Francesca Pezzetta

Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study

HEMORRHAGIC STROKE IN THE STROKE PREVENTION BY AGGRESSIVE REDUCTION IN CHOLESTEROL LEVELS STUDY To the Editor: The investigators of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study1 analyze the increased risk of hemorrhagic stroke in patients with a history of cerebrovascular disease treated with statins. Since statin use is associated with an increased risk of hemorrhagic stroke in patients with a history of cerebrovascular disease, this study is important because it identifies at-risk subgroups of patients.2 The authors emphasize that hemorrhagic stroke as an entry event is associated with hemorrhagic stroke during follow-up. Since patients with hemorrhagic stroke are usually not treated with statins for secondary prevention, this observation is of minor clinical importance. Far more interesting is the increased risk of hemorrhagic stroke in patients with lacunar stroke, caused by cerebral small vessel disease (hazard ratio [HR] 4.99, 95% confidence interval [CI] 1.71 to 14.61), treated with statins. The authors discuss that increased hemorrhagic strokes in small vessel disease might lack validity, because secondary outcomes in isolated subgroups have a high risk of false-positive findings. Although we agree with the authors from a statistical point of view, we believe that future investigations should focus on whether statin treatment might be contraindicated in patients with small vessel disease. Patients with cerebral small vessel disease often have intracerebral microhemorrhages.3 These microhemorrhages may change into macrohemorrhages if patients are treated with statins. Statins exert pleiotropic effects on, for example, the coagulation cascade and fibrinolytic system. It is still unclear from the SPARCL study whether statins in patients with small vessel disease prevent only minor (lacunar) strokes and whether the risk of fatal hemorrhagic stroke is increased in this group of patients. We would ask the SPARCL investigators to present data on benefit vs complications in the subgroup of patients with small vessel disease (lacunar stroke).

EPIDEMIOLOGY OF DISTAL SYMMETRICAL NEUROPATHIES IN THE ITALIAN ELDERLY

Objectives: To estimate prevalence and incidence of distal symmetric neuropathies (DSN) in the Italian elderly, and to evaluate the accuracy of our procedure to screen for DSN. Methods: In eight Italian municipalities, a population-based sample was directly evaluated both at baseline (1992) and after a 3-year follow-up. Cohort members who had died were studied. DSN diagnosis and subtyping were made according to specified diagnostic criteria. Results: Our screening procedure proved accurate (sensitivity 94.7%, specificity 70%, positive predictive value 18.9%), and provided an adjusted prevalence of 7.0 (95% CI, 6.9 to 7.0). Women outnumber men both in the oldest age groups and as a whole. Rates increase with increasing age in both genders. Among the 2,845 individuals re-screened at the follow-up and the 221 deceased subjects with reliable information, we identified 100 incident cases of DSN. Adjusted annual incidence rate (per 1,000 person-years) in the population 65 to 84 years of age is 7.9 (95% CI, 6.3 to 9.5), and for the nondiabetic DSN is 5.76 (95% CI, 4.3 to 7.3). Age significantly predicted the onset of DSN both in diabetic individuals (for every increasing year of age RR = 1.07; 95% CI, 1.01 to 1.14) and in the entire study population (RR = 1.05; 95% CI, 1.02 to 1.09). Conclusions: We provide the first population-based distal symmetric neuropathies incidence data, as well as prevalence rates from an unselected sample of Italian elderly. Distal symmetric neuropathies are an age-associated condition, but the frequency of diabetic distal symmetric neuropathies declines with age, coincident with an increase in nondiabetic cases.Objectives: To estimate prevalence and incidence of distal symmetric neuropathies (DSN) in the Italian elderly, and to evaluate the accuracy of our procedure to screen for DSN. Methods: In eight Italian municipalities, a population-based sample was directly evaluated both at baseline (1992) and after a 3-year follow-up. Cohort members who had died were studied. DSN diagnosis and subtyping were made according to specified diagnostic criteria. Results: Our screening procedure proved accurate (sensitivity 94.7%, specificity 70%, positive predictive value 18.9%), and provided an adjusted prevalence of 7.0 (95% CI, 6.9 to 7.0). Women outnumber men both in the oldest age groups and as a whole. Rates increase with increasing age in both genders. Among the 2,845 individuals re-screened at the follow-up and the 221 deceased subjects with reliable information, we identified 100 incident cases of DSN. Adjusted annual incidence rate (per 1,000 person-years) in the population 65 to 84 years of age is 7.9 (95% CI, 6.3 to 9.5), and for the nondiabetic DSN is 5.76 (95% CI, 4.3 to 7.3). Age significantly predicted the onset of DSN both in diabetic individuals (for every increasing year of age RR = 1.07; 95% CI, 1.01 to 1.14) and in the entire study population (RR = 1.05; 95% CI, 1.02 to 1.09). Conclusions: We provide the first population-based distal symmetric neuropathies incidence data, as well as prevalence rates from an unselected sample of Italian elderly. Distal symmetric neuropathies are an age-associated condition, but the frequency of diabetic distal symmetric neuropathies declines with age, coincident with an increase in nondiabetic cases.

The double-edged sword of statin immunomodulation

Statin drugs are widely prescribed to achieve aggressive low-density lipoprotein lowering in order to decrease cardiovascular disease. Although some of the immunomodulatory effects of statins may stabilize atherosclerotic plaque, they may be harmful in certain segments of the population. Recently, statins have been shown to increase the concentration of regulatory T cells (Tregs), in vivo. There is evidence that this increases the risk of many cancers, particularly in the elderly. Furthermore, a statin induced increase in Tregs may be detrimental in neurodegenerative disorders, such as amyotrophic lateral sclerosis; and a myriad of infectious diseases. These include, but are not limited to, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, and varicella zoster virus. These issues need our attention, and call for a heightened state of vigilance among those prescribing statins.

Physical activity in statin-treated patients

Physical inactivity is increasing in virtually all developed and developing countries and is estimated to cause 2 million deaths worldwide annually. Conversely, regular exercise contributes to the primary and secondary prevention of cardiovascular disease, improves wellness, attenuates age-related decline and reduces risk of premature death. However, it is widely believed that lifestyle interventions are difficult to institute and difficult to maintain and drugs, particularly statins, should be considered as the fundamental tool in the prevention of coronary artery disease. It is therefore a concern that statins may adversely affect the muscles ability to appropriately respond to physical exertion. Statin therapy can induce skeletal muscle damage in treated patients, despite their being asymptomatic and without increment of serum creatine kinase level. In clinical practice, muscle complaints due to statin therapy are easily dismissed by the patient and physician. Such muscle effects are likely related to mitochondrial dysfunction and may well affect 25% of statin users who exercise and thus constitute one of the most common and underappreciated side effects of statins. Physical activity is affordable to all, as opposed to statins, and should be regarded as one of the most cost-effective ways to prevent cardiovascular disease. Physicians should be aware that statins may interfere with patients activity levels.

Explaining sex difference in coronary heart disease: is it time to shift from the oestrogen hypothesis to the iron hypothesis?

We suggest that lower body iron stores, and not the loss of ovarian function, explain the differences between men and women, and between fertile and menopausal women in the development of coronary heart disease.

Iron, type 2 diabetes mellitus, and Alzheimer’s disease

Go¨tz et al. [1] analyzed common clinical and biochemicalfeatures between type 2 diabetes mellitus (T2DM) andAlzheimer’s disease (AD). However, among the suggestedcommon pathogenic mechanisms between these disorders,they did not appear to mention the role of iron.Iron is a strong pro-oxidant which catalyzes severalcellular reactions that yield reactive oxygen species. Thisproperty, while essential for its metabolic functions, makesiron potentially hazardous. Indeed, the amount of free ironavailable at sites of oxidative or inflammatory injuryappears to be a function of the stored iron level.Accumulating evidence suggests that iron plays apathogenic role in T2DM and its complications such asmicroangiopathy and atherosclerosis [2, 3]. In addition tothe induction of oxidative stress, iron may also impedeinsulin extraction in the liver, impair pancreatic insulinsecretion, and interfere with insulin action and glucoseuptake in adipocytes. Of note, a reduction in iron overloadwith either phlebotomy or iron chelation therapy hasbeen shown to reverse or improve glycemic control inT2DM [2].On the other hand, it is well known that neurons are notonly vulnerable to impaired iron metabolism as a result of areduced iron supply, but also that abnormal high cellulariron levels may lead to disordered neuronal function. Inparticular, an important pathological finding of AD is theiron accumulation that occurs in the same brain regionscharacterized by amyloid

Monoclonal antibody therapy and non-Hodgkin's lymphoma.

n engl j med 360;2 nejm.org january 8, 2009 192 ous-monitoring group were less likely to use the continuous-glucose-monitoring device regularly, but those who did had a reduction in the glycated hemoglobin level that was of similar magnitude to the reduction seen in the adults (among subjects in the continuous-monitoring group, who averaged 6.0 or more days per week of continuous-glucose-monitor use over the 26-week period of the study, the mean decrease in the glycated hemoglobin level from baseline to 26 weeks was 0.5% in subjects ≥25 years old, 0.5% in those 15 to 24 years old, and 0.7% in those 8 to 14 years old). In response to Finlayson et al.: the hypoglycemia event rate (≥20 minutes with a glucose level of <54 mg per deciliter), with combined data for the week after the 13-week visit and the week after the 26-week visit, was 0.25 event per 24 hours in the continuous-monitoring group and 0.33 event per 24 hours in the control group (P = 0.03). Treatment-group differences in event rates ranged from 0.08 to 0.10 in the three age groups. These data provide further support for the ability of continuous glucose monitoring to reduce glycated hemoglobin levels in adults without increasing hypoglycemia.

Reduced body iron stores and atherosclerosis in patients with cyanotic congenital heart disease

Cyanotic patients with congenital heart disease have been shown to be protected against atherosclerosis [1,2]. The mechanisms underlying this association are not fully elucidated. We suggest that the erythropoietic adaptations with consequent changes in iron metabolism that occur when cyanotic patients are exposed to hypoxia may have an important role in reducing the development of atherosclerosis. The adaptive response to hypoxia is primarily mediated by the transcription factor hypoxia-inducible factor-1 (HIF-1) due to upregulation of an array of genes required for the adaptive response to low oxygen levels [3]. Indeed, it was found that the expression of HIF-1α (an oxygen-sensitive subunit of HIF-1) and global HIF-1 activity were elevated in the myocardium of infants with cyanotic congenital heart disease compared to those with acyanotic congenital heart disease, and that this response directly correlated with the degree of hypoxemia [4]. Iron plays a central role in the protection from hypoxemia, as it is incorporated in the newly synthesized haemoglobin throughout erythropoiesis. In this setting, it has been shown that

Aspirin-associated iron loss as an anticancer mechanism

A consensus view has emerged favoring an anticancer effect of long-term aspirin use. Aspirin-induced loss of stored iron from chronic gastrointestinal bleeding is proposed as a mechanism underlying this beneficial effect. In iron depletion, less iron may be available for carcinogenesis through free-radical mediated mechanisms and for promotion of tumor growth. Low-dose aspirin increases gastrointestinal losses of transfused radiolabeled autologous red cells. Observational studies report lower serum ferritin values with regular aspirin use. A protective effect of induced iron reduction against cancer mortality has been confirmed in a recent trial (FeAST) with subjects randomized to iron reduction or observation. Serum ferritin reductions in the FeAST trial were within conventionally normal reference ranges and were quantitatively similar to ferritin reductions in observational studies in regular aspirin users. Delayed anticancer effects of aspirin are compatible with the proposed mechanism, as continual microbleeding has a gradual cumulative effect on stored iron.

Angiotensin-receptor blockade, cancer, and concerns

www.thelancet.com/oncology Vol 11 September 2010 817 immunodysregulatory eff ects of chronic stress. As a result of evidence from epidemiological and laboratory studies, the International Agency for Research on Cancer has determined that circadian rhythm disruption is probably carcinogenic to humans (group 2A). Ondicova and Mravec also discuss input signals from tumours that aff ect the CNS through the paraventricular hypothalamic nucleus. The paraventricular hypothalamic nucleus is anatomically and physiologically linked to the suprachiasmatic nucleus, and both nuclei are sensitive to blood-borne signals from peripheral organs. Tumour-associated pro-infl ammatory cytokines are important signalling molecules involved in major cancer-related symptoms such as depression and the disruption of sleep and circadian rhythms. Sleep disruption in women with metastatic breast cancer is associated with reduced parasympathetic tone as measured by respiratory sinus arrhythmia, thus providing a connection between Ondicova and Mravec’s observation of oncological eff ects of autonomic nervous system activity and circadian rhythm disruption. In summary, we believe that the circadian rhythms of brain-body interactions are a major aspect of CNS–tumour crosstalk. Understanding of the benefi cial healthpromoting role of regulated circadian rhythms and the harmful eff ects of circadian dysregulation could improve cancer-prevention strategies and the pharmacological and behavioural treatment of cancer, and provide novel biological and behavioural targets for intervention.