Showing papers by "Clinical Trial Service Unit published in 2003"

Homocysteine and brain atrophy on MRI of non-demented elderly

Abstract: Patients with Alzheimer's disease have higher plasma homocysteine levels than controls, but it is uncertain whether higher plasma homocysteine levels are involved in the early pathogenesis of the disease. Hippocampal, amygdalar and global brain atrophy on brain MRI have been proposed as early markers of Alzheimer's disease. In the Rotterdam Scan Study, a population-based study of age-related brain changes in 1077 non-demented people aged 60-90 years, we investigated the association between plasma homocysteine levels and severity of hippocampal, amygdalar and global brain atrophy on MRI. We used axial T(1)-weighted MRIs to visualize global cortical brain atrophy (measured semi-quantitatively; range 0-15) and a 3D HASTE (half-Fourier acquisition single-shot turbo spin echo) sequence in 511 participants to measure hippocampal and amygdalar volumes. We had non-fasting plasma homocysteine levels in 1031 of the participants and in 505 of the participants with hippocampal and amygdalar volumes. Individuals with higher plasma homocysteine levels had, on average, more cortical atrophy [0.23 units (95% CI 0.07-0.38 units) per standard deviation increase in plasma homocysteine levels] and more hippocampal atrophy [difference in left hippocampal volume -0.05 ml (95% CI -0.09 to -0.01) and in right hippocampal volume -0.03 ml (95% CI -0.07 to 0.01) per standard deviation increase in plasma homocysteine levels]. No association was observed between plasma homocysteine levels and amygdalar atrophy. These results support the hypothesis that higher plasma homocysteine levels are associated with more atrophy of the hippocampus and cortical regions in elderly at risk of Alzheimer's disease.

Mortality from cardiovascular disease more than 10 years after radiotherapy for breast cancer: nationwide cohort study of 90 000 Swedish women.

Abstract: Increased cardiovascular mortality more than 10 years after diagnosis of breast cancer is compatible with radiotherapy causing a substantial hazard During radiotherapy for breast cancer there is often some irradiation of the heart and major blood vessels, which could increase cardiovascular mortality many years later.1–3 The dose of radiation to the heart is generally higher when the left rather than the right breast is affected. Therefore, indirect evidence on the magnitude of any risk is available where the tumour laterality (left or right breast) can be linked to subsequent cardiovascular mortality. 1 2 Studies of the survivors of the atomic bombing of Japan who received single doses to the whole body of 0–4 Gy show that the cardiovascular disease risk is dose related and increases by about 14% per gray.4 View this table: Mortality ratio for women with left sided breast cancer versus women with right sided breast cancer during and after the first 10 …

Amplification of AML1 on a duplicated chromosome 21 in acute lymphoblastic leukemia: a study of 20 cases.

Abstract: This study identifies multiple copies of the AML1 gene on a duplicated chromosome 21, dup(21), as a recurrent abnormality in acute lymphoblastic leukemia (ALL). Clusters of AML1 signals were visible at interphase by fluorescence in situ hybridization (FISH). In metaphase, they appeared tandemly duplicated on marker chromosomes of five distinct morphological types: large or small acrocentrics, metacentrics, submetacentrics or rings. The markers comprised only chromosome 21 material. Karyotypes were near-diploid and, besides dup(21), no other established chromosomal changes were observed. A total of 20 patients, 1.5 and <0.5% among consecutive series of childhood and adult ALL respectively, showed this phenomenon. Their median age was 9 years, white cell counts were low and all had a pre-B/common immunophenotype. Although this series is not the first report of this abnormality, it is the largest, permitting a detailed description of the variety of morphological forms that duplicated chromosome 21 can assume.

Stability of plasma analytes after delayed separation of whole blood: implications for epidemiological studies

Abstract: Results In whole blood stored at room temperature for up to 7 days, concentrations of albumin, apolipoproteins A1 and B (apoA1 and apoB), cholesterol, high density lipoprotein (HDL), total protein, and triglycerides changed by less than 4%, and low density lipoprotein (LDL) by less than 7%. Whilst alanine transaminase (ALT), creatine kinase (CK), creatinine, and γ-glutamyl transferase (GGT) concentrations changed substantially at room temperature, there was less than 4% change during chilled storage up to 7 days. By contrast, aspartate transaminase (AST) concentrations increased markedly under both conditions. Conclusions A wide range of important analytes, including lipids, change by only a few per cent in whole blood during storage at room temperature for several days. Mailed transport of whole blood samples may, therefore, be a simple and cost-effective option for large-scale epidemiological studies.

CNS-Directed Therapy for Childhood Acute Lymphoblastic Leukemia: Childhood ALL Collaborative Group Overview of 43 Randomized Trials

Abstract: Purpose: A collaborative meta-analysis was performed to clarify the relative effects on relapse and survival of different types of therapies directed at the CNS in childhood acute lymphoblastic leukemia. Materials and Methods: Data were sought for each individual patient in all trials started in or before 1993 that included unconfounded randomized comparisons of such treatments. Log-rank survival analyses were performed for each trial, and overall results for groups of trials addressing similar questions were obtained from the totals of the observed minus expected number of events and their variances. Results: Radiotherapy and long-term intrathecal therapy gave similar outcomes, with no significant difference in event-free survival despite random assignment of treatment to 2,848 patients, 1,001 of whom suffered relapse or death. Intravenous methotrexate reduced non-CNS rather than CNS relapses, and hence, the addition of intravenous methotrexate to a treatment regimen including radiotherapy or long-term i...

Amplification of AML1 in acute lymphoblastic leukemia is associated with a poor outcome

Abstract: A total of 28 children and nine adults with relapsed T-ALL were analyzed for the configuration of their T-cell receptor (TCR) and TAL1 genes at diagnosis and relapse to evaluate their stability throughout the disease course. A total of 150 clonal TCR and TAL1 gene rearrangements were identified in the 37 patients at diagnosis. In 65% of cases all rearrangements and in 27% of cases most rearrangements found at diagnosis were preserved at relapse. Two children with unusually late T-ALL recurrences displayed completely different TCR gene rearrangement sequences between diagnosis and relapse. This indicates that a proportion of very late T-ALL recurrences might represent second T-ALL. Specifically, 88% of clonal rearrangements identified at diagnosis in truly relapsed T-ALL were preserved at relapse. This is significantly higher as compared to previously studied precursor-B-ALL (~70%). Thus, from biological point of view, immunogenotype of T-ALL is more stable as compared with precursor-B-ALL. The overall stability of TCR gene rearrangements was higher in adult T-ALL (97%) than in childhood T-ALL (86%). Based on the stability of TCR gene rearrangements, we propose a strategy for PCR target selection (TCRD+TAL1 TCRB TCRG), which probably allows reliable minimal residual disease detection in all T-ALL patients.

Smoking and liver cancer in China: case-control comparison of 36,000 liver cancer deaths vs. 17,000 cirrhosis deaths

Abstract: Liver cancer and liver cirrhosis are common causes of death in China, where chronic lifelong hepatitis B infection is a major cause of both diseases. To help determine whether smoking is a cofactor for the development of liver cancer, we ascertained retrospectively the smoking habits of 36,000 adults who had died from liver cancer (cases) and 17,000 who had died from cirrhosis (controls) in 24 Chinese cities and 74 rural counties. Calculations of the smoker vs. nonsmoker risk ratios (RR) for liver cancer mortality were standardised for age and locality. Among adult men (aged 35+) there was a 36% excess risk of death from liver cancer among smokers (smoker vs. nonsmoker standardised risk ratio [RR] =1.36, with 95% confidence interval [CI] 1.29-1.43, 2p<0.00001; attributable fraction 18%). In the general male population this indicates absolute risks of death from liver cancer before age 70 of about 4% in smokers and 3% in nonsmokers (in the absence of other causes). Most liver cancer, however, occurs among the 10-12% of men with haematological evidence of chronic hepatitis B infection, so among them the corresponding risks would be about 33% in smokers and 25% in nonsmokers. The RR was approximately independent of age, was similar in urban and rural areas, was not significantly related to the age when smoking started but was significantly (p<0.001) greater for cigarette smokers than for smokers of other forms of tobacco. Among men who smoked only cigarettes, the RR was significantly (p<0.001 for trend) related to daily consumption, with a greater hazard among those who smoked 20/day (RR 1.50, 95% CI 1.39-1.62) than among those who smoked fewer (mean 10/day: RR=1.32, 95% CI 1.23-1.41). Smoking was also associated with a significant excess of liver cancer death in women (RR 1.17, 95% CI 1.06-1.29, 2p=0.003; attributable fraction 3%), but fewer women (17%) than men (62%) were smokers, and their cigarette consumption per smoker was lower. Among women who smoked only cigarettes, there was a significantly greater hazard among those who smoked at least 20/day (mean 22/day: RR=1.45, 95% CI 1.18-1.79) than among those who smoked fewer (mean 8/day: RR=1.09, 95% CI 0.94-1.25). These associations indicate that tobacco is currently responsible for about 50,000 liver cancer deaths each year in China, chiefly among men with chronic HBV infection.

Health effects of residential radon: A European perspective at the end of 2002

Abstract: Surveys of indoor radon concentrations, when taken together with estimates of the risk of lung cancer from studies in miners of uranium and other hard rocks, suggest that residential radon is responsible for many thousands of deaths from lung cancer each year in Europe. The vast majority of these deaths are likely to occur in individuals who also smoke cigarettes. Because of the skewed nature of the distribution of the indoor radon concentrations in most populations, most of the deaths will occur in individuals who are exposed at moderate rather than at very high radon concentrations. In order to enable appropriate policies to be developed for managing the consequences of exposure to radon, more reliable estimates of the risk of lung cancer resulting from it are needed. To achieve this, a European Collaborative Group on Residential Radon and Lung Cancer was initiated and its findings should be published in 2004.

Regression dilution bias in blood total and high-density lipoprotein cholesterol and blood pressure in the Glostrup and Framingham prospective studies.

Abstract: Background In epidemiological studies, within-person variability in measured values of a risk factor may underestimate the association between prolonged or 'usual' levels of a risk factor with risk of disease - 'regression dilution'. The importance of regression dilution for high-density lipoprotein (HDL)-cholesterol and the extent to which this may differ from that for total cholesterol is not known. The aim of this study was to assess the magnitude of regression dilution bias for HDL-cholesterol, total cholesterol and blood pressure after varying intervals of follow-up in two prospective cohort studies. Methods Regression dilution ratios were estimated for each risk factor using the correlations between baseline and re-survey values in the Glostrup Population Studies and the NHLBI Framingham Heart Study after various time intervals. The regression dilution ratios in each cohort after a fixed interval between measurements were compared. Results The regression dilution ratios after 10 years were 0.51 and 0.56 for systolic blood pressure in Glostrup and Framingham, respectively; 0.52 and 0.54 for diastolic blood pressure; and 0.68 and 0.63 for total cholesterol. In both studies, the regression dilution ratios for these risk factors became more extreme with increasing intervals between measurements. The regression dilution ratio for HDL-cholesterol after 10 years in Glostrup was 0.72, which suggests that the importance of regression dilution for HDL-cholesterol was similar to that for total cholesterol. Conclusion Failure to correct for increasing regression dilution with longer follow-up may account for some of the discrepant results obtained for the importance of these risk factors in epidemiological studies at varying intervals of follow-up.

Intraocular relapse of childhood acute lymphoblastic leukaemia.

Abstract: Relapse of childhood acute lymphoblastic leukaemia (ALL) involving the eye is a rare but challenging problem. Twenty cases occurred in patients treated on the Medical Research Council United Kingdom Acute Lymphoblastic Leukaemia XI and ALL97 trials between 1991 and 2001, representing 2.2% of ALL relapses. Seventeen occurred as a first relapse, either in isolation or combined with relapse at another site, and three occurred as a second relapse. All patients with intraocular disease at first relapse were treated with both chemotherapy and radiotherapy, but the doses and protocols used varied. Eleven of these 17 patients are alive and in complete remission with a median follow up of 4 years 2 months from relapse. All 11 children that were treated with a full chemotherapy relapse protocol, together with local radiotherapy have survived. Patients treated with chemotherapy of shorter duration and intensity, despite radiotherapy and/or bone marrow transplantation, did poorly with only one survivor, currently in chronic relapse. Consequently, we suggest that children with eye relapse of ALL be treated with an intensive relapse chemotherapy protocol with local ocular radiotherapy, whether the relapse occurs in isolation or in combination with relapse at another site.

The centenary of the one-gene one-enzyme hypothesis.

Abstract: THE early history of mouse genetics has been recently described by Paigen ([2003][1]), but one episode in this history perhaps has not received sufficient recognition. In 1900, as soon as Mendel’s work was rediscovered, the French biologist Lucien Cuenot decided to see whether Mendel’s rules

Prognostic factors and outcome for children after second central nervous system relapse of acute lymphoblastic leukaemia.

Abstract: The Medical Research Council acute lymphoblastic leukaemia trials (UKALL X and XI) recruited 3,702 children with ALL between January 1985 and March 1997. Seventy-nine children had central nervous system (CNS) involvement in their first two relapses. Fourteen children survived at a median follow-up of 22 months from second relapse; seven (9%) in third remission, two in later remissions and five with disease. Factors predictive of survival from second relapse were site (isolated CNS was better than combined CNS, P = 0.02) and time from diagnosis to second CNS relapse (longer time was better, P = 0.004). Prognosis after second CNS relapse is extremely poor, and palliative therapy is appropriate.

Stabilization of Homocysteine in Unseparated Blood over Several Days: A Solution for Epidemiological Studies

Abstract: Increased blood homocysteine is a potentially modifiable risk factor for cardiovascular disease. In a recent metaanalysis of individual participant data from prospective epidemiologic studies, a 25% lower homocysteine concentration was associated with an 11% lower risk for ischemic heart disease and a 19% lower risk for stroke (1). Blood homocysteine is easily lowered by folic acid supplementation, and several large-scale randomized trials are currently underway to assess the effects of homocysteine-lowering vitamin supplements on the risk of vascular disease. If such trials demonstrate benefit, there will be increasing interest in homocysteine determinations to assess vascular disease risk. In addition, further large-scale epidemiologic studies may be required to investigate the association between homocysteine and cardiovascular disease in a wider range of populations. These would be facilitated by simple and cost-effective methods for blood collection and analysis. One of the chief constraints in homocysteine measurements is the continuing production and release of homocysteine by red blood cells after venipuncture, which causes an artificial increase in plasma concentration of ∼10% per hour (2)(3). It has been recommended, therefore, that blood samples for homocysteine measurements be drawn into tubes containing EDTA, chilled, or placed on ice immediately after collection and that the plasma be separated from the red cells within 1 h. Such procedures can be difficult to implement in large-scale epidemiologic studies or other situations in which samples have to be collected remotely (e.g., in multiple clinics or in people’s homes) and transported to a central laboratory. Use of NaF or acidic citrate has been advocated for stabilization of homocysteine in whole blood at ambient temperature …

The importance of cholesterol, blood pressure and smoking for coronary heart disease.

Abstract: See doi:10.1016/S1095-668X(03)00471-8 for the article to which this editorial refers Worldwide cardiovascular diseases account for half of all deaths in middle age (and considerable additional disability) and one third of all deaths in old age. Most of these deaths involve ischaemic heart disease (IHD) or stroke. Epidemiological studies carried out over the last half century have shown that cigarette smoking, elevated blood pressure and dyslipidaemia increase the risk of cardiovascular diseases and randomized trials have shown that lowering blood pressure and cholesterol prevents cardiovascular disease. Nevertheless, there are popular misconceptions about the relative importance of these classical risk factors, including the widely held belief that they only account for about half of all cardiovascular diseases.1 The underestimation of the importance of these risk factors has arisen from analyses of prospective cohort studies in which measurements of blood pressure or cholesterol recorded on enrolment to the study (the ‘baseline’ survey) were related to subsequent risk of developing IHD. But, due to the combined effects of measurement errors, short-term biological variability and longer-term systematic changes within individuals, baseline measurements often do not reliably indicate the long-term average, or ‘usual’, level of a risk factor either at around the time of the baseline measurement or during a later …

The risk of lethals for hypermutating bacteria in stationary phase.

Abstract: WHEN stationary phase populations of Escherichia coli are subjected to intense selection for reversion of a frameshift in lacZ they are found to have accumulated a wide variety of other mutations. Furthermore, cells bearing multiple mutations are much more common than would be expected, and this has

Cholesterol Lowering for the Prevention of Stroke

Abstract: INTRODUCTION Worldwide, stroke is the second most common cause of death and the sixth most common cause of disability (Murray and Lopez 1997). By 2020 it is projected to remain the second most common cause of death but to rise to the fourth most common cause of disability. During the second half of the 20th century death rates due to stroke declined by about half in Western Europe and the USA, even more in Japan (Sarti 2000 et al ). However, in Eastern European countries (Levi et al 2002) and China (Chinese Ecological Study 2003), rates have been gradually increasing over the last 20 years. These mortality trends are likely to be related to changes in the known risk factors for stroke, including smoking, blood pressure and diabetes, and they may also reflect changes in cholesterol levels. These trends broadly parallel those of coronary heart disease (Lawlor et al 2003), reminding