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

Η προβληματική του φύλου στον Κάτουλλο, c. 63 και στα επύλλια του Οβιδίου, Ίφις και Ιάνθη (Μετ. 9.669-797) και Ερμαφρόδιτος και Σαλμακίδα (Μετ. 4.285-388).

Στην παρούσα εργασία εξετάζεται η προβληματική του φύλου στα επύλλια του Οβιδίου Ίφις και Ιάνθη (Μετ. 9.669-797), και Ερμαφρόδιτος και Σαλμακίδα (Μετ. 4.285-388) και στην ιστορία του Κατούλλου για τον Άττι, όπως αυτή καταγράφεται στο ποίημα 63 του Κατούλλου. Το ερωτικό-ελεγειακό στοιχείο διέπει και τα τρία αφηγήματα και εκφράστηκε μέσω του λογοτεχνικού είδους της Ελεγείας. Η γυναίκα στην ελεγεία δεν περιβάλλεται μόνο από αισθησιασμό αλλά κατέχει κυρίαρχο ρόλο στο ερωτικό παιχνίδι ενώ ο άνδρας είναι αιχμάλωτος, καθυποταγμένος στη δύναμη της γυναίκας. Παράλληλα, σημαντική επιρροή στις ανωτέρω αφηγήσεις υπήρξε η εξάπλωση στην Ρώμη ανατολικών θρησκειών, όπως η λατρεία της Κυβέλης, οι οποίες προσφέρουν προβεβλημένο ρόλο στις γυναικείες θεότητες. Η ακολουθία της θεάς από ευνούχους ιερείς, τους Γάλλους, λειτούργησε ως σύμβολο της απολεσθείσας θηλυπρέπειας των προγόνων των Ρωμαίων, Τρώων, συμβάλλοντας στον επαναπροσδιορισμό της έμφυλης ταυτότητας του σύγχρονου ανθρώπου. Οι ανωτέρω παράγοντες συνέβαλαν στην αναθεώρηση των έμφυλων στερεοτύπων της πατριαρχικής κοινωνίας της Respublica και ως εκ τούτου συνιστούν σημαντική επιρροή στις εξεταζόμενες αφηγήσεις. Πιο συγκεκριμένα, στο επύλλιο του Οβιδίου Ίφις και Ιάνθη η Ίφις ούσα μεγαλωμένη ως άνδρας έχει υιοθετήσει το κοινωνικό φύλο του ανδρός, γεγονός το οποίο έρχεται σε σύγκρουση με την αμηχανία της, όταν συνειδητοποιεί τη βιολογική αδυναμία της να ολοκληρώσει τον έρωτα της με την Ιάνθη λόγω της έλλειψης ανδρικού μορίου. Η Ίφις δεν απεκδύεται του κοινωνικού της φύλου αλλά προσπαθεί να το εκπληρώσει, αδυνατεί όμως λόγω της θηλυκής της φύσης. Η διείσδυση είναι ο μοναδικός τρόπος ολοκλήρωσης της ερωτικής πράξης και οποιαδήποτε πράξη ξεφεύγει από αυτό τον κανόνα θεωρείται μη κανονική. Υπό αυτό το πρίσμα, και ύστερα από τη θαυμαστή επέμβαση της θεάς Ίσιδος, η Ίφις μεταμορφώνεται σε άνδρα για να μπορεί να ολοκληρώσει τον έρωτα της. Η αλλαγή της έμφυλης ταυτότητας του ήρωα συναντάται και στην ιστορία του Κατούλλου για τον Άττι. Ο Άττις όντας σε κατάσταση ένθεης μανίας αυτοευνουχίζεται χάνοντας, έτσι, την ταυτότητα τους ως έφηβος νέος και μετατρέπεται σε ευνούχο ακόλουθο της θεάς Κυβέλης. Ο ευνουχισμός είναι η αρχή μιας γενικευμένης εκθήλυνσης του Άττι και των συντρόφων του αφού πλέον δεν ανήκουν στο ανδρικό φύλο αλλά στο μεταίχμιο κλίνοντας περισσότερο προς το θηλυκό. Αξίζει να σημειωθεί ο αυτοευνουχισμός του Άττι και των συντρόφων συμβαίνει με σκοπό την αποφυγή του συζυγικού ζυγού και της επακόλουθης ενηλικίωσης, και σημαίνει την γενικότερη αποστροφή προς την ετεροφυλοφιλική σεξουαλική πράξη. Προσπάθεια αποφυγής της ετεροφυλοφιλικής πράξης συναντάται και στο επύλλιο Ερμαφρόδιτος και Σαλμακίδα του Οβιδίου. Αναλυτικότερα, το ερωτικό παιχνίδι εξελίσσεται με ανεστραμμένους τους ρόλους κυνηγού-θηράματος ανατρέποντας τα έμφυλα στερεότυπα. Τον ρόλο του κυνηγού τον οποίο ενσαρκώνει συνήθως ο άνδρας του ερωτικού παιχνιδιού, παίζει η Σαλμακίδα, η οποία, αφού θαυμάζει την ομορφιά του νεαρού, τον κυνηγά επιδιώκοντας την ερωτική επαφή. Αντίθετα, τον κατά τα σύγχρονα στερεότυπα θηλυκό ρόλο του θηράματος, κατέχει ο Ερμαφρόδιτος όντας το αντικείμενο του πόθου. Η αντίθεση επιτείνεται με τον βιασμό του Ερμαφρόδιτου από τη νύμφη και την απορρόφηση της από τον νεαρό ως τιμωρία για την προκλητική της συμπεριφορά. Τέλος, η παρούσα εργασία ολοκληρώνεται με αναφορά και ανάπτυξη της θεωρίας της σεξουαλικότητας του Freud και εφαρμογή αυτής στις τρεις αφηγήσεις.In this paper, the issue of gender is examined in Ovid's gardens of Iphis and Ianthi (Met. 9.669-797), in the episode of Hermaphroditus and Salmacis (Met. 4.285-388) and in the story of Catullus about Attis, as recorded in Catullus’ poem 63. The erotic-elegiac element governs all three narratives and is expressed through the literary genre of Elegy. The woman in the elegy not only is surrounded by sensuality but holds a dominant role in the love game while the man is captive, subjet to the power of the woman. At the same time, a significant influence on the above narratives was the spread in Rome of Eastern religions, such as the cult of Cybele, which offer a prominent role to female deities. The retinue of the goddess by eunuchs, the Galli, functioned as a symbol of the lost femininity of the mythical ancestors of the Roman people, the Trojans, contributing to the redefinition of modern man's gender identity. The above factors contributed to the revision of the gender stereotypes of the patriarchal society of the Respublica and therefore exercise a significant influence on the narratives under consideration in this thesis. More specifically, in Ovid's account of Iphis and Ianthi, the (biologically) female Iphis, raised as a man, has adopted the social gender of a man, a fact which underwrites her embarrassment when she realizes her biological inability to consummate her love affair with Ianthi due to the lack of a penis. Iphis does not escape her social gender but tries to fulfill it, yet she fails due to her feminine physiology. Penetration is the only way to complete the love act and any act that deviates from this rule is considered irregular. In this light, Iphis must transform into a man in order to consummate her love; this is exactly what happens in the end of the story, following the miraculous intervention of the goddess Isis. The change of gender identity of the hero is also found in the story of Catullus’ Attis. Attis, being in a state of intense rage, castrates himself thus losing his identity as an adolescent youth and turns into a eunuch follower of the goddess Cybele. The castration is the beginning of an emasculation process that affects alike Attis and his companions, and as a result of which they occupy the gray area between genders leaning more towards the female. It is worth noting that the self-castration of Attis and his companions occurs in order to avoid the conjugal yoke and the subsequent coming of age, and signifies their general aversion to the heterosexual sexual act. An similar attempt to avoid the heterosexual act is also found in Ovid's story of Hermaphroditus and Salmacis. In this story, the love game builds on the reversal of roles of the hunter and the prey (the male, traditionally the hunter, in this story becomes the prey of the female), subverting gender stereotypes. The role of the hunter usually embodied by the man in the love game is played by Salmacis, who, after expressing her admiration for the youth's beauty, pursues him in pursuit of sexual intercourse. Along similar lines, the female role of prey is occupied by Hermaphroditus, being the object of desire, and completely unable to resist to the attack of the hunter/female. The contrast culminates on the rape of Hermaphroditus by the nymph, and concludes with the absorption of the female rapist by her male victim into one body, as punishment for her defiant behavior. The last section of this thesis is devoted to a brief study of Freud's theory of sexuality as it applies to the three aforenoted narratives

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

Tuberculosis in people with rheumatic disease in Finland 1995–2007: a nationwide retrospective register study

Peer reviewe

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