Role of Pro-Apoptotic Bcl2-Homology-3 Domain (BH3)-Only Proteins in the Mutant SOD1 Mouse Model of ALS

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease involving rapid degeneration of motor neurons in the spinal cord and retraction of their axonal projections to the neuromuscular junctions. Several known mutations linked to some familial cases of ALS have been linked to mutations in Cu/Zn superoxide dismutase (SOD1), resulting in mitochondrial oxidative stress and intrinsic apoptosis. Transgenic mice expressing a G93A mutant of SOD1 provide an in vivo model to investigate motor neuron death during disease progression. The principal regulators of intrinsic apoptosis are the Bcl-2 family proteins. While some members of this family are pro-survival, the Bcl-2 homology-3 domain (BH3)-only proteins are pro-apoptotic. Since cooperation of various BH3-only proteins is often necessary to induce apoptosis, we hypothesized that multiple BH3-only proteins are induced in spinal motor neurons during the progression of ALS. Furthermore, we postulated that these pro-apoptotic proteins act in a coordinated manner to cause motor neuron death. We utilized laser capture microdissection (LCM) to collect highly enriched populations of spinal motor neurons from wild type vs. SOD1 mutant mice. RNA was then isolated from the captured motor neurons and used for quantitative real time PCR analysis of BH3-only transcript expression. We did not detect any significant differences in the expression of BH3-only transcripts between end stage SOD1 mutant mice and age-matched wild type animals. In contrast, immunohistochemical staining for the BH3-only proteins, Bik, Bad, BNip3, Bid, Noxa, Puma, and Hrk/Dp5, demonstrated selective staining of Hrk/Dp5, Bnip3, and Bid in astrocytes of lumbar spinal cord from end stage mutant SOD1 mice. Hrk/Dp5, Bnip3, and Bid were not observed in astrocytes of wild type mouse spinal cords. These novel findings indicate a potentially important role for astrocytes expressing Hrk/Dp5, Bnip3, and Bid in ALS disease progression

Acquired Human Papilloma Virus Type 6-Associated Epidermodysplasia Verruciformis in a Patient With Systemic Lupus Erythematosus

Although historically known as a genetic disorder, epidermodysplasia verruciformis (EV) might be acquired in patients with a noninherited defective cell-mediated immunity. This article reports a case of EV in a patient with systemic lupus erythematosus and a history of 3 years immunosuppressive methylprednisolone treatment. The microscopic features of the skin biopsy showed morphologic changes of the keratinocytes characteristic of human papilloma virus (HPV) infections and immunoreactivity to p16. HPV genotyping demonstrated the presence of HPV 6 which belongs to a low-risk mucosal HPV group and has not been reported in EV previously. The clinical recognition of EV in immunocompromised patients and subsequent HPV typing is important because some patients will develop squamous cell carcinoma

A Catastrophic-Onset Longitudinal Myelitis Accompanied by Bilateral Internuclear Ophthalmoplegia in a Patient with Systemic Lupus Erythematosus

Transverse myelitis (TM) extending from midbrain to the entire spinal cord accompanied by internuclear ophthalmoplegia is extremely rare but cause serious central nervous system complications in patients with systemic lupus erythematosus. We report a case of a 28-yr-old woman with TM extending from the midbrain to the conus medullaris longitudinally and internuclear ophthalmoplegia associated with systemic lupus erythematosus. Her neurological symptoms had an abrupt catastrophic onset and rapidly progressed to respiratory failure within 24 hr. Bilateral internuclear ophthalmoplegia was also followed by TM. Brain MR images showed definite brainstem lesions, which were deeply associated with internuclear ophthalmoplegia, and diffuse signal changes in the whole spinal cord, medulla, pons and midbrain. Clinical improvement of her ophthalmoplegia and of neurological dysfunction of the upper extremities was noted after prompt and aggressive treatment with intravenous pulsed methylprednisolone and cyclophosphamide. However, the neurological dysfunction of the lower limbs and bladder and colon paralysis were almost unchanged until six months passed

The prevalence of rheumatic diseases in central Greece: a population survey

<p>Abstract</p> <p>Background</p> <p>Rheumatic diseases are a major health and financial burden for societies. The prevalence of rheumatic diseases may change over time, and therefore, we sought to estimate the prevalence of rheumatic diseases in an adult population of central Greece.</p> <p>Methods</p> <p>In this prospective cross-sectional population survey, a random sample of adult population was drawn from poll catalogues of a region in central Greece. A postal questionnaire was sent to 3,528 people for the presence of any rheumatic disease. All positive cases were further confirmed by clinical examination using the American College of Rheumatoloy criteria. Multiple regression analysis was used to assess risk factors for rheumatic diseases.</p> <p>Results</p> <p>The response rate was 48.3% (1,705 answers). Four hundred and twenty individuals (24.6%) had a rheumatic disease. The prevalence of rheumatoid arthritis was 0.58% (95% confidence interval [CI], 0.32-0.87), of psoriatic arthritis was 0.35% (95% CI, 0.33-1.13), of ankylosing spondylitis was 0.29% (95% CI, 0.28-0.94), of primary Sjögren's syndrome was 0.23% (95% CI, 0.22-0.75) and of systemic lupus erythematosus was 0.11% (95% CI, 0.11-0.37). One individual had systemic sclerosis (prevalence, 0.058%), 1 individual had dermatomyositis (prevalence, 0.058%; 95% CI, 0.05-0.18), 2 individuals had vasculitis (prevalence 0.11%; 95% CI, 0.11-0.37), 81 individuals had gout (prevalence, 4.75%; 95% CI, 4.41-5.13), and 304 individuals had osteoarthritis (OA) (prevalence 17.82%; 95% CI, 16.50-19.34). Gout was associated with male gender, diabetes mellitus, and hypertension, and OA was associated with age, female gender, and hypertension.</p> <p>Conclusions</p> <p>Rheumatic diseases are common in central Greece, affecting nearly a quarter of adult population. OA and gout are the most common joint disorders.</p

Short-term efficacy of physical interventions in osteoarthritic knee pain. A systematic review and meta-analysis of randomised placebo-controlled trials.

BACKGROUND: Treatment efficacy of physical agents in osteoarthritis of the knee (OAK) pain has been largely unknown, and this systematic review was aimed at assessing their short-term efficacies for pain relief. METHODS: Systematic review with meta-analysis of efficacy within 1-4 weeks and at follow up at 1-12 weeks after the end of treatment. RESULTS: 36 randomised placebo-controlled trials (RCTs) were identified with 2434 patients where 1391 patients received active treatment. 33 trials satisfied three or more out of five methodological criteria (Jadad scale). The patient sample had a mean age of 65.1 years and mean baseline pain of 62.9 mm on a 100 mm visual analogue scale (VAS). Within 4 weeks of the commencement of treatment manual acupuncture, static magnets and ultrasound therapies did not offer statistically significant short-term pain relief over placebo. Pulsed electromagnetic fields offered a small reduction in pain of 6.9 mm [95% CI: 2.2 to 11.6] (n = 487). Transcutaneous electrical nerve stimulation (TENS, including interferential currents), electro-acupuncture (EA) and low level laser therapy (LLLT) offered clinically relevant pain relieving effects of 18.8 mm [95% CI: 9.6 to 28.1] (n = 414), 21.9 mm [95% CI: 17.3 to 26.5] (n = 73) and 17.7 mm [95% CI: 8.1 to 27.3] (n = 343) on VAS respectively versus placebo control. In a subgroup analysis of trials with assumed optimal doses, short-term efficacy increased to 22.2 mm [95% CI: 18.1 to 26.3] for TENS, and 24.2 mm [95% CI: 17.3 to 31.3] for LLLT on VAS. Follow-up data up to 12 weeks were sparse, but positive effects seemed to persist for at least 4 weeks after the course of LLLT, EA and TENS treatment was stopped. CONCLUSION: TENS, EA and LLLT administered with optimal doses in an intensive 2-4 week treatment regimen, seem to offer clinically relevant short-term pain relief for OAK

ELSA in industrial robotics

Purpose of ReviewIndustry is changing; converging technologies allow a fourth Industrial Revolution, where it is envisaged that robots will work alongside humans. We investigate how the research community is responding to the ethical, legal, and social aspects of industrial robots, with a primary focus on manufacturing industry.Recent FindingsThe literature shows considerable interest in the impact of robotics and automation on industry. This interest spans many disciplines, which is to be expected given that the ELS impacts of industrial robotics may be profound in their depth and far-reaching in their scope.SummaryWe suggest that the increasing importance of human-robot interaction (HRI) reduces the differentiation between industrial robotics and other robotic domains and that the main challenges to successful adoption for the benefit of human life are above all political and economic. Emerging standards and legal frameworks may scaffold this success, but it is apparent that getting it wrong might have repercussions that last for generations

Rituximab versus an alternative TNF inhibitor in patients with rheumatoid arthritis who failed to respond to a single previous TNF inhibitor: SWITCH-RA, a global, observational, comparative effectiveness study.

OBJECTIVES: To compare the effectiveness of rituximab versus an alternative tumour necrosis factor (TNF) inhibitor (TNFi) in patients with rheumatoid arthritis (RA) with an inadequate response to one previous TNFi. METHODS: SWITCH-RA was a prospective, global, observational, real-life study. Patients non-responsive or intolerant to a single TNFi were enrolled ≤4 weeks after starting rituximab or a second TNFi. Primary end point: change in Disease Activity Score in 28 joints excluding patient's global health component (DAS28-3)-erythrocyte sedimentation rate (ESR) over 6 months. RESULTS: 604 patients received rituximab, and 507 an alternative TNFi as second biological therapy. Reasons for discontinuing the first TNFi were inefficacy (n=827), intolerance (n=263) and other (n=21). A total of 728 patients were available for primary end point analysis (rituximab n=405; TNFi n=323). Baseline mean (SD) DAS28-3-ESR was higher in the rituximab than the TNFi group: 5.2 (1.2) vs 4.8 (1.3); p<0.0001. Least squares mean (SE) change in DAS28-3-ESR at 6 months was significantly greater in rituximab than TNFi patients: -1.5 (0.2) vs -1.1 (0.2); p=0.007. The difference remained significant among patients discontinuing the initial TNFi because of inefficacy (-1.7 vs -1.3; p=0.017) but not intolerance (-0.7 vs -0.7; p=0.894). Seropositive patients showed significantly greater improvements in DAS28-3-ESR with rituximab than with TNFi (-1.6 (0.3) vs -1.2 (0.3); p=0.011), particularly those switching because of inefficacy (-1.9 (0.3) vs -1.5 (0.4); p=0.021). The overall incidence of adverse events was similar between the rituximab and TNFi groups. CONCLUSIONS: These real-life data indicate that, after discontinuation of an initial TNFi, switching to rituximab is associated with significantly improved clinical effectiveness compared with switching to a second TNFi. This difference was particularly evident in seropositive patients and in those switched because of inefficacy