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Carolina Bologna,1 Antonio Cozzolino,1 Andrea Ferraro,1 MariaVittoria Guerra,1 Anna Guida,1 Marina Lugarà,1 Maria Gabriella Coppola,1 Paolo Tirelli,1 Marilena Sicignano,1 Pasquale Madonna,1 Pierpaolo Di Micco2 1UOC Medicina Generale Ospedale del Mare ASL Na 1, Naples, Italy; 2UOC Medicina Interna Fatebenefratelli, Naples, ItalyCorrespondence: Carolina Bologna, Tel +393473002271, Email carolina.bologna@libero.itBackground: Waldenstrom’s disease is characterized by the presence of pathological changes in the B lymphocytes that are in the last stages of maturation. One characteristic of WM is the production of an abnormal high amount of IgM and hyper viscosity syndrome. The MW gets worse, symptoms such as fatigue, weight loss, night sweats, fever, recurrent infections and swollen lymph nodes develop in patients who have a known history of MGUS. In this clinical case, our patient without history of MGUS, presents for the first time for medical observation only for ascites and the presence of an interportocaval lymph node package. An atypical presentation of the disease that makes us reflect on the difficulty of making a diagnosis in the elderly patient and on pathogenetic hypotheses of ascites not yet explored.Case Presentation: Seventy-three-year-old patient, hospitalized for the onset of ascites with sloping edema, diffuse left pulmonary opacification. At the ultrasound check, cava and portal vessels patent and of regular caliber, however with inversion of flow in correspondence with the right branch and of the door to the hilum, with a subdiaphragmatic retrocaval focus with a maximum diameter of about 3 cm, which cannot be better viewed. CT scan of the abdomen with confirmation of the presence of an interportocaval lymph node package. After evidence of the electrophoretic protein picture of a double component, probably monoclonal with positive urinary immunofixation for free K chains. IgM dosage equal to 2190 mg. Serum immunofixation practice that confirms the diagnosis of type B lymphoproliferative syndrome as per Waldenstrom’s disease, confirmed by bone marrow aspiration with morphological and flow cytometric study. Immediately begin chemotherapy with Bendamustine 120 mg. After 4 weeks of therapy with the reduction of IgM values, the patient no longer presented ascites.Conclusion: This case has an unusual presentation of this disease and we could shed a new light on the possible pathogenesis of portal hypertension in Waldenstrom’disease.Keywords: ascites, portal hypertension, Waldenstrom’s disease, elderly

Aims Adeno-associated virus type 2 ( AAV) is a nonpathogenic parvovirus that is a promising tool for gene therapy. We aimed to construct plasmids for optimal expression and assembly of capsid proteins and evaluate adenovirus (Ad) protein effect on AAV single-stranded DNA (ss DNA) formation in Saccharomyces cerevisiae. Methods and Results Yeast expression plasmids have been developed in which the transcription of AAV capsid proteins ( VP1,2,3) is driven by the constitutive ADH1 promoter or galactose-inducible promoters. Optimal VP1,2,3 expression was obtained from GAL1/10 bidirectional promoter. Moreover, we demonstrated that AAP is expressed in yeast and virus-like particles ( VLPs) assembled inside the cell. Finally, the expression of two Ad proteins, E4orf6 and E1b55k, had no effect on AAV ss DNA formation. Conclusions This study confirms that yeast is able to form AAV VLPs; however, capsid assembly and ss DNA formation are less efficient in yeast than in human cells. Moreover, the expression of Ad proteins did not affect AAV ss DNA formation. Significance and Impact of the Study New manufacturing strategies for AAV-based gene therapy vectors ( rAAV) are needed to reduce costs and time of production. Our study explores the feasibility of yeast as alternative system for rAAV production. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess regulation of mononuclear cell (MNC) traffic to human synovial tissue by TNF-α and IL-1 and the involvement of ICAM-1 in MNC retention in rheumatoid synovial tissue. Human rheumatoid arthrilis synovium was engrafted subcutaneously in 6-8-week-old SCID/CB17 mice. Three weeks later, we injected 20 × 106 human peripheral blood mononuclear cells (PBMC) previously labelled with 111indium intraperitoneally into mice containing control or cytokine-injected grafts. Total body seintigraphy was performed 72 h post-injection. The graft was removed and immunochemical analysis carried out to assess ICAM-I. Vascular cell adhesion molecule-I (VCAM-I land E-selectin expression. In some experiments, mice were treated intravenously with 500 μg MoAb anti-ICAM-1 (BIRR-I) or an isotype-matched control MoAb before introduction of MNC. TNF-α, but not IL-1&alpga;. enhanced MNC retention in the rheumatoid synovial graft 72 h post-injection (graft activity 989 ± 1227ct/min per 200 pixels or 3.36 ± 4.16% of initial injected activity versus 411 ± 157 ct/min per 200 pixels or 1.13 ± 0.45% in controls; P < 0.03). TNF-α enhanced ICAM-1 expression by synovial cells and endothelial cells, whereas VCAM-I or E-selectin expression was not enhanced on either cell type. After MoAb treatment of ICAM-l. synovial lymphocyte recruitment of TNF-α-treated mice decreased significantly to levels below that of control mice (160 ± 97 ct/min per 200 pixels, 0.54 ± 0.33%; P < 0.01). Mononuclear cell retention in rheumatoid synovial tissue engrafted into SCID mice was up-regulated by TNF-α and blocked by MoAb to ICAM-1. These results suggest that ICAM-1 is involved in mononuclear cell retention in rheumatoid synovium. [ABSTRACT FROM AUTHOR]

Objectives: To determine the effects of impaired renal function on the pharmacokinetics of methotrexate (MTX) in rheumatoid arthritis (RA) patients.Methods: 77 RA patients were included in this study. MTX was administered intramuscularly (7.5 to 15 mg). Subjects were divided into four groups, according to their creatinine clearance (CLCR); group 1: CLCR lower than 45 ml/min; group 2: CLCR between 45 and 60 ml/min, group 3: CLCR between 61 and 80 ml/min and group 4: CLCR higher than 80 ml/min. Blood samples were collected from each subject before drug administration and at two and eight hours after administration. Individual pharmacokinetic parameters were estimated using a Bayesian approach.Results: MTX concentrations (total and free) were 1.3 to 1.6-times higher in group 1 than in groups 2, 3, and 4. For total and free MTX, t1/2 eliminations were 22.7 hours in group 1, 13.5 hours in group 2, 12 hours in group 3, and 11 hours in group 4. Clearance of total MTX was 64, 92, 96, 115 ml/min in groups 1 to 4, respectively, it was 118, 163, 171, 206 ml/min in groups 1 to 4 for the free MTX, respectively. Volume of distribution averaged 2.16 l/kg in group 1, 1.92 l/kg in group 2, 1.61 l/kg in group 3, and 1.56 l/kg in group 4. Elimination half life was significantly increased and total clearance was significantly reduced with the degree of renal impairment. Linear regression revealed good correlations between clearance values of MTX and creatinine clearance.Conclusion: Individual testing is required rather than a general decrease of the MTX dose based only on CLCR. [ABSTRACT FROM AUTHOR]

A total of 453 rheumatoid arthritis (RA) patients were followed up for 35.2 +/- 27.9 months (range 3-106). The clinical parameters decreased significantly after 6 months. Twenty-eight patients were in remission (6.4%). Rheumatoid factor (RF) positivity was less common in the group of patients in remission, with a higher frequency of visits and methotrexate (MTX) onset after 65 yr. There was a significant degradation of radiographic lesions (n = 60). A total of 101 patients (23.1%) stopped MTX, for toxicity (n = 61) and failure (n = 20). The onset of MTX after 65 yr, a low number of visits and the occurrence of side-effects were predictive of MTX withdrawal. A total of 259 patients (59.3%) had side-effects. A Ritchie's index < or = 10, a lower polymorphonuclear cell count and the absence of RF were predictive of side-effects. The probability of being on MTX at 5 yr was 73%. This study confirms the high efficacy of MTX in RA. [ABSTRACT FROM PUBLISHER]

The objective of this study was to assess the influence of age on the efficacy and toxicity of methotrexate in rheumatoid arthritis. Four hundred and sixty-nine patients were separated according to the age of onset of methotrexate treatment; before 65 yr (group l, n = 416) and after 65 yr (group 2, n = 53). No difference was found in the evolution of clinical and biological parameters between the two groups. The number of patients in remission at the end of the study was equal. The frequency and type of side-effects were similar. No significant difference was found in the frequency and reasons for methotrexate withdrawal. We noted a trend towards lower therapeutic maintenance of methotrexate when prescribed after the age of 65 yr (P = 0.07, actuarial method). In conclusion, the age at initiation of methotrexate treatment probably did not influence its efficacy and toxicity in rheumatoid arthritis. [ABSTRACT FROM PUBLISHER]

The pharmacokinetic profile of total and free methotrexate (MTX) and the effect of piroxicam on MTX pharmacokinetics was studied in 20 rheumatoid arthritis patients receiving a stable dosage of MTX (10 mg/week). Plasma protein bindingranged from 25 to 55%. To describe the variations with time of the unbound fractions a mathematical characterization relationship between the total and free MTX was used. Total and free MTX were correlated with the sigmoid maximum effect model. The slope factor (gamma) was proportional to the number of binding sites. The free fraction for a given patient canbe evaluated from this relationship. Total clearance of MTX was not statistically different with piroxicam (8.01/h for total MTX, 13.71/h for free MTX) vs without piroxicam. Likewise, there were no significant difference in (, area under the plasma concentration vs time curve, distribution and elimination half-lives, mean resonance time, and volumes of distribution. Although the highest observed total MTX concentration was significantly lower with piroxicam, there were no significant pharmacokinetic interactions between low-dose MTX and piroxicam. [ABSTRACT FROM PUBLISHER]

The authors' objective was to study the serum secretory immunoglobulin A (S-IgA) concentration and the presence of rheumatoid factor (RF) complexed with a secretory component (SC) in rheumatoid arthritis (RA). Sixty-three RA patients were studied. There were 49 healthy subjects in the control group. The S-IgA concentration and the presence of IgA isotype RF were determined by ELISA in the serum. The presence of SC complexed to RF (SC–RF) was studied by a sandwich-type enzyme-linked immunosorbent assay with an antibody against the SC used to capture S-immunoglobulin, and associated anti-globulin activity was revealed with a peroxidase-conjugated human IgG Fc fragment. We observed a significant increase in S-IgA in RA (mean 76.8 μg/ml ± 152.9 S.D.), as compared to controls (mean 13.6 μg/ml± 11.9 S.D.) ( <0.01). Forty-one per cent of RA patients presented a S-IgA concentration above the upper threshold, but we did not observe any association with disease activity. S-IgA concentration was correlated with the presence of IgA-RF. Twenty-seven RA patients had a positive SC–RF versus one in the control group (<0.01). The presence of SC–RF was associated with an increased S-IgA concentration ( <0.0001), and the presence of RF-IgA ( <0.002). However, no association with disease activity was noted. Our study showed that serum S-IgA was increased in RA, and that part of the RF were complexed with SC. These results suggest contribution of mucosal lymphocytes in the pathogenesis of RA. [ABSTRACT FROM PUBLISHER]

We report nine cases of arthritis associated with a monoclonal gammapathy. Joint involvement was noted simultaneously or after the diagnosis of monoclonal gammapathy was made. The cases had oligoarthritis or polyarthritis mimicking rheumatoid arthritis. However, rheumatoid factor was absent in all patients, and distal interphalangeal joints were involved in two cases and sacroiliitis in one. The plasma cell dyscrasia was a multiple myeloma in two cases and monoclonal gammapathy of undetermined significance in the other patients. The light chain isotype was kappa in eight of our patients. A type I cryoglobulinaemia was associated in four cases; it was detected in the synovial fluid of two of them. We suggest that the occurrence of paraproteinaemia with chronic arthritis is more than a chance association. Moreover, a monoclonal gammapathy should be searched for in patients presenting with atypical seronegative arthritis. [ABSTRACT FROM PUBLISHER]