Mineralocorticoid-stimulating activity of adipose tissue

Obesity is strongly associated with arterial hypertension. A positive correlation between obesity and plasma aldosterone levels has been observed by different investigators, suggesting that an abnormal secretion of aldosterone in obesity contributes to the development of arterial hypertension in obese subjects. The mechanisms proposed to explain this abnormal aldosterone production mainly involve the adipose renin-angiotensin system, an indirect effect of increased fatty acids, and direct adrenal stimulation by adipocyte secretory products. Indeed, adipose mineralocorticoid-stimulating activity was recently observed in isolated human adipocytes, suggesting a hitherto unknown direct involvement of adipose tissue in the regulation of blood pressure in obesity.     

Carotid artery stenting in the presence of contralateral carotid occlusion: mind the hyperperfusion syndrome!

Stroke is the third cause of death in western countries and its complications lead to significant socio-economic problems related to the prolonged hospitalization and rehabilitation of patients with neurological lesions. Severe atherosclerotic lesions of the carotid artery are the main cause of stroke and transient ischemic attacks. Their incidence may reach 5-7% per year in patients with carotid artery stenosis > 70% with or without symptoms. Time-honored carotid endarterectomy is still regarded as the gold standard therapy for primary and secondary prevention of stroke. However, surgery is not free of complications and the rate of perioperative stroke ranges from 5.1 to 14.3%. A group of patients at a particularly high risk of stroke during surgical endarterectomy is represented by patients with significant carotid stenosis in the presence of an occluded contralateral artery. Indeed, carotid cross-clamping during operative surgery in the absence of an adequate collateral flow may result in a critical flow reduction during the operation and therefore increases the risk of periprocedural strokes. In the North American Symptomatic Carotid Endarterectomy (NASCET) trial, the overall risk of stroke was 5.1%, whereas it increased up to 14.3% in patients with an occluded contralateral carotid artery. Recently, carotid stenting has been increasingly used as an endovascular technique for carotid revascularization, especially after the introduction of neuroprotection devices which improved the safety of the procedure. Therefore, it may be an attractive alternative to carotid endarterectomy, especially when the surgical risk is too high. We describe the immediate and late outcomes of 3 patients treated with carotid artery stenting in the presence of contralateral carotid occlusion.     

Proteinase-activated receptor-2: physiological and pathophysiological roles

Protease-activated receptor 2 (PAR2) is the second member of a new subfamily of G-protein coupled receptors: the protease-activated receptors (PARs). At present, four different PARs have been cloned and all of them share the same basic mechanism of activation. A serine protease cleaves the extended, extracellular N-terminus of the receptor at a specific site within the protein chain to expose an N-terminal tethered ligand domain, which binds to and activates the cleaved receptor. In this manner, trypsin and mast cell beta-tryptase activate PAR2. PARs are single use receptors because proteolytic activation is irreversible and the cleaved receptors are degraded in lysosomes. Thus, PARs play important roles in emergency situations, such as trauma and inflammation. Emerging evidence indicates that PAR2 is involved in the cardiovascular, pulmonary and gastrointestinal systems, where it controls inflammation and nociception. Work with selective agonists and knockout animals suggests a contribution of PAR2 to certain inflammatory diseases. Therefore, selective antagonists or agonists of these receptors may be useful therapeutic agents for the treatment of human diseases.     

Substantia nigra in Parkinson’s disease: a multimodal MRI comparison between early and advanced stages of the disease

This study focused on the substantia nigra (SN) in Parkinson’s disease (PD). We measured its area and volume, mean diffusivity (MD), fractional anisotropy (FA) and iron concentration in early and late PD and correlated the values with clinical scores. Twenty-two early PD (EPD), 20 late PD (LPD) and 20 healthy subjects (age 64.7 ± 4.9, 60.5 ± 6.1, and 61 ± 7.2 years, respectively) underwent 1.5 T MR imaging with double-TI-IR T1-weighted, T2*-weighted and diffusion tensor imaging scans. Relative SN area, MD, FA and R2* were measured in ROIs traced on SN. Correlation with Unified Parkinson Disease Rating Scale (UPDRS) scores was assessed. In LPD, the SN area was significantly reduced with respect to EPD (p = 0.04) and control subjects (p < 0.001). In EPD, the SN area was also significantly smaller than in controls (p = 0.006). Similarly, the SN volume significantly differed between LPD and controls (p = 0.001) and between EPD and LPD (p = 0.049), while no significant differences were found between controls and EPD. Both SN area (r = 0.47, p = 0.004) and volume (r = 0.46, p = 0.005) correlated with UPDRS scores. At 1.5 T, SN morphological measurements were sensitive to early PD changes and able to track the disease progression, while MD and FA measures and relaxometry did not provide significant results.     

Extended experience with a non-cytotoxic DNMT1-targeting regimen of decitabine to treat myeloid malignancies

The nucleoside analogue decitabine can deplete the epigenetic regulator DNA methyltransferase 1 (DNMT1), an effect that occurs, and is saturated at, low concentrations/doses. A reason to pursue this molecular-targeted effect instead of the DNA damage/cytotoxicity produced with high concentrations/doses, is that non-cytotoxic DNMT1-depletion can cytoreduce even p53-null myeloid malignancies while sparing normal haematopoiesis. We thus identified minimum doses of decitabine (0·1–0·2 mg/kg) that deplete DNMT1 without off-target anti-metabolite effects/cytotoxicity, and then administered these well-tolerated doses frequently 1–2X/week to increase S-phase dependent DNMT1-depletion, and used a Myeloid Malignancy Registry to evaluate long-term outcomes in 69 patients treated this way. Consistent with the scientific rationale, treatment was well-tolerated and durable responses were produced (~40%) in genetically heterogeneous disease and the very elderly.     

Large granular lymphocytic leukaemia after solid organ and haematopoietic stem cell transplantation

T-cell large granular lymphocytic leukaemia (T-LGLL) is a chronic clonal lymphoproliferative disorder of cytotoxic T lymphocytes which commonly occurs in older patients and is often associated with autoimmune diseases. Among 246 patients with T-LGLL seen at our institution over the last 10 years, we encountered 15 cases following solid organ or haematopoietic stem cell transplantation. Here, we studied the clinical characterization of these cases and compared them to de novo T-LGLL. This experience represented a clear picture of the intricate nature of the disease manifestation and the complexities of several immune mechanisms triggering the clonal expansion.