B cells in systemic sclerosis: a possible target for therapy

Systemic sclerosis (SSc) is an autoimmune disease characterized by excessive extracellular matrix (ECM) deposition in the skin and other visceral organs and it is associated with immune activation characterized by autoantibody production, release of various cytokines and T-lymphocyte activation. Several recent lines of evidence in animal models and in SSc patients indicate a potential role for B cells in the SSc. B cells have arisen as a possible player in tissue fibrosis in some experimental models and, since IL-6 produced by B cells, along with TGF-β, may induce matrix synthesis and less collagen degradation, targeting B cells could be one way to reduce ECM deposition and reduce the inflammatory background. Both SSc patients and tight-skin mice, a genetic model of SSc, have intrinsic B-cell abnormalities characterized by chronic B-cell activation. SSc patients present an increased number of na?ve B cells and an activation of memory B cells, despite a reduction in their number. B cells from SSc patients exhibit increased expression of CD19. Remarkably, CD19 loss or B-cell depletion using antimouse CD20 antibody suppresses the development of skin hyperplasia and autoimmunity in tight-skin mice. Additionally, recent studies revealed a possible beneficial effect of anti-human CD20 antibody (Rituximab) therapy on skin fibrosis and lung involvement in SSc patients. These studies reported also the safety of Rituximab in SSc patients. All these findings suggest a possible role of antiCD20 treatment in SSc patients.     

Fibroblast growth factor 23 (FGF23) gene polymorphism in children with Kawasaki syndrome (KS) and susceptibility to cardiac abnormalities

Background

Fibroblast Growth Factor (FGF) 23 influences endothelial integrity and few reports have studied the association between FGF23 and Kawasaki syndrome (KS), a childhood vasculitis displaying a high risk of subsequent cardiac abnormalities (CaA).

Aim

To investigate the genetic variation in the FGF23 gene in a cohort of KS children and its association with serum FGF23 levels and eventual development of CaA, including both coronary artery dilatations and aneurysms.

Patients and methods

84 Italian KS children were recruited; 24/84 (28.6%) developed CaA. Each patient underwent evaluation of serum FGF23 levels and FGF23 genotype: the frequency of the c.212-37insC (rs3832879) polymorphism in intron 1 was examined and compared with sex, age at disease onset, fever duration, laboratory data, and occurrence of CaA. Univariate statistical analysis of categorical parameters was performed by the Pearson’s Chi-square test or Fisher’s exact test as appropriate. Parametric variables were assessed by Student’s t-test for unpaired data. Independent predictors of disease were studied by a logistic regression model.

Results

28/84 patients carried the FGF23 polymorphism (33.3%) and had higher serum FGF23 levels (p <?0.01). FGF23 polymorphism was significantly associated with CaA compared to wild type FGF23 children (respectively, p =?0.03 and p =?0.05). The comparison with demographical, clinical or laboratory data was not significant.

Conclusions

The prevalent segregation of the c.212-37insC polymorphism in children with CaA advocates a possible functional FGF23 role in the predisposition to higher serum levels of FGF23 and potential occurrence of any coronary artery abnormalities in KS.

     

Anionic phospholipids calcium binding sites in Duchenne and murine X-linked muscular dystrophy

Duchenne muscular dystrophy (DMD) and murine X-linked muscular dystrophy (mdx) are genetically homologous and both characterized by absence of dystrophin. The function of this protein is not defined nor is the pathogenesis of the severe muscle necrosis and progressive weakness found in DMD but not in mdx. Recently we found that anionic phospholipid (AP) calcium binding sites are lacking at the muscle cell surface in DMD and we correlated these data with dystrophin deficiency and muscle necrosis. In order to verify the role of AP lack in the pathogenesis of muscle necrosis in DMD we studied the ultrastructural localization of these Ca⁺⁺ receptors in mdx muscle membrane showing that they are normally represented as they are in control mouse and normal human muscle. The absence of AP in DMD compared with a normal distribution in mdx suggests that these calcium binding site alterations play an important and specific role in muscle fiber necrosis. © 1994 John & Sons, Inc.     

Invasive tumor cells and prognosis in a selected population of patients with glioblastoma multiforme

BACKGROUND: After surgical resection, the residual, invasive glioblastoma (GBM) cells give rise to a recurrent tumor, which, in 96% of patients, arises adjacent to the resection margin. METHODS: In this study, the authors prospectively enrolled 25 patients with GBM who underwent gross total resection followed by adjuvant radiochemotherapy (with temozolomide). Tumor removal was achieved with resection margins that included the neighboring, apparently normal tissue (between 1 cm and 2 cm from the tumor border [B area]) and the tumor. RESULTS: Patients who had an absence of tumor cells in the neighboring, apparently normal white matter (B area) had better survival than patients who had the presence of tumor cells in the B area (21 months vs 12 months). This difference was statistically significant in univariate analysis (P = .005) and in multivariate analysis (P = .01). CONCLUSIONS: Aggressive tumor removal may improve survival, but the current results indicated that biologic commitment of 'penumbra' cells appear to be the most relevant factor for tumor recurrence and accounts for the fatal outcome of the disease.     

Factors Associated with Ease of Using Community-Based Systems of Care for CSHCN in Hawai’i

Objectives: To study factors contributing to difficulty using community-based services by families of children with special health care needs (CSHCN) in Hawai’i. Methods: Data source was the 2001 National Survey of Children With Special Health Care Needs. The study population included the 449 respondents who were surveyed after additional items were added to the original questionnaire. Outcome of interest was “% of CSHCN whose families report community-based service systems are organized so they can use them easily.” Explanatory variables included child health conditions (functional limitation, degree of severity, types of service needs), child and family characteristics (child age, maternal education, poverty level), and health services characteristics (partnership of family in decision making, family-centered coordinated care, adequate health insurance). Results: Children with special health care needs comprised 11.0% of < 18 years old children. Overall, 69% of respondents reported that community-based services could be used easily. Logistic regression analysis showed that the odds of reporting difficulties in using community-based services were almost 5 times higher for families who did not partner in decision making, 2.9 times higher for families who did not receive family-centered coordinated care, and 2.7 times higher for families who did not have adequate health insurance compared with families who were satisfied with the care received. Need for services contributed independently to reporting difficulties in community-based service use. Contrary to the hypothesized associations, severe health conditions or limited functionality did not contribute significantly to reporting difficulties in service use. Conclusions: Families who reported difficulties in using community-based services were those who have children who need extensive and varied services. Lack of involvement in decision making, lack of coordinated care in a medical home, and insufficient health insurance were the main obstacles to their ability to use community-based services easily.     

A study of factors influencing urinary arsenic excretion in exposed workers

This study was designed to evaluate the influence of occupational and non-occupational factors on urinary arsenic excretion in workers exposed to iAs (inorganic arsenic) in the dismantlement of a factory which once produced fertilisers. We measured iAs and its methylated metabolites in 108 urinary samples of workers exposed to iAs in July 2006. A total of 13.9% of the samples showed levels higher than the Biological Exposure Index (BEI) of 35 μg/l (mean value 23.9 μg/l). After the improvement of working conditions, in August–October 2006 we collected urinary samples from each of the 108 workers enrolled. We also administrated a questionnaire, in order to investigate the influence of occupational and non-occupational factors on the urinary arsenic excretion. A significant difference was observed in relation with seafood consumption and age stratification. We have found a significant reduction of urinary arsenic excretion between the two phases of biological monitoring, probably due to appropriate hygiene work-related interventions.     

Sensitivity and Reproducibility of Fast-FLAIR,FSE, and TGSE Sequences for the MRI Assessment of Brain Lesion Load in Multiple Sclerosis: A Preliminary Study

Fast fluid-attenuated inversion recovery (fast-FLAIR), fast spin echo (FSE), and turbo-gradient spin echo (TGSE), new pulse sequences for magnetic resonance imaging (MRI), are able to display multiple sclerosis (MS) lesions more conspicuously (fastFLAIR) and with shorter imaging times (FSE, TGSE) than is conventional spin-echo MRI. In this study, we scanned 7 MS patients, using fast-FLAIR (18 axial brain slices), FSE (27 slices), and TGSE (9 slices) sequences in the same session, to compare the brain MRI lesion loads detected by these different sequences and the intraobserver reproducibility of these measurements. On the subset of slices (n = 9) covered by all three measurements, the mean lesion load was 7,577 mm3 on fast-FLAIR, 5,248 mm³ on FSE, and 3,080 mm³ on TGSE (p = 0.006) sequences. The mean intraobserver coefficients of variation were 2. 92% for fast-FLAIR, 2.86% for FSE, and 4.31% for TGSE (not significant). These findings demonstrate that both fast-FLAIR and FSE sequences may be potentially useful for serial MRI studies for monitoring clinical trials, while TGSE might be useful for speeding diagnostic MRI in MS patients. Longitudinal, clinically correlated studies using these new MRI sequences are needed to confirm these preliminary data.     

The Effect of Omeprazole on Serum Concentrations of Theophylline, Pepsinogens A and C, and Gastrin in Elderly Duodenal Ulcer Patients

With the aim of verifying the effect of omeprazole treatment on theophyline serum concentration in elderly peptic ulcer patients, we studied 10 male subjects aged >65 years (mean age = 75.2, range = 67--86) with chronic obstructive bronchopneumonia and endoscopically diagnosed duodenal ulcer in acute phase. All subjects were treated with a slow-release formulation of theophylline 200 mg b.i.d. plus omeprazole 20 mg daily for 4 weeks. In all subjects serum concentrations of azote, creatinine, theophylline were determined at the beginning and after 1 and 4 weeks; at the beginning and end of the study, pepsinogen group A (PGA), pepsinogen group C(PGC) and gastrin were measured. Statistical analysis was performed with the Student's t-test for paired data. The results showed no statistically significant differences after 1 and 4 weeks of omeprazole treatment in serum concentrations of theophylline (T(0) = 7.4, T(1 week) = 7.5, T(4 weeks) = 6.0, p = ns), azote (T(0) = 45.2, T(1 week) = 30.5, T(4 weeks) = 36.1, p = ns), creatinine (T(0) = 1.27, T(1 week) = 1.02, T(4 weeks) = 1.16, p = ns), PGA (T(0) = 99.5, T(4 weeks) = 126.2, p = ns), and PGC (T(0) = 10.6, T(4 weeks) = 12.1, p = ns); however serum gastrin increased from T(0) = 70.2 plus minus 13.2 to T(4 weeks) = 130.3 plus minus 18.3 (p < 0.0001). It was concluded that (1) serum concentration of theophylline is not affected by the concomitant omeprazole treatment lasting 1 month in elderly patients suffering from chronic obstructive bronchopneumonia and peptic ulcer, (2) modifications of dosages of theophylline and/or omeprazole are not necessary in the elderly with normal renal function, (3) the increase in fasting serum gastrin after 4 weeks of treatment may indicate that omeprazole 20 mg daily is efficacious in inhibiting gastric acid secretion in the elderly people.     

Constitutive knockout of Surf1 is associated with high embryonic lethality,mitochondrial disease and cytochrome c oxidase deficiency in mice

We report here the creation of a constitutive knockout mouse for SURF1, a gene encoding one of the assembly proteins involved in the formation of cytochrome c oxidase (COX). Loss-of-function mutations of SURF1 cause Leigh syndrome associated with an isolated and generalized COX deficiency in humans. The murine phenotype is characterized by the following hallmarks: (1) high post-implantation embryonic lethality, affecting approximately 90% of the Surf1(-/-) individuals; (2) early-onset mortality of post-natal individuals; (3) highly significant deficit in muscle strength and motor performance; (4) profound and isolated defect of COX activity in skeletal muscle and liver, and, to a lesser extent, heart and brain; (5) morphological abnormalities of skeletal muscle, characterized by reduced histochemical reaction to COX and mitochondrial proliferation; (6) no obvious abnormalities in brain morphology, reflecting the virtual absence of overt neurological symptoms. These results indicate a function for murine Surf1 protein (Surf1p) specifically related to COX and recapitulate, at least in part, the human phenotype. This is the first mammalian model for a nuclear disease gene of a human mitochondrial disorder. Our model constitutes a useful tool to investigate the function of Surf1p, help understand the pathogenesis of Surf1p deficiency in vivo, and evaluate the efficacy of treatment.