Hyperinsulinaemia as long-term predictor of death and ischaemic heart disease in nondiabetic men: The Malmö Preventive Project

Abstract. Nilsson P, Nilsson J‐Å, Hedblad B, Eriksson K‐F, Berglund G. (University Hospital, Malmö, Sweden) Hyperinsulinaemia as long‐term predictor of death and ischaemic heart disease in nondiabetic men: The Malmö Preventive Project. J Intern Med 2003; 253: 136–145. Objectives. Prospective studies have indicated that hyperinsulinaemia/insulin resistance is a risk factor for ischaemic heart disease (IHD), the risk decreasing with time of follow‐up. Few studies have so far investigated the role of hyperinsulinaemia in the prediction of long‐term total mortality. Setting. Section of Preventive Medicine, Department of Medicine, University Hospital, Malmö, Sweden. Subjects. A total of 6074 nondiabetic, middle‐aged, healthy Swedish males. Screening examination. We determined IHD risk factors including blood glucose and plasma insulin before and 2 h after an oral glucose tolerance test (OGTT). Total follow‐up time was 19 years. Hyperinsulinaemia was defined as values above the 10th decentile of fasting or 2 h insulin concentration. Main outcome measures. Total mortality and cardiac event (CE) rate for IHD. Results. Unadjusted relative risks (RRs) for both death and CE were J‐shaped with the highest relative risk (RR: 1.4–1.6) in the hyperinsulinaemic group compared with all other men. The RRs for death and CE were significant for fasting insulin but became nonsignificant after adjustment for other risk factors and also with a longer follow‐up. The risk of death in hyperinsulinaemic men, defined on the basis of 2‐h insulin level, increased with time of follow‐up and was still significantly increased after 19 years [RR: 1.32 (95% CI: 1.05–1.65], even after adjustment for other risk factors. Conclusions. Fasting hyperinsulinaemia was a predictor of total mortality and IHD in nondiabetic men, although not more significantly after adjustment for other risk factors and with lengthening of follow‐up time. The 2‐h postglucose hyperinsulinaemia appeared to be a stronger and independent predictor of mortality over long‐term follow‐up. These findings support the view that insulin resistance with associated cluster of risk factors predicts increased long‐term risk of mortality and IHD.     

Family burden of cardiovascular mortality: risk implications for offspring in a national register linkage study based upon the Malmö Preventive Project

Objective. To investigate the adjusted relative risk of cardiovascular disease (CVD) events in offspring of parents with cardiovascular mortality before 75 years. Setting. The city of Malmö, Sweden. Design. A follow‐up study based on register linkage analyses. Subjects and methods. In the Malmö Preventive Project (MPP), a total of 22 444 men and 10 902 women attended the screening programme between 1974 and 1992. At the screening conventional risk factors for CVD were measured (blood pressure, lipids, glucose, smoking and social class). Main outcome measures. Parental CVD mortality was determined via register linkage analysis between the Multiple‐Generation Register and the National Mortality Register (NMR). CVD events (morbidity and mortality) in offspring were collected from national registers. The relative risk for CVD events in offspring, in relation to parental CVD mortality, was adjusted for age and risk factors at screening. Results. The age‐adjusted relative risk (RR; 95%CI) for a son to experience a CVD event was increased in relation to a maternal positive family history of CVD mortality before 75 years when compared with no maternal history, RR 1.74 (1.43–2.11). This RR decreased to 1.51 (1.23–1.84; P < 0.001) after full adjustment for risk factors. The corresponding fully adjusted RRs for father–son heritage was RR 1.22 (1.02–1.47; P < 0.05), mother–daughter RR 0.87 (0.54–1.41), and father–daughter RR 1.20 (0.83–1.73). Conclusion. The existence of maternal CVD mortality before the age of 75 years implies a substantial risk increase for CVD morbidity and mortality in sons that cannot be explained by social background, lifestyle, or conventional cardiovascular risk factors in the adult offspring.     

The enigma of increased non-cancer mortality after weight loss in healthy men who are overweight or obese

Abstract. Nilsson PM, Nilsson J‐A, Hedblad B, Berglund G, Lindgärde F. (University Hospital, Malmö, Sweden). The enigma of increased non‐cancer mortality after weight loss in healthy men who are overweight or obese. J Intern Med 2002; 252: 70?78. Objective. To study effects on non‐cancer mortality of observational weight loss in middle‐aged men stratified for body mass index (BMI), taking a wide range of possible confounders into account. Design. Prospective, population based study. Setting. Male population of Malmö, Sweden. Participants. In all 5722 men were screened twice with a mean time interval of 6 years in Malmö, southern Sweden. They were classified according to BMI category at baseline (<21, 22?25, overweight: 26?30, and obesity: 30+ kg m^?2) and weight change category until second screening (weight stable men defined as having a baseline BMI ± 0.1 kg m^?2 year^?1 at follow‐up re‐screening). Main outcome measures. Non‐cancer mortality calculated from national registers during 16 years of follow‐up after the second screening. Data from the first year of follow‐up were excluded to avoid bias by mortality caused by subclinical disease at re‐screening. Results. The relative risk (RR; 95% CI) for non‐cancer mortality during follow‐up was higher in men with decreasing BMI in all subgroups: RR 2.64 (1.46?4.71, baseline BMI <21 kg m^?2), 1.39 (0.98?1.95, baseline BMI 22?25 kg m^?2), and 1.71 (1.18?2.47, baseline BMI 26+ kg m^?2), using BMI‐stable men as reference group. Correspondingly, the non‐cancer mortality was also higher in men with increasing BMI, but only in the obese group (baseline BMI 26+ kg m^?2) with RR 1.86 (1.31?2.65). In a subanalysis, nonsmoking obese (30+ kg m^?2) men with decreased BMI had an increased non‐cancer mortality compared with BMI‐stable obese men (Fischer's test: P=0.001). The mortality risk for nonsmoking overweight men who increased their BMI compared with BMI‐stable men was also significant (P=0.006), but not in corresponding obese men (P=0.094). Conclusions. Weight loss in self‐reported healthy but overweight middle‐aged men, without serious disease, is associated with an increased non‐cancer mortality, which seems even more pronounced in obese, nonsmoking men, as compared with corresponding but weight‐stable men. The explanation for these observational findings is still enigmatic but could hypothetically be because of premature ageing effects causing so‐called weight loss of involution.     

New approaches in the immunotherapy of haematological malignancies

Advances in the management of haematological malignancies have allowed to obtain improved remission rates. Nonetheless, relapses impair these results and justify the search for novel therapeutic strategies. Clinical data demonstrate that the immune system plays an important role in the control of haematological malignancies. An increased frequency of haematological malignancies is observed in immunodeficiency states. Reversal of the immunosuppression is sometimes sufficient to induce tumour regression (withdrawal of cyclosporine in post-transplant lymphoproliferations, highly active anti-retroviral treatment in human immunodeficiency virus related Kaposi's disease). Another line of evidence for the involvement of the immune system in the anti-tumour response comes from the observation of spontaneous anti-tumour responses that parallel the occurrence of paraneoplastic immune-mediated syndromes. Finally, the efficiency of allogeneic transplantation in the haematological field has been clearly demonstrated to depend on the immune-mediated graft vs. leukaemia effect. Nonetheless, tumours develop in immune competent patients because of various tumour escape mechanisms, such as loss of human leucocyte antigen class I antigens, absence of target recognition by deficient adhesion/co-stimulatory molecule expression, tumour cell counterattack against immune effectors, direct (contact-dependent) or indirect (cytokine-mediated) impairment of T-lymphocyte activation. Novel immunotherapy approaches are now orientated in a convergent direction, i.e. the reversal of immune escape mechanisms either via the correction of deficient phases of the immune response or by the amplification of physiological mechanisms.     

Prognostic value of proliferative responses to HIV-1 antigen in chronically HIV-infected patients under antiretroviral therapy.

BACKGROUND: In the chronic stage of HIV infection T cell proliferative responses to HIV antigens are rare, mostly of low level, and the influence of responses on antiretroviral therapy is not known. OBJECTIVES: To determine a potential correlation between HIV-specific proliferative responses and the subsequent course of infection under antiretroviral therapy. STUDY DESIGN: Proliferation assays were performed with freshly isolated blood mononuclear cells from 45 chronically HIV-infected HAART treated individuals using HIV-p24, other recall antigens, and mitogens as stimulants. Virus load was monitored at the time of stimulation and during 33 months follow-up. RESULTS: A proliferative response to HIV antigen stimulation was detectable in 7 of 45 patients (15.5% responders). This group showed elevated reactions against tetanus toxoid and tuberculin, whereas reactions against standard mitogens were equal in the HIV responder and nonresponder groups. None of the seven HIV-specific responders had a blood virus load rebound of more than 1000 genome copies/ml during follow-up, whereas in 50% of the non-responders higher virus rebounds occurred. CD4 cell levels were slightly higher in the responder group, but mostly independent of virus rebound within the non-responders. Only four patients with high and continuous virus rebound experienced a significant CD4 cell decline. CONCLUSIONS: In patients under HAART, HIV-specific proliferative response is frequently related to anamnestic antigen responses and an enduring control of virus replication.     

The effects of acetylsalicylic acid on proliferation,apoptosis, and invasion of cyclooxygenase-2 negative colon cancer cells

BACKGROUND: Acetylsalicylic acid (ASA, aspirin), the most common nonsteroidal anti-inflammatory drug (NSAID), has been shown to have a protective effect against the incidence and mortality of colorectal cancer. However, the mechanism of its anticancer function remains unclear. The aim of this study was to determine the effects of acetylsalicylic acid on proliferation, apoptosis, and invasion in human cyclooxygenase-2 (COX-2) negative colorectal cancer cell lines. MATERIALS AND METHODS: After treatment with various concentrations of ASA, cell proliferation was measured in the human colon cancer cell line SW480. Apoptotic cells were identified by transmission electron microscopy, acridine orange staining, and flow cytometry. The invasive potential of SW480 cells was detected using an in vitro invasion assay. The production of carcinoembryonic antigen was measured by microparticle enzyme immunoassay. Expression of Bcl2, Bax, CD44v6, and nm23 were evaluated by immunocytochemistry. RESULTS: ASA significantly inhibited the proliferation of SW480 cells and stimulated apoptosis. Production of carcinoembryonic antigen and the invasive potential of SW480 cells were also inhibited by ASA. After treatment with ASA, down-regulation of Bcl2 and CD44v6 expression and up-regulation of nm23 expression were observed in SW480 cells. No obvious effect of ASA was found on Bax expression. CONCLUSION: Our findings reveal that ASA inhibits the proliferation and promotes apoptosis in the human colon cancer cell line SW480. Down-regulation of Bcl2 expression might represent a potential mechanism by which ASA induces apoptosis in this COX-2 negative colon cancer cell line. Our results also suggest that ASA decreases the invasive potential of these colon cancer cells. Decreased CEA content and CD44v6 expression and elevated nm23 expression may contribute to the effect of ASA on invasive potential of SW480 colon cancer cells.     

Influence of oestrogen receptor alpha and beta on the immune system in aged female mice

Oestrogen has a dichotomous effect on the immune system. T and B lymphopoiesis in thymus and bone marrow is suppressed, whereas antibody production is stimulated by oestrogen. In this study the importance of the oestrogen receptors (ER) ER-alpha and ER-beta in the aged immune system was investigated in 18 months old-wild type (WT), ER-alpha (ERKO), ER-beta (BERKO) and double ER-alpha and ER-beta (DERKO) knock-out mice, and compared with 4 months old WT mice. Cell phenotypes in bone marrow, spleen and thymus, and the frequency of immunoglobulin (Ig) spot forming cells (SFC) were determined. We show here that the 17-beta-oestradiol (E2)-induced downregulation of B lymphopoietic cells in bone marrow of young ovariectomized mice can be mediated through both ER-alpha and ER-beta. However, only ER-alpha is required for the age-related increased frequency of immunoglobulin M (IgM) SFC in the bone marrow, as well as for the increased production of interleukin-10 (IL-10) from cultured splenocytes in aged mice. Furthermore, increased age in WT mice resulted in lower levels of both pro- and pre-B cells but increased frequency of IgM SFC in the bone marrow, as well as increased frequency of both IgM and IgA SFC in the spleen. Results from this study provide valuable information regarding the specific functions of ER-alpha and ER-beta in the aged immune system.