- Ariel University, Israel
- Title:Intensity-Dependent Effects of Exercise Training in Experimental Multiple Sclerosis
- Time :
Background: Exercise training (ET) has beneficial effects in Multiple Sclerosis (MS)patients and in experimental autoimmuneencephalomyelitis (EAE), the animal model of MS. However, the intensity-dependent effects of ET on the systemic immune system and/or the central nervous system (CNS) remain undefined.
Purpose: To compare the systemic immune-modulatory- and direct neuroprotectiveeffects of moderate vs. high intensity ET protocols on EAE development.
Methods: Healthy mice performed moderate- or high-intensity treadmill runningprograms. Proteolipid protein (PLP)-induced transfer EAE was utilized to enable differentiation between effects of ET on systemic autoimmunity vs. direct effects on the CNS. To investigate the immune-modulatory effects of ET, lymph-node (LN)-T cells from trained- vs. sedentary donor mice were transferred to naïve recipients. EAE severity in recipient mice was assessed by clinical assessment and histopathological analysis. LN-T cells derived from donor trained vs. sedentary PLP-immunized mice were analyzed in vitro for proliferation by flow cytometry analysis, and for cytokine and chemokine receptor gene expression using real-time PCR. To investigate the neuroprotective effects of ET, PLP-reactive, encephalitogenic T cells were transferred into recipient mice that underwent the training program prior to EAE transfer, and disease severity was compared to that in recipient sedentary mice.
Results: High-intensity training in healthy donor mice induced significantly greater inhibition than moderate-intensity training on proliferation and generation of encephalitogenic T-cells in response to PLP-immunization, and on EAE severity upon their transfer into recipient mice. Additionally, whereas moderate intensity ET did not have direct neuroprotective effects, transfer of PLP-reactive, encephalitogenic LN-T cells resulted in less severe EAE in recipient mice that were subjected to high intensity training program prior to EAE transfer.
Conclusions: Our data, obtained by using a unique experimental design, indicate superior effects of high intensity training on both systemic immune-modulation and direct neuroprotection to inhibit autoimmunity in EAE. This study is of clinical significance and may provide a basis for defining exercise recommendations (that are currently lacking) for MS patients.
Dr.Ofira Einstein graduated physical therapy school in 1999 (B.P.T.) and she completed her doctorate studies in neurobiology in 2006 (Ph.D.). She joined as a faculty of the Physical Therapy department at Ariel University in 2009 and served as the head of the department in years 2011-2017. Prof. Einstein’s research areas are neuro-immunology and neuroregeneration. Her first studies concerned on the neurobiology of neural stem cells and cell therapy, specifically on animal models of human Multiple Sclerosis (MS). Her work published in 2003 was the first to show that transplanted neural stem cells have anti-inflammatory effects on the rodent brain. This finding was a breakthrough for further research of her group, as well as other research groups around the world. Her current research focuses on neuro-immunological, neuro-protective and neuroregenerative effects of exercise training on neuro-inflammatory and neuro-degenerative diseases. These studies are particularly carried on experimental autoimmune encephalomyelitis (EAE), the animal model of her studies involve animal physical training, clinical evaluations, histopathological analyses, cell cultures and molecular biology techniques.
- Inra Research Centre, France
- Title:Stunning and Slaughter Techniques: Neurological Mechanisms and Indicators of Consciousness and Unconsciousness
- Time :
At slaughter, animals are generally stunned before bleeding, but society and field workers sometimes question efficacy. Recently, work was undertaken to understand better the neurobiological mechanisms involved in the stunning and killing process of animals. The mechanisms underlying the loss of consciousness depend on the technique used: mechanical, electrical or gas stunning. Direct exsanguination without prior stun, for religious slaughter, causes also a loss of consciousness, before inducing death. Stunning techniques use stun guns, electrified devices or gas mixtures. The principles of stunning and bleeding involve mechanical shock waves and the mechanical destruction of neurons, electrical fields, the reduction or arrest of cerebral blood circulation, or high and/or low levels of CO2 and/or O2, respectively, in inspired air. Effects involve cerebral anoxia or ischemia, the depolarisation, acidification and/or the destruction of brain neurons. Targeted brain structures are the reticular formation, the ascending reticular activating system or thalamus, or the cerebral hemispheres in a general manner. Some of the techniques induce an immediate loss of consciousness, other techniques a progressive loss of consciousness.
To ensure that the animal is unconscious, before further processing, indicators of consciousness and of unconsciousness are verified. They evaluate different aspects of cerebral functioning. As they are imprecise, it necessary to monitor several. As animals may regain consciousness, they are observed until the end of bleeding. Animals are considered unconscious if signs of consciousness are absent, and signs of unconsciousness are present.
Examples of indicators of unconsciousness are the absence of standing posture and of righting movements, the absence of a corneal reflex and respiratory arrest. Indicators of consciousness are the standing posture, coordinated righting movements, specifies-specific vocalizations and a response to the threat test. Often various movements are observed following the stun and during bleeding, including eye tracking, eyeball rotation, nystagmus, head and neck movements and leg paddling. Their presence often leads to confusion on the field as they may be reflex movements, but sometimes they indicate consciousness. Their interpretation needs further discussion.
The techniques used to diagnose brain death in humans cannot be used in the slaughterhouse. Under field conditions, at the end of bleeding, the absence of breathing and of brainstem reflexes and the adequacy of the exsanguination are verified. If these three aspects are confirmed, in the context of the slaughterhouse and at this stage of the slaughter process, the loss of vital functions is irreversible and the animal considered dead.
- Dankook University College of Medicine, Kore
- Title:Endovascular Treatment with Stents in Ruptured Complex Aneurysms
- Time :
Stent using in intracranial aneurysms has been avoided by most operators because of concerns about the risk of using dual antiplatelet therapy in the setting of acute SAH.
In case of posterior communicating artery aneurysm with fetal type artery incorporated on aneurysm or broad necked appearance, it was regarded as very difficult to treat endovascularly. However with intracranial stenting maneuver introducing recently, it can be treated completely by retrograde navigation of stent through anterior communicating artery and further coiling with staged approach.
And flow diverters also play important role to treat aneurysms.
The author introduces several technical extensions to overcome the pitfalls in treating the intracranial
Dr. Young Joon Kim is a Korean neurosurgeon, educator. His achievements include research in endovascular aneurysm coiling with stent & endovascular care of acute stroke. He is a member of Korean Society Neurosurgery (board directors since 1998) and he is also a member of Korean Society Intravascular Neurosurgery (president 2002-2004).
- Bloodworks Northwest, USA
- Title:Traumatic Brain Injury-Induced Coagulopathy
- Time :
Uncontrolled hemorrhage accounts for 30–50% of all trauma fatalities and is caused by direct injury to the vasculature and by secondary coagulopathy. Common causes of coagulopathy after severe trauma to the body and limbs include significant blood loss (hemorrhagic shock), hemodilution and hypothermia due to fluid resuscitation, systemic metabolic acidosis due to tissue ischemia, dysfunctional platelets and coagulation, and hyperfibrinolysis. However, coagulopathy is also common in patients with severe traumatic brain injury, even though these patients lack the key causal factors for trauma-induced coagulopathy. Traumatic brain injury-induced coagulopathy (TBI-IC) is a bleeding diathesis that result in secondary, delayed, or recurrent intracranial or intracerebral hemorrhage. It is mechanistically distinct from deficient and dilutional coagulopathy arising after extracranial trauma and hemorrhagic shock. Extensive clinical and laboratory findings suggest that TBI-IC is consumptive in nature and is developed through a rapid transition from a trauma-induced hypercoagulable state to a hypocoagulable state. Brain-derived extracellular vesicles (BDEVs) have been identified as a key disseminating and causal factor for TBI-IC because these BDEVs express multiple procoagulant factors such as tissue factor and abundant anionic phospholipids such as phosphatidylserine. Upon release into the circulation, these BDEVs serve as circulating platforms on which extrinsic coagulation is initiated and propagated, thus consuming the coagulation factors.
Dr. Jing-fei Dong, MD, PhD is a member of the Bloodwork Research Institute and a professor of medicine in the Division of Hematology, Department of Medicine, the University of Washington School of Medicine. His research focuses on bleeding and thrombotic complications of traumatic brain injury. He is particularly interested in studying the pathways through which TBI induces a systemic hypercoagulable state and resultant coagulopathy. He also studies the structure-functional correlations of the adhesive ligand von Willebrand factor and its cleaving metalloprotease ADAMTS-13 for regulating hemostasis, which is a physiological process of preventing bleeding, and thrombosis, which develops when the hemostatic process becomes aberrant or excessive.
- Indiana University Health, USA
- Title:Compounding Nimodipine Oral Suspension for Subarachnoid Hemorrhage
- Time :
What happens when there is an entire patient population, not just a specific patient, which cannot take a commercial pharmaceutical product due to significant adverse effects, although the commercial product has a U.S. Food and Drug Administration-approved indication for the medical problem? What should or can be done in this situation? This presentation discusses this dilemma using subarachnoid hemorrhage as an example of a true documented medical need, and discuss the option and circumstances surrounding the compounding of a nimodipine oral suspension, a U.S. Food and Drug Administration-approved indication for the treatment of subarachnoid hemorrhage.
The learning objectives include the following:
• Discuss the need for an oral nimodipine liquid.
• Provide options for treating patients with subarachnoid hemorrhage.
• Provide information on compounding nimodipine oral suspension to avoid adverse effects.
Dr. McElhiney is the Team Lead Compounding Pharmacist and a preceptor for Indiana University Health in Indianapolis, Indiana. It is one of the largest health-systems in the United States, consisting of 20 hospitals and dozens of outpatient clinics and surgery centers.
She is an author for the International Journal of Pharmaceutical Compounding and contributing author in pharmacy and medical textbooks. Dr. McElhiney is a full fellow in the American College of Apothecaries (ACA), American Society of Health-System Pharmacists (ASHP), and the International Academy of Compounding Pharmacists (IACP). She has served on several national committees and board of directors in professional pharmacy organizations and received several awards. Dr. McElhiney currently serves as the President-Elect for the American College of Apothecaries.
Dr. McElhiney earned a B.S. in Pharmacy from Purdue University in 1984. Dr. McElhiney earned a Pharm.D. (2002) and a Masters (2012) from the University of Florida.
- SUNY Downstate Health Sciences University, USA
- Title:Early Levetiracetam Treatment Prevents the Development of Evoked and Spontaneous Epileptiform Discharges In In Vitro and an In Vivo Model of Cortical Neurotrauma: Clinical Implications
- Time :
Traumatic brain injury (TBI) is a major public health problem and a significant cause of epilepsy worldwide. Effective interventions to prevent post-traumatic epilepsy have proved elusive, in part because TBI is a complex and heterogeneous condition. Our research group has studied 2 rat models of TBI associated epileptogenesis, the in vitro traumatized slice and the in vivo controlled cortical impact (CCI) model. This presentation will describe our recent investigations into the antiepileptogenic efficacy of the pyrrolidine antiseizure drug, levetiracetam (LEV) may prevent epileptogenesis after TBI.
In vitro studies were conducted on traumatized slices of rat neocortex (P21-32) that were prepared using published methods. Randomly selected traumatized slices were treated with clinically correlated concentrations of LEV added to the bath for 1 hour starting immediately after the injury or after a delay of up to 80 min. Treated and untreated slices were examined for epileptiform activity using intra- and extracellular recordings. For the in vivo model, rats (P24-32) were subjected to non-penetrating focal CCI using published methods. Immediately after injury the injured rats were then given a single dose of either LEV or the saline vehicle intraperitoneally. Ex vivo neocortical slices were prepared 2-3 weeks after CCI and examined for epileptiform activity. The results from the in vitro traumatized slice experiments showed that LEV treatment within 60 minutes of injury significantly reduced the proportion of slices that exhibited stimulus-evoked epileptiform activity by more than 50%. LEV treatment also increased the stimulus intensity required to trigger epileptiform bursts by 2-4 fold. Consistent with these findings, in vivo LEV treatment of CCI-injured rats significantly reduced the percentage of animals that exhibited spontaneous and stimulus-evoked epileptiform bursts compared to saline-treated controls. In addition, LEV also significantly increased the stimulus intensity required to evoke epileptiform bursts in slices prepared from CCI-treated animals. These results suggest that early administration of LEV has the potential to prevent or reduce posttraumatic epileptogenesis and highlights that there may be a narrow time window for successful therapeutic intervention. The challenges of using animal models for human epileptogenesis, the clinical implications and limitations of these two models of posttraumatic epileptogenesis, and potential strategies to address prevention or mitigation of post-traumatic epilepsy will be discussed.
Dr. Helen A. Valsamis is a Professor of Clinical Neurology at SUNY Downstate Health Sciences University and the Chief of the Neurology Service at H+H Kings County Hospital. As a clinician-scientist she travels between the clinical and research worlds, now often by virtual means. For the past 15 years she had served as the Chief of the Neurology Service in the second largest public hospital in the United States. She had also been a Residency Program Director for Adult Neurology and an educator of residents, fellows, medical students, attending physicians, nurses, nurse practitioners, EEG technicians, EMTs, patients, and patients’ families. At Kings County Hospital they have a developing neuroscience center which, in partnership with SUNY Downstate Health Sciences University includes a neuroscience research program they have participated in the NETT, SIREN, and Neuro NeXT networks.
- Cedars-Sinai Medical Center, Canada
- Title:Identification and Management of Cerebrospinal Fluid Leak after Lumbar Total Disc Replacement
- Time :
Lumbar total disc replacement (TDR) is an increasingly common intervention for discogenic back pain, particularly in the younger patient where motion preservation is paramount. This procedure however is not without complications. A CSF leak after lumbar TDR is rare; as such there is a paucity of literature regarding the operative approach to this uncommon pathology. Identification of the CSF leak is the primary step toward successful repair. Multiple modalities may be required such as MRI, CT myelogram, or digital subtraction myelogram (DSM). Successful CSF leak after lumbar TDR may range from simple procedures such as epidural blood patching or lumbar drain, while more significant dural injuries may require repeat operative intervention. Repeat surgery may involve transdural repair or additional measures such as replacement with an alternative implant and primary repair of the leak.
Dr. Julie L. Chan is currently a Neurosurgery Resident at Cedar-Sinai Medical Center. She received her B.S. in Neurobiology from the University of California, Irvine and her M.D.-Ph.D. in Neuroscience from the Medical College of Virginia. Her clinical and research interests include spinal deformity and spine outcomes.
- Antwerp University Hospital, Belgium
- Title:The Clinical and Genetic Spectrum in Infants with (an) Unprovoked Cluster(s) of Focal Seizures
- Time :
Self-limited (familial) infantile epilepsy (S(F)IE), formerly known as benign (familial) infantile convulsions (B(F)IC), is an infantile cluster epilepsy with in rule a complete recovery. It is one of common self-limited epilepsy syndromes affecting children. This large group includes benign syndromes like epilepsy with centrotemporal spikes (‘rolandic epilepsy’), Panayiotopoulos syndrome, and the occipital epilepsies (Gastaut and photosensitive types). Landau-Kleffner is a not always benign form.
In self-limited epilepsy syndromes, there is evidence there is both a role for oligogenic and polygenic component in self-limited focal epilepsies. Recently, in 20 out of 57 patients rare candidate variants were identified with typical or atypical self-limited focal epilepsies in childhood.
We analysed a cohort of 23 patients from 21 families, all with an initial diagnosis of self-limited infantile epilepsy. In 12 individuals a pathogenic variation in PRRT2 gene or complete deletion was identified. Pathogenic variants in PCDH19 and KCNQ2 were found in respectively 3 and 1 individuals. One individual had a non-pathogenic variant in ATP1A3 and in 6 others no variants were identified. Most had only one cluster of seizures. We conclude that most children with unprovoked clusters of focal seizures carry a PRRT2 mutation. When clusters reoccur frequently, when seizures are more therapy-resistant and when seizures persist beyond the age of 2 years, another diagnosis or causative gene (than PRRT2) is likely.
- Manmohan Memorial Eastern Regional Community Hospital, Birtamode, Nepal
- Title:Pathway to Care in Patients having Mental Illness in Eastern Nepal
- Time :
Background: Patients with mental illness are treated at various levels before receiving specialist treatment. In doing so, the duration of illness is prolonged, treatments received are sub-optimal, and productivity lessened impacting overall outcome. This study aimed to elaborate on the various pathways of care that a mentally ill patient has to go through and its association with socio-demographic profiles. Methods: A cross-sectional study was carried out among patients presenting to Neuropsychiatric outpatient department who along with their caregivers were interviewed using semi-structured proforma and WHO Pathway Interview Schedule. Results: Of the total participants attending the outpatient clinic, 30% were either first attended by a local practitioner or hospital doctor. The duration of illness in 40% was less than a month whereas in 1/3rd of the patients was more than 12 months before presenting to the first treatment. Similarly, 38.8% had treatment latency of at least 31 months duration before receiving specialist treatment.
Conclusion: Majority of patients with mental illness approached health-professionals at first with majority being prescribed psychotropics. Time to approach for first help seeking was better but approach to psychiatric care was delayed. There is a need for improving mental health awareness at different levels to motivate early help-seeking and proper treatment.
Keywords: Mental illness, patients, specialist, treatment
Dr. Sandarba Adhikari, had received Masters Degree in Psychiatry from Institute Of Medicine, Tribhuvan University, Kathmandu, Nepal. He had worked as a Lecturer in Department of Neuropsychiatry, B&C Medical college Teaching Hospital and Research Centre, Birtamode, Province 1 (April 2018- September 2020) and thereafter currently started Psychiatry services in Regional Community Hospital. His professional interests focus on addiction psychiatry, community Psychiatry and Researches. He is fluent in Nepali, English and Hindi. He has done his thesis on “Disulfiram and Naltrexone for Relapse Prevention in Cases of Alcohol Dependence Syndrome” (MD Psychiatry 2017) and few publications in national and international journals. He is also selected as Trainer in WHO E-mhGAP project (Emilia). He is a lifetime member at Psychiatrists’ Association of Nepal (PAN).
- Maastricht University Medical Center, The Netherlands
- Title:Subclinical Myasthenia Gravis in Thymomas
- Time :
Background A proportion of thymoma-patients without a history of myasthenia gravis (MG) before thymectomy, appears to have positive anti-AChR-antibodies in the serum. These subclinical MG-patients could be underdiagnosed because analyzation of anti-AChR-antibodies in thymomas is not always performed in patients who did not experience neurological symptoms. The prevalence and long-term outcomes of subclinical MG are never described in literature yet.
Methods: We retrospectively analyzed 398 consecutive patients who underwent a robotic-assisted thoracoscopic surgery at the Maastricht University Medical Center+ (MUMC+) between April 2004 and December 2018. In the MUMC+, a robotic approach is the standard surgical approach in patients with thymic diseases. Inclusion criteria were thymomas, thymectomy performed in the MUMC+ with a follow-up of at least one year and age above 18 years old. Exclusion criteria were patients with thymic carcinomas, refused participation, or those who were lost to follow-up.
Of the 102 included thymoma-patients, 87 patients (85%) were tested for anti-AChR-antibodies before thymectomy, of which 57 patients were diagnosed with clinical MG and seven subclinical MG-patients were found. Of the 15 patients who were not tested for anti-AChR-antibodies, four more subclinical MG-patients were discovered in the years after thymectomy. The median follow-up time was 62 months. In total, 11 subclinical MG-patients were found, with a mean age of 54 years and predominantly females (64%). Ten subclinical MG-patients (91%) developed clinical-MG, within six years after thymectomy. Immunosuppressive drugs were prescribed in five patients. Four patients were diagnosed with a recurrence of the thymoma. No surgical mortality was reported. Two patients died due to a myasthenic crisis.
The prevalence of subclinical MG in thymomas was found to be 10.8%. One in four patients who experienced no neurological symptoms before thymectomy, appeared to have anti-AChR-antibodies and 91% of these patients developed clinical MG within six years after the thymectomy. Analyzing anti-AChR-antibodies in the serum is recommended in all suspected thymomas before a thymectomy is performed.
Key words: thymomas, thymectomy, myasthenia gravis, anti-acetylcholinereceptor-antibodies
Dr. Florit Marcuse is a resident in Pulmonology and PhD Candidate in the Departments of Pulmonology of the Maastricht University Medical Center+ (MUMC+) and School for Mental Health and Neuroscience (MheNS) of the University of Maastricht. In the Netherlands, the MUMC+ is the main center of expertise for the treatment of patients with thymic disorders. Dr. Marcuse has special interest in thymic oncology and associated thymic diseases in myasthenia gravis. Her research focuses on patients who underwent a robotic thymectomy, which is a standard treatment for patients with a thymoma and in most of the patients with myasthenia gravis. The thymic team of the MUMC+ is internationally known for participation in (inter)national research and collaborations.
- Cairo University, Egypt
- Title:Renin Angiotensin System Activation in Diabetes Induced Cognitive Impairment
- Time :
There is a great concern in learning and memory deficits that develop over time in patients with poorly controlled diabetes. Hyperactivity of the renin- angiotensin system (RAS) is directly associated with β-cell dysfunction and diabetic complications, including cognitive impairment. There is correlation between RAS components found in areas of the brain and cognition, behavior and locomotion. RAS modifiers; aliskiren and captopril protective and molecular effects were investigated on cognitive deficits in the rat hippocampus, a key brain region responsible for memory and cognition. Poorly controlled STZ-diabetic rats were injected subcutaneously with ineffective daily doses of insulin for 4 weeks. The hyperglycemia and pancreatic atrophy caused memory disturbances that were identifiable in behavioral tests, hippocampal neurodegeneration,and the following significant changes in the hippocampus, increases in the inflammatory marker interleukin 1β, cholinesterase, the oxidative stress marker malondialdehyde and protein expression of phosphorylated extracellular-signal-regulated kinase and glycogen synthase kinase-3 beta versus decrease in the antioxidant reduced glutathione and protein expression of phosphorylated glycogen synthase kinase-3 beta. Blocking RAS with either drug along with insulin restored all previously mentioned parameters to normal. Aliskiren stabilized the blood glucose level and restored normal pancreatic integrity and hippocampal MDA level. Aliskiren showed superior protection against the hippocampal degeneration displayed in the earlier behavioral modification in the passive avoidance test and aliskiren group outperformed the control group in the novel object recognition test. We, therefore, conclude that aliskiren and captopril reversed the diabetic state and cognitive deficits through the renin inhibitory effect and blockade of
RAS. Captopril protective effect is related to a reduction in Ang II synthesis. At last, dwindling RAS activity reduce oxidative stress, inflammation state, and modulating protein expression.
Dr. Madonna Magdy Youssef, MSc, received her pharmacy degree from Ain Shams University and master’s degree in the field of pharmacology at faculty of pharmacy, Cairo University in 2019. Currently she is employed as quality assurance specialist in Egyptian Drug Authorization (EDA), she granted a quality management diploma in 2020. The Ph.D. research work is in progress in fruitful collaboration with the National Research Center and the Academy of Scientific Research. The study related to neurocognitive protection from Alzheimer’s disease for healthy aging as well as investigation of possible enhancement of insulin release and sensitivity for diabetic patients. She serves as a reviewer for Elsevier international journal “Pharmacology and Therapeutics”. Her Research interests are overly concerned with critical pathways and applicable drugs related to neurological and cognitive disorders, diabetes as well as immunological diseases.
- University of Illinois at Chicago, USA
- Title:Predicting Autism Spectrum Disorder Using Domain-Adaptive Cross-Site Evaluation
- Time :
The advances in neuroimaging methods reveal that resting-state functional fMRI (rs-fMRI) connectivity measures can be potential diagnostic biomarkers for autism spectrum disorder (ASD). Recent data sharing projects help us replicating the robustness of these biomarkers in different acquisition conditions or preprocessing steps across larger numbers of individuals or
sites. It is necessary to validate the previous results by using data from multiple sites by diminishing the site variations. We investigated partial least square regression (PLS), a domain adaptive method to adjust the effects of multicenter acquisition. A sparse Multivariate Pattern Analysis (MVVPA) framework in a leave one site out cross validation (LOSOCV) setting has been proposed to discriminate ASD from healthy controls using data from six sites in the Autism Brain Imaging Data Exchange (ABIDE). Our results showed that two or more informative connections are Dorsolateral Prefrontal Cortex, Somatosensory Association Cortex, Primary Auditory Cortex, Inferior Temporal Gyrus and Temporopolar area. These interrupted regions are involved in executive function, speech, visual perception, sense and language which are associated with ASD. Our findings may support early clinical diagnosis or risk determination by identifying neurobiological markers to distinguish between ASD and healthy controls.
Dr. Bhaumik is a research assistant professor at Biostatistical Research Center, in the Department of Psychiatry. Her research focuses on Longitudinal Data Analysis, Multivariate Statistical analysis, Graph Theory and applications of Machine Learning Algorithms to Neuroscience and other fields.
- University of California, USA
- Title:Integrated Stress Response Inhibitor Reverses Sex-Dependent Behavioral and Cell-Specific Deficits After Mild Repetitive Head Trauma
- Time :
Mild repetitive traumatic brain injury (rTBI) induces chronic behavioral and cognitive alterations and increases the risk for dementia. Currently there are no therapeutic strategies to prevent or mitigate chronic deficits associated with rTBI. We previously developed an animal model of rTBI that recapitulates some of the cognitive and behavioral deficits observed in humans. Here we report that rTBI results in an increase in risk-taking behavior in male but not female mice. This behavioral phenotype is associated with cell-specific synaptic alterations in the type A subtype of layer V pyramidal neurons in the medial prefrontal cortex (mPFC). Strikingly, by briefly treating animals’ weeks after injuries with ISRIB, a selective inhibitor of the integrated stress response (ISR), we permanently reverse the increased risk-taking behavioral phenotype and restore cell-specific synaptic function in the affected mice. Our results indicate that targeting the ISR even at late time points after injury can permanently reverse behavioral changes. As such, pharmacological inhibition of the ISR emerges as a promising avenue to combat rTBI-induced behavioral dysfunction.
Dr. Susanna Rosi is a Professor in the Departments of Physical Therapy Rehabilitation Science and Neurological Surgery and the Director of Neurocognitive Research in the Brain and Spinal Injury Center. She is a member of the UCSF Weill Institute for Neurosciences, Kavli Institute for Fundamental Neuroscience, Hellen Diller Cancer Center, Neuroscience Graduate Program, Biomedical Science Graduate Program. Originally from Tuscany, She earned her undergraduate degree and PhD in Biology from the University of Florence, Italy. She trained in the Neural System Memory and Aging center at the University of Arizona before becoming a Faculty Member of UCSF. Her research is focused on understanding the mechanisms responsible for the cognitive dysfunctions observed after brain injury. Her final goal is to identify diagnostic tools for treatment and prevention. She demonstrated the key role that neuroinflammation plays in the development of cognitive deficits. Most notably, she identified therapeutic strategies able to both prevent and restore lost cognition. She received the Bridging the Gap Award from the California Institute for Quantitative Biosciences, the Innovation Award from the Weill Institute for Neurosciences. She serves as PI on NIH (NIA, NINDS and NCI) funded grants, a NASA grant and she also serves as a standing member of the Molecular Neurogenetic study section at the National Institutes of Health and Associate Editor for the Journal of Neuroinflammation.
- The Johns Hopkins University, USA
- Title: Imaging Neurovascular Abnormalities in Neurodegenerative Diseases
- Time :
Energy metabolism is crucial for maintenance of normal brain functions. As the supply of adequate oxygen and energy substrates for local metabolic demands is controlled by blood vessels in the brain, neurovascular abnormalities
may contribute to the neuropathology and functional deficits in brain diseases. Here, I will discuss our work on the investigation of microvascular and metabolic abnormalities in neurodegenerative diseases measured by advanced
MRI technologies developed at ultra-high magnetic field.
Dr. Hua is an Associate Professor in the F.M. Kirby Research Center for Functional Brain Imaging at Kennedy
Krieger Institute, and the Russell H. Morgan Department of Radiology at Johns Hopkins University. Dr. Hua’s research has centered on the development of novel MRI technologies for in vivo functional and physiological imaging in the brain, and the application of such methods for studies in healthy and diseased brains. These include the development of human and animal MRI methods to measure functional brain activities, cerebral perfusion and oxygen metabolism at high (3 Tesla) and ultra-high (7 Tesla and above) magnetic fields. He is particularly
interested in novel MRI approaches to image small blood and lymphatic vessels in the brain. Collaborating with clinical investigators, these techniques have been applied 1) to detect functional, vascular and metabolic abnormalities in the brain in neurodegenerative diseases such as Huntingdon’s disease (HD), Parkinson’s disease (PD), Alzheimer’s disease (AD) and mental disorders such as schizophrenia; and 2) to map brain functions
and cerebrovascular reactivity for presurgical planning in patients with vascular malformations, brain tumors and epilepsy.
- Neuro-Horizon Pharma, USA
- Title:Drug Development for the Treatment of Amyotrophic Lateral Sclerosis
- Time :
We have previously identified the interaction between mammalian V-ATPase a2-subunit isoform and cytohesin-2 (CTH2) and studied molecular details of binding between these proteins. In particular, we found that six peptides derived from the N-terminal cytosolic domain of a2-subunit (a2N1–402) are involved in the interaction with CTH2 . However, the actual 3D binding interface was not determined in that study due to the lack of high-resolution structural information about a-subunits of V-ATPase. Here, using a combination of homology modeling and NMR analysis, we generated the structural model of complete a2N1–402 and uncovered the CTH2-binding interface. First, using the crystal structure of the bacterial M. rubber Icyt-subunit of A-ATPase as a template , we built a homology model of mammalian a2N1–352 fragment. Next, we combined it with the determined NMR structures of peptides a2N368–395 and a2N386–402 of the C-terminal section of a2N1–402. The complete molecular model of a2N1–402 revealed that six CTH2 interacting peptides are clustered in the distal and proximal lobe sub-domains of a2N1–402, showing that a2-subunit of V-ATPase interacts with two molecules of CTH2. Indeed, using Sec7/Arf-GEF activity assay we experimentally confirmed our model. These data are critical for drug development using: i) in silico computer-aided drug design (CADD) and ii) TR-FRET based high throughput screening (HTS) of the libraries of BBB-permeable small molecules [3,4]. In particular, it was shown that CTH2 interacts with mutant superoxide dismutase 1 (SOD1), a known cause of familial amyotrophic lateral sclerosis (ALS) . Inhibition of CTH2 activity by small molecules protects against ER stress, enhances autophagic flux and reduces the burden of misfolded SOD1. These data indicate that targeting of cytohesins by peptides and/or small molecules in motor neurons may be beneficial for the treatment of ALS.
- University of Nebraska, USA
- Title:Neuron Model with Conductance-Resistance Symmetry
- Time :
We will derive a mathematical model for neuron by imposing only a principle of symmetry that two modelers must obtain the same model when one models the conductances of neural channels and the other models the channels’ resistances. Conductance-voltage characteristics for ion transport channels and protein gating channels are both derived. They are expressed as products of maximal conductances and opening probabilities for both types of channel. It gives an explanation to the critical role of spontaneous firing of individual channel pores and to the origin of leak current. The model has a better fit to a classical data than the Hodgkin-Huxley model does. It can also be reduced to a 2-dimensional model qualitatively similar to the FitzHugh-Nagumo equation and be expanded to a model of three ion channels capable of spike bursts. It gives an electrical circuit design for true artificial neuron. The channel opening probability function derived can also be used in the area of AI.
Dr. Bo Deng is a mathematician working in the field of Mathematical Biology. He obtained his PhD from Michigan State University in US. He has been a professor in the Department of Mathematics, University of Nebraska – Lincoln, US, since 1988. He has done researches in a few areas of Mathematical Biology, including Evolutionary Genetics, Population Genetics, Bioinformatics, Neurosciences, Evolutionary Ecology, and Community Ecology. He has also published works in the areas of Dynamical Systems, Bifurcation Theory, and Chaos Theory.
- Nara Medical University Hospital, Japan
- Title:Searching for Baby-Friendly Phototherapy to prevent Bilirubin Encephalopathy in Premature Infants
- Time :
Kernicterus (bilirubin encephalopathy), a neurological complication of neonatal hyperbilirubinemia, has been reported, especially in preterm infants, and neonatal hyperbilirubinemia management remains an important issue for neonatal care. Premature infants in severe jaundice often do not have the typical kernicterus symptoms shown, and in infancy, present with hearing loss and athetoid cerebral palsy. Needless to say, phototherapy is a treatment method for neonatal hyperbilirubinemia that has spread worldwide. There is a tendency to think that phototherapy has no adverse events other than effects on the retina. However, according to Morris et al, aggressive phototherapy for extremity very low birth weight infants did not change mortality or the incidence of neurological sequelae. On the contrary, the mortality rate increased for neonates with a birth weight of 500-750 g (Morris BH, et al. N Engl J Med.359, 2008). For this reason, phototherapy is not necessarily a safe treatment. Since 2010, we have conducted clinical studies on neonatal jaundice and animal studies using young rats with jaundice models. As a result, green light has an advantage in reducing photo-oxidative stress response, but blue wavelength is essential to reduce blood bilirubin. (Uchida Y, et al. Early Hum Dev. 91, 2015).This result motivated the pursuit of what would be an effective and harmless treatment to excrete bilirubin more quickly. Under the current management of jaundice, the decision to start or stop treatment is based on blood total bilirubin and unbound bilirubin levels, and bilirubin excretion has not been directly evaluated. In newborns only a few days old, especially preterm infants, liver enzymes and circulation are immature. In addition, bilirubin excreted in the intestinal tract is absorbed into the blood again by the entero-hepatic circulation, so that it is insufficient to evaluate the phototherapy effect used for jaundice treatment only by the blood bilirubin value. That is, the effect of reducing blood bilirubin in a short period of time with phototherapy is presumed to be excreted as a photo-isomer in urine, but currently it can only be detected by a special analysis method such as high-performance liquid chromatography (HPLC). That is, it is difficult to easily measure urinary bilirubin excretion immediately at the bedside. I would also like to mention at this meeting our ongoing work to establish a new method to assess urinary bilirubin excretion using the fluorescent protein UnaG, which binds specifically and strongly to unconjugated bilirubin.
Dr. Yumiko Uchida is a lecturer of division of neonatal intensive care, maternal, fetal and neonatal medical center, Nara Medical University Hospital. She graduated from Nara Medical University in 1995 and majored in Pediatrics at Nara Medical University Hospital. She has been engaged in neonatal intensive care since 1996. She has been studying neonatal hyperbilirubinemia in the last 10 years.