Bosentan fosters microvascular de-remodelling in systemic sclerosis

Bosentan, a dual endothelin receptor antagonist, may reduce blood pressure by blocking the vasoconstrictor effect of endothelin-1. In systemic sclerosis (SSc) nailfold videocapillaroscopy (NVC); allows diagnostic and follow-up of microvascular damage. Distinct NVC patterns have been identified for the evaluation of severity of SSc microvascular damage. The objective of this study is to evaluate the modification of the microvasculature under Bosentan therapy in SSc patients with pulmonary arterial hypertension (PAH). Nine patients with PAH related to SSc in New York Heart Association classes III?CIV were treated with Bosentan 125?mg twice a day. NVC optical probe videocapillaroscopy equipped with 100× and 200× contact lenses and connected to image analyse software was performed before and after 12?months of Bosentan therapy to evaluate the modification of microvasculature. Nine PAH SSc patients treated with Iloprost were used as controls. Before Bosentan therapy, seven patients showed at NVC severe loss of capillaries with large avascular areas and vascular architectural disorganisation which are typically ??late?? SSc pattern. After 12?months of Bosentan, NVC pattern changed in seven patients from ??late?? into ??active?? SSc pattern. The disappearance of avascular areas and capillary haemorrhages was the most striking result. Two patients had an ??active?? SSc pattern, not modified by Bosentan treatment. These data show that Bosentan may improve NVC pattern in SSC and the presence of new capillaries suggests that it may favour angiogenesis. Bosentan may improve and stabilise the microvasculature in long-term treatment modulating the structural modifications detected by NVC.     

Calcium and calmodulin-enhanced in vitro phosphorylation of hen brain cold-stable microtubules and spinal cord neurofilament triplet proteins after a single oral dose of tri-o-cresyl phosphate.

The effect of a single 750-mg/kg oral dose of tri-o-cresyl phosphate (TOCP) on the endogenous phosphorylation of brain microtubule preparations and spinal cord neurofilaments was assessed in hens after the development of delayed neurotoxicity. Protein phosphorylation with [gamma-32P]ATP was analyzed by one-dimensional and two-dimensional gel electrophoresis, autoradiography, and microdensitometry. TOCP treatment enhanced the Ca2+- and calmodulin-dependent phosphorylation of tubulin in crude chicken brain cytosol (160% for alpha-tubulin and 140% for beta-tubulin) and cold-stable microtubules (165% and 155% for alpha- and beta-tubulin, respectively). Microtubule-associated protein 2 (MAP-2) phosphorylation was also increased in brain fractions studied--i.e., brain cytosol (145%), cold-stable microtubules (133%), and cold-labile microtubules (328%). There was significant increase in phosphorylation of a 70-kDa protein in the brain cytosol and in the cold-stable microtubule fractions. TOCP also stimulated the phosphorylation of spinal cord proteins of 70 kDa (119%) and 160 kDa (129%) in a Mg2+-dependent manner. Addition of Ca2+ and calmodulin further enhanced the phosphorylation of these 70-kDa (563%) and 160-kDa (221%) proteins as well as of 52-, 59-, and 210-kDa proteins by as much as 126%, 160%, and 196%, respectively. Two-dimensional electrophoresis was carried out to identify these proteins. They were confirmed as alpha- and beta-tubulin (52 and 59 kDa) in brain and spinal cord preparations and the neurofilament triplet proteins (70, 160, and 210 kDa) in the spinal cord preparation. The 70-kDa protein in brain was not neurofilament in origin. Peptide mapping using Staphylococcus aureus V8 protease showed the brain and spinal cord cytoskeletal proteins have identical phosphopeptide patterns in control and TOCP-treated hens, indicating that it was unlikely that the phosphorylation sites were altered by TOCP treatment.     

High rate of disease remission in moderate rheumatoid arthritis on etanercept therapy: data from GISEA, the Italian biologics register

The aim of this study was to evaluate the clinical outcomes of etanercept in rheumatoid arthritis (RA) patients with moderate or severe disease activity. We analyzed data from the Italian biologics register Gruppo Italiano Studio Early Arthritides (GISEA) to investigate the rate of disease remission and functional improvement, based on the 28-Joint Disease Activity Score (DAS28) and the (Health Assessment Questionnaire (HAQ) score in RA patients with moderate or severe disease activity beginning etanercept therapy. Disease was defined as severe (H-RA) with DAS28 ≥5.1 and moderate (M-RA) with DAS28 ≥3.2 to 5.1 at baseline. Patients were considered in remission if DAS28 was ≤2.6, and HAQ ≤0.5 defined normal function. We enrolled 953 RA patients, 320 with M-RA and 633 H-RA. Age and disease duration were similar in the two cohorts, but H-RA patients had significantly more comorbidities (p?<?0.01) and took significantly more disease-modifying antirheumatic drugs (p?<?0.001) than M-RA patients. After 1 year, the percentage of patients achieving disease remission and normal function (DAS28 ≤2.6 plus HAQ ≤0.5) was higher in M-RA (21.4 %) than in H-RA patients (14.8 %, p?=?0.007), regardless of the disease duration. Additionally, female gender (p?=?0.006) and H-RA class (p?=?0.002) negatively predicted disease remission at 1 year. However, the drug survival rate did not differ between the two subsets. This study confirms that etanercept was effective in the treatment of active RA, but best response, in terms of disease remission and normal function ability, was greater and easier to attain in M-RA patients. These findings may aid clinicians to choose the best strategy to treat RA.     

The pathophysiology of osteoarthritis

Osteoarthritis (OA) is a complex disease whose pathogenesis includes the contribution of biomechanical and metabolic factors which, altering the tissue homeostasis of articular cartilage and subchondral bone, determine the predominance of destructive over productive processes. A key role in the pathophysiology of articular cartilage is played by cell/extra-cellular matrix (ECM) interactions, which are mediated by cell surface integrins. In a physiologic setting, integrins modulate cell/ECM signaling, essential for regulating growth and differentiation and maintaining cartilage homeostasis. During OA, abnormal integrin expression alters cell/ECM signaling and modifies chondrocyte synthesis, with the following imbalance of destructive cytokines over regulatory factors. IL-1, TNF-alpha and other pro-catabolic cytokines activate the enzymatic degradation of cartilage matrix and are not counterbalanced by adequate synthesis of inhibitors. The main enzymes involved in ECM breakdown are metalloproteinases (MMPs), which are sequentially activated by an amplifying cascade. MMP activity is partially inhibited by the tissue inhibitors of MMPs (TIMPs), whose synthesis is low compared with MMP production in OA cartilage. Intriguing is the role of growth factors such as TGF-beta, IFG, BMP, NGF, and others, which do not simply repair the tissue damage induced by catabolic factors, but play an important role in OA pathogenesis.     

Toxicity evaluation of petroleum blending streams: inhalation subchronic toxicity/neurotoxicity study of a light catalytic reformed naphtha distillate in rats

A 13-wk whole-body inhalation study was conducted with Sprague-Dawley CD rats (16/sex/group) exposed to a light catalytic reformed naphtha distillate (LCRN-D, CAS number 64741-63-5) at target concentrations of 0, 750, 2500, and 7500 ppm for 6 h/d, 5 d/wk. Sixteen rats per sex in the control and high-dose groups were maintained after final exposure for a 4-wk recovery period. The highest exposure concentration was 75% of the lower explosive limit. Standard parameters of subchronic toxicity were measured throughout the study; at necropsy, organs were weighed and tissues processed for microscopic evaluation. Neurotoxicity evaluations consisted of motor activity (MA) and a functional operational battery (FOB) measured pretest, throughout exposure and after the recovery period. Neuropathology was evaluated at termination. No test-related mortality or effects on physical signs, body weight, food consumption, or clinical chemistry were observed. In males exposed to 7500-ppm LCRN-D, a statistically significant decrease in white blood cell counts and lymphocyte counts was observed at the termination of exposure that was not present in animals after the 4-wk recovery period. However, mean corpuscular volume was slightly decreased in high-dose males after the recovery period. Statistically significant increases in kidney weights relative to body weights in 7500-ppm male rats correlated with microscopically observed hyaline droplet formation and renal tubule dilation, indicative of light hydrocarbon nephropathy, a condition in male rats that is not toxicologically significant for humans. Statistically significant decrease in absolute and relative spleen weights in 7500-ppm male rats correlated with decreases in hematologic parameters but had no microscopic correlate and was not observed in animals after 4 wk of recovery. This mild, reversible effect in white blood cell populations may relate to the presence of aromatics in the distillate. The only effect of LCRN-D on neurobehavioral parameters was significantly higher motor activity counts among high-dose (7500 ppm) males after the 4-wk recovery period, suggesting a possible delayed effect of LCRN-D. However, there was no evidence of hyperactivity or abnormal behavior from the functional observational battery evaluations, and there were no microscopic changes in neural tissue to support this observation. The no-observed-adverse-effects level (NOAEL) for LCRN-D was 2500 ppm for both subchronic toxicity and neurotoxicity. The no-observed-effects level (NOEL) was 750 ppm.     

Sarcoidosis presenting with Raynaud's syndrome: a case report

We report a case of association between sarcoidosis and Raynaud's syndrome. A 39 year old female presented fatigue, Raynaud's syndrome, IgG and erithrosedimentation rate (ESR) increase, polyarthralgy in which disseminated micronodular infiltration in the chest X-ray and histological demonstration of non-caseating epitheloid microgranulomas led to a diagnosis of concomitant sarcoidosis. Clues to the diagnosis of sarcoidosis coexisting with autoimmune disease are discussed.