Rheumatoid factor-producing CD21low anergic clonal B-cells in essential mixed cryoglobulinaemia: a model for autoantigen-driven pathogenesis of infectious and non-infectious cryoglobulinaemias.

OBJECTIVES: Essential mixed cryoglobulinaemia (EMC) is a disorder of B-cells producing rheumatoid factor (RF), and is clinically and immunologically similar to mixed cryoglobulinaemia (MC) related to hepatitis C virus (HCV-MC). We report here the first comprehensive analysis of B-cell clonality, phenotype and function in EMC. METHODS: The study population included 16 patients with EMC and 24 patients with HCV-MC. Molecular analysis was done for the detection of circulating clonal B cells and for B cell receptor sequencing. B-cell phenotype, proliferative response, apoptosis and ERK signaling were analysed by flow cytometry. RESULTS: Molecular analysis of immunoglobulin genes rearrangements revealed circulating B-cell clones in about half of patients, on average of smaller size than those found in HCV-MC patients. Sequence analysis showed usage of the same stereotyped RF-encoding B-cell receptors frequently expressed in HCV-MC and in primary Sjögren's syndrome. B-cells with low expression of CD21 (CD21low) and unusual homing and inhibitory receptors were increased in EMC and in HCV-MC, but at a significantly lower extent in the former. The CD21low B-cells of EMC and HCV-MC patients shared functional features of exhaustion and anergy, namely reduced proliferation upon ligation of Toll-like receptor 9, high constitutive expression of phosphorylated ERK, and proneness to spontaneous apoptosis. CONCLUSIONS: Our findings suggest a common pathogenetic mechanism in EMC, HCV-MC and primary Sjögren's syndrome, consisting of autoantigen-driven clonal expansion and exhaustion of selected RF-producing B-cells. The more massive clonal expansion in HCV-MC may be due to co-stimulatory signals provided by the virus.

Large and extremely low loss: the unique challenges of gravitational wave mirrors.

This paper describes the making of large mirrors for laser interferometer gravitational wave detectors. These optics, working in the near infrared, are among the best optics ever created and played a crucial role in the first direct detection of gravitational waves from black holes or neutron star fusions.

Bulk optical absorption of high resistivity silicon at 1550 nm.

We report on the measurement of the optical absorption of bulk crystalline silicon at 1550 nm. Using the photodeflection technique, absorption as low as 5 ppm/cm has been measured on a sample with a resistivity of 10 kΩ·cm. The absorption as a function of the resistivity has been derived for n-type silicon.

Cryogenic measurements of mechanical loss of high-reflectivity coating and estimation of thermal noise.

We report on low-frequency measurements of the mechanical loss of a high-quality (transmissivity T<5 ppm at λ(0)=1064 nm, absorption loss <0.5 ppm) multilayer dielectric coating of ion-beam-sputtered fused silica and titanium-doped tantala in the 10-300 K temperature range. A useful parameter for the computation of coating thermal noise on different substrates is derived as a function of temperature and frequency.

Observation of a Correlation Between Internal friction and Urbach Energy in Amorphous Oxides Thin Films.

We have investigated by spectroscopic ellipsometry (SE, 190-1700 nm) the optical properties of uniform, amorphous thin films of Ta2O5 and Nb2O5 as deposited and after annealing, and after so-called "doping" with Ti atoms which leads to mixed oxides. Ta2O5 and Ti:Ta2O5 are currently used as high-index components in Bragg reflectors for Gravitational Wave Detectors. Parallel to the optical investigation, we measured the mechanical energy dissipation of the same coatings, through the so-called "loss angle" ϕ = Q-1, which quantifies the energy loss in materials. By applying the well-known Cody-Lorentz model in the analysis of SE data we have been able to derive accurate information on the fundamental absorption edge through important parameters related to the electronic density of states, such as the optical gap (Eg) and the energy width of the exponential Urbach tail (the Urbach energy EU). We have found that EU is neatly reduced by suitable annealing as is also perceptible from direct inspection of SE data. Ti-doping also points to a minor decrease of EU. The reduction of EU parallels a lowering of the mechanical losses quantified by the loss angle ϕ. The correlation highlights that both the electronic states responsible of Urbach tail and the internal friction are sensitive to a self-correlation of defects on a medium-range scale, which is promoted by annealing and in our case, to a lesser extent, by doping. These observations may contribute to a better understanding of the relationship between structural and mechanical properties in amorphous oxides.

Macrophage Activation Syndrome as Onset of Systemic Lupus Erythematosus: A Case Report and a Review of the Literature.

Macrophage activation syndrome (MAS) is a potentially fatal condition. It belongs to the hemophagocytic lymphohistiocytosis group of diseases. In adults, MAS is rarely associated with systemic lupus erythematosus, but it also arises as complication of several systemic autoimmune disorders, like ankylosing spondylitis, rheumatoid arthritis, and adult-onset Still's disease. Several treatment options for MAS have been reported in the literature, including a therapeutic regimen of etoposide, dexamethasone, and cyclosporine. Here we report a case of 42-year-old woman in whom MAS occurred as onset of systemic lupus erythematosus.

Posterior reversible encephalopathy syndrome--Insight into pathogenesis, clinical variants and treatment approaches.

Posterior reversible encephalopathy syndrome is a rare clinicoradiological entity characterized by typical MRI findings located in the occipital and parietal lobes, caused by subcortical vasogenic edema. It was first described as a distinctive syndrome by Hinchey in 1996. Etiopathogenesis is not clear, although it is known that it is an endotheliopathy of the posterior cerebral vasculature leading to failed cerebral autoregulation, posterior edema and encephalopathy. A possible pathological activation of the immune system has been recently hypothesized in its pathogenesis. At clinical onset, the most common manifestations are seizures, headache and visual changes. Besides, tinnitus and acute vertigo have been frequently reported. Symptoms can be reversible but cerebral hemorrhage or ischemia may occur. Diagnosis is based on magnetic resonance imaging, in the presence of acute development of clinical neurologic symptoms and signs and arterial hypertension and/or toxic associated conditions with possible endotheliotoxic effects. Mainstay on the treatment is removal of the underlying cause. Further investigation and developments in endothelial cell function and in neuroimaging of cerebral blood flow are needed and will help to increase our understanding of pathophysiology, possibly suggesting novel therapies.

Efficacy of low-dose rituximab for the treatment of mixed cryoglobulinemia vasculitis: Phase II clinical trial and systematic review.

OBJECTIVE: To evaluate whether rituximab at a low dose of 250 mg/m(2) × 2 may be as effective as at higher dosages, most commonly 375 mg/m(2)×4, used in previous studies on the treatment of patients with refractory mixed cryoglobulinemia (MC) vasculitis associated with hepatitis C virus (HCV) infection. METHODS: We conducted a phase 2, single-arm two-stage trial (EUDRACT n. 2008-000086-38) of low-dose rituximab in 52 patients with HCV-associated MC who were ineligible/intolerant or non-responder to antiviral therapy. The primary outcomes were response of vasculitis evaluated by the Birmingham Vasculitis Activity Score (BVAS) at months 3, 6 and 12, rate of relapses and time to relapse, and rate of adverse events. Our data were compared with those reported in 19 published studies selected among 291 reviewed in a literature search. RESULTS: The cumulative response rate (complete and partial) at month 3 was 81% in our patients, and 86% in 208 patients from studies using high-dose rituximab. The relapse rate and median time to relapse were, respectively, 41% and 6 months in our study, and 32% and 7 months in high-dose studies. Treatment-related adverse events were 11.5% in our study and 19.9% in high-dose studies. None of these differences was statistically significant. CONCLUSION: Rituximab at a low dosage of 250 mg/m(2) × 2 is as effective as at higher dosages for treating MC vasculitis. This low-dose regimen may improve the cost/benefit profile of rituximab therapy for MC.

Efficacy of low-dose rituximab for mixed cryoglobulinemia.

Rituximab at 375 mg/m(2) x 4 is effective for refractory HCV-related mixed cryoglobulinemia. We conducted a pilot study to assess the efficacy of a lower dosage, 250 mg/m(2) x 2. Six consecutive patients with mixed cryoglobulinemia were treated. All patients had severe or life-threatening disease manifestations, including necrotizing skin ulcers, renal disease, hyperviscosity or intestinal vasculitis. Four of five evaluable patients (excluding one early death) had >80% decrease of cryocrit and remission of vasculitis at the end of a 22- to 55-week (median 40) follow-up. The non-responder failed to respond to additional rituximab treatment, suggesting intrinsic resistance rather than insufficient dosage as the cause of treatment failure. No sustained increase of HCV viremia after rituximab was observed. Rituximab at 250 mg/m(2) x 2 may be as effective as at 375 mg/m(2) x 4 for treating mixed cryoglobulinemia. Larger studies are required to assess the efficacy of low-dose rituximab.