Silencing miR-21-5p in sensory neurons reverses neuropathic allodynia via activation of TGF-ß-related pathway in macrophages.

Neuropathic pain remains poorly managed by current therapies, highlighting the need to improve our knowledge of chronic pain mechanisms. In neuropathic pain models, dorsal root ganglia (DRG) nociceptive neurons transfer miR-21 packaged in extracellular vesicles to macrophages that promote a proinflammatory phenotype and contribute to allodynia. Here we show that miR-21 conditional deletion in DRG neurons was coupled with lack of upregulation of chemokine CCL2 after nerve injury and reduced accumulation of CCR2-expressing macrophages, which showed TGF-ß-related pathway activation and acquired an M2-like antinociceptive phenotype. Indeed, neuropathic allodynia was attenuated after conditional knockout of miR-21 and restored by TGF-ßR inhibitor (SB431542) administration. Since TGF-ßR2 and TGF-ß1 are known miR-21 targets, we suggest that miR-21 transfer from injured neurons to macrophages maintains a proinflammatory phenotype via suppression of such an antiinflammatory pathway. These data support miR-21 inhibition as a possible approach to maintain polarization of DRG macrophages at an M2-like state and attenuate neuropathic pain.

Cardiovascular prevention in 50-year-old adults: an Italian intervention study.

AIMS: Cardio50 is a project of active risk identification and cardiovascular prevention implemented in an Italian cohort of healthy people aged 50. METHODS: A total of 3127 individuals were invited for a screening visit with lifestyle interview and registration of BMI, blood pressure (BP), glucose, cholesterol and classified into groups: A (normal), B (abnormal lifestyle, normal parameters), C (at least one abnormal parameter). People in group C were offered a free blood test and a specialistic medical visit to investigate the suspect of hypertension, dyslipidemia or dysglycemia. Those in groups B and C were scheduled for a follow-up visit after 4-6 months and finally readdressed to the general practitioner. RESULTS: A total of 2325 invited individuals attended the screening visit: 18% were classified in group A, 32% in B, 42% in C, 8% met exclusion criteria and were not classifiable. In group C, 86% attended to the cardiologist visit, 76% had dyslipidemia, 35% hypertension, 1% diabetes, 14% impaired fasting glycemia, 19% obesity, 21% metabolic syndrome; 21% were smokers, 11% at risk of alcoholism. At follow-up, we appreciated a decrease in BP in group C individuals. After lifestyle intervention, physical activity increased, whereas metabolic syndrome, impaired fasting glucose and risky drinking decreased. CONCLUSION: The current project is coherent with modern strategies based on multifactorial actions. After the intervention, we observed an early reduction in BP and some improvements in lifestyle. This simple and low-technology program allowed us to detect and treat large numbers of individuals at high risk for cardiovascular events.

Available oral lipid-lowering agents could bring most high-risk patients to target: an estimate based on the Dyslipidemia International Study II-Italy.

AIMS: The analysis evaluated the contemporary percentage of patients with established coronary heart disease (CHD) reaching the European guidelines recommended LDL-cholesterol (LDL-C) levels of less than 70 mg/dl and the threshold required for proprotein convertase subtlisin/kexin type 9 reimbursement in Italy (100 mg/dl). It also assessed how these percentages would change in case of diffuse use of ezetimibe. METHODS: The Dyslipidemia International Study II enrolled CHD patients aged at least 18 either on lipid-lowering therapy (LLT) for at least 3 months or not on LLT at the time of the lipid profile. Distribution of LLTs and LDL-C target attainment were assessed. Multivariate logistic regression evaluated predictors of LDL-C target attainment. A 24% LDL-C lowering was modeled in patients not taking ezetimibe to assess its potential effects. RESULTS: Among 676 Italian CHD patients enrolled, LDL-C concentrations were lower among the 631 patients (93.3%) who were on LLT (82 versus 118 mg/dl; P < 0.001). The LDL-C target was attained by 35.4% of patients. Statin dose (median atorvastatin dose 40 mg/day) was the sole significant predictor of LDL-C target attainment. The simple addition of ezetimibe in the model reduced the percentage of patients more than 70 and 100 mg/dl from 64.6 to 37.9% and from 25.1 to 11.8%, respectively. CONCLUSION: Despite treatment in more than 90%, only one-third of Italian stable CHD patients attained the recommended LDL-C target. Statin dose was the sole predictor of the target achievement. The addition of ezetimibe would almost double patients at target and halve the potential candidates for reimbursement of more expensive agents such as proprotein convertase subtlisin/kexin type 9 inhibitors.