First operation in SPIDER and the path to complete MITICA.

The requirements of ITER neutral beam injectors (1 MeV, 40 A negative deuterium ion current for 1 h) have never been simultaneously attained; therefore, a dedicated Neutral Beam Test Facility (NBTF) was set up at Consorzio RFX (Padova, Italy). The NBTF includes two experiments: SPIDER (Source for the Production of Ions of Deuterium Extracted from Rf plasma), the full-scale prototype of the source of ITER injectors, with a 100 keV accelerator, to investigate and optimize the properties of the ion source; and MITICA, the full-scale prototype of the entire injector, devoted to the issues related to the accelerator, including voltage holding at low gas pressure. The present paper gives an account of the status of the procurements, of the timeline, and of the voltage holding tests and experiments for MITICA. As for SPIDER, the first year of operation is described, regarding the solution of some issues connected with the radiofrequency power, the source operation, and the characterization of the first negative ion beam.

Multi-scale laboratory routine in the efficacy assessment of conservative products for natural stones.

The evaluation of conservative treatments' efficacy on natural building stones are usually based on standard recommendation routines finalized to evaluate compatibility and harmfulness of products in turn of the substrate. However, the visualization and the quantification of products inside pore structure of natural stones is not immediate through standard tests, so that imaging and advanced techniques are recently proposed in material conservation field to improve knowledge on penetration depth, modification of pore-air interface at different scale and monitor dynamic absorption processes. Moreover, natural stones are usually characterized by complex structure, which changes due to conservative treatments have to be inspected at different scale (from micrometer to nanometer). In this prospective, the assessment of laboratory practices able to integrate multiscale methods and give back a complete overview on interaction between new conservative formulates and natural stones is of high interest. In this paper, we propose a methodological routine for efficacy assessment of conservative products, incorporating classical and innovative nondestructive techniques. Validation of the workflow has been verified on a high porous natural stone treated with new hybrid formulates appropriately customized for conservation issues. •The study intends to add new insights on problems related to consolidation of high porous carbonate stone, application methods in consolidating natural stones and methods to evaluate efficacy of new products.•A multi-scale laboratory investigation procedure is proposed by integrating standard and innovative nondestructive methods. Merits and limits of each applied method are discussed during validation.•The possibility to incorporate standard routines and/or substitute destructive testing with non-destructive ones seem to be a valid alternative to evaluate efficiency and monitor behavior of stones treated with consolidating products.

Bilateral Non-arteritic Anterior Ischaemic Optic Neuropathy as the Presentation of Systemic Amyloidosis.

A 75-year-old hypertensive female with stable idiopathic intermediate uveitis presented with bilateral sequential optic neuropathy with optic disc swelling. The optic neuropathy in the first affected eye (right) was thought to be due to non-arteritic anterior ischaemic optic neuropathy (NAION). Asymptomatic left optic disc swelling was found at routine review 2 months later, and a diagnosis of giant cell arteritis (GCA) was sought. Temporal artery duplex ultrasound showed the "halo sign," but a subsequent temporal artery biopsy showed light-chain (AL) amyloidosis with no signs of giant cell arteritis. In this case, bilateral sequential ischaemic optic neuropathy mimicking non-arteritic anterior ischaemic optic neuropathy was the presenting sign of systemic amyloidosis involving the temporal arteries.

A new deflection technique applied to an existing scheme of electrostatic accelerator for high energy neutral beam injection in fusion reactor devices.

A scheme of a neutral beam injector (NBI), based on electrostatic acceleration and magneto-static deflection of negative ions, is proposed and analyzed in terms of feasibility and performance. The scheme is based on the deflection of a high energy (2 MeV) and high current (some tens of amperes) negative ion beam by a large magnetic deflector placed between the Beam Source (BS) and the neutralizer. This scheme has the potential of solving two key issues, which at present limit the applicability of a NBI to a fusion reactor: the maximum achievable acceleration voltage and the direct exposure of the BS to the flux of neutrons and radiation coming from the fusion reactor. In order to solve these two issues, a magnetic deflector is proposed to screen the BS from direct exposure to radiation and neutrons so that the voltage insulation between the electrostatic accelerator and the grounded vessel can be enhanced by using compressed SF6 instead of vacuum so that the negative ions can be accelerated at energies higher than 1 MeV. By solving the beam transport with different magnetic deflector properties, an optimum scheme has been found which is shown to be effective to guarantee both the steering effect and the beam aiming.

Synovial CD4+ T-cell-derived GM-CSF supports the differentiation of an inflammatory dendritic cell population in rheumatoid arthritis.

OBJECTIVE: A population of synovial inflammatory dendritic cells (infDCs) has recently been identified in rheumatoid arthritis (RA) and is thought to be monocyte-derived. Here, we investigated the role and source of granulocyte macrophage-colony-stimulating factor (GM-CSF) in the differentiation of synovial infDC in RA. METHODS: Production of GM-CSF by peripheral blood (PB) and synovial fluid (SF) CD4+ T cells was assessed by ELISA and flow cytometry. In vitro CD4+ T-cell polarisation experiments were performed with T-cell activating CD2/CD3/CD28-coated beads in the absence or presence of pro-Th1 or pro-Th17 cytokines. CD1c+ DC and CD16+ macrophage subsets were flow-sorted and analysed morphologically and functionally (T-cell stimulatory/polarising capacity). RESULTS: RA-SF CD4+ T cells produced abundant GM-CSF upon stimulation and significantly more than RA-SF mononuclear cells depleted of CD4+ T cells. GM-CSF-producing T cells were significantly increased in RA-SF compared with non-RA inflammatory arthritis SF, active RA PB and healthy donor PB. GM-CSF-producing CD4+ T cells were expanded by Th1-promoting but not Th17-promoting conditions. Following coculture with RA-SF CD4+ T cells, but not healthy donor PB CD4+ T cells, a subpopulation of monocytes differentiated into CD1c+ infDC; a process dependent on GM-CSF. These infDC displayed potent alloproliferative capacity and enhanced GM-CSF, interleukin-17 and interferon-γ production by CD4+ T cells. InfDC with an identical phenotype to in vitro generated cells were significantly enriched in RA-SF compared with non-RA-SF/tissue/PB. CONCLUSIONS: We demonstrate a therapeutically tractable feedback loop of GM-CSF secreted by RA synovial CD4+ T cells promoting the differentiation of infDC with potent capacity to induce GM-CSF-producing CD4+ T cells.

Mesenchymal stromal cells overexpressing vascular endothelial growth factor in ovine myocardial infarction.

Mesenchymal stromal cells (MSCs) are cardioprotective in acute myocardial infarction (AMI). Besides, we have shown that intramyocardial injection of plasmid-VEGF(165) (pVEGF) in ovine AMI reduces infarct size and improves left ventricular (LV) function. We thus hypothesized that MSCs overexpressing VEGF(165) (MSCs-pVEGF) would afford greater cardioprotection than non-modified MSCs or pVEGF alone. Sheep underwent an anteroapical AMI and, 1 week later, received intramyocardial MSCs-pVEGF in the infarct border. One month post treatment, infarct size (magnetic resonance) decreased by 31% vs pre-treatment. Of note, myocardial salvage occurred predominantly at the subendocardium, the myocardial region displaying the largest contribution to systolic performance. Consistently, LV ejection fraction recovered to almost its baseline value because of marked decrease in end-systolic volume. None of these effects were observed in sheep receiving non-transfected MSCs or pVEGF. Although myocardial retention of MSCs decreased steeply over time, the treatment induced significant capillary and arteriolar proliferation, which reduced subendocardial fibrosis. We conclude that in ovine AMI, allogeneic VEGF-overexpressing MSCs induce subendocardial myocardium salvage through microvascular proliferation, reducing infarct size and improving LV function more than non-transfected MSCs or the naked plasmid. Importantly, the use of a plasmid rather than a virus allows for repeated treatments, likely needed in ischemic heart disease.

Thymic function in juvenile idiopathic arthritis.

OBJECTIVE: Thymic function declines exponentially with age. Impaired thymic function has been associated with autoimmune disease in adults but has never been formally assessed in childhood autoimmunity. Therefore, thymic function in children with the autoimmune disease juvenile idiopathic arthritis (JIA) was determined. METHODS: Thymic function was measured in 70 children and young adults with JIA (age range 2.1-30.8 (median 10.4)) and 110 healthy age-matched controls using four independent assays. T cell receptor excision circles (WBLogTREC/ml) and the proportion of CD4(+) CD45RA(+)CD31(+) T cells (representing recent thymic emigrants; %RTEs) were quantified and intrathymic proliferation measured by calculating the alphaTREC/SigmabetaTREC ratio. Lastly, regulatory T cells (T(Reg)) of thymic origin (CD4(+)FOXP3(+)) were quantified in peripheral blood to assess the ability of the thymus in JIA to generate this T cell subset. RESULTS: Thymic function was equivalent by all four parameters in JIA when compared with the control population. Furthermore, there was no consistent effect of JIA subtype on thymic function, although intrathymic proliferation was higher in the small rheumatoid factor (RF)(+) polyarticular group. There were no significant effects of disease-modifying antirheumatic drugs (DMARDs) or oral corticosteroids on thymic function, although those with the worst prognostic ILAR (International League of Associations for Rheumatology) subtypes were also those most likely to be on a DMARD. CONCLUSIONS: It is demonstrated that children and young adults with JIA, unlike adults with autoimmune diseases, have thymic function that is comparable with that of healthy controls. The varied pathologies represented by the term "JIA" suggest this observation may not be disease specific and raises interesting questions about the aetiology of thymic impairment in adult autoimmunity.

Determination of thymic function directly from peripheral blood: a validated modification to an established method.

The thymus contributes naïve, self MHC reactive, self tolerant T cells to the peripheral immune system throughout life, albeit with a log-linear decline with age. Quantification of thymic function is clinically relevant in the setting of lymphoablation, but a phenotypic marker distinguishing recent thymic emigrants from long lived naïve T cells remains elusive. T cell receptor excision circles (TREC) are present in thymocytes exiting the thymus and quantification of the most frequent of these, the deltarec-psiJalpha rearrangement has been widely used as a measure of recent thymic function. However, interpretation of results presented as TREC per cell has been criticised on the basis that extra-thymic cellular proliferation impacts on peripherally determined TREC numbers. TREC/ml is now considered to be more representative of thymic function than TREC/cell, especially where significant cellular proliferation occurs (e.g. during reconstitution following stem cell transplantation). Here we describe the validation of a novel variation to the established assay, directly quantifying TREC/ml from 300 microl whole blood. We show the assay to be reproducible, robust and stable longitudinally and we show equivalence of performance when compared with more standard assays. This assay particularly lends itself to the measurement of thymic function in children and where monitoring clinical variables is limited by tissue availability.

Modification of thrombomodulin plasma levels in refractory myeloma patients during treatment with thalidomide and dexamethasone.

Deep venous thrombosis (DVT) has been variably reported in multiple myeloma patients during treatment with thalidomide alone or in combination with chemotherapy or dexamethasone. With the aim of investigating this complication, we performed, on a cohort of 13 relapsed refractory MM patients treated with low-dose thalidomide (100 mg/day) and dexamethasone (20 mg p.o./day for 4 days every 2 weeks), a serial evaluation of different laboratory parameters implicated in DVT. No significant abnormalities in all genetic, serologic, or plasmatic parameters studied were registered, apart from thrombomodulin which showed significant variations between baseline and 1st-month values and 1st- and 3rd-month values. In conclusion, the evidence of significant variations of thrombomodulin values in the 1st month of therapy, which is considered to involve the highest risk of thrombosis, might support a role for thrombomodulin in this complex mechanism.

Urinary proteins in multiple myeloma: correlation with clinical parameters and diagnostic implications.

Renal failure is one of the worst complications occurring in multiple myeloma (MM) patients. It does not affect survival if reverted by a prompt chemotherapy before the damage becomes irreversible; therefore, the early diagnosis of renal dysfunction is crucial. High and low molecular weight urinary proteins have proved to be helpful in diagnosing initial renal damage since they are more sensitive than urea and creatinine serum levels or creatinine clearance. We studied the renal function of 111 MM patients through serum creatinine, urea, urinary IgG, alpha(1)-microglobulin (alpha(1)-M), and albumin (Alb). Two successive controls were made in a subset of 30 patients, categorized in three groups (improved, stable, worsened) according to the behavior of tumor burden markers (bone marrow plasmacytosis, monoclonal component, and beta(2)-microglobulin). In every group, we evaluated the behavior of urinary proteins. Renal dysfunction evaluated with serum parameters was present in 19 patients (17%), while if studied with urinary proteins was revealed in 71 patients (64.5%). Urinary proteins statistically correlated with each other. They correlated with creatinine, IgG, and alpha(1)-M also with urea. By contrast, they showed a variable correlation with clinical parameters: alpha(1)-M correlated with bone marrow plasmacytosis (BMPC) ( p=0.02) and beta(2)-M ( p=0.000001), IgG with all three disease parameters (MC p=0.0005, BMPC p=0.009, beta(2)-M p=0.007), and Alb only with beta(2)-M ( p=0.0004). In the subset of 30 patients followed with two successive controls, urinary proteins showed a parallel behavior with the indices of tumor burden. In conclusion, IgG, alpha(1)-microglobulin, and albumin are reliable and sensitive to precociously reveal renal damage, and we recommend their routine use for the definition and monitoring of renal function in multiple myeloma patients, mainly those in early stage, to better identify initial signs of progression.

Multiple sclerosis and pregnancy.

Multiple sclerosis causes disability in young adults and, like most autoimmune diseases, affects women more commonly than men. The disease can therefore present at a time when many have, or are considering, starting a family. The effect of pregnancy on the outcome of multiple sclerosis is reviewed and the management of pregnant women who have multiple sclerosis is discussed.

Gastric antral vascular ectasia in systemic sclerosis: complete resolution with methylprednisolone and cyclophosphamide.

A case of severe, transfusion dependent anaemia in a 72 year old woman, which on endoscopy was found to be due to gastric antral vascular ectasia (GAVE), is reported. Repeated endoscopic sclerotherapy was ineffective. She subsequently developed Raynaud's phenomenon and on further investigation was found to have classical systemic sclerosis with lung involvement. Treatment with pulses of intravenous methylprednisolone and cyclophosphamide resulted in significant improvement in her pulmonary function tests and skin score. Coincidentally, her haemoglobin stabilised and further endoscopic examinations were normal. This is the first report of cyclophosphamide and methylprednisolone leading to complete and sustained resolution of GAVE in association with systemic sclerosis.

Biochemical markers of bone disease in asymptomatic early stage multiple myeloma. A study on their role in identifying high risk patients.

BACKGROUND AND OBJECTIVES: Skeletal involvement is typical of multiple myeloma (MM) and its occurrence increases with the progression of the disease. We performed a study to evaluate the clinical importance of osteocalcin (bone gla-protein, BGP) and bone alkaline phosphatase (b-AP) as indices of osteoblastic activity, and deoxypyridoline (DPD) as a marker of bone resorption. DESIGN AND METHODS: Fifty-two MM patients, 39 patients with monoclonal gammopathy of undetermined significance (MGUS), and 30 normal controls entered the study. Of the 52 MM patients, 10 showed lytic lesions at standard X-rays and 42 did not; 21 were untreated and 31 had been treated with chemotherapy (combined with bisphophonates in 15). Of these last, 12 had progressive disease and 19 were in plateau phase. RESULTS: DPD levels were higher in MM patients than in patients with MGUS or healthy controls (p = 0.0001 and p = 0.0008, respectively). No statistical differences were seen between patients with MGUS and healthy controls. BGP serum levels were significantly lower in MM patients than in MGUS patients (p = 0.001) or healthy controls (p = 0.001). b-AP was significantly higher in MGUS patients than in MM patients (p = 0.04). Biochemical parameters were analyzed in a continuous fashion and after dichotomization into low and high values with respect to normal ones. Abnormal high values of DPD showed statistically significant correlations with presence of osteolysis (p = 0.008), advanced stage (p = 0.03) and abnormal beta2-microglobulin (beta2M) values (p = 0.03), while DPD as a continuous variable correlated significantly only with the presence of osteolysis (p = 0.02). In contrast, neither BGP nor b-AP showed statistical correlations with the presence of lytic lesions, or with other clinical or laboratory parameters. In 15 patients followed with serial controls, modifications of DPD levels reflected bone disease status well. Of the 42 patients without radiologic evidence of skeletal lesions, 15 had abnormal DPD values. Spinal magnetic resonance imaging (MRI) showed initial lytic lesions in 10 of them. INTERPRETATION AND CONCLUSIONS: Biochemical markers of bone metabolism are useful in evaluating and monitoring skeletal involvement in MM patients. They may help clinicians to identify: 1) from among patients without radiologic evidence of lytic lesions, those who deserve more accurate radiologic examinations (namely MRI); 2) from among asymptomatic patients, and in association with spinal MRI, those patients at higher risk of progression who might benefit from early treatment.