Objectives: To evaluate further in a phase III, double blind trial the efficacy of infliximab in patients with active psoriatic arthritis (PsA), as observed in the smaller IMPACT trial. Methods: 200 ...patients with active PsA unresponsive to previous treatment were randomised to infusions of infliximab 5 mg/kg or placebo at weeks 0, 2, 6, 14, and 22. Patients with inadequate response entered early escape at week 16. The primary measure of clinical response was ACR20. Other measures included Psoriatic Arthritis Response Criteria (PsARC), Psoriasis Area and Severity Index (PASI), and dactylitis and enthesopathy assessments. Results: At week 14, 58% of patients receiving infliximab and 11% of those receiving placebo achieved an ACR20 response and 77% of infliximab patients and 27% of placebo patients achieved PsARC (both p<0.001). Among the 85% of patients with at least 3% body surface area psoriasis involvement at baseline, 53/83 (64%) patients receiving infliximab had at least 75% improvement in PASI compared with 2/87 (2%) patients receiving placebo at week 14 (p<0.001). These therapeutic effects were maintained through the last evaluation (week 24). Fewer infliximab patients than placebo patients had dactylitis at week 14 (18% v 30%; p = 0.025) and week 24 (12% v 34%; p<0.001). Fewer infliximab patients (22%) than placebo patients (34%) had active enthesopathy at week 14 (p = 0.016); corresponding figures at week 24 were 20% and 37% (p = 0.002). Infliximab was generally well tolerated, with a similar incidence of adverse events in each group. Conclusions: Infliximab 5 mg/kg through 24 weeks significantly improved active PsA, including dactylitis and enthesopathy, and associated psoriasis.
We report on the first long-term application of squeezed vacuum states of light to improve the shot-noise-limited sensitivity of a gravitational-wave observatory. In particular, squeezed vacuum was ...applied to the German-British detector GEO 600 during a period of three months from June to August 2011, when GEO 600 was performing an observational run together with the French-Italian Virgo detector. In a second period, the squeezing application continued for about 11 months from November 2011 to October 2012. During this time, squeezed vacuum was applied for 90.2% (205.2 days total) of the time that science-quality data were acquired with GEO 600. A sensitivity increase from squeezed vacuum application was observed broadband above 400 Hz. The time average of gain in sensitivity was 26% (2.0 dB), determined in the frequency band from 3.7 to 4.0 kHz. This corresponds to a factor of 2 increase in the observed volume of the Universe for sources in the kHz region (e.g., supernovae, magnetars). We introduce three new techniques to enable the long-term application of squeezed light, and show that the glitch rate of the detector did not increase from squeezing application. Squeezed vacuum states of light have arrived as a permanent application, capable of increasing the astrophysical reach of gravitational-wave detectors.
Regulatory T cell-mediated dominant tolerance has been demonstrated to play an important role in the prevention of autoimmunity. Here, we present data arguing that the forkhead transcription factor ...Foxp3 acts as the regulatory T cell lineage specification factor and mediator of the genetic mechanism of dominant tolerance. We show that expression of Foxp3 is highly restricted to the subset αβ of T cells and, irrespective of CD25 expression, correlates with suppressor activity. Induction of Foxp3 expression in nonregulatory T cells does not occur during pathogen-driven immune responses, and Foxp3 deficiency does not impact the functional responses of nonregulatory T cells. Furthermore, T cell-specific ablation of Foxp3 is sufficient to induce the identical early onset lymphoproliferative syndrome observed in Foxp3-deficient mice. Analysis of Foxp3 expression during thymic development suggests that this mechanism is not hard-wired but is dependent on TCR/MHC ligand interactions.
Currently available treatments for moderate to severe psoriasis are either incompletely effective in some patients, or are associated with toxic effects. Since tumour necrosis factor α (TNF-α) is ...thought to have a role in the pathogenesis of psoriasis, we did a double-blind, randomised trial to assess the clinical benefit and safety of infliximab-a monoclonal antibody against TNF-α.
33 patients with moderate to severe plaque psoriasis were randomly assigned intravenous placebo (n=11), infliximab 5 mg/kg (n=11), or infliximab 10 mg/kg (n=11) at weeks 0, 2, and 6. Patients were assessed at week 10 for the primary endpoint (score on the physician's global assessment PGA). Analysis was by intention to treat.
Of the 33 patients enrolled, three dropped out. Nine of 11 (82%) patients in the infliximab 5 mg/kg group were responders (good, excellent, or clear rating on PGA), compared with two of 11 (18%) in the placebo group (difference 64% 95% CI 20–89, p=0·0089), and ten of 11 (91%) patients in the infliximab 10 mg/kg group were responders (difference from placebo 73% 30-94, p=0·0019). The median time to response was 4 weeks for patients in both infliximab groups. There were no serious adverse events, and infliximab was well tolerated.
In this controlled trial, patients receiving the anti-TNF-α agent infliximab as monotherapy experienced a high degree of clinical benefit and rapid time to response in the treatment of moderate to severe plaque psoriasis compared with patients who received placebo. These findings suggest that TNF-α has a pivotal role in the pathogenesis of psoriasis.
Thymectomy of neonatal mice can result in the development of autoimmune pathology. It has been proposed that thymic output of regulatory T (T reg) cells is delayed during ontogeny and that the ...development of autoimmune disease in neonatally thymectomized mice is caused by the escape of self-reactive T cells before thymectomy without accompanying T reg cells. However, the kinetics of T reg cell production within the thymus during ontogeny has not been assessed. We demonstrate that the development of Foxp3-expressing T reg cells is substantially delayed relative to nonregulatory thymocytes during ontogeny. Based on our data, we speculate that induction of Foxp3 in developing thymocytes and, thus, commitment to the T reg cell lineage is facilitated by a signal largely associated with the thymic medulla.
We estimated international/national temporal trends in sit-ups performance for children and adolescents, and examined relationships between national trends in sit-ups performance and national trends ...in health-related/sociodemographic indicators. Data were obtained by systematically searching studies reporting on temporal trends in sit-ups performance for apparently healthy 9-17 year-olds, and by examining nationally representative fitness datasets. Trends at the country-sex-age level were estimated by sample-weighted regression models relating the testing year to mean sit-ups performance. International/national trends were estimated by a post-stratified population-weighting procedure. Pearson's correlations quantified relationships between national trends in sit-ups performance and national trends in health-related/sociodemographic indicators. A total of 9,939,289 children and adolescents from 31 countries/special administrative regions between 1964 and 2017 collectively showed a large improvement of 38.4% (95% CI: 36.8 to 40.0) or 7.1% per decade (95% CI: 6.8 to 7.4). Large international improvements were experienced by all age and sex groups, with the rate of improvement slowing from 1964 to 2000, stabilizing near zero until 2010, before declining. Trends differed between countries, with national trends in vigorous physical activity a strong, positive correlate of national trends in sit-ups performance. More sit-ups data are needed from low- and middle-income countries to better monitor trends in muscular fitness.
CRD42013003657.
Research priorities of people living with Turner syndrome Sandberg, David E; Singer, Dianne; Bugajski, Benjamin ...
American journal of medical genetics. Part C, Seminars in medical genetics,
March 2019, Volume:
181, Issue:
1
Journal Article
Open access
Despite major discoveries, traditional biomedical research has not always addressed topics perceived as priorities by patients and their families. Patient-centered care is predicated on research ...taking such priorities into account. The present study surveyed women with Turner syndrome (TS; 18+ years; n = 543), parents of women with TS (n = 232), and parents of younger daughters with TS (<18 years; n = 563), regarding their priorities for research. The study also included a quantitative audit of research categorized as either predominantly biomedical or psychological in the medical and other scientific literature. The overwhelming majority of all surveyed stakeholders (84% and higher) rated both biomedical and psychological research in TS as "very important," yet only approximately 9% of published research focused on psychological aspects of TS. The odds of women with TS identifying psychological research as "most important" was significantly lower (OR: 0.607; 95% CI: 0.375, 0.982 than the odds of parents making the same prioritization. Despite the majority of participants rating research as very important, only approximately half-rated participation in research as similarly important. The majority of respondents in all three groups (59%-73%) indicated they would "very likely" participate in research pertaining to eating or nutrition, quality of life, or genetic studies in TS. Substantially fewer expressed similar eagerness to participate in studies involving the study of a new medicine or medical device. Increased engagement of patient and family stakeholders in research requires that investigators select topics of study important to that community.
Small cell lung cancer (SCLC) is an aggressive cancer often diagnosed after it has metastasized. Despite the need to better understand this disease, SCLC remains poorly characterized at the molecular ...and genomic levels. Using a genetically engineered mouse model of SCLC driven by conditional deletion of Trp53 and Rb1 in the lung, we identified several frequent, high-magnitude focal DNA copy number alterations in SCLC. We uncovered amplification of a novel, oncogenic transcription factor, Nuclear factor I/B (Nfib), in the mouse SCLC model and in human SCLC. Functional studies indicate that NFIB regulates cell viability and proliferation during transformation.
The development of animal models of lung cancer is critical to our understanding and treatment of the human disease. Conditional mouse models provide new opportunities for testing novel ...chemopreventatives, therapeutics and screening methods that are not possible with cultured cell lines or xenograft models. This protocol describes how to initiate tumors in two conditional genetic models of human non-small cell lung cancer (NSCLC) using the activation of oncogenic K-ras alone or in combination with the loss of function of p53. We discuss methods for sporadic expression of Cre in the lungs through engineered adenovirus or lentivirus, and provide a detailed protocol for the administration of the virus by intranasal inhalation or intratracheal intubation. The protocol requires 1-5 min per mouse with an additional 30-45 min to set-up and allow for the recovery of mice from anesthesia. Mice may be analyzed for tumor formation and progression starting 2-3 weeks after infection.
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