 to 1999. Data collected included the causes and degree of ischaemia, additional procedures required, vessel patency, limb salvage and complications encountered. RESULTS: twenty-two limbs underwent exploration of the crural/pedal vessels with ankle level arteriotomies under local anaesthetic in 12 cases, general anaesthetic in nine and epidural in one. The causes of ischaemia were cardiac emboli (8), "trash foot" (7), emboli from aortic and popliteal aneurysms (3) and thrombotic occlusion of crural vessels (4). The vessel patency rate was 69% and limb salvage rate 62% (13/21) up to 5-years follow-up. Six of the seven cases with "trash foot" were salvaged while one required an amputation at 3-months post-operatively. The 30-day mortality was 22% (5/22). CONCLUSIONS: microtibial embolectomy is effective in acute occlusion of the crural/pedal arteries including cases of "trash foot", offering limb salvage to a worthwhile proportion of cases.

Aged↗
PubMed2003

Randomized crossover comparison of the ProSeal laryngeal mask airway with the Laryngeal Tube during anaesthesia with controlled ventilation.

BACKGROUND: The Laryngeal Tube (LT) performs similarly to the classic laryngeal mask airway during controlled ventilation but with an improved airway seal. We compared the laryngeal tube with the ProSeal laryngeal mask airway (PLMA) throughout anaesthesia. METHODS: Thirty-two patients were studied using a randomized cross-over design. The primary outcome measure was airway seal pressure. Secondary outcome measures included peak and plateau airway pressures, time to achieve an airway, ease of insertion, airway manipulations required to achieve a patent airway and grade of fibre-optic laryngoscopy. The proportion of patients in whom good, fair or failed ventilation was achieved was also calculated. RESULTS: No significant difference was found in regard to seal pressure (PLMA, median 26.5 cm H2O, range 10-40; LT, median 24, range 6-40; P=0.7, 95% confidence interval of the difference 3.5 to -4.0). There were two failures of insertion or ventilation in the LT group and none in the PLMA group. The peak airway pressure with the PLMA was lower than with the LT but the difference was clinically unimportant (PLMA, mean 16.2 cm H2O, SD 3.52; LT, mean 17.9, SD 5.21; P=0.02, 95% confidence interval of the difference -3.1 to -0.28). The PLMA took significantly less time to insert than the LT (PLMA, median 18.5 s, interquartile range 14-26; LT, median 22, interquartile range 15-36.5; P<0.02, 95% confidence interval of the difference -21.5 to -1.0). The PLMA gave a significantly better view on fibre-optic laryngoscopy than the LT (P<0.001, 95% confidence interval of the difference in grade -2.0 to -1.0). In the 16 patients in whom the PLMA was used during maintenance of anaesthesia ventilation was good in 15, fair in none and failed in one. The equivalent figures for the LT were good in nine, fair in six and failed in one (P=0.009). There was no significant difference in the plateau airway pressure, ease of insertion of the devices, number of manipulations required to achieve or maintain an airway, or in overall complications. CONCLUSION: The two devices performed equally well in terms of seal pressure. The PLMA was quicker to insert. Efficacy of ventilation was significantly better with the PLMA than the LT. The PLMA allowed a significantly better view of the larynx with a fibre-optic laryngoscope, and may therefore be of more use in cases where visualization of the larynx is required.

Adolescent↗
PubMed2003

Upregulation of the oncogene c-myc in Barrett's adenocarcinoma: induction of c-myc by acidified bile acid in vitro.

BACKGROUND AND AIMS: C-myc over expression is implicated in malignancy although to date this has not been studied in Barrett's metaplasia. We sought to determine c-myc expression in the malignant progression of Barrett's metaplasia and whether it may be induced by bile acids seen in gastro-oesophageal refluxate. METHODS: C-myc protein and mRNA levels were assessed in 20 Barrett's metaplasia and 20 oesophageal adenocarcinoma samples by western blotting and real time polymerase chain reaction. Levels of c-myc and proliferation were also assessed in cell lines OE21, OE33, SW-480, and TE-7 stimulated with pulses or continuous exposure to the bile acids deoxycholic acid and chenodeoxycholic acid. RESULTS: C-myc protein was upregulated in 50% of Barrett's metaplasia and 90% of oesophageal adenocarcinoma samples compared with squamous, gastric, and duodenal controls. C-myc immunolocalisation in Barrett's metaplasia revealed discrete nuclear localisation, becoming more diffuse with progression from low to high grade dysplasia to adenocarcinoma. Both continual and pulsed bile acid induced c-myc at pH 4, with no effect at pH 7 or with acidified media alone. Pulsed bile acid treatment induced proliferation (p<0.05); in contrast, continuous exposure led to suppression of proliferation (p<0.05). CONCLUSIONS: We have shown upregulation of c-myc with malignant progression of Barrett's metaplasia and suggest that acidified bile may be a novel agent responsible for induction of this oncogene.

Adenocarcinoma↗
PubMed2003

Central and total obesity in middle aged men and women in relation to lifetime socioeconomic status: evidence from a national birth cohort.

STUDY OBJECTIVE: To investigate the influence of social class in childhood, young adulthood and middle age, and intergenerational mobility, on adult central and total obesity. DESIGN: Prospective, population based, birth cohort study. PARTICIPANTS AND SETTING: 1472 men and 1563 women born in 1946 in England, Scotland, and Wales. OUTCOME MEASURES: Waist-hip ratio, waist-height ratio, waist circumference, and body mass index at age 53 years. MAIN RESULTS: Father's social class at participant's age 4 years was inversely associated with adult central and total obesity at age 53 years in men and women. For example, the mean difference of waist-hip ratio (95% confidence intervals) between father's professional social class I and unskilled manual social class V was 2.6% (0.7 to 4.6) for men and 2.5% (0.5 to 4.4) for women. The effect of father's social class remained after adjustment for participant's own social class in young adulthood and middle age. Both adult social classes were inversely related to obesity among women, but not men, after adjustment for childhood circumstances. Upwardly mobile men and women were less obese than participants remaining in their father's social class and their levels of obesity tended to be between the class they left and the class they joined. CONCLUSIONS: The effect of social class on adult obesity differed according to the stage in the life course at which social class was measured, and gender. Childhood circumstances had enduring influences on adult obesity, although our results on intergenerational mobility indicate potential reversibility of early life disadvantage.

Anthropometry↗
PubMed2002

Birth weight, childhood growth and abdominal obesity in adult life.

OBJECTIVE: To examine the relationship of adult abdominal obesity to birth weight, childhood growth and lifetime socioeconomic circumstances. METHODS: A cohort of 3200 men and women with measured waist and hip circumference, height and weight at age 43 who have been followed since their birth in March 1946 in England, Scotland and Wales. Regression models were used to examine mean waist-hip ratio and waist circumference in relation to prospective measures of birth weight, weight relative to height in childhood at ages 4, 7, 11 and 15 and adult body mass index, and to test the independent and interactive nature of the associations and adjust for childhood and adult social class. RESULTS: There was a small inverse effect of birth weight on waist-hip ratio (P=0.037) but not waist circumference in women, after adjustment for current body size. Relative weight at age 7 was inversely related to waist-hip ratio and waist circumference in men (P<0.001 for both) and waist circumference in women (P=0.007) after adjustment for current body size. These relationships were attenuated in men of large body mass index (P<0.01 for interactions between relative weight at 7 y and body mass index in both cases) but were not modified by birth weight. Relative weights at other ages showed similar patterns to those observed at age 7, the effect being weakest at age 4. These findings were independent of lifetime socioeconomic circumstances. CONCLUSION: This study found a small prenatal inverse effect of fetal growth on adult waist-hip ratio due to a reduced hip size. There was also an inverse postnatal effect of childhood growth such that for any given adult body size those who had been lighter in childhood were more at risk of abdominal obesity. These relationships were independent of childhood socioeconomic circumstances and support the idea that insulin resistance may be linked to low weight in childhood.

Abdomen↗