Potential Mechanisms of Benefit with Thalidomide in Chronic Heart Failure

This review considers the recent clinical and relevant preclinical evidence that thalidomide may have therapeutic benefit in chronic heart failure (HF), and considers some of the mechanisms by which thalidomide may elicit potentially beneficial effects. Persistent inflammation, involving increased levels of inflammatory cytokines, seems to play a pathogenic role in chronic HF by influencing heart contractility, inducing matrix degradation and fibrosis, and promoting apoptosis, contributing to myocardial remodeling. On the basis of these issues, immunomodulating therapy has emerged as an option in the management of chronic HF. Failure of anti-tumor necrosis factor (TNF) therapy has lead to further interest in a more general immunomodulatory approach, directed against the imbalanced cytokine network rather than at one particular cytokine.Some recent studies suggest that thalidomide, a glutamic acid derivative with proposed antiangiogenic, anti-inflammatory, and immunomodulatory properties, should be added to the list of potential immunomodulating agents in chronic HF. Thus, in a recent double-blind, placebo-controlled study in patients with chronic HF, thalidomide was found to significantly improve left ventricular ejection fraction. Although thalidomide has been regarded as an anti-TNF drug, it was found to increase plasma levels of TNFalpha in a placebo-controlled study in patients with HF, suggesting that other mechanisms may contribute to its beneficial effects. Such mechanisms could involve inhibition of neutrophils, matrix stabilizing, and antifibrotic effects, as well as a thalidomide-mediated decrease in the heart rate. However, our knowledge of the mechanisms of action of this drug is still scarce and will have to be further examined in forthcoming studies. Such studies should include experiments in animal models of HF as well as further preclinical trials, attempting to identify the potential mechanisms by which thalidomide may be beneficial in human HF.     

Who is maintaining weight in a middle-aged population in Sweden? A longitudinal analysis over 10 years

Background  

Obesity has primarily been addressed with interventions to promote weight loss and these have been largely unsuccessful. Primary prevention of obesity through support of weight maintenance may be a preferable strategy although to date this has not been the main focus of public health interventions. The aim of this study is to characterize who is not gaining weight during a 10 year period in Sweden.     

Determination of Cause of Death Among Breast Cancer Cases in the Swedish Randomized Mammography Screening Trials: A comparison between official statistics and validation by an endpoint committee

Between 1976 and 1982, four randomized mammography screening trials started in five screening centres in Sweden, involving 282 777 women (156 911 invited and 125 866 controls) with the aim to study if invitation to screening reduced the breast cancer mortality. An overview of the trials was performed to reduce the confidence intervals for the relative risk estimates. All 1 296 deaths occurring in women with breast cancer detected after randomization were evaluated by an independent endpoint committee (EPC), consisting of four physicians who reviewed collected medical information that was blinded regarding mammography screening. If there was disagreement between the EPC members at the initial individual evaluation the final classification was made at concensus meetings. In only 6.9% (n = 89) of the cases was there disagreement as to whether breast cancer was or was not the underlying cause of death. It was also found that 'breast cancer as underlying cause of death' and 'breast cancer as underlying or contributory cause of death' according to Statistics Sweden resulted in relative risk estimates very similar to those based on the classification by the EPC. The study thus supports the use of official health statistics in the evaluation of randomized breast screening trials in Sweden.     

Cancer risk after renal transplantation in the nordic countries, 1964–1986

The theory that cancer may arise under conditions of reduced immune capacity is supported by observations of humans with immune deficiencies such as occur following organ transplants. However, no study on humans has been done in which the reference population was the same as that in which the cancer cases arose and in which there was a sufficiently long period of follow-up. Information on 5,692 Nordic recipients of renal transplants in 1964–1982 was linked with the national cancer registries (1964-1986) and population registries. Person-years at risk were calculated from the date of first transplantation until death or the end of the study period and were multiplied by the appropriate age- and calender-specific incidence rates to obtain the expected numbers of cancers. Standardized incidence ratios (SIR) were calculated after stratification by a number of recorded variables. Altogether, 32,392 person-years were accrued, and 471 cancers occurred, yielding overall SIR of 4.6 (95% CI, 4.0 to 5.2) for males and 4.5 (95% CI, 4.0 to 5.2) for females. Significant overall 2- to 5-fold excess risks in both sexes were seen for cancers of the colon, larynx, lung and bladder, and in men also for cancers of the prostate and testis. Notably high risks, 10-fold to 30-fold above expectation, were associated with cancers of the lip, skin (non-melanoma), kidney and endocrine glands, also with non-Hodgkin's lymphoma, and in women also with cancers of the cervix and vulva-vagina. Among a number of donor and recipient variables studied, including tissue types and compatibility (ABO, HLA, DR), age below 45 years at the time of transplantation was the most important determinant for increased risk at most sites. Kidney transplantation increases the risk of cancer in the short and in the long term, consistent with the theory that an impaired immune system allows carcinogenic factors to act. The tumor risk is small in comparison with the benefits of transplants, but patients should be followed up for signs of cancer. © 1995 Wiley-Liss. Inc.     

Is residence in areas of endemic goiter a risk factor for thyroid cancer?

The association between an indicator of iodine deficiency and differentiated thyroid cancer has been investigated in a population-based case-control study. This included all incident cases (N = 484) of papillary and follicular thyroid cancer diagnosed during the years 1980–1992 in a Swedish Health Care Region among residents born in Sweden, and as many individually matched controls. Cases were included after a uniform review of their histopathological specimens. Residence in areas where goiter had been severely endemic in the 1930s was used as exposure indicator. Odds ratios (OR) and 95% confidence intervals as estimates of relative risk were calculated as a measure of association using logistic regression. A trend toward an association was found with a duration of residence in goiter areas between 21 and 40 years, most prominent among follicular cancer cases and in the group diagnosed at age ? 50 years compared to not exposed. Exposure for the first time during adolescence (between 11 and 20 years) was associated with an increased risk of papillary cancer. This was especially evident among women, both when compared to not exposed and to those exposed during the first year of life; the association was strengthened after adjustment for duration of residence. These findings support the hypothesis of distinct causation patterns from iodine deficiency to the 2 most common histological types of thyroid cancer. © 1995 Wiley-Liss, Inc.     

Cancer incidence among male railway engine-drivers and conductors in Sweden, 1976–90

During recent years, the relationship between exposure to magnetic fields and cancer has attracted increasing interest. In Sweden, train personnel are exposed to comparatively strong magnetic fields in their work. The aim of the present study was to investigate cancer incidence, particularly leukemia and brain tumors, among male railway engine drivers and conductors, respectively, and to compare their cancer incidence with that of the general male population. The study population comprised all male railway engine drivers (n=7,466) and conductors (n=2,272) who were ever employed at the Swedish State Railways during the period 1976–90. The study population was observed with regard to cancer incidence by means of the National Cancer Register for the period 1976–90. The total cancer incidence (all tumors included) among railway engine drivers was lower than in the general Swedish population. An increased incidence of lymphocytic leukemia was observed among railway engine drivers and conductors combined (relative risk = 2.3; 95 percent confidence interval = 1.3–3.2), with the same point estimate for both occupational groups. For brain tumor (astrocytoma), the observed relative risk was close to one. The study provides evidence of an excess risk of lymphocytic leukemia in railway engine drivers and conductors, workers with known occupational exposure to magnetic fields.Drs Alfredsson and Hammar are with the Division of Epidemiology, Institute of Environmental Medicine, Karolinska Instituter, Stockholm, Sweden. Dr Alfredsson is also with the Department of Occupational Health, Karolinska Hospital, Stockholm, Sweden. Dr Karlehagen is with the National Occupational Health Services, Örebro, Sweden. Address correspondence to Dr Alfredsson, Division of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Box 210, S-171 77 Stockholm, Sweden. The study was supported by the Swedish State Railway Company.     

Smoking Is a Risk Factor for Recurrence of Groin Hernia

Studies of connective tissue from patients with inguinal hernia have shown that smoking may be associated with hernia formation due to a defective connective tissue metabolism. Whether smoking is a risk factor for recurrence, too, was examined in this study. From December 1990 through December 1995, 649 patients underwent hernia repair as open sutured repair (Cooper ligament or abdominal ring repair) or as open mesh repair. Five hundred forty-four eligible patients were evaluated for recurrence 2 years postoperatively. Association between recurrence and 17 patient-, disease-, and intraoperative variables were analyzed by multiple logistic regression. The results showed that smoking was significantly and independently associated with recurrence compared to nonsmoking [odds ratio (OR = 2.22; 95% confidence interval (95% CI) = 1.19–4.15)]. Open sutured repair compared to open mesh repair was the most significant predictor for recurrence (OR = 7.23; 95% CI = 3.01–17.37). Surprisingly, local anesthesia was associated with a higher risk of recurrence compared to general anesthesia (OR = 2.44; 95% CI = 1.19–5.09). Potential confounders and other risk factors for hernia recurrence such as age, alcohol consumption, previous surgery, and anatomical characteristics of the hernia were adjusted for in the analysis. In conclusion, smoking is an important risk factor for recurrence of groin hernia, presumably due to an abnormal connective tissue metabolism in smokers.