Systemic gene therapy rescues retinal dysfunction and hearing loss in a model of Norrie disease

Deafness affects 5% of the world's population, yet there is a lack of treatments to prevent hearing loss due to genetic causes. Norrie disease is a recessive X‐linked disorder, caused by NDP gene mutation. It manifests as blindness at birth and progressive sensorineural hearing loss, leading to debilitating dual sensory deprivation. To develop a gene therapy, we used a Norrie disease mouse model (Ndp$^{tm1Wbrg}$), which recapitulates abnormal retinal vascularisation and progressive hearing loss. We delivered human NDP cDNA by intravenous injection of adeno‐associated viral vector (AAV)9 at neonatal, juvenile and young adult pathological stages and investigated its therapeutic effects on the retina and cochlea. Neonatal treatment prevented the death of the sensory cochlear hair cells and rescued cochlear disease biomarkers as demonstrated by RNAseq and physiological measurements of auditory function. Retinal vascularisation and electroretinograms were restored to normal by neonatal treatment. Delivery of NDP gene therapy after the onset of the degenerative inner ear disease also ameliorated the cochlear pathology, supporting the feasibility of a clinical treatment for progressive hearing loss in people with Norrie disease

Systemic gene therapy rescues retinal dysfunction and hearing loss in a model of Norrie disease

Deafness affects 5% of the world's population, yet there is a lack of treatments to prevent hearing loss due to genetic causes. Norrie disease is a recessive X-linked disorder, caused by NDP gene mutation. It manifests as blindness at birth and progressive sensorineural hearing loss, leading to debilitating dual sensory deprivation. To develop a gene therapy, we used a Norrie disease mouse model (Ndptm1Wbrg ), which recapitulates abnormal retinal vascularisation and progressive hearing loss. We delivered human NDP cDNA by intravenous injection of adeno-associated viral vector (AAV)9 at neonatal, juvenile and young adult pathological stages and investigated its therapeutic effects on the retina and cochlea. Neonatal treatment prevented the death of the sensory cochlear hair cells and rescued cochlear disease biomarkers as demonstrated by RNAseq and physiological measurements of auditory function. Retinal vascularisation and electroretinograms were restored to normal by neonatal treatment. Delivery of NDP gene therapy after the onset of the degenerative inner ear disease also ameliorated the cochlear pathology, supporting the feasibility of a clinical treatment for progressive hearing loss in people with Norrie disease

Research to develop Spiritual Pedagogy, Awareness and Change

This is an Accepted Manuscript of an article published by Taylor & Francis in British Journal of Guidance and Counselling on 21-4-16, available online: http://dx.doi.org/10.1080/03069885.2016.1174976A co-operative inquiry group consisting of 8 counsellors met for 11 months to explore their experience of spirituality in their counselling training and in their work with clients (Swinton, 2010; 2015). The aim was to explore whether spirituality was absent from the process of counselling training, specifically to discover (1) how counsellors perceived and described their experience of spirituality in their training and (2) with a view to developing spiritual pedagogy; how spirituality could be incorporated into the training process of practitioner

Status of low-energy accelerator-based BNCT worldwide and in Argentina

Existing and active low-energy Accelerator-Based BNCT programs worldwide will be reviewed and compared. In particular, the program in Argentina will be discussed which consists of the development of an Electro-Static-Quadrupole (ESQ) Accelerator-Based treatment facility. The facility is conceived to operate with the deuteron-induced reactions 9Be(d,n)10B and 13C(d,n)14N at 1.45 MeV deuteron energy, as neutron sources. Neutron production target development status is specified. The present status of the construction of the new accelerator development laboratory and future BNCT centre is shown.Fil: Cartelli, Daniel Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; Argentina. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología; ArgentinaFil: Capoulat, Maria Eugenia. Comisión Nacional de Energía Atómica; Argentina. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Baldo, M.. Comisión Nacional de Energía Atómica; ArgentinaFil: Suárez Sandín, J. C.. Comisión Nacional de Energía Atómica; ArgentinaFil: Igarzabal, M.. Comisión Nacional de Energía Atómica; ArgentinaFil: del Grosso, Mariela Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Valda, A. A.. Comisión Nacional de Energía Atómica; Argentina. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología; ArgentinaFil: Canepa, N.. Comisión Nacional de Energía Atómica; ArgentinaFil: Gun, M.. Comisión Nacional de Energía Atómica; ArgentinaFil: Minsky, Daniel Mauricio. Comisión Nacional de Energía Atómica; Argentina. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Conti, G.. Comisión Nacional de Energía Atómica; ArgentinaFil: Erhardt, J.. Comisión Nacional de Energía Atómica; ArgentinaFil: Somacal, Héctor Rubén. Comisión Nacional de Energía Atómica; Argentina. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología; ArgentinaFil: Bertolo, A. A.. Comisión Nacional de Energía Atómica; ArgentinaFil: Bergueiro, J.. Comisión Nacional de Energía Atómica; ArgentinaFil: Gaviola, P. A.. Comisión Nacional de Energía Atómica; ArgentinaFil: Kreiner, Andres Juan. Comisión Nacional de Energía Atómica; Argentina. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

The timing of auditory sensory deficits in Norrie disease has implications for therapeutic intervention

Norrie disease is caused by mutation of the NDP gene, presenting as congenital blindness followed by later onset of hearing loss. Protecting patients from hearing loss is critical for maintaining their quality of life. This study aimed to understand the onset of pathology in cochlear structure and function. By investigating patients and juvenile Ndp-mutant mice, we elucidated the sequence of onset of physiological changes (in auditory brainstem responses, distortion product otoacoustic emissions, endocochlear potential, blood-labyrinth barrier integrity) and determined the cellular, histological, and ultrastructural events leading to hearing loss. We found that cochlear vascular pathology occurs earlier than previously reported and precedes sensorineural hearing loss. The work defines a disease mechanism whereby early malformation of the cochlear microvasculature precedes loss of vessel integrity and decline of endocochlear potential, leading to hearing loss and hair cell death while sparing spiral ganglion cells. This provides essential information on events defining the optimal therapeutic window and indicates that early intervention is needed. In an era of advancing gene therapy and small-molecule technologies, this study establishes Ndp-mutant mice as a platform to test such interventions and has important implications for understanding the progression of hearing loss in Norrie disease

Пародонтопротекторна дія квертуліна у щурів, які отримували преднізолон

Преднизолон вызывает у крыс развитие иммунодефицита и снижение уровня защитных систем, что приводит к развитию дисбиоза и, как следствие, воспаления в пародонте (в десне и в костной ткани). В костной ткани пародонта преднизолон снижает минерализующую активность. Оральные аппликации геля «Квертулин» снижают степень иммунодефицита, повышают уровень защитных систем, снижают степень дисбиоза и воспаления, повышают в кости минерализующую активность и степень ее минерализованности, что в конечном итоге снижает атрофию пародонта.The objective: To determine parodontoprotective action of quertulin in rats, which received prednisolone. Materials and methods: Prednisolone was introduced per os into rats in dose 10 mg/kg (first 2 days) and 5 mg/kg (next 12 days). The gel of quertulin was applicated in rat gum in dose 0,3 ml every day during 14 days. After killing rats, the activity of elastase, urease, lysozyme, catalase and the contents of malonic dialdehide (MDA) and hyaluronic acid were determined into gum. The activity of phosphatase, elastase, protease, the contents calcium, and protein were determined into the parodontale bone. The degree of caries and the degree of parodonte atrophy were determined. Results: the raising of the activities of elastase, urease and the content of MDA but the lowering of lysozyme and catalase activities has been established. The activity of acid phosphatase and elastase raised into parodontale bone after prednisolone but mineralisation index and content of hyaluronic acid lowered into rats which received prednisolone. The oral application of gel “Quertulin” lowered the activities of elastase and urease and the content of MDA, but raised the activity lysozyme, catalase and the content of hyaluronic acid. The content of calcium, mineralisation index and the degree of mineralisation raised after application of gel “Quertulin”. Conclusion: Prednisolone cause immunodeficite, dysbiosis, periodontitis. The oral application of gel “Quertulin” realize antidysbiotic and parodontoprotective effects.Преднізолон викликає у щурів розвиток імунодефіцита та зниження рівня захисних систем, що приводить до розвитку дисбіоза і, як наслідок, запалення в пародонті (в яснах і в кістковій тканині). В кістковій тканині пародонта преднізолон знижує мінералізуючу активність. Оральні аплікації гелю «Квертулін» знижують ступінь імунодефіциту, підвищують рівень захисних систем, знижують ступінь дисбіоза і запалення, підвищують в кістці мінералізуючу активність і ступінь її мінералізації, що з рештою знижує атрофію пародонта

The role of immunodeficite in the development of corticosteroid stomatitis in rats

У крыс, получавших в течение 14 дней преднизолон, в слизистой полости рта развивается дисбиоз и воспаление, которые являются следствием иммунодефицита как специфического (лимфоцитарного), так и неспецифического (лизоцимного).У щурів, які отримували на протязі 14 днів преднізолон, в слизовій оболонці порожнини рота розвивається дисбіоз і запалення, які є наслідком імунодефіциту, як специфічного (лімфоцитарного), так і неспецифічного (лізоцимного).To determine state of specific and nonspecific immunities and stomatitis presence in rats which received prednisolone. Prednisolone introduced rats by per os in dose 10 mg/kg firts 2 days and in dose 5 mg/kg following 12 days. The content of leucocytes, lymphocytes and neutrophils determined in blood. The lysozyme activity determined in serum, liver and oral mucosa. The levels of activity urease, elastase, catalase and content of malonic dialdehide determined into oral mucosa

Роль імунодефіциту в розвитку кортикостероїдного стоматиту у щурів

У крыс, получавших в течение 14 дней преднизолон, в слизистой полости рта развивается дисбиоз и воспаление, которые являются следствием иммунодефицита как специфического (лимфоцитарного), так и неспецифического (лизоцимного).The aim. To determine state of specific and nonspecific immunities and stomatitis presence in rats which received prednisolone. The materials and methods. Prednisolone introduced rats by per os in dose 10 mg/kg firts 2 days and in dose 5 mg/kg following 12 days. The content of leucocytes, lymphocytes and neutrophils determined in blood. The lysozyme activity determined in serum, liver and oral mucosa. The levels of activity urease, elastase, catalase and content of malonic dialdehide determined into oral mucosa. The findings. The specific immunity (lymphocyte) and nonspecific immunity (lysozyme) decreased after prednisolone introduce into all tissues. The stomatitis and dysbiosis developed into oral mucosa rats, which received prednisolone.У щурів, які отримували на протязі 14 днів преднізолон, в слизовій оболонці порожнини рота розвивається дисбіоз і запалення, які є наслідком імунодефіциту, як специфічного (лімфоцитарного), так і неспецифічного (лізоцимного)

Canakinumab relieves symptoms of acute flares and improves health-related quality of life in patients with difficult-to-treat Gouty Arthritis by suppressing inflammation: results of a randomized, dose-ranging study

INTRODUCTION: We report the impact of canakinumab, a fully human anti-interleukin-1β monoclonal antibody, on inflammation and health-related quality of life (HRQoL) in patients with difficult-to-treat Gouty Arthritis. METHODS: In this eight-week, single-blind, double-dummy, dose-ranging study, patients with acute Gouty Arthritis flares who were unresponsive or intolerant to--or had contraindications for--non-steroidal anti-inflammatory drugs and/or colchicine were randomized to receive a single subcutaneous dose of canakinumab (10, 25, 50, 90, or 150 mg) (N = 143) or an intramuscular dose of triamcinolone acetonide 40 mg (N = 57). Patients assessed pain using a Likert scale, physicians assessed clinical signs of joint inflammation, and HRQoL was measured using the 36-item Short-Form Health Survey (SF-36) (acute version). RESULTS: At baseline, 98% of patients were suffering from moderate-to-extreme pain. The percentage of patients with no or mild pain was numerically greater in most canakinumab groups compared with triamcinolone acetonide from 24 to 72 hours post-dose; the difference was statistically significant for canakinumab 150 mg at these time points (P < 0.05). Treatment with canakinumab 150 mg was associated with statistically significant lower Likert scores for tenderness (odds ratio (OR), 3.2; 95% confidence interval (CI), 1.27 to 7.89; P = 0.014) and swelling (OR, 2.7; 95% CI, 1.09 to 6.50, P = 0.032) at 72 hours compared with triamcinolone acetonide. Median C-reactive protein and serum amyloid A levels were normalized by seven days post-dose in most canakinumab groups, but remained elevated in the triamcinolone acetonide group. Improvements in physical health were observed at seven days post-dose in all treatment groups; increases in scores were highest for canakinumab 150 mg. In this group, the mean SF-36 physical component summary score increased by 12.0 points from baseline to 48.3 at seven days post-dose. SF-36 scores for physical functioning and bodily pain for the canakinumab 150 mg group approached those for the US general population by seven days post-dose and reached norm values by eight weeks post-dose. CONCLUSIONS: Canakinumab 150 mg provided significantly greater and more rapid reduction in pain and signs and symptoms of inflammation compared with triamcinolone acetonide 40 mg. Improvements in HRQoL were seen in both treatment groups with a faster onset with canakinumab 150 mg compared with triamcinolone acetonide 40 mg. TRIAL REGISTRATION: clinicaltrials.gov: NCT00798369