Development of new therapeutic approaches in mouse models of Amyotrophic Lateral Sclerosis

La sclérose latérale amyotrophique (SLA) est une pathologie neurodégénérative caractérisée par une perte progressive des neurones moteurs et par de l’atrophie musculaire menant à de la paralysie. Bien que plusieurs mécanismes pathologiques aient été élucidés, la SLA reste un mystère médical puisqu’il n’existe toujours pas de traitement efficace. Nous avons développé deux stratégies dans le but de traiter la SLA. La première stratégie fut de cibler la protéine SOD1 mal repliée (chapitre 2) et la deuxième consistait à traiter la neuroinflammation présente dans la maladie (chapitre 3). Dans le chapitre 2, nous avons tenté de diminuer le niveau de la protéine SOD1 mal repliée présent dans le système nerveux de souris transgéniques développant un phénotype de SLA. Pour ce faire, nous avons testé une nouvelle approche thérapeutique basée sur l’utilisation d’ « adeno-associated virus (AAV) ». Ce virus contient une séquence d’ADN qui encode pour un anticorps à chaîne unique variable (scFv). Cet anticorps est composé d’une des deux chaînes légères et lourdes de l’anticorps D3H5 ciblant de manière spécifique la protéine SOD1 mal repliée. Une injection intra-thécale unique de l’AAV encodant l’anticorps à chaîne unique dans des souris SOD1G93A repousse le début de la maladie et augmente la survie des souris de 28%. Nous avons démontré que la Withaferin A (WA), un inhibiteur du facteur NF-κB, diminuait le phénotype neurologique retrouvé chez le modèle de souris transgénique TDP-43. Donc, nous avons testé la Withaferin A sur deux autres lignées de souris transgéniques exprimant des mutations dans la protéine SOD1, soit la lignée de souris SOD1G93A et la lignée de souris SOD1G37R. L’effet bénéfique de la WA chez les souris SOD1G93A était accompagné d’un soulagement de la neuroinflammation, d’une diminution du niveau de protéine SOD1 mal repliée dans la moelle épinière et d’une baisse de la mortalité des neurones moteurs. En considérant ces résultats, l’utilisation d’AAV encodant un anticorps à chaîne unique contre la protéine SOD1 mal repliée ainsi que l’utilisation de Withaferin A devrait toutes les deux être considérées comme des approches pour traiter la SLA.Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease associated with motor neuron degeneration, muscle atrophy and paralysis. Although numerous pathological mechanisms have been elucidated, ALS still remains a medical mystery in the absence of any effective therapy. Riluzole is the only therapeutic drug approved for ALS with regard to prolonging survival. Here, we have developed two strategies for treatment of ALS, first targeting the misfolded SOD1 (chapter 2) and other targeting neuroinflammation (chapter 3). In chapter 2, we aimed to reduce the level of misfolded SOD1 species in the nervous system. We tested a novel therapeutic approach based on adeno-associated virus (AAV)-mediated tonic expression of a DNA construct encoding a secretable single chain fragment variable (scFv) antibody composed of the variable heavy and light chain regions of a monoclonal antibody (D3H5) binding specifically to misfolded SOD1. A single intrathecal injection of the adeno-associated virus encoding the single chain antibody in SOD1G93A mice delayed disease onset and extended the life span by up to 28%, in direct correlation with scFv titers in the spinal cord. Our second treatment strategy which is aimed to target neuroinflammation is based on previous reports from our lab where it has been shown that Withaferin A (WA), an inhibitor of NF-κB activity was efficient in reducing disease phenotype in TDP-43 transgenic mouse model of ALS. We tested WA in mice from two transgenic lines expressing different ALS-linked SOD1 mutations, SOD1G93A and SOD1G37R. The beneficial effects of WA in SOD1G93A mice model was accompanied by alleviation of neuroinflammation, decrease in level of misfolded SOD1 species in spinal cord, a reduction in loss of motor neurons, resulting in delayed disease progression and mortality. Based on these evidences, AAV encoding a secretable scFv against misfolded SOD1 and WA should be considered as a potential treatment for ALS

The Value of Postoperative Appointments following Full Mouth Dental Rehabilitation under General Anesthesia

Purpose: Follow-up appointments after full mouth dental rehabilitation under general anesthesia (GA) have been suggested as a method for preventing future caries and need for repeat treatment under GA. The purpose of this study is to determine current practitioner and parental perceived value of the postoperative GA appointment. Methods: Three separate surveys were administered for this study. The pre-appointment survey asked about the guardian’s desire to have a follow-up appointment. At the follow-up appointment, the post-appointment survey ascertained the level of patient satisfaction with their follow-up appointment and postoperative experience. American Academy of Pediatric Dentistry (AAPD) members were e-mailed a survey asking them to indicate their clinical practice concerning the offering of routine follow-up appointments after general anesthesia. Results: Most AAPD respondents (72%) reported scheduling a follow-up visit. The most commonly selected challenge was the high no-show rate (46%), followed by the appointment being non-reimbursable (34%). Providers generally agreed or strongly agreed that the postoperative appointments are important (69%) and that it should be a reimbursable visit (73%). Guardians who attended the follow-up appointment reported pain as the most common symptom (41%). The second most common was bleeding (19%). Before the GA, most frequent answer parents indicated as the topics they would like to discuss at their follow-up appointment was “how to prevent future caries” with 67%. Of those who attended follow-up, 96.3% agreed or strongly agreed that the postoperative visit was useful. Conclusion: Both pediatric dentists and guardians of patients undergoing FMDR under GA agree the postoperative follow-up visit is valuable. The follow-up appointment may be beneficial for continued patient management of the chronic carious disease process

TRENDS IN GLOBAL CARBON DIOXIDE EMISSIONS IN THE ATMOSPHERE

This study is an attempt to identify the level of increase carbon dioxide gas emission and atmospheric temperature in the last 5 years. National Geographic noted that there is a exchange of energy between the source (the Sun), & the Earth's surface, the Earth's atmosphere, and the ultimate sink outer space. The ability of the atmosphere to capture and recycle energy emitted by the Earth surface is the defining characteristic of the Green House Effect.CO2, CH4, N2O, H2O are green house gases which are responsible for Green House Effect. Out of all these CO2 is mainly responsible for Green House Effect. Therefore a need was felt to study the variations in carbon dioxide concentration to be fundamental factor influencing climatic variations over this time scale. In this study, researchers have chosen only CO2 gas and its increasing value worldwide. Study reveals that the recent phenomenon of global warming has been attributed primarily due to increasing atmospheric carbon dioxide concentration in Earth's atmosphere. The research reveals the truth from that the concentration of carbon dioxide and temperature in the atmosphere have  increased during  past five years

The upsurge of deep learning for computer vision applications

Artificial intelligence (AI) is additionally serving to a brand new breed of corporations disrupt industries from restorative examination to horticulture. Computers can’t nevertheless replace humans, however, they will work superbly taking care of the everyday tangle of our lives. The era is reconstructing big business and has been on the rise in recent years which has grounded with the success of deep learning (DL). Cyber-security, Auto and health industry are three industries innovating with AI and DL technologies and also Banking, retail, finance, robotics, manufacturing. The healthcare industry is one of the earliest adopters of AI and DL. DL accomplishing exceptional dimensions levels of accurateness to the point where DL algorithms can outperform humans at classifying videos & images. The major drivers that caused the breakthrough of deep neural networks are the provision of giant amounts of coaching information, powerful machine infrastructure, and advances in academia. DL is heavily employed in each academe to review intelligence and within the trade-in building intelligent systems to help humans in varied tasks. Thereby DL systems begin to crush not solely classical ways, but additionally, human benchmarks in numerous tasks like image classification, action detection, natural language processing, signal process, and linguistic communication process

Contrast-induced acute kidney injury following coronary angiography in patients with end-stage liver disease

Background: Contrast-induced acute kidney injury (CIAKI) following coronary angiography is frequently observed in the general population. End-stage liver disease (ESLD) patients are at a particularly increased risk for development of CIAKI following coronary angiography due to preexisting renal hypoperfusion. Methods: We performed a retrospective study of 544 consecutive cardiac catheterizations in ESLD patients from December 2003 to May 2013 to calculate the incidence of CIAKI post-coronary angiography and to identify risk factors for CIAKI. CIAKI was defined as a serum creatinine increase of either \u3e/= 25% or \u3e/= 0.5 mg/dL from baseline within 72 hours. Multivariable and Cox regression analysis was performed for development of CIAKI and all-cause mortality, respectively. Results: Overall, 179 cases of coronary angiography were included in the final analysis. CIAKI occurred in 23% of patients. All-cause mortality was 52% in the CIAKI group and 37% in the non-CIAKI group, with a mean follow-up of 2.2 +/- 3.8 years. Multivariable analysis identified intensive care unit admission (OR 2.72, CI 1.05-7.01, p \u3c 0.05) and baseline estimated glomerular filtration rate (OR 1.02, CI 1.002-1.035, p \u3c 0.05) as independent predictors of CIAKI. Cox regression analysis identified pre-angiography beta-blocker use (HR 2.13, CI 1.04-4.38, p \u3c 0.05), international normalized ratio (HR 1.37, CI 1.05-1.78, p \u3c 0.05) and Mehran risk score (HR 1.13, CI 1.02-1.25, p \u3c 0.05) as independent predictors of all-cause mortality. Conclusions: CIAKI in ESLD patients undergoing coronary angiography occurs at a moderately elevated rate when compared to the general population

Post-traumatic high vaginal stricture and hematocolpos impersonating vaginal septum in adolescent girl: a case report

Vaginal stenosis was once a well-known condition in various nations. Vaginal stenosis can be caused by a variety of factors and manifest in a variety of ways. Because its occurrence is based on misinformation and cultural beliefs, acquired gynaetresia continues to be a major public health concern in underdeveloped nations, despite the fact that it is preventable. Traditional treatment involves an abdomino-perineal approach that requires a laparotomy. We are presenting a rare instance of vaginal stenosis following perineal trauma in an adolescent girl, which resulted in hematocolpos, and also as a novel laparoscopic technique to the management of significant vaginal stenosis

E- Help Desk

Ehelpdesk is a system which helps in solving the complaints systematically and efficiently. The objectives are to provide a good customer service for an organization and provide responsive services on time. Moto of implementing this system is to make complaints easier to handle and monitor and can also track the status of complaints and history of complaints. Ehelpdesk is a complaint management system in which lodged complaints would be solved according to the priority also analyze the complaints and can generate reports respectively as per needs

Survey of use of over the counter drug and other than over the counter drugs among medical students, nursing and technician staff of a tertiary care teaching hospital

Background: To find out pattern and extent of use of OTC and other than OTC drugs among medical students, nursing and technician staff.Methods: Study began after taking permission and approval from Institutional Review Board (IRB). Medical student, nursing and technician staff of tertiary care teaching hospital was enrolled after written informed consent. Pre validated questionnaire regarding use of such use was administered to each participant.Results: A total of 200 participants responded to questionnaire, M:F ratio was 1:1.7. Majority of the participants had taken OTC drugs for cough/cold (72.6%) followed by headache/ body ache (71.1%). Paracetamol (81%) followed by Diclofenac (42.5%), ibuprofen (37.8%) were the most common drugs taken. About 85% participants had taken antimicrobial considering it as an OTC product. Most commonly used antimicrobials were metronidazole (19.4%) followed by levofloxacin (17.9%).Most common reason for self medication was the perception that the disease wasn’t serious (44.8%), favourable prior advertisement (34.3%). About 52% requested for drug by mentioning name of drug. Most (50.7%) felt that OTC drug improved their illness. 45.9% stopped when symptoms disappeared. Majority of the participants (57.2%) believed use of OTC drug is a good practice. Most of the participants (56.7%) believed they can treat symptoms with OTC drugs.64.7% participants believed use of OTC drug is beneficial for them. Most of the participants lack the knowledge for dose (73.6%) and frequency (68.2%) of drug. A substantial number of participants (58.61%) were taking drugs outside OTC list.Conclusions: Awareness and dangers of misuse of OTC medications among all the participants was less. Therefore it is suggested that proper education should be imparted regarding illness where self-administration of OTC drugs to be employed