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The increased use of abdominal cross-sectional imaging has contributed to a greater detection of incidental small renal masses. Treatment options for localized disease renal cell carcinoma include radical nephrectomy or partial nephrectomy (PN), the former being preferred for treatment of early-stage tumors. The most adopted technique for follow-up imaging is contrast-enhanced computed tomography (CT), whose findings can cause uncertainty and unnecessary repetition of examinations. Our purpose is to describe CT findings after PN and to describe evolution in time of such images.

Objective To investigate the safety, tolerability, pharmacokinetics, and efficacy of apilimod mesylate, an oral interleukin-12 (IL-12)/IL-23 inhibitor, in patients with rheumatoid arthritis (RA). Methods We performed a phase IIa, randomized, double-blind, placebo-controlled proof-of-concept study of apilimod, in combination with methotrexate, in 29 patients with active RA (3:1 ratio of apilimod-treated to placebo-treated patients) in 3 stages. Patients received apilimod 100 mg/day or placebo for 4 weeks (stage 1) or 8 weeks (stage 2). In stage 3, patients received apilimod 100 mg twice a day or placebo for 8 weeks, with an optional extension of 4 weeks. Clinical response (Disease Activity Score in 28 joints [DAS28] and American College of Rheumatology [ACR] criteria) was assessed throughout; synovial tissue samples collected at baseline and on day 29 (stages 1 and 2) or day 57 (stage 3) were stained for cellular markers and cytokines for immunohistochemistry analysis. Results While only mild adverse events were observed in stages 1 and 2, in stage 3, all patients experienced headache and/or nausea. Among apilimod-treated patients (100 mg/day), there was a small, but significant, reduction in the DAS28 on day 29 and day 57 compared with baseline. ACR20 response was reached in only 6% of patients on day 29 and 25% of patients on day 57, similar to the percentage of responders in the placebo group. Increasing the dosage (100 mg twice a day) did not improve clinical efficacy. Consistent with clinical results, apilimod did not have an effect on expression of synovial biomarkers. Of importance, we also did not observe an effect of apilimod on synovial IL-12 and IL-23 expression. Conclusion Our results do not support the notion that IL-12/IL-23 inhibition by apilimod is able to induce robust clinical improvement in RA.

Sjogren's syndrome is an autoimmune exocrinopathy, mainly affecting the lacrimal and salivary glands, and resulting in ocular and oral dryness (keratoconjunctivitis sicca and xerostomia). The aetiology and pathogenesis are largely unknown, and only palliative treatment is currently available. Data obtained from experimental animal and human studies using biological agents or gene therapeutics can offer insight into the disease process of Sjogren's syndrome. This article reviews the current literature on these approaches and assesses the lessons learnt about the pathogenesis of Sjogren's syndrome.

Vasoactive intestinal peptide (VIP) is a small neuropeptide, which exerts pleiotropic functions. Based on its immunomodulatory, secretory, and possibly trophic effects, VIP is a valuable candidate molecule for the management of autoimmune disease. The purpose of this study was to develop a recombinant viral vector capable of directing the expression of functional VIP. The vector rAd5CMVhVIP was constructed and used to infect 293 cells. VIP expression was measured by an ELISA and function was evaluated by measurement of intracellular cAMP formation. rAd5CMVhVIP directed VIP expression and the transgenic VIP elicited a dose-dependent increase of intracellular cAMP, mediated through the VIP receptor VPAC(1). This is the first report showing the construction of a recombinant viral vector encoding biologically active VIP.

The aim of the study was to assess the strength of the online tool RiskCheck Bladder Cancer©, version 5.0 (RCBC) for early detection of bladder cancer (BC).RCBC was evaluated retrospectively based on the data of 241 patients, of which 141 were suffering from BC. Statistical analysis was performed by descriptive statistics, nonparametric group comparison, classification tree analysis and ROC analysis.ROC analysis of the risk classification showed a sensitivity of 71.6%, a specificity of 56.5%, a positive predictive value of 67.8%, a negative predictive value of 52% and an accuracy of 63.5%. BC risk factors ranked by importance are time of smoking (p0.0001), gender (within the nonsmoking group: p0.009), occupational toxin exposure (within the group35 years of smoking: p0.048) and amount of consumed cigarettes resulting in a 95% association with BC (within the group35 years of smoking: p0.0001).The high predictive power of RCBC for the identification of asymptomatic patients living under risk could be demonstrated.

Personalised medicine has the potential to increase therapeutic effectiveness, reduce side effects and lower cost. This approach has recently taken off in oncology where different malignancies may be treated with specific drugs based on genetic biomarkers or other tumour characteristics. This type of tailored therapy could also be developed for immune-mediated inflammatory disease, for which rheumatoid arthritis (RA) may serve as a prototype. While novel treatments are able to halt or even prevent disease progression, not all RA patients respond, and stratification of patient groups is needed. The identification of biomarkers predictive of the clinical response to specific treatments in subsets of patients may soon become reality in a variety of diseases.

Inflammation of synovium is one of the hallmarks of rheumatoid arthritis (RA). Analysis of synovial tissue has increased our understanding of RA pathogenesis, aided in identifying potential therapeutic targets and has been used in the response and mechanistic evaluation of antirheumatic treatments. In addition, studies are ongoing, aimed at the identification of diagnostic and prognostic biomarkers in the synovium. This paper outlines the currently used procedures for sampling and processing of synovial tissue, and presents a standardised recommendation to support multicentre translational research.

The aim of this study was to evaluate sex- and age-related variations of the nutritional status in the aged population of central Sardinia, a geographical area with a high frequency of long-lived people, particularly men.The sample consisted of 200 subjects over 70 years of age (men: N= 100, age= 81.0 +/- 7.0 years; women: N= 100, age= 81.5 +/- 7.3 years).Orroli (central Sardinia, Italy).Mini nutritional assessment (MNA) and bioelectrical impedance vector analysis (BIVA) were used to evaluate nutritional status and body composition.The indicators revealed a generally good nutritional status. The MNA results (men: 24.6 +/- 2.2; women: 23.4 +/- 2.5) showed that 64.1% of the subjects had a normal nutritional status and only a small proportion (1.2%) could be classified as malnourished. BIVA showed that most subjects (74.2%) were normal, while the prevalence of low body cell mass was 10.7% and that of dehydration 11.2%. According to the MNA, the nutritional status was significantly better in the men. Almost three-quarters of the men (73.1%) were well nourished vs. half of the women (50.6%). A worsening of the nutritional status with age was observed. The proportion of malnourished individuals, as assessed by MNA, increased from 0% to 9.1% from 70-79 to90 years.With respect to their contemporaries from other regions, the elderly of Orroli presented a better nutritional status, a similar worsening with age and generally higher sexual dimorphism.

Depleted uranium (DU) intake rates and subsequent dose rates were estimated for personnel entering armored combat vehicles perforated with DU penetrators (level II and level III personnel) using data generated during the Capstone Depleted Uranium (DU) Aerosol Study. Inhalation intake rates and associated dose rates were estimated from cascade impactors worn by sample recovery personnel and from cascade impactors that served as area monitors. Ingestion intake rates and associated dose rates were estimated from cotton gloves worn by sample recovery personnel and from wipe test samples from the interior of vehicles perforated with large caliber DU munitions. The mean DU inhalation intake rate for level II personnel ranged from 0.447 mg h-1 based on breathing zone monitor data (in and around a perforated vehicle) to 14.5 mg h-1 based on area monitor data (in a perforated vehicle). The mean DU ingestion intake rate for level II ranged from 4.8 mg h-1 to 38.9 mg h-1 based on the wipe test data including surface to glove transfer factors derived from the Capstone data. Based on glove contamination data, the mean DU ingestion intake rates for level II and level III personnel were 10.6 mg h-1 was and 1.78 mg h-1, respectively.more » Effective dose rates and peak kidney uranium concentration rates were calculated based on the intake rates. The peak kidney uranium concentration rate cannot be multiplied by the total exposure duration when multiple intakes occur because uranium will clear from the kidney between the exposures.« less

Objectives. Altered lipid levels may occur in autoimmune diseases, for example low cholesterol levels have been described in rheumatoid arthritis (RA). Serum lipid profiles in patients with Sjogren's syndrome (SS) have not been investigated. We hypothesized decreased lipid levels in SS patients and an inverse relationship with disease activity. Methods. Serum lipid levels (total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides) and additional data regarding disease measures (clinical immunology parameters, focus score from labial salivary gland biopsy, salivary flow and ophthalmological measures) were available for 46 primary SS patients and 12 xerostomic controls. Results. Significant differences between SS patients and controls means (S.D.) were seen for HDL (P^ 0.04) and total cholesterol (P^ 0.02). LDL (P^ 0.12) and triglyceride (P^ 0.08) levels were not different. In SS patients, but not in controls, total cholesterol (P^ 0.003) and HDL cholesterol (P^ 0.003) predicted immunoglobulin G levels. Anti-SSA antibodies were related to a lower total cholesterol (P^ 0.02) and anti-SSB antibodies to a lower HDL cholesterol level (P^ 0.0497). Conclusions. Significant differences were seen in serum lipid levels of primary SS patients and these were associated with serological measures of inflammation. Our results are comparable to earlier findings in RA patients and raise questions related to adverse cardiovascular consequences in SS. Altered lipid levels have been reported in patients with active autoimmune disorders. For example, several groups have reported on various changes in lipid levels in rheumatoid arthritis (RA) patients (1-9). A decreased level of high-density lipoprotein (HDL) cholesterol with inflammation seems to be a consistent finding. Additionally, a higher risk of atherosclerosis and cardiovascular mortality is seen in RA (10). Increased lipid levels have been found in patients with systemic lupus erythematosus (SLE), where disease activity may be related to increases in levels of triglyceride and very low-density lipoprotein (VLDL) cholesterol, while HDL cholesterol was decreased. Inflammatory proteins and autoanti- bodies in SLE are possibly associated with an increased risk of cardiovascular disease (11, 12). Sjogren's syndrome (SS) is a systemic autoimmune disease mainly characterized by ocular and oral dryness (keratoconjuncti- vitis sicca and xerostomia). There is a distinction between primary SS and secondary SS, the latter developing in the presence of other connective tissue diseases, like SLE or RA (13). Sjogren's syndrome occurs predominantly in peri- and post-menopausal women. Detailed investigations of serum lipid profiles or the prevalence of atherosclerosis in patients with SS have yet to be performed. One of the few studies related to this topic has concentrated on the distinction between pseudo-Sjogren's syndrome in patients with hyperlipidaemia and genuine SS using magnetic resonance imaging (MRI) (14). In the present study, we sought to compare serum lipid profiles in patients with primary SS and non-SS xerostomic patients. We hypothesized that serum lipid levels in SS patients would be lower than those in xerostomic controls. Additionally, we investigated the relationship between serum lipid levels and measures of inflammatory disease activity in patients with SS. Based on reports for other autoimmune diseases, we postulated an inverse relationship for such measures with lipid levels.

Objectives: Congenital heart block occurring in the foetus and neonate may be associated with maternal anti-SS-A/anti-SS-B autoantibodies (anti-SSA/anti-SSB). The adult atrioventricular node is generally thought to be resistant to the damaging effects of anti-SSA/anti-SSB. However, case reports suggest that heart block developing in adult Sjogren's syndrome (SS) patients may be associated with these autoantibodies. Therefore, we investigated the relationship between serum antibodies and heart block in adult SS patients. Methods: We abstracted data from clinic patient records. Diagnosis of primary SS was based on American European classification criteria. Electrocardiograms (EKGs), laboratory immunology parameters, lipid profiles, and focus scores from labial salivary gland biopsies were available for 51 SS patients. Fifteen patients had follow-up EKGs. PR interval >= 200 ms was considered to be first-degree heart block. Results: Five patients showed prolonged PR intervals; the presence of heart block was not related to the presence of anti-SSA antibodies. However, significant differences between patients with prolonged and normal PR intervals were seen for mean focus scores (p

The aim of the study was to assess the value of liquid-based urinary cytology as a tool to perform uCyt+ and Multicolour-FISH in patients under follow-up after urothelial cancer. Therefore, standard cytology was compared to liquid-based cytology with the addition of the uCyt+ test, which traces the three monoclonal antibodies M344, LDQ10 and 19A211 in exfoliated urothelial cells; and Multicolour-FISH (including centromere-specific probes for chromosomes 3, 7, 17 and a locus-specific probe for 9p21/p16) performed on thin-layer specimens. UCyt+ showed an overall sensitivity of 86.2% and cytology of 45.0%. Overall sensitivity of both the tests combined was 90%. Sensitivity of Multicolour-FISH was 96.4%. All conventional cytology diagnoses were confirmed by liquid-based cytology. Liquid-based cytology is a valid tool for the performance of adjunctive analyses, such as uCyt+ and Multicolour-FISH, on residual cellular material.

Female nonobese diabetic (NOD) mice develop spontaneous autoimmune sialadenitis and loss of salivary flow, and are a widely used model of Sjögren's syndrome. We examined the feasibility of local salivary gland immunomodulatory gene delivery to alter these sequelae in NOD mice. We constructed recombinant adeno-associated virus (rAAV) vectors encoding either human interleukin 10 (rAAVhIL-10) or beta-galactosidase (rAAVLacZ, control vector). Mice received rAAVhIL-10 or rAAVLacZ by retrograde submandibular ductal instillation either at age 8 weeks (early, before onset of sialadenitis), or at 16 weeks (late, after onset of sialadenitis). As a systemic treatment control, separate mice received intramuscular delivery of rAAVhIL-10 at each time point. Both submandibular and intramuscular delivery of vector led to low circulating levels of hIL-10. After submandibular administration of rAAVhIL-10, salivary flow rates at 20 weeks for both the early and late treatment groups were significantly higher than for both rAAVLacZ-administered and untreated mice. Systemic delivery of rAAVhIL-10 led to improved salivary flow in the late treatment group. Inflammatory infiltrates in submandibular glands, however, were significantly reduced only in mice receiving rAAVhIL-10 locally in the salivary gland compared with mice receiving this vector intramuscularly, or rAAVLacZ or no treatment. In addition, after submandibular rAAVhIL-10 delivery, NOD mice exhibited significantly lower blood glucose, and higher serum insulin, levels than all other groups, indicating some systemic benefit of this treatment. These studies show that expression of hIL-10 by rAAV vectors can have disease-modifying effects in the salivary glands of NOD mice, and suggest that local immunomodulatory gene transfer may be useful for managing the salivary gland pathology in Sjögren's syndrome.

Clinical applications of gene transfer technology initially targeted the treatment of inherited monogenetic disorders and cancers refractory to conventional therapies. Today, gene transfer approaches are being developed for most tissues and for multiple disorders including those affecting quality of life. The focus herein is eventual application of gene transfer technology for the management of organ-directed autoimmunity. A specific example is presented: Sjögren's syndrome and localized salivary gland gene transfer. The status of relevant pre-clinical gene transfer studies is reviewed, with an emphasis on use of adenoviral and adeno-associated viral vectors. Current limitations of effective organ-directed gene transfer are also discussed.

The limitations of cytology and the invasiveness of cystoscopy for detecting bladder cancer generate increasing interest in noninvasive, urine bound diagnostic tools. We assessed the diagnostic value of the newly developed immunocytochemical test, Immunocyt, which detects cellular markers specific for transitional cell cancer in the voided urine of patients with bladder cancer.Participating in our prospective study were 264 consecutive patients with a mean age of 65.9 years, including 114 in whom symptoms were suggestive of bladder cancer and 150 who were being followed after complete transurethral resection of superficial transitional cell carcinoma. Voided urine specimens were evaluated by standard cytology and the Immunocyt test, which traces the monoclonal antibodies M344, LDQ10 and 19A211 against transitional cell carcinoma in exfoliated urothelial cells. In all cases cystoscopy was subsequently performed and any suspicious lesion was evaluated by biopsy.Histologically proved transitional cell carcinoma was found in 79 patients. Immunocyt with cytology had 89.9% sensitivity overall (84, 88 and 96.5% in grades 1 to 3 disease, respectively). A total of 34 (43%), 3 (3.8%) and 34 (43%) cases were positive on Immunocyt only, cytology only and both evaluations, respectively. In 8 cases (10.1%) both tests were negative. Overall Immunocyt only was 86.1% sensitive (84, 84 and 89.6% in grades 1 to 3 disease, respectively) and 79.4% specific. Overall cytology only was 46.8% sensitive (4, 52 and 79.3% in grades 1 to 3 disease, respectively) and 98.2% specific.Immunocyt is a noninvasive, highly sensitive test for detecting transitional cell carcinoma of all grades and stages. When combined with conventional urinary cytology, it may replace cystoscopy in select patients, especially in followup protocols of low grade transitional cell carcinoma.