Exaggerated local hand sympathetic but not renin-angiotensin system activation in patients with primary Raynaud's phenomenon

In Raynaud's disease (RD), an overactivity of sympathetic nervous system (SNS) was hypothesized but only indirect proofs were obtained. Complex interactions between the renin-angiotensin system (RAS) and SNS were reported without clear demonstrations of a RAS involvement. Recently, the use of ACE inhibitors and AT1 receptor antagonists in RD patients showed mixed results. The study of total and regional kinetics of tritiated noradrenaline (NA) and the measurements of local Angiotensin (Ang) I and II arterial-venous gradient were performed in 10 RD patients and 10 controls both in rest conditions and following a cold pressor test (CPT). Hand blood flow (HBF) was measured by strain-gauge plethysmography. Baseline HBF was slightly lower in patients than in controls, but during CPT, it significantly decreased only in RD patients (P < 0.01). Total (3H)-NA clearance and spillover were similar in the two groups throughout the study. On the contrary, baseline hand NA spillover was higher in RD patients than in controls and the difference further increased during CPT. Hand NA spillover was linearly related to HBF (P < 0.001). Arterial-venous Ang I and Ang II gradients were positive without difference between controls and patients throughout the study. In conclusion in RD patients, a pathological waste of NA from sympathetic nervous endings of the hand region, exaggerated by sympathetic stimulation, occurs but an enhanced local Ang II formation was not demonstrable.     

Cholesterol crystal embolism syndrome in dialysis patients: an emerging clinical diagnosis?

BACKGROUND: Cholesterol crystal embolism syndrome (CCE) is an increasing end-stage renal disease cause. Few cases have been described on dialysis, despite the high prevalence of the predisposing factors. METHODS: The diagnostic criteria of the present study were: skin lesions, myalgia, fatigue, fever and acute inflammatory serologic signs, in the presence of severe vasculopathy. The precipitating factors were: anticoagulation, endovascular intervention and ulcerated atherosclerotic plaque. RESULTS: Between October 2003 and September 2005, CCE was diagnosed in 6 dialysis patients (of 200-210 on chronic treatment): 5 males, 1 female, median age 59.5 years (47-70) and end-stage renal disease follow-up 11.5 years (3-25). All had severe vasculopathy, 5 cardiopathy, and 4 were failed graft recipients. The treatment included: peritoneal dialysis, daily dialysis, 'conventional' hemodialysis (2 cases) and hemodiafiltration. The diagnosis was based on the clinical-laboratory picture in 1 patient. In the 5 others clues were present (dicumarol therapy, angioplasty, femoral artery thrombosis, CCE predialysis and ulcerated aortic plaque). The therapeutic approach consisted of corticosteroids (5 cases), statins (4 cases) and prostaglandin analogues (4 cases). CONCLUSION: The differential diagnosis of CCE should also be considered in dialysis patients (necrotic lesions, limb pain and vasculitis-like signs).     

Mechanism of platelet adhesion to von Willebrand factor and microparticle formation under high shear stress

We describe here the mechanism of platelet adhesion to immobilized von Willebrand factor (VWF) and subsequent formation of platelet-derived microparticles mediated by glycoprotein Ibalpha (GPIbalpha) under high shear stress. As visualized in whole blood perfused in a flow chamber, platelet attachment to VWF involved one or few membrane areas of 0.05 to 0.1 microm(2) that formed discrete adhesion points (DAPs) capable of resisting force in excess of 160 pN. Under the influence of hydrodynamic drag, membrane tethers developed between the moving platelet body and DAPs firmly adherent to immobilized VWF. Continued stretching eventually caused the separation of many such tethers, leaving on the surface tube-shaped or spherical microparticles with a diameter as low as 50 to 100 nm. Adhesion receptors (GPIbalpha, alphaIIbbeta3) and phosphatidylserine were expressed on the surface of these microparticles, which were procoagulant. Shearing platelet-rich plasma at the rate of 10,000 s(-1) in a cone-and-plate viscosimeter increased microparticle counts up to 55-fold above baseline. Blocking the GPIb-VWF interaction abolished microparticle generation in both experimental conditions. Thus, a biomechanical process mediated by GPIbalpha-VWF bonds in rapidly flowing blood may not only initiate platelet arrest onto reactive vascular surfaces but also generate procoagulant microparticles that further enhance thrombus formation.     

Dyspnea and asthma

PURPOSE OF REVIEW: Dyspnea--the perception of respiratory discomfort--is a primary symptom of asthma. This review examines possible ways to link mechanisms, measurement and treatment that will increase our understanding of this condition. RECENT FINDINGS: Functional neuroimaging methods have proven to be powerful tools that serve as advanced models of sensor motor brain function. Studies examining functional neuroimaging methods have revealed activation of distinct brain areas associated with increased dyspnea. Pulmonary hyperinflation has been proposed to influence the perception of dyspnea. The association of hyperinflation with minor levels of bronchoconstriction reflects the partition of the sensory effect of airway narrowing per se from that of the attendant elastic loading of the inspiratory muscles. There is evidence to suggest, however, that hyperinflation does not play an important role in the pathogenesis of exercise dyspnea as it does during induced bronchoconstriction. Decreased levels of perception of airway obstruction may be a risk factor associated with life-threatening asthma. A poor perceiver may be vulnerable to further hypoxia-induced suppression of respiratory sensation. Monitoring the response to bronchodilator therapy with formoterol and salbutamol in patients with acute or chronic asthma has resulted in significantly faster improvement in dyspnea, within 2 min. SUMMARY: Regardless of the factors involved, much variability in dyspnea scores remains unexplained. Quantitative and qualitative assessment of the perception of dyspnea, symptom measurement and quality of life complement physiological measurements and contribute to our understanding of dyspnea in asthma.     

Hepatitis C virus carriers with persistently normal ALT levels: biological peculiarities and update of the natural history of liver disease at 10 years

Some chronic hepatitis C (CHC) patients exhibit persistently normal alanine aminotransferase (ALT) levels (PNAL). Patients with PNAL experience significantly milder disease. In order to understand the differences between CHC patients with elevated ALT levels compared with those with PNAL better, we compared epidemiological, immunological and histological findings, in particular, the value of proliferating hepatocyte activity (PCNA) between the two groups of patients. We studied 40 chronic hepatitis C virus (HCV) carriers with increased ALT who underwent liver biopsy for histological diagnosis and determination of clinical prognosis, and 24 PNAL patients under follow-up for 10 years. Immunological response to different HCV genomic epitopes was tested in both the control group and in PNAL subjects. PCNA values from liver specimens of all patients as well as liver biopsies of PNAL patients at time points 0 and 5 years were calculated according to Hall et al.Age, sex and body mass index (BMI) were not significantly different between the two groups. The median liver histology stage was significantly higher in HCV carriers vs the PNAL group (2.5, range = 2-6 vs 1.5, range = 1-2; P < 0.01). Among PNAL patients, histological stage was not statistically different at the three time points considered. Interferon (IFN)-gamma production was comparable in the two groups. PCNA was significantly higher in the group with elevated ALT levels vs the PNAL group (8%, range = 4-15%vs 5% range = 3-8%; P < 0.05) and no statistically significant differences were found in PNAL patients at time points 0, 5 and 10 years. This study confirms that progression to cirrhosis is slow or absent in PNAL patients after 10 years of follow-up. Accordingly, the hepatic proliferative activity index is low and seems to be stable over time.     

Activity of irinotecan and the tyrosine kinase inhibitor CEP-751 in medullary thyroid cancer

CONTEXT: Medullary thyroid cancer (MTC) is a cancer of the parafollicular C cells that commonly presents with an inherited or acquired RET gene mutation. There is currently no effective systemic treatment for MTC. OBJECTIVE: The objective of this study was to investigate a systemic therapeutic approach to treat MTC. We studied the sensitivity of an MTC cell line and xenograft to irinotecan, alone and in combination with the tyrosine kinase inhibitor, CEP-751. RESULTS: In TT cell culture and xenografts, irinotecan treatment was highly effective. This effect was augmented by treatment with CEP-751. Treatment of TT cell xenografts resulted in durable complete remission in 100% of the mice, with median time to recurrence of 70 d for irinotecan alone and more than 130 d for irinotecan plus CEP-751. Although irinotecan induced an S phase checkpoint arrest in TT cells, CEP-751 in combination with irinotecan resulted in a loss of this arrest. CEP-751 induced a loss in the induction of the DNA repair program marked by phospho-H2AX and the checkpoint pathway marked by the activated Chk1 pathway. CONCLUSIONS: Irinotecan treatment was highly effective in a preclinical model of human MTC, resulting in complete remission in 100% of the xenografts treated. The duration of remission was further enhanced by combination with the kinase inhibitor, CEP-751. These results suggest that irinotecan, alone or in combination, may be useful for the treatment of MTC.     

Adenosine deaminase as costimulatory molecule and marker of cellular immunity

Adenosine deaminase (ADA) is an enzyme of purine metabolism which has been the subject of much interest because the congenital defect of this enzyme causes severe combined immunodeficiency syndrome. One of the three isoforms of the enzyme (ecto-ADA) is capable of binding to the glycoprotein CD26 and adenosine receptors A1 and A2B. ADA-CD26 interaction produces a costimulatory signal in the events of T cell activation and secretion of IFN-gamma, TNF-alpha and IL-6. During this activation, the enzyme activity is regulated positively by IL-2 and IL-12 and negatively by IL-4, based on the mechanism of translocation. Diverse studies suggest that seric and plasmatic levels of ADA rise in some diseases caused by microorganisms infecting mainly the macrophages and in hypertensive disorders, which may represent a compensatory mechanism resulting from increased adenosine levels and the release of hormones and inflammatory mediators estimulated by hipoxia.     

The functional anatomy of the cerebrocerebellar circuit: A review and new concepts

The cerebrocerebellar circuit is a feedback circuit that bidirectionally connects the neocortex and the cerebellum. According to the classic view, the cerebrocerebellar circuit is specifically involved in the functional regulation of the motor areas of the neocortex. In recent years, studies carried out in experimental animals by morphological and physiological methods, and in humans by magnetic resonance imaging, have indicated that the cerebrocerebellar circuit is also involved in the functional regulation of the nonmotor areas of the neocortex, including the prefrontal, associative, sensory and limbic areas. Moreover, a second type of cerebrocerebellar circuit, bidirectionally connecting the hypothalamus and the cerebellum, has been detected, being specifically involved in the regulation of the hypothalamic functions. This review analyzes the morphological features of the centers and pathways of the cerebrocerebellar circuits, paying particular attention to their organization in different channels, which separately connect the cerebellum with the motor areas and nonmotor areas of the neocortex, and with the hypothalamus. Actually, a considerable amount of new data have led, and are leading, to profound changes on the views on the anatomy, physiology, and pathophysiology of the cerebrocerebellar circuits, so much they may be now considered to be essential for the functional regulation of many neocortex areas, perhaps all, as well as of the hypothalamus and of the limbic system. Accordingly, clinical studies have pointed out an involvement of the cerebrocerebellar circuits in the pathophysiology of an increasing number of neuropsychiatric disorders.     

Colonic perforation due to severe cytomegalovirus disease in granulomatosis with polyangiitis after immunosuppression

Clinical Rheumatology - Granulomatosis with polyangiitis (GPA) is a small-vessel necrotizing granulomatous vasculitis typically involving upper airways, lungs, and kidneys, which may lead to...