Effects of Simvastatin on Proinflammatory Cytokines and Matrix Metalloproteinases in Hypercholesterolemic Individuals

Statins are potent lipid-lowering drugs but anti-inflammatory effects have also been suggested. Our aim was to investigate the effects of simvastatin on proinflammatory cytokines and matrix metalloproteinases (MMPs). Eighty hypercholesterolemic men were randomized to simvastatin 40 mg or placebo for 6 weeks. Simvastatin treatment significantly reduced C-reactive protein (CRP) levels while interleukin (IL)-6 levels remained unchanged. The ex vivo release of IL-1β and IL-6 was not altered by simvastatin, whereas the release of TNF-α and IL-8 increased after 6 weeks of simvastatin treatment. Similarly, the circulating levels of MMP-3 and TIMP-1 remained unaffected by simvastatin while MMP-9 increased. However, none of the effects except for the CRP reduction within the simvastatin group reached statistical significance when compared to the placebo group. Our findings are in contrast to previous in vitro and animal data and question the in vivo relevance of some of the pleiotropic effects of simvastatin.     

Evaluation of acute antiapoptotic effects of Li<Superscript>+</Superscript> in neuronal cell cultures

Summary Li⁺ exerts protective effect against several neurotoxins in neuronal cell preparations. Here we examined the antiapoptotic effects of GSK3β in cerebellar granule neurons (CGNs) in the presence of several neurotoxins. Acute treatment with Li⁺ protected neurons against nocodazole and serum/potassium (S/K) deprivation, but were ineffective against kainic acid and MPP⁺. Li⁺ 5 mM also decreased caspase-3 activation induced by nocodazole and S/K deprivation as measured by Ac-DEVD-p-nitroaniline and the breakdown of α-spectrin. All the neurotoxins used in the present study activated GSK3β, evaluated with a specific antibody phospho-GSK-3β (Ser9) by Western-blot and immunocytochemistry and were always inhibited by Li⁺ 5 mM. Our results implicate Li⁺ in the regulation of apoptosis mediated by caspase activation (Type I). Furthermore inhibition of GSK3β by acute treatment with Li⁺ 5 mM is not an indicator of neuroprotection. The acute antiapoptotic function of Li⁺ is discussed in terms of its inhibition of Type I pathway, the intrinsic (mitochondrial) apoptotic pathway in cerebellar granule cells.     

Antiapoptotic drugs: a therapautic strategy for the prevention of neurodegenerative diseases

The purpose of this review is to discuss potential pathways involved in the pathogenesis of neurodegenerative diseases, highlighting current pharmacological drug targets in neuronal apoptosis prevention. The incidence of these disorders is expected to rise in the coming years and so finding effective treatments represents a significant challenge for medicine. Alzheimer's disease and Parkinson's disease were both described almost a century ago and are the most important neurodegenerative disorders in the developed world. However, the molecular mechanisms that lead to the development of the neuronal pathology in both diseases are unclear. For this reason, despite substantial research in the area, an effective treatment for these diseases does not yet exist. In the present study we discuss in depth the pathways involved in apoptosis and neuronal death in neurodegenerative diseases. We also examine drugs that may have a neuroprotective effect. Inhibition of apoptosis mediated by oxidative stress generation and mitochondrial alteration or by the blockade of NMDA receptors could constitute a suitable therapeutic strategy for Alzheimer's disease. A multiple therapy with antioxidants, cell cycle inhibitors, GSK3β inhibitors, and STATINS could, in the future, represent a suitable strategy for delaying the progression of neurodegenerative diseases. This research contributes to the development of new methods in the field of apoptosis inhibitors that could provide the future tools for the treatment of Alzheimer's and Parkinson's disease, as well as other neurodegenerative diseases.     

Risks of nontraumatic lower-extremity amputations in patients with type 1 diabetes: a population-based cohort study in Sweden

OBJECTIVE—The purpose of this study was to estimate the risks of nontraumatic lower-extremity amputations (LEAs) in patients with type 1 diabetes.RESEARCH DESIGN AND METHODS—We identified 31,354 patients with type 1 diabetes (15,001 women and 16,353 men) in the Swedish Inpatient Register between 1975 and 2004. The incidence of nontraumatic LEAs was followed up until 31 December 2004 by cross-linkage in the Inpatient Register and linkage to the Death and Migration registers. Poisson regression modeling was used to compare the risks of nontraumatic LEAs during different calendar periods of follow-up, with adjustment for both sex and attained age at follow-up. Standardized incidence ratios (SIRs) were used to estimate the relative risks (RRs) with the age-, sex-, and calendar period–matched general Swedish population as reference. The cumulative probability of nontraumatic LEAs was calculated by the Kaplan-Meier method.RESULTS—In total, 465 patients with type 1 diabetes underwent nontraumatic LEAs. The risk was lower during the most recent calendar period (2000–2004) than during the period before 2000 (RR 0.6 [95% CI 0.5–0.8]). However, even in this most recent period, the risk for nontraumatic LEAs among these relatively young patients was 86-fold higher than that in the matched general population (SIR 85.8 [72.9–100.3]). By age 65 years, the cumulative probability of having a nontraumatic LEA was 11.0% for women with type 1 diabetes and 20.7% for men with type 1 diabetes.CONCLUSIONS—Although the risks appeared to have declined in recent years, patients with type 1 diabetes still have a very high risk for nontraumatic LEAs.Ulceration of the foot is the most common first indicator of impending nontraumatic lower-extremity amputations (LEAs) related to diabetes, and it has been estimated worldwide that one lower limb is amputated every 30 s as a consequence of this condition. Of all nontraumatic LEAs, 50–70% are associated with diabetes (1). Diabetic foot ulceration involves a complex underlying pathophysiology and a multifactorial approach to care, including preventive foot care, aggressive management of acute foot ulceration, control of infections, and early recognition of vascular disease, which are all of major importance in this context (2,3). In addition to reducing quality of life and enhancing morbidity, disability, and premature mortality (4,5), diabetic foot complications are a considerable financial burden on society and individual patients (6), accounting for ∼20% of the total expenditure on health care for patients with diabetes (1).The incidence of nontraumatic LEAs as a consequence of diabetes is considered to be a key indicator of the quality of foot care for such patients (7). In 1989, the World Health Organization and International Diabetes Federation initiated a joint program called the Saint Vincent Declaration for improving the care of patients with diabetes (8). The goals set forth included a >50% reduction in major nontraumatic LEAs caused by diabetes. It is unclear whether this goal has been attained in the case of type 1 diabetes, as most relevant epidemiological studies reported have been concerned with patients with type 2 diabetes or a mixture of type 1 and type 2 diabetic patients (9–11). Therefore, the aim of this register-based study involving a large cohort was to obtain an estimate of the risk of nontraumatic LEAs in patients with type 1 diabetes.     

Active cytomegalovirus replication in patients with coronary disease

OBJECTIVES: To study the prevalence of active cytomegalovirus (CMV) infection in patients with stable and unstable conditions of coronary artery disease (CAD). DESIGN: Forty patients with acute coronary syndrome (ACS), 50 patients with stable angina and angiographically verified CAD (SA) and 50 clinically healthy controls were included. Monocytes were isolated from peripheral blood and CMV-RNA expression was determined by a nested RT-PCR assay. CMV IgM and IgG antibodies, interleukin-(IL)-6, IL-10 and CRP were measured in serum. RESULTS: The prevalence of active CMV infection was significantly higher in patients with ACS (15%) and in patients with SA (10%) compared with controls (2%) (p<0.001). The presence of an active CMV infection was associated with increased serum concentrations of IL-6. CONCLUSIONS: Active CMV infection was found to a larger extent in CAD patients than in healthy controls. The data indicate that CAD patients are more susceptible to reactivation of CMV and put new focus on the role of CMV in atherosclerosis.     

Increased plasma concentration of matrix metalloproteinase-7 in patients with coronary artery disease

BACKGROUND: Plaque rupture is often associated with breakdown of the extracellular matrix in the shoulder region of a plaque. We tested whether plasma concentrations of various matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase-1 (TIMP-1) could serve as markers for plaque instability as well as relationships between plasma MMPs and inflammatory markers. METHODS: The study group included 65 men with angiographically verified CAD (45 with stable and 20 with unstable CAD) and 28 healthy controls. Circulating MMP, TIMP-1, C-reactive protein, and cytokine concentrations were measured by ELISA. Leukocyte subtype counts in whole blood were determined, and T-cell subsets and natural killer cells were measured by flow cytometry. Differences in continuous variables between groups were tested by ANOVA with the Scheffé F-test used as a post hoc test, and correlations were analyzed by a linear regression method. RESULTS: The plasma concentration of MMP-7 was increased in patients with stable and unstable CAD, whereas MMP-2 and -3 concentrations were decreased. The plasma concentration of TIMP-1 was significantly increased in patients with unstable CAD. MMP-2, -3, and -7 showed no correlations with established markers of inflammation. However, MMP-2 correlated positively with the number of natural killer cells in patients with stable and unstable CAD. CONCLUSION: Plasma concentrations of MMPs and TIMPs may be markers of CAD but appear to be differentially regulated.