Expression of Bcl-2 protein is decreased in colorectal adenocarcinomas with microsatellite instability.
Bcl-2 is known to inhibit apoptosis and is thought to play a role in colorectal tumour development. Studies of the promoter region of bcl-2 have indicated the presence of a p53 responsive element which downregulates bcl-2 expression. Since p53 is commonly mutated in colorectal cancers, but rarely in those tumours showing microsatellite instability (MSI), the aim of this study was to examine the relationship of bcl-2 protein expression to MSI, as well as to other clinicopathological and molecular variables, in colorectal adenocarcinomas. Expression of bcl-2 was analysed by immunohistochemistry in 71 colorectal cancers which had been previously assigned to three classes depending upon their levels of MSI. MSI-high tumours demonstrated instability in three or more of six microsatellite markers tested, MSI-low tumours in one or two of six, and MSI-null in none of six. Bcl-2 expression in tumours was quantified independently by two pathologists and assigned to one of five categories, with respect to the number of cells which showed positive staining: 0, up to 5%; 1, 6-25%; 2, 26-50%; 3, 51-75%; and 4, > or =76%. Bcl-2 negative tumours were defined as those with a score of 0. Bcl-2 protein expression was tested for association with clinicopathological stage, differentiation level, tumour site, age, sex, survival, evidence of p53 inactivation and MSI level. A significant association was found between bcl-2 expression and patient survival (P = 0.012, Gehan Wilcoxon test). Further, a significant reciprocal relationship was found between bcl-2 expression and the presence of MSI (P = 0.012, Wilcoxon rank sum test). We conclude that bcl-2 expressing colorectal cancers are more likely to be MSI-null, and to be associated with improved patient survival. (+info
Comparative total mortality in 25 years in Italian and Greek middle aged rural men.
STUDY OBJECTIVE: Mortality over 25 years has been low in the Italian and very low in the Greek cohorts of the Seven Countries Study; factors responsible for this particularity were studied in detail. PARTICIPANTS AND SETTINGS: 1712 Italian and 1215 Greek men, aged 40-59 years, cohorts of the Seven Countries Study, representing over 95% of the populations in designated rural areas. DESIGN: Entry (1960-61) data included age, systolic blood pressure (SBP), smoking habits, total serum cholesterol, body mass index (BMI), arm circumference, vital capacity (VC), and forced expiratory volume in 3/4 seconds (FEV); the same data were obtained 10 years later. Multivariate Cox analysis was performed with all causes death in 25 years as end point. MAIN RESULTS: Italian men had higher entry levels of SBP, arm circumference, BMI, and VC; Greek men had higher cholesterol levels, smoking habits, and FEV. Mortality of Italian men was higher throughout; at 25 years cumulative mortality was 48.3% and 35.3% respectively. Coronary heart disease and stroke mortality increased fivefold in Italy and 10-fold in Greece between years 10 and 25. The only risk factor with a significantly higher contribution to mortality in Italian men was cholesterol. However, differences in entry SBP (higher in Italy) and FEV (higher in Greece) accounted for, according to the Lee method, 75% of the differential mortality between the two populations. At 10 years increases in SBP, cholesterol, BMI, and decreases in smoking habits, VC, FEV, and arm circumference had occurred (deltas). SBP increased more and FEV and VC decreased more in Italy than in Greece. Deltas, fed stepwise in the original model for the prediction of 10 to 25 years mortality, were significant for SBP, smoking, arm circumference, and VC in Greece, and for SBP and VC in Italy. CONCLUSION: Higher mortality in Italian men is related to stronger positive effects of entry SBP and weaker negative (protective) effects of FEV; in addition 10 year increases in SBP are higher and 10 year decreases in FEV are larger in Italy. Unaccounted factors, however, related to, for example, differences in the diet, may also have contributed to the differential mortality of these two Mediterranean populations. (+info
Do housing tenure and car access predict health because they are simply markers of income or self esteem? A Scottish study.
OBJECTIVE: To investigate relations between health (using a range of measures) and housing tenure or car access; and to test the hypothesis that observed relations between these asset based measures and health are simply because they are markers for income or self esteem. DESIGN: Analysis of data from second wave of data collection of West of Scotland Twenty-07 study, collected in 1991 by face to face interviews conducted by nurse interviewers. SETTING: The Central Clydeside Conurbation, in the West of Scotland. SUBJECTS: 785 people (354 men, 431 women) in their late 30s, and 718 people (358 men, 359 women) in their late 50s, participants in a longitudinal study. MEASURES: General Health Questionnaire scores, respiratory function, waist/hip ratio, number of longstanding illnesses, number of symptoms in the last month, and systolic blood pressure; household income adjusted for household size and composition; Rosenberg self esteem score; housing tenure and care access. RESULTS: On bivariate analysis, all the health measures were significantly associated with housing tenure, and all except waist/hip ratio with car access; all except waist/hip ratio were related to income, and all except systolic blood pressure were related to self esteem. In models controlling for age, sex, and their interaction, neither waist/hip ratio nor systolic blood pressure remained significantly associated with tenure or care access. Significant relations with all the remaining health measures persisted after further controlling for income or self esteem. CONCLUSIONS: Housing tenure and car access may not only be related to health because they are markers for income or psychological traits; they may also have some directly health promoting or damaging effects. More research is needed to establish mechanisms by which they may influence health, and to determine the policy implications of their association with health. (+info
Cohort study of art glass workers in Tuscany, Italy: mortality from non-malignant diseases.
This investigation studies cause-specific mortality of art glass workers employed in 17 industrial facilities in Tuscany, Italy. A cohort of 3,390 workers employed for at least 1 year was enumerated from company payrolls. Follow-up was between the start of employment in each factory and 31 December 1993. The cause-specific expected mortality was computed relative to Tuscany rates and specified for gender, 5-year age groups and calendar year. Separate analyses were carried out for the jobs of makers and formers and for batch mixers. Among males (3, 180 individuals) observed mortality for non-cancer causes was higher than expected for hypertensive disease [standardized mortality ratio (SMR) = 178, 90% confidence interval (90% CI) = 96-301], pneumoconiosis (SMR = 200, 90% CI = 94-376) and diseases of the genitourinary system (SMR = 169, 90% CI = 95-279). Increases for the above causes were shown also among makers and formers: hypertensive disease (SMR = 182, 90% CI = 85-341), pneumoconiosis (SMR = 250, 90% CI = 109-493) and diseases of the genitourinary system (SMR = 224, 90% CI = 121-380). For batch mixers an increase was present for cerebrovascular disease. The observed mortality for cancer causes was above the expected for cancers of the larynx, lung, stomach and brain. This study points to the existence for Tuscan glass workers of health effects in addition to cancer; previously observed carcinogenic effects were also confirmed. (+info
Measurement of serum TSH in the investigation of patients presenting with thyroid enlargement.
In otherwise euthyroid patients presenting with thyroid enlargement, reduction in serum thyrotrophin (TSH) concentrations measured in a sensitive assay may be a marker of thyroid autonomy and may therefore indicate a benign underlying pathology. We investigated prospectively a cohort of 467 subjects presenting consecutively to our thyroid clinic with nodular or diffuse enlargement of the thyroid. Subjects were divided into those with normal (0.4-5.5 mU/l), low but detectable (0.1-0.39 mU/l) or undetectable (< 0.1 mU/l) serum TSH concentrations. The final pathological diagnosis was defined by fine-needle aspiration cytology and clinical follow-up of at least 2 years or by fine-needle aspiration cytology and histology following surgical treatment. Serum TSH concentrations below normal were found in 75 patients (16.1%), those with low serum TSH results having higher mean free T4 concentrations, were older and were more likely to be female. In those with undetectable serum TSH, no patient had a diagnosis of thyroid neoplasia and in those with low but detectable TSH, thyroid neoplasms were diagnosed in two patients (3.4%). In those with normal serum TSH, 12.0% had a final diagnosis of thyroid neoplasm (p = 0.013). Overall, thyroid malignancy was found in one patient (1.3%) of those with a serum TSH measurement below the normal range and 6.9% of those with normal serum TSH (p < 0.06). Reduction in serum TSH at presentation may identify a group which requires less intensive investigation and follow-up than those without biochemical evidence of thyroid autonomy. (+info
Late referral of end-stage renal failure.
We studied all new patients accepted for renal replacement therapy (RRT) in one unit from 1/1/96 to 31/12/97 (n = 198), to establish time from nephrology referral to RRT, evidence of renal disease prior to referral and the adequacy of renal management prior to referral. Sixty four (32.3%, late referral group) required RRT within 12 weeks of referral. Fifty-nine (29.8%) had recognizable signs of chronic renal failure > 26 weeks prior to referral. Patients starting RRT soon after referral were hospitalized for significantly longer on starting RRT (RRT within 12 weeks of referral, median hospitalization 25.0 days (n = 64); RRT > 12 weeks after referral, median 9.7 days (n = 126), (p < 0.001)). Observed survival at 1 year was 68.3% overall, with 1-year survival of the late referral and early referral groups being 60.5% and 72.5%, respectively (p = NS). Hypertension was found in 159 patients (80.3%): 46 (28.9%) were started on antihypertensive medication following referral, while a further 28 (17.6%) were started on additional antihypertensives. Of the diabetic population (n = 78), only 26 (33.3%) were on an angiotensin-converting-enzyme inhibitor (ACEI) at referral. Many patients are referred late for dialysis despite early signs of renal failure, and the pre-referral management of many of the patients, as evidenced by the treatment of hypertension and use of ACEI in diabetics, is less than optimal. (+info
Obstetric and neonatal outcome following chronic hypertension in pregnancy among different ethnic groups.
We retrospectively studied pre-eclampsia rate and obstetric outcome in a cohort of 436 pregnancies amongst 318 women of different ethnic backgrounds attending an antenatal hypertension clinic from 1980-1997, identifying 152 women (213 pregnancies) with chronic essential hypertension. The ethnic breakdown was: White, 64 (30.0%) pregnancies in 48 (31.5%) women; Black/Afro-Caribbean, 79 (37.1%) pregnancies in 56 (36.8%) women; and Indo-Asians, 70 (32.3%) pregnancies in 48 (31.6%) women. The prevalences of pre-eclampsia in White, Black and Indo-Asian women were 17.2%, 12.7% and 18.6%, respectively (p = 0.58). Pregnancies of Indo-Asian women were of shorter gestation, and babies in this group also had lower birth weight and ponderal index compared to those of White and Black women (all p < 0.05). The proportions of overall perinatal mortality were 1.6% for Whites (1/64), 3.8% for Blacks (3/79) and 10.0% for Indo-Asians (7/70), suggesting increased risk in the Indo-Asian group. Indo-Asian women with chronic essential hypertension need careful antenatal care and observation during pregnancy. (+info
Maternal second trimester serum tumor necrosis factor-alpha-soluble receptor p55 (sTNFp55) and subsequent risk of preeclampsia.
Preeclampsia is characterized by diffuse vascular endothelial dysfunction. Tumor necrosis factor-alpha (TNF-alpha), which plays a key role in the cytokine network responsible for immunoregulation, is also known to contribute to endothelial dysfunction and other metabolic disturbances noted in preeclampsia. Results from cross-sectional studies and one longitudinal study indicate that TNF-alpha (or its soluble receptor, sTNFp55) is increased in the peripheral circulation and amniotic fluid of women with preeclampsia as compared with normotensive women. Between December 1993 and August 1994, prediagnostic sTNFp55 concentrations (a marker of excessive TNF-alpha release) were measured in 35 women with preeclampsia and 222 normotensive women to determine whether elevations precede the clinical manifestation of the disorder. Logistic regression procedures were used to calculate maximum likelihood estimates of odds ratios and 95% confidence intervals. Mean second trimester (15-22 weeks' gestation) serum sTNFp55 concentrations, measured by enzyme-linked immunosorbent assay, were 14.4% higher in preeclamptic women than in normotensive controls (716.6 pg/ml (standard deviation 193.6) vs. 626.4 pg/ml (standard deviation 158.0); p = 0.003). The relative risk of preeclampsia increased across successively higher quintiles of sTNFp55 (odds ratios were 1.0, 1.3, 2.1, and 3.7, with the lowest quintile used as the referent; p for trend = 0.007). After adjustment for maternal age, adiposity, and parity, the relative risk between extreme quintiles was 3.3 (95% confidence interval 0.8-13.4). These findings indicate that the level of TNF-alpha in maternal circulation is increased prior to the clinical manifestation of the disorder, and they are consistent with the hypothesized role of cytokines in mediating endothelial dysfunction and the pathogenesis of preeclampsia. Further work is needed to identify modifiable risk factors for the excessive synthesis and release of TNF-alpha in pregnancy, and to assess whether lowering of TNF-alpha concentrations in pregnancy alters the incidence and severity of preeclampsia. (+info