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Objectives: Determine global skin transcriptome patterns of early diffuse systemic sclerosis (SSc) and how they differ from later disease.Methods: Skin biopsy RNA from 48 patients in the Prospective Registry for Early Systemic Sclerosis (PRESS) cohort (mean disease duration 1.3 years) and 33 matched healthy controls was examined by next-generation RNA sequencing. Data were analysed for cell type-specific signatures and compared with similarly obtained data from 55 previously biopsied patients in Genetics versus Environment in Scleroderma Outcomes Study cohort with longer disease duration (mean 7.4 years) and their matched controls. Correlations with histological features and clinical course were also evaluated.Results: SSc patients in PRESS had a high prevalence of M2 (96%) and M1 (94%) macrophage and CD8 T cell (65%), CD4 T cell (60%) and B cell (69%) signatures. Immunohistochemical staining of immune cell markers correlated with the gene expression-based immune cell signatures. The prevalence of immune cell signatures in early diffuse SSc patients was higher than in patients with longer disease duration. In the multivariable model, adaptive immune cell signatures were significantly associated with shorter disease duration, while fibroblast and macrophage cell type signatures were associated with higher modified Rodnan Skin Score (mRSS). Immune cell signatures also correlated with skin thickness progression rate prior to biopsy, but did not predict subsequent mRSS progression.Conclusions: Skin in early diffuse SSc has prominent innate and adaptive immune cell signatures. As a prominently affected end organ, these signatures reflect the preceding rate of disease progression. These findings could have implications in understanding SSc pathogenesis and clinical trial design. [ABSTRACT FROM AUTHOR]

Study design:Two randomized, double-blind, placebo-controlled trials.Objective:To evaluate the efficacy and safety of fampridine sustained-release tablets (fampridine-SR) 25 mg twice daily for moderate-to-severe spasticity in patients with chronic spinal cord injury (SCI).Setting:United States and Canada.Methods:Patients with incomplete chronic SCI were randomized to twice daily fampridine-SR 25 mg or placebo, with a 2-week single-blind placebo run-in, a 2-week titration, 12 weeks of stable dosing, 2 weeks of downward titration and 2 weeks of untreated follow-up. Co-primary end points were the change from baseline, averaged over the double-blind treatment period, for Ashworth score (bilateral knee flexors and extensors) and a 7-point Subject Global Impression of treatment (SGI; 1, terrible; 7, delighted). Secondary end points were: Penn Spasm Frequency Scale; the motor/sensory score from the International Standards for Neurological Classification of SCI; Clinician's Global Impression of Change of neurological status; and the International Index of Erectile Function (men) or the Female Sexual Function Index (women).Results:The populations were 212 and 203 patients in the two studies, respectively. Changes from baseline in Ashworth score were −0.15 (placebo) and −0.19 (fampridine-SR) in the first study, and −0.16 (placebo) and −0.28 (fampridine-SR) in the second study. The between-treatment difference was not significant for either the Ashworth score or the SGI and, with few exceptions, neither were the secondary end points. Fampridine-SR was generally well tolerated; treatment-emergent adverse events (TEAEs) and serious TEAEs were reported with similar frequency between treatments.Conclusion:Fampridine-SR was well tolerated. No significant differences were observed between treatment groups for the primary end points of Ashworth score and SGI. [ABSTRACT FROM AUTHOR]

Study design:Double-blind, placebo-controlled, flexible-dose study.Objective:To evaluate the efficacy, safety and tolerability of oral sildenafil in women with female sexual arousal disorder as a result of SCI (paraplegia/tetraplegia).Setting:The study was conducted at clinical practice sites in North America (n =23), 11 European countries (n =23), Australia (n =4) and South Africa (n =2).Methods:129 women were randomized and treated with sildenafil or matching placebo. A 4-week baseline period was followed by 12 weeks of treatment, which could be increased from 50 to 100 mg or decreased to 25 mg once during the treatment period, depending on efficacy and tolerability. By use of an event log, sexual activity was monitored between screening and the end of treatment. The Sexual Function Questionnaire, the Sexual Quality of Life Questionnaire-Female, a global efficacy question and Sexual Distress Question were also assessed.Results:Sildenafil-treated women and placebo-treated women had an increase in their percentage of sexual activities throughout the course of the study, with no statistically significant difference between groups in the percentage of successful sexual activities at end of treatment versus baseline. There were also no statistically significant differences between sildenafil- and placebo-treated women on the aforementioned measures. The most common adverse events included headache and vasodilatation.Conclusion:The results of this study are similar to other reports regarding a lack of clinically meaningful benefit of sildenafil in other populations of women.Sponsorship:This study was sponsored by Pfizer Inc. [ABSTRACT FROM AUTHOR]

In a double-blind comparative trial of sulpiride (600-1,800 mg/day) and trifluoperazine (15-45 mg/day) in 38 chronic schizophrenic patients, ratings of therapeutic results and unwanted effects were made at two-weekly interviews during the six weeks treatment period. The results show that sulpiride has neuroleptic properties and a spectrum of therapeutic activity similar to that of trifluoperazine. There was an association between plasma sulpiride levels and therapeutic response after four weeks' treatment. [ABSTRACT FROM AUTHOR]