This document discusses the challenges of conducting preclinical safety studies evaluating biologics administered directly to the central nervous system (CNS) via routes such as intrathecal or intracerebroventricular administration. Key points include the need for control groups to differentiate effects caused by the test article versus the delivery device, customized tissue sampling schemes to thoroughly assess local and distant effects in the brain and spinal cord, and characterization of pharmacokinetics, exposure levels, and potential immunogenicity issues which can impact interpretation of safety results. The document provides recommendations for designing preclinical CNS administration studies to help enable translation of results for first-in-human clinical trials.
This document summarizes expert opinions on the management of CLN2 disease based on a survey of 23 disease experts. It finds that while guidelines do not exist, management strategies are consistent worldwide. A multidisciplinary approach is critical and should include specialists in neurology, palliative care, genetics, physiotherapy, and patient advocacy. Key aspects of management include seizure control using antiepileptic drugs, management of movement disorders, maintaining nutrition, early palliative care involvement, and addressing sleep, pain, and end-of-life issues. The goals of care evolve over the course of the disease from maintaining function to preserving quality of life as symptoms progress.
1) The document summarizes the findings of an international survey of CLN2 experts regarding the natural history, diagnosis and management of CLN2 disease.
2) CLN2 disease is a rare, fatal pediatric neurological disorder caused by TPP1 enzyme deficiency. Initial symptoms typically include seizures, speech/language delays, and developmental regression between 1.5-5 years of age.
3) The survey found delays of 1-4 years between first symptoms and CLN2 diagnosis due to low disease awareness. Timely diagnosis is important to enable future treatment options.
The Role of DaT Scan in Diagnosing Parkinson Disease Ade Wijaya
1) The diagnosis of Parkinson's disease is traditionally based on clinical examination, however around 20% of cases are initially misdiagnosed.
2) DaT scan is used when it is uncertain if clinical parkinsonism reflects degeneration of dopaminergic neurons, to assist in diagnosis and treatment decisions.
3) DaTscan imaging helps distinguish between nigrostriatal dopaminergic degeneration and other causes of parkinsonism, improving diagnostic accuracy and informing medication management.
1. Critically ill patients often require high doses of opioids for pain management and sedation, which can lead to opioid tolerance, dependence, withdrawal, and opioid-induced hyperalgesia.
2. Opioid tolerance develops when higher and more frequent doses are needed to achieve the same pain relief effect due to reduced susceptibility, and can be seen in patients with major trauma, prolonged ventilation, or pediatric patients.
3. Unrelieved pain has physiological, psychological, and immune consequences that affect patient outcomes, so appropriate pain management is important in critical care.
This document discusses lysosomal biomarkers for neuronal ceroid lipofuscinosis (NCL), a group of rare genetic disorders. The author identifies two key points: 1) Lysosomal changes can provide a rapid method to determine if treatments for NCLs are effective, as these diseases progress slowly and standard clinical methods make efficacy difficult to evaluate. 2) Studying lysosomal changes may provide insights into the functions of deficient NCL proteins and why their deficiency causes disease. The author has identified secondary alterations in lysosomal proteins in mouse models of three NCL types (CLN1, CLN2, CLN3) using mass spectrometry and aims to validate potential biomarkers in cerebrospinal fluid.
Vagal Nerve stimulation
Vagus nerve stimulation (VNS) is a medical treatment that involves delivering electrical impulses to the vagus nerve. It is used as an add-on treatment for certain types of intractable epilepsy and treatment-resistant depression. Frequent side effects include coughing and shortness of breath. Serious side effects may include trouble talking and cardiac arrest.
Fetal nigral transplantation involves surgically transplanting dopamine-producing neurons from human fetal tissue grafts into the brains of Parkinson's disease patients. This aims to reinnervate the dopamine-depleted striatum and restore motor function. Studies have found the grafts can survive long-term, improve motor symptoms, and allow some patients to reduce their need for dopamine medication. However, fetal tissue transplantation still carries risks of dyskinesia and varying degrees of success, and is unlikely to become a routine therapy for Parkinson's disease.
This document provides an overview and summary of a presentation on assessing pain, sedation, and delirium in intensive care unit patients. It discusses:
- The importance of using validated scales like the Richmond Agitation-Sedation Scale (RASS) and Sedation-Agitation Scale (SAS) to accurately assess sedation levels in patients receiving sedatives.
- The challenges of assessing delirium given confounding factors like a patient's sedation level, wakefulness, and other psychiatric diagnoses. Scales like the Confusion Assessment Method for the ICU (CAM-ICU) are used but their accuracy depends on a patient's sedation.
- How pharmacokinetic factors like drug-
This document summarizes expert opinions on the management of CLN2 disease based on a survey of 23 disease experts. It finds that while guidelines do not exist, management strategies are consistent worldwide. A multidisciplinary approach is critical and should include specialists in neurology, palliative care, genetics, physiotherapy, and patient advocacy. Key aspects of management include seizure control using antiepileptic drugs, management of movement disorders, maintaining nutrition, early palliative care involvement, and addressing sleep, pain, and end-of-life issues. The goals of care evolve over the course of the disease from maintaining function to preserving quality of life as symptoms progress.
1) The document summarizes the findings of an international survey of CLN2 experts regarding the natural history, diagnosis and management of CLN2 disease.
2) CLN2 disease is a rare, fatal pediatric neurological disorder caused by TPP1 enzyme deficiency. Initial symptoms typically include seizures, speech/language delays, and developmental regression between 1.5-5 years of age.
3) The survey found delays of 1-4 years between first symptoms and CLN2 diagnosis due to low disease awareness. Timely diagnosis is important to enable future treatment options.
The Role of DaT Scan in Diagnosing Parkinson Disease Ade Wijaya
1) The diagnosis of Parkinson's disease is traditionally based on clinical examination, however around 20% of cases are initially misdiagnosed.
2) DaT scan is used when it is uncertain if clinical parkinsonism reflects degeneration of dopaminergic neurons, to assist in diagnosis and treatment decisions.
3) DaTscan imaging helps distinguish between nigrostriatal dopaminergic degeneration and other causes of parkinsonism, improving diagnostic accuracy and informing medication management.
1. Critically ill patients often require high doses of opioids for pain management and sedation, which can lead to opioid tolerance, dependence, withdrawal, and opioid-induced hyperalgesia.
2. Opioid tolerance develops when higher and more frequent doses are needed to achieve the same pain relief effect due to reduced susceptibility, and can be seen in patients with major trauma, prolonged ventilation, or pediatric patients.
3. Unrelieved pain has physiological, psychological, and immune consequences that affect patient outcomes, so appropriate pain management is important in critical care.
This document discusses lysosomal biomarkers for neuronal ceroid lipofuscinosis (NCL), a group of rare genetic disorders. The author identifies two key points: 1) Lysosomal changes can provide a rapid method to determine if treatments for NCLs are effective, as these diseases progress slowly and standard clinical methods make efficacy difficult to evaluate. 2) Studying lysosomal changes may provide insights into the functions of deficient NCL proteins and why their deficiency causes disease. The author has identified secondary alterations in lysosomal proteins in mouse models of three NCL types (CLN1, CLN2, CLN3) using mass spectrometry and aims to validate potential biomarkers in cerebrospinal fluid.
Vagal Nerve stimulation
Vagus nerve stimulation (VNS) is a medical treatment that involves delivering electrical impulses to the vagus nerve. It is used as an add-on treatment for certain types of intractable epilepsy and treatment-resistant depression. Frequent side effects include coughing and shortness of breath. Serious side effects may include trouble talking and cardiac arrest.
Fetal nigral transplantation involves surgically transplanting dopamine-producing neurons from human fetal tissue grafts into the brains of Parkinson's disease patients. This aims to reinnervate the dopamine-depleted striatum and restore motor function. Studies have found the grafts can survive long-term, improve motor symptoms, and allow some patients to reduce their need for dopamine medication. However, fetal tissue transplantation still carries risks of dyskinesia and varying degrees of success, and is unlikely to become a routine therapy for Parkinson's disease.
This document provides an overview and summary of a presentation on assessing pain, sedation, and delirium in intensive care unit patients. It discusses:
- The importance of using validated scales like the Richmond Agitation-Sedation Scale (RASS) and Sedation-Agitation Scale (SAS) to accurately assess sedation levels in patients receiving sedatives.
- The challenges of assessing delirium given confounding factors like a patient's sedation level, wakefulness, and other psychiatric diagnoses. Scales like the Confusion Assessment Method for the ICU (CAM-ICU) are used but their accuracy depends on a patient's sedation.
- How pharmacokinetic factors like drug-
Rituximab is a monoclonal antibody that targets B cells. It is used to treat various neurological conditions associated with autoantibodies or B cell dysfunction, including refractory myasthenia gravis, NMOSD, autoimmune encephalitis, and relapsing MS. The document discusses B cell biology, mechanisms of action of rituximab, indications, dosing, efficacy evidence, risks and monitoring considerations for rituximab's use in neurology. Key risks include infusion reactions and secondary infections due to prolonged B cell depletion.
The document summarizes recent discoveries in spinal cord injury pathophysiology and treatment from The Miami Project to Cure Paralysis. It discusses promising neuroprotective and regenerative treatments currently being studied, including hypothermia, stem cells, and Schwann cell transplantation. It also outlines ongoing clinical trials, such as the ARCTIC trial evaluating hypothermia and a proposed phase 1 trial of autologous Schwann cell transplantation in humans with spinal cord injuries. The overall goal is to translate bench research into new clinical applications and improve outcomes for spinal cord injury patients.
Leigh syndrome is a rare neurodegenerative disease caused by mitochondrial dysfunction from a genetic defect. It is characterized by bilateral brain lesions seen on imaging and variable symptoms. While it typically presents in infancy, it can occasionally present in adulthood. The diagnosis involves identifying characteristic brain lesions. Treatment focuses on nutritional supplementation like biotin and thiamine, as well as managing symptoms, but there is no cure for the underlying genetic condition.
This document summarizes research into developing a long-term treatment for CLN2 disease using enzyme replacement therapy. The researchers are using a dog model of CLN2 to test delivering the missing TPP1 enzyme to the brain and eyes. They take bone marrow cells, modify them to produce TPP1, and inject them into the eye and brain where they continue long-term production of TPP1. Preliminary results show a single injection of these stem cells into the eyes preserves visual function for over 7 months by preventing retinal lesions. It also suggests treating the brain preserves cognitive function long-term. The goal is to develop a one-time curative treatment for CLN2 disease.
Multiple sclerosis as a simultaneous "2 components" diseaseF.R.S. - FNRS
Multiple sclerosis is emerging as a "two components" disease rather than simply a "two stages" disease. It involves two distinct pathways - a peripheral T-cell mediated pathway that leads to focal inflammatory lesions, and a CNS-resident cell pathway involving activated astrocytes and microglia that results in diffuse neurodegeneration. Both pathways contribute to neurodegeneration and disability, but the diffuse pathology correlates more strongly with long-term disability. Evidence suggests neurodegenerative processes exist even in early MS, independent of peripheral inflammation.
Have you ever tried to sleep in a brightly lit room with tubes and wires attached to you and people periodically talking to you ! moving you ! and touching you !
Can brain atrophy measurement help us in monitoring MS progression in routine...MS Trust
This presentation by Dana Horáková, Department of Neurology and Centre of Clinical Neuroscience at the Charles University in Prague, looks at why and how we should measure brain atrophy.
It was presented at the MS Trust Annual Conference in November 2014.
This study found that redheads require more of the anesthetic desflurane than people with dark hair. Specifically:
1) Redheads required a 19% higher concentration of desflurane on average (6.2% vs 5.2%) to prevent movement in response to electrical stimulation, a statistically significant difference.
2) Genetic analysis found that 9 of the 10 redhead participants carried mutations in the melanocortin-1 receptor gene, which is responsible for red hair, while only 5 of 10 dark-haired participants carried mutations.
3) This confirms the anecdotal impression that redheads require higher doses of inhalational anesthetics and provides evidence that anesthetic requirement can be linked to human
This document provides an overview of neuroblastoma, including:
- Neuroblastoma is cancer of neural crest cells that give rise to sympathetic neural ganglia and adrenal medulla. It has a diverse presentation and prognosis ranging from spontaneous regression to aggressive metastatic tumors.
- Risk classification involves assessing histopathology, DNA index, MYCN amplification, and other factors to determine prognosis as favorable or unfavorable.
- A clinical trial evaluated adding dinutuximab, GM-CSF, and IL-2 to standard isotretinoin therapy in patients with high-risk neuroblastoma and found common side effects included pain, hypersensitivity reactions, and capillary leak syndrome.
This document summarizes research investigating the molecular basis of neuronal ceroid lipofuscinosis (NCL), a group of genetic disorders. The research aims to improve diagnosis and develop treatments by:
1) Using genetic model organisms and human cell cultures to study how mutations in NCL genes disrupt cellular processes and lead to symptoms;
2) Identifying new drug targets and screening drug libraries to find potential treatments; and
3) Collaborating with other groups to advance understanding of NCL diseases at the molecular level in order to develop better targeted therapies.
This document provides an overview of bioelectronic medicine (BEM). It defines BEM as implantable devices that treat disease by changing electric impulses in nerves. The history and advantages/disadvantages of BEM are discussed. Examples of current BEM technologies are provided, such as vagus nerve stimulation and bionic eyes. Future applications of BEM could include treatments for diabetes, hypertension, and movement disorders. The document concludes that BEM is promising for improving medicine by providing targeted, electrical treatments.
The document summarizes Pierre Zwiegers' thesis defense for a Master of Science degree. Zwiegers investigated targeted lentiviral-mediated delivery of progranulin cDNA in a genetic model of amyotrophic lateral sclerosis (ALS). The thesis included background on ALS and the neurotrophic properties of progranulin. Experiments assessed whether early-stage progranulin upregulation could lessen behavioral and neuropathological symptoms in transgenic mSOD1 mice. Results found no effect on disease onset, survival, neuronal loss or inflammation. Discussion addressed limitations of mSOD1 models for clinical translation and need for replicative pre-clinical studies.
The document discusses the relationship between the immune system and brain conditions from a toxicological perspective. It summarizes several studies that found:
1) The immune system plays an important role in brain development and any immune activation during development can affect later neural function, immune function, mood and cognition.
2) A drug called fingolimod that modulates sphingosine-1-phosphate receptors, reducing lymphocyte migration from lymph nodes, significantly reduced relapse rates and disability progression in multiple sclerosis patients compared to placebo.
3) Systemic immune status can influence local brain tissue conditions, and this effect could be considered a type of toxicological effect worth further investigation to better understand disease pathogenesis and develop new pharmacological
1) The document discusses the relationship between the immune system and brain development/function. Alterations in immune function can impact neurodevelopment and be associated with various neuropsychiatric disorders.
2) Studies show that drugs like fingolimod that modulate sphingosine-1-phosphate receptors and prevent lymphocyte egress from lymph nodes can significantly reduce relapse rates and disability progression in multiple sclerosis patients.
3) Autism disorders may involve abnormalities in certain brain areas and a complex symptomatology related to genetic and environmental factors that can disrupt normal brain growth and the immune situation. The immune status, specific time periods, microenvironment, and genetics may all provide insights into autism pathogenesis.
1) The document discusses emerging proteomics and genomics biomarkers for diagnosing Alzheimer's disease (AD), noting that current biomarkers like cerebrospinal fluid levels have limited accuracy.
2) It suggests that multi-biomarker approaches combining proteins associated with AD and vascular diseases may improve diagnostic accuracy.
3) MicroRNAs found in biofluids like cerebrospinal fluid and blood show potential as AD biomarkers, and combining multiple biomarkers into diagnostic profiles could help predict which individuals will progress from mild cognitive impairment to AD dementia.
Killer Drugs and the Supplement Hall of FameLouis Cady, MD
In the fourth and final lecture of his series at the IMMH Conference in Chicago, IL at McCormick Place, September 22, 2013, Dr. Cady covers the "for sure" interactions to watch out for between specific drugs and their common points of interaction.
After examining those potentially toxic interaction, he continues into a review of peer-reviewed evidence for the appropriate, thoughtful, and precise use of specific supplements in a targeted approach. The role of good basic antioxidant protection is discussed, as is the need for B-vitamins, Omega 3 fatty acids, and several others.
Erik Boot - Studying Psychosis in 22q11 Deletion Syndromewef
Presentation made July 28, 2016 at the live webinar hosted by the Schizophrenia Research Forum and titled Studying Psychosis in 22q11 Deletion Syndrome. More details and video recording at http://www.schizophreniaforum.org/for/live/detail.asp?liveID=100
1. Klaus Schmierer presents disclosures related to research funding and speaking engagements from various pharmaceutical companies involved in multiple sclerosis treatment.
2. He discusses two important lessons about MS treatment - that the disease is progressive from the start, and patients have a better chance of avoiding disability if treated early.
3. Selective immune reconstitution therapy (SIRT) and treatments like alemtuzumab and cladribine that deplete memory B cells have been shown to be highly effective at controlling disease activity, with alemtuzumab demonstrating similar efficacy to cladribine but with different adverse effect profiles.
Carrie Bearden: Studying Psychosis in 22q11 Deletion Syndromewef
Presentation made at the live webinar hosted by Schizophrenia Research Forum on the 28th of July, 2016, titled Studying Psychosis in 22q11 Deletion Syndrome. Additional recording and materials available at the SRF website: http://www.schizophreniaforum.org/for/live/detail.asp?liveID=100
Este documento analiza cinco artículos de revistas científicas de educación publicados entre los años 2000 y 2012. Resume cada artículo, evaluando factores como las referencias a autores, la antigüedad de las citas, y las revistas científicas citadas. Concluye que ha analizado los artículos cuantitativamente para evaluar la cantidad y calidad de la información presentada en función de las citas y fuentes utilizadas.
Este documento describe los artículos determinados e indeterminados en español. Los artículos determinados incluyen el, los, la y las y varían según el género y número del sustantivo. Los artículos indeterminados son un, unos, una y unas, también variando según el género y número. Se dan ejemplos de cómo se usan correctamente los artículos con diferentes sustantivos.
Rituximab is a monoclonal antibody that targets B cells. It is used to treat various neurological conditions associated with autoantibodies or B cell dysfunction, including refractory myasthenia gravis, NMOSD, autoimmune encephalitis, and relapsing MS. The document discusses B cell biology, mechanisms of action of rituximab, indications, dosing, efficacy evidence, risks and monitoring considerations for rituximab's use in neurology. Key risks include infusion reactions and secondary infections due to prolonged B cell depletion.
The document summarizes recent discoveries in spinal cord injury pathophysiology and treatment from The Miami Project to Cure Paralysis. It discusses promising neuroprotective and regenerative treatments currently being studied, including hypothermia, stem cells, and Schwann cell transplantation. It also outlines ongoing clinical trials, such as the ARCTIC trial evaluating hypothermia and a proposed phase 1 trial of autologous Schwann cell transplantation in humans with spinal cord injuries. The overall goal is to translate bench research into new clinical applications and improve outcomes for spinal cord injury patients.
Leigh syndrome is a rare neurodegenerative disease caused by mitochondrial dysfunction from a genetic defect. It is characterized by bilateral brain lesions seen on imaging and variable symptoms. While it typically presents in infancy, it can occasionally present in adulthood. The diagnosis involves identifying characteristic brain lesions. Treatment focuses on nutritional supplementation like biotin and thiamine, as well as managing symptoms, but there is no cure for the underlying genetic condition.
This document summarizes research into developing a long-term treatment for CLN2 disease using enzyme replacement therapy. The researchers are using a dog model of CLN2 to test delivering the missing TPP1 enzyme to the brain and eyes. They take bone marrow cells, modify them to produce TPP1, and inject them into the eye and brain where they continue long-term production of TPP1. Preliminary results show a single injection of these stem cells into the eyes preserves visual function for over 7 months by preventing retinal lesions. It also suggests treating the brain preserves cognitive function long-term. The goal is to develop a one-time curative treatment for CLN2 disease.
Multiple sclerosis as a simultaneous "2 components" diseaseF.R.S. - FNRS
Multiple sclerosis is emerging as a "two components" disease rather than simply a "two stages" disease. It involves two distinct pathways - a peripheral T-cell mediated pathway that leads to focal inflammatory lesions, and a CNS-resident cell pathway involving activated astrocytes and microglia that results in diffuse neurodegeneration. Both pathways contribute to neurodegeneration and disability, but the diffuse pathology correlates more strongly with long-term disability. Evidence suggests neurodegenerative processes exist even in early MS, independent of peripheral inflammation.
Have you ever tried to sleep in a brightly lit room with tubes and wires attached to you and people periodically talking to you ! moving you ! and touching you !
Can brain atrophy measurement help us in monitoring MS progression in routine...MS Trust
This presentation by Dana Horáková, Department of Neurology and Centre of Clinical Neuroscience at the Charles University in Prague, looks at why and how we should measure brain atrophy.
It was presented at the MS Trust Annual Conference in November 2014.
This study found that redheads require more of the anesthetic desflurane than people with dark hair. Specifically:
1) Redheads required a 19% higher concentration of desflurane on average (6.2% vs 5.2%) to prevent movement in response to electrical stimulation, a statistically significant difference.
2) Genetic analysis found that 9 of the 10 redhead participants carried mutations in the melanocortin-1 receptor gene, which is responsible for red hair, while only 5 of 10 dark-haired participants carried mutations.
3) This confirms the anecdotal impression that redheads require higher doses of inhalational anesthetics and provides evidence that anesthetic requirement can be linked to human
This document provides an overview of neuroblastoma, including:
- Neuroblastoma is cancer of neural crest cells that give rise to sympathetic neural ganglia and adrenal medulla. It has a diverse presentation and prognosis ranging from spontaneous regression to aggressive metastatic tumors.
- Risk classification involves assessing histopathology, DNA index, MYCN amplification, and other factors to determine prognosis as favorable or unfavorable.
- A clinical trial evaluated adding dinutuximab, GM-CSF, and IL-2 to standard isotretinoin therapy in patients with high-risk neuroblastoma and found common side effects included pain, hypersensitivity reactions, and capillary leak syndrome.
This document summarizes research investigating the molecular basis of neuronal ceroid lipofuscinosis (NCL), a group of genetic disorders. The research aims to improve diagnosis and develop treatments by:
1) Using genetic model organisms and human cell cultures to study how mutations in NCL genes disrupt cellular processes and lead to symptoms;
2) Identifying new drug targets and screening drug libraries to find potential treatments; and
3) Collaborating with other groups to advance understanding of NCL diseases at the molecular level in order to develop better targeted therapies.
This document provides an overview of bioelectronic medicine (BEM). It defines BEM as implantable devices that treat disease by changing electric impulses in nerves. The history and advantages/disadvantages of BEM are discussed. Examples of current BEM technologies are provided, such as vagus nerve stimulation and bionic eyes. Future applications of BEM could include treatments for diabetes, hypertension, and movement disorders. The document concludes that BEM is promising for improving medicine by providing targeted, electrical treatments.
The document summarizes Pierre Zwiegers' thesis defense for a Master of Science degree. Zwiegers investigated targeted lentiviral-mediated delivery of progranulin cDNA in a genetic model of amyotrophic lateral sclerosis (ALS). The thesis included background on ALS and the neurotrophic properties of progranulin. Experiments assessed whether early-stage progranulin upregulation could lessen behavioral and neuropathological symptoms in transgenic mSOD1 mice. Results found no effect on disease onset, survival, neuronal loss or inflammation. Discussion addressed limitations of mSOD1 models for clinical translation and need for replicative pre-clinical studies.
The document discusses the relationship between the immune system and brain conditions from a toxicological perspective. It summarizes several studies that found:
1) The immune system plays an important role in brain development and any immune activation during development can affect later neural function, immune function, mood and cognition.
2) A drug called fingolimod that modulates sphingosine-1-phosphate receptors, reducing lymphocyte migration from lymph nodes, significantly reduced relapse rates and disability progression in multiple sclerosis patients compared to placebo.
3) Systemic immune status can influence local brain tissue conditions, and this effect could be considered a type of toxicological effect worth further investigation to better understand disease pathogenesis and develop new pharmacological
1) The document discusses the relationship between the immune system and brain development/function. Alterations in immune function can impact neurodevelopment and be associated with various neuropsychiatric disorders.
2) Studies show that drugs like fingolimod that modulate sphingosine-1-phosphate receptors and prevent lymphocyte egress from lymph nodes can significantly reduce relapse rates and disability progression in multiple sclerosis patients.
3) Autism disorders may involve abnormalities in certain brain areas and a complex symptomatology related to genetic and environmental factors that can disrupt normal brain growth and the immune situation. The immune status, specific time periods, microenvironment, and genetics may all provide insights into autism pathogenesis.
1) The document discusses emerging proteomics and genomics biomarkers for diagnosing Alzheimer's disease (AD), noting that current biomarkers like cerebrospinal fluid levels have limited accuracy.
2) It suggests that multi-biomarker approaches combining proteins associated with AD and vascular diseases may improve diagnostic accuracy.
3) MicroRNAs found in biofluids like cerebrospinal fluid and blood show potential as AD biomarkers, and combining multiple biomarkers into diagnostic profiles could help predict which individuals will progress from mild cognitive impairment to AD dementia.
Killer Drugs and the Supplement Hall of FameLouis Cady, MD
In the fourth and final lecture of his series at the IMMH Conference in Chicago, IL at McCormick Place, September 22, 2013, Dr. Cady covers the "for sure" interactions to watch out for between specific drugs and their common points of interaction.
After examining those potentially toxic interaction, he continues into a review of peer-reviewed evidence for the appropriate, thoughtful, and precise use of specific supplements in a targeted approach. The role of good basic antioxidant protection is discussed, as is the need for B-vitamins, Omega 3 fatty acids, and several others.
Erik Boot - Studying Psychosis in 22q11 Deletion Syndromewef
Presentation made July 28, 2016 at the live webinar hosted by the Schizophrenia Research Forum and titled Studying Psychosis in 22q11 Deletion Syndrome. More details and video recording at http://www.schizophreniaforum.org/for/live/detail.asp?liveID=100
1. Klaus Schmierer presents disclosures related to research funding and speaking engagements from various pharmaceutical companies involved in multiple sclerosis treatment.
2. He discusses two important lessons about MS treatment - that the disease is progressive from the start, and patients have a better chance of avoiding disability if treated early.
3. Selective immune reconstitution therapy (SIRT) and treatments like alemtuzumab and cladribine that deplete memory B cells have been shown to be highly effective at controlling disease activity, with alemtuzumab demonstrating similar efficacy to cladribine but with different adverse effect profiles.
Carrie Bearden: Studying Psychosis in 22q11 Deletion Syndromewef
Presentation made at the live webinar hosted by Schizophrenia Research Forum on the 28th of July, 2016, titled Studying Psychosis in 22q11 Deletion Syndrome. Additional recording and materials available at the SRF website: http://www.schizophreniaforum.org/for/live/detail.asp?liveID=100
Este documento analiza cinco artículos de revistas científicas de educación publicados entre los años 2000 y 2012. Resume cada artículo, evaluando factores como las referencias a autores, la antigüedad de las citas, y las revistas científicas citadas. Concluye que ha analizado los artículos cuantitativamente para evaluar la cantidad y calidad de la información presentada en función de las citas y fuentes utilizadas.
Este documento describe los artículos determinados e indeterminados en español. Los artículos determinados incluyen el, los, la y las y varían según el género y número del sustantivo. Los artículos indeterminados son un, unos, una y unas, también variando según el género y número. Se dan ejemplos de cómo se usan correctamente los artículos con diferentes sustantivos.
El documento resume 10 de las aplicaciones favoritas de Jorge Simón, incluyendo navegadores web como Firefox y Mozzila, reproductores de medios como iTunes, Windows Media Player y Real Player, herramientas de productividad como Microsoft Office 2010, programas de comunicación como Skype, y utilidades como antivirus McAfee, WinRar, Adobe Flash Player y Audacity. La mayoría se pueden descargar gratuitamente desde sus respectivas páginas web.
Uma alimentação saudável é composta por proteínas, hidratos de carbono, gorduras, fibras, minerais e vitaminas em quantidades adequadas. Ela serve para o desenvolvimento intelectual, bem-estar e prevenção de doenças. A Roda dos Alimentos indica os grupos alimentares e suas quantidades diárias recomendadas.
El documento describe los tipos de mantenimiento de computadoras, preventivo y correctivo. El mantenimiento preventivo incluye limpieza física y de software para proteger los equipos de fallas. El mantenimiento correctivo implica reparaciones y reemplazo de piezas con fallas potenciales. Ambos tipos tienen ventajas como confiabilidad y menores costos, pero también desventajas como costos elevados o dificultad para predecir tiempos de reparación.
O documento descreve o Dia Mundial da Usabilidade, um evento anual que ocorre em mais de 40 países e 120 cidades para promover o design centrado no usuário e assegurar que serviços e produtos sejam acessíveis e fáceis de usar. O texto também fornece detalhes sobre a programação do evento no Brasil.
Áreas comuns entregues equipadas e decoradas;
Hall com portaria;
Espaço Gourmet localizado na cobertura com vista panorâmica da cidade;
Salão de Festas no Pavimento Térreo;
Banheiros, cozinha e sacadas entregues com
porcelanato Portinari;
Churrasqueira à carvão em todos os apartamentos;
Esquadrias Gold;
Vagões com espaço para 02 automóveis médios;
Universidad técnica de ambat1 informe de ntc's bllogerEl pensamiento 2B
Este documento describe cómo crear un blog usando la plataforma Blogger de Google. Primero, se debe crear una cuenta de Gmail para acceder a Blogger. Luego, se siguen los pasos para crear el blog, incluyendo elegir un nombre, tema y configuración. Finalmente, se explica cómo publicar contenido y personalizar la configuración y diseño del blog. El documento también brinda definiciones breves de herramientas como Cool Text, Voki y Textanim que pueden usarse para agregar gráficos y animaciones al blog.
Google Analytics es un servicio gratuito que ofrece estadísticas e informes sobre el tráfico y el comportamiento de los usuarios en un sitio web. Proporciona información útil para ejecutivos, responsables de marketing y administradores de sitios web. Entre los informes disponibles se incluyen datos sobre usuarios únicos, rendimiento de campañas, posicionamiento en buscadores y análisis de contenido.
La invitación al evento solo se envió a los estudiantes matriculados en el curso que proporcionaron un correo electrónico válido. El documento incluye enlaces para participar en el evento y una nota indicando que se puede presionar "no" si no se cuenta con micrófono o webcam.
Este documento presenta una plantilla para crear una webquest educativa. Incluye secciones para la introducción, tarea, proceso, recursos, evaluación, conclusión y guía didáctica. Explica brevemente el propósito de cada sección y ofrece consejos sobre cómo redactar el contenido para cada una.
Los estudiantes disfrutaron de la actividad dirigida por Belén para hacer manualidades para el Día del Padre, y aprendieron a hacer regalos creativos como coches, motos y diplomas. Muchos esperan que Belén vuelva a dirigir otras actividades similares en el futuro.
El artículo describe la importancia de realizar mediciones precisas y confiables del tiempo en actividades industriales para calcular el tiempo estándar. Se destaca la importancia del muestreo probabilístico para determinar el número de observaciones necesarias. Luego, aplica el muestreo aleatorio simple para calcular el tiempo normal de las actividades básicas de una empresa de envases plásticos con el fin de establecer tiempos estándar que permitan la planificación. Finalmente, presenta un caso real sobre el proceso de soplado y tampografía de la empresa.
Slides da palestra "O Sonho também é meu" feita pelo Alexandre Tarifa do MinhaVida realizada no EPICENTRO no dia 3 de Maio em São Paulo. Para maiores informações visite http://www.oepicentro.com.br
La lluvia ácida se produce cuando el pH del agua de lluvia es inferior a 5.6 debido a los óxidos de nitrógeno y azufre emitidos por la combustión. Esto causa la acidificación de aguas, corroe infraestructuras y perjudica los bosques. Algunas soluciones incluyen reducir el azufre en combustibles, controlar emisiones industriales con tecnologías y promover el uso de gas natural.
El documento describe la historia y actividades de la Fundación Clarós desde 1992 hasta 2013. La Fundación comenzó su labor humanitaria en India en 1992 y fue oficialmente establecida en 1997. Desde entonces, ha realizado misiones médicas en numerosos países de África, Asia e Europa del Este, proporcionando cirugía gratuita, audífonos y formación médica. La Fundación se ha centrado principalmente en el tratamiento de la sordera y otras enfermedades de oído, nariz y garganta.
This document examines the encephalogenic and HLA-DR binding capacities of various myelin peptides. It constructs recombinant HLA-DRβ1 complexes containing peptides from myelin proteolipid protein, myelin oligodendrocyte glycoprotein, and myelin basic protein. These complexes are transfected into insect cells to evaluate surface expression and autoantigenic activity. Individual myelin peptides are also tested for their ability to induce experimental autoimmune encephalomyelitis in transgenic mice. The data shows that two specific sheath peptides induced multiple sclerosis-like paralysis when injected into HLA-DRβ1-15.01 mice, indicating a role in multiple sclerosis induction. Ultimately, the peptide-HLA complexes will be used
This document summarizes a study on the role of transcription factors Ets-1 and NF-κB in the progression of cerebral aneurysms. The study found that Ets-1 and NF-κB regulate inflammatory genes that stimulate vascular smooth muscle cell growth and aneurysm development. Inhibiting these transcription factors through synthesized oligodeoxynucleotides reduced aneurysm size and inflammation in rat models. The results suggest controlling Ets-1 and NF-κB expression may help prevent cerebral aneurysm formation and rupture in humans.
This document provides an introduction to a lecture on drugs used to treat central nervous system disorders and pain. It begins with the goal of introducing the functional organization of the CNS and its neurotransmitters. It then classifies common CNS drug classes and lists major neuropsychiatric disorders treated. Methods for studying CNS pharmacology are outlined. An overview of CNS cell types including neurons and glia is given. The most studied neurotransmitters like norepinephrine, dopamine, serotonin, acetylcholine, GABA, and glutamate are discussed. CNS drugs and their potential side effects are also briefly covered.
Brain specific drug targetting stratergieskoorishma
The document discusses strategies for targeting drugs to the brain by circumventing the blood-brain barrier (BBB). The BBB normally prevents many drugs from entering the brain. Recent advances discussed include using nanoparticles, receptor-mediated transport, and various mechanisms to temporarily disrupt the BBB, such as intranasal delivery, convection-enhanced delivery directly to brain tissue, osmotic disruption using mannitol, and ultrasound-mediated opening. Imaging techniques like MRI and PET are also used to evaluate drug distribution and therapeutic response in the brain. Potential applications mentioned include treating neurodegeneration, brain tumors, and lysosomal storage diseases.
HCSPHARMA Importance of microenvironment in cerebral in vitro models for phen...HCS Pharma
Aim: About 90% of drug-candidates failed in clinical trials, in particular in neurology, due to a lack of efficacy. That highlights a lack of relevance in preclinical models, including in vitro models, which do not take into account the microenvironment, composed by glial cells and the Extracellular Matrix (ECM). The objective was to study the influence of the microenvironment in cerebral in vitro models, in the frame of Parkinson’s Disease (PD).
Methods: First, we analyzed the influence of astrocytes on Luhmes cell sensitivity, a dopaminergic neuronal cell line, in 2D culture. Then, we developed a hyaluronic acid-based hydroscaffold for 3D cell culture, which mimics the ECM, and study the sensitivity of Luhmes cells in this model. Thirdly, we performed a co-culture of Luhmes cells and astrocytes in this matrix, to form a complex model including both the glial and the matricial microenvironments.
Results: We observed a protective effect of astrocytes in 2D culture. In the hydroscaffold, Luhmes cells displayed a lower sensitivity compared to 2D culture, that was explained by a partial retention of toxic molecules in the matrix, and differences in neuronal protein expression. In the co-culture, we observed spheroids containing both neurons and astrocytes.
Conclusions: This work highlighted that the microenvironment of neurons can modify the neuronal response in vitro, and should thus be considered carefully in academic research and in drug discovery. This model can be now used to study the microenvironment modifications in pathological conditions, and to develop innovative drugs targeting the microenvironment.
Raghu Solanki presented on using nano diamonds for drug delivery of efavirenz to treat HIV. Key points:
- Nano diamonds are 2-8 nm in diameter and can attach drugs like efavirenz to their surface for delivery.
- Efavirenz is effective against HIV but has low bioavailability and drug resistance.
- Nano diamonds could help deliver efavirenz due to their biocompatibility and ability to increase drug solubility and provide sustained release.
- Experiments showed nano diamonds effectively adsorbed and released efavirenz in vitro and could deliver it across a blood brain barrier model while avoiding side effects.
The document discusses gene therapy as a potential treatment for various neurological disorders, describing how gene therapy works and the types of gene therapy products being studied. It also examines several specific neurological disorders like Alzheimer's disease, Parkinson's disease, and Huntington's disease, and explores the role of physical therapy in treating the symptoms and slowing the progression of these conditions.
Autologous Bone Marrow Cell Therapy for Autism: An Open Label Uncontrolled C...remedypublications2
The aim of this study is to assess the safety and effectiveness of autologous bone marrow
mononuclear stem cell (BMMNC) transplantation in patients with autism.
This document summarizes a project investigating whether mitochondrial DNA-encoded oxidative phosphorylation (OXPHOS) transcripts are dysregulated in the blood of patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) compared to controls. The student researcher designed primers, conducted quantitative real-time PCR on blood samples from controls and patients, and found several mtDNA-encoded OXPHOS transcripts were significantly more abundant in MCI and AD patients. This suggests peripheral changes in mitochondrial gene expression occur early in AD and could provide biomarkers for early diagnosis and monitoring disease progression and treatment responses.
The Indian Consensus Document on Cardiac BiomarkerApollo Hospitals
Despite recent advances, the diagnosis and management of heart failure evades the clinicians. The etiology of congestive heart failure (CHF) in the Indian scenario comprises of coronary artery disease, diabetes mellitus and hypertension. With better insights into the pathophysiology of CHF, biomarkers have evolved rapidly and received diagnostic and prognostic value. In CHF biomarkers prove as measures of the extent of pathophysiological derangement; examples include biomarkers of myocyte necrosis, myocardial remodeling,
neurohormonal activation, etc.
My presentation delivered at the MS Symposium of the Jewish Hospital Berlin (https://www.juedisches-krankenhaus.de/home.html) held on 29 Nar 2023 at the Centrum Judaicum, Oranienburger Strasse, Berlin
How chronic inflammation in rheumatoid arthritis affects brain previnay tuteja
Rheumatoid arthritis is an inflammatory disease that can affect multiple systems beyond the joints. While joint involvement is most common, the disease may also impact the brain through several mechanisms. Chronic systemic inflammation from rheumatoid arthritis is associated with increased levels of pro-inflammatory cytokines that can impact cognition. Several studies have found evidence of cognitive impairment in 30-70% of rheumatoid arthritis patients involving domains like attention, memory and flexibility. Brain imaging of patients has shown signs of hypoperfusion and increased white matter lesions that correlate with cognitive dysfunction. Higher inflammation levels are also linked to changes in functional and structural brain networks that relate to increased fatigue, pain and cognitive problems in rheumatoid arthritis. Effectively treating the inflammatory components of the disease may
Invasive approaches to bypassing the blood-brain barrier include direct intracerebral implantation, intraventricular infusion, and blood-brain barrier disruption. Intracerebral implantation involves direct injection or implanting controlled release matrices in the brain parenchyma. Intraventricular infusion uses an implanted reservoir to infuse drugs into the ventricles. Blood-brain barrier disruption temporarily opens tight junctions using hyperosmotic solutions, irradiation, or focused ultrasound to increase drug delivery. However, these invasive methods require anesthesia and surgery and risk neuronal damage from blood components entering the brain.
Summary
Neurodevelopment is a complex process governed by both intrinsic and extrinsic signals. While historically studied by researching the brain, inputs from the periphery impact many neurological conditions. Indeed, emerging data suggests communication between the gut and the brain in anxiety,
depression, cognition and autism spectrum disorder (ASD). The development of a healthy, functional brain depends on key pre- and post-natal events that integrate environmental cues, such as molecular signals from the gut. These cues largely originate from the microbiome, the consortium of symbiotic bacteria that reside within all animals. Research over the past few years reveals that the gut microbiome plays a role in basic neurogenerative processes such as the formation of the blood-brainbarrier, myelination, neurogenesis, and microglia maturation, and also modulates many aspects of animal behavior. Herein, we discuss the biological intersection of neurodevelopment and the microbiome, and explore the hypothesis that gut bacteria are integral contributors to development and function of the nervous system, and the balance between mental health and disease.
Translational Neuroscience Approach in psychiatry..pptxkrishray616
Translational neuroscience aims to bridge the gap between fundamental scientific research and clinical applications to treat neurological disorders. It focuses on applying discoveries from preclinical research, like animal and cell models, to develop new therapies. Translational neuroscience research occurs across both wet labs, which use experimental techniques, and dry labs, which analyze data through computational methods. The goal is to more quickly translate basic scientific findings into clinical applications that can improve patient outcomes. Identifying biomarkers that indicate disease mechanisms or predict treatment responses is an important part of translational research efforts.
Nuckolls U Iowa Aug 2016 (education).pptxDrAmanSaxena
1) The NIH supports muscular dystrophy research through multiple institutes like NINDS and NIAMS, with over $77 million provided in FY2015.
2) The Wellstone Centers program coordinates research across six centers focused on specific types of muscular dystrophy.
3) The Muscular Dystrophy Coordinating Committee promotes collaboration between government agencies, researchers, and patient advocacy groups.
This document discusses depression, including its epidemiology, definitions, classification, diagnostic criteria, and treatment. Some key points:
- Depression is the 3rd leading cause of disease burden worldwide and is projected to become the leading cause by 2030.
- Major depression has a prevalence of 5% and 15% of the population will experience a major depressive episode at some point in their life.
- Depression is classified based on severity from mild to severe. Diagnosis requires a certain number of symptoms from major and minor criteria groups.
- Depression can be classified as unipolar (recurrent depression only) or bipolar (episodes of mania and depression).
- Causes of depression involve biological factors like neurotransmitter im
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This document summarizes research on using stem cell transplantation as a potential therapy for neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS). It discusses how stem cell transplantation has shown effectiveness in animal models of ALS through mechanisms like cell replacement, neurotrophic factor release, and endogenous stem cell proliferation. Early clinical trials transplanting stem cells into ALS patients showed feasibility and no severe side effects. However, more research is still needed to fully understand stem cell mechanisms and maximize their therapeutic potential for neurodegenerative diseases.
Managing Autoimmunity is an informative slide show of key points to healthy immune regulatory factors. These basic items: toxic load, diet, nutritional stores, immune triggers, glutathione stores and genetics converge to create or deny a certain immune level of activity. Delivered to the Functional Medicine Club at SCUHS
This document lists 38 published works by Dr. Sven Korte, including research papers, book chapters, conference abstracts and posters presented between 1996-2013. The publications cover a range of topics including ecological studies of starfish populations, feasibility studies of intravenous infusion and port catheter techniques in marmoset monkeys, and reference data for marmosets and cynomolgus monkeys. Many of the publications were presented at annual conferences of the Society of Toxicology, Japanese Society of Toxicology, and other scientific meetings.
This document lists 50 published works by Dr. Sven Korte, including research papers, book chapters, conference abstracts and posters presented between 1996-2015. The publications cover a wide range of topics related to using marmoset and cynomolgus monkeys as models for biomedical research and toxicology studies. Many of the publications describe developing and validating techniques for procedures in monkeys such as intravenous infusion, blood pressure monitoring, CSF collection and behavioral observations. The list demonstrates Dr. Korte's extensive experience over nearly 20 years in applying non-human primates, especially marmosets and cynomolgus monkeys, as models for pre-clinical safety testing.
This study investigated alternative subcutaneous port placements for cerebrospinal fluid (CSF) sampling in chair-restrained cynomolgus monkeys. Three monkeys had intrathecal catheters implanted connecting to ports placed in different subcutaneous regions: under the shoulder blade (standard technique), in the thoracolumbar region, or in the sacral region. CSF collection was most successful from the sacral port placement, allowing for easier needle insertion and fixation while the monkey was restrained. The sacral port placement seems most promising for fast and easy CSF collection in restrained monkeys.
This document summarizes a study that investigated the toxicological profile of JNJ-37822681, a fast dissociating dopamine D2 receptor antagonist intended for the treatment of schizophrenia, in cynomolgus monkeys and Sprague–Dawley rats. The monkeys showed severe extrapyramidal side effects like abnormal posture and eye movements at low doses of JNJ-37822681, unlike rats, which did not show these side effects. Both species showed elevated prolactin levels, but only rats exhibited prolactin-related tissue changes. The cynomolgus monkey responses to JNJ-37822681 were more predictive of human adverse events than responses in rats.
This document discusses a case study of a cynomolgus monkey that underwent MRI imaging as part of a diagnostic evaluation. The MRI revealed an enlarged stomach and liver, and a narrowed opening from the stomach to the duodenum. Necropsy found the stomach filled with food, an empty intestine, and thickening of the pancreas around the opening of the pancreatic and biliary ducts. Histopathology determined the cause of death was obstructive pancreatic necrosis and pyloric stenosis, due to a primary blockage of the pancreatic duct that caused acute pancreatic death, narrowing of the opening from the stomach, malabsorption, and liver damage. This case demonstrates how enhanced imaging like MRI can improve diagnostics and
An existing intravenous infusion technique for administering pharmaceuticals to nonhuman primates was transferred to a new laboratory setting. As part of the technique transfer, port catheters were surgically implanted in two cynomolgus monkeys (Macaca fasicularis) and the animals underwent a 4-week recovery. Continuous intravenous infusion of an unspecified substance was then administered for 24 hours using a portable infusion pump in a backpack. The technique transfer was successful, with no significant clinical issues observed during recovery or dosing. Post-mortem examination found common histopathological lesions at the catheter tip and port site. The transferred technique allows longer intravenous dosing studies in cynomolgus monkeys in accordance with the 3Rs principles
The document summarizes findings from long-term intrathecal bolus administration studies in cynomolgus monkeys. Transient neurological findings were observed in control animals after intrathecal dosing and anesthesia, including temporarily reduced or absent patellar reflex and absence of the anal reflex lasting up to 8 hours. Single cases of ataxia, leg lameness, or slight tremor lasted up to 4 hours. Background clinical signs observed throughout the studies were similar to those seen with oral or subcutaneous dosing and included injuries, lesions, fractures, swellings, hair loss, diarrhea and others. The document provides details on study designs, housing conditions, dosing procedures, and expected background findings to aid in differentiating treatment effects
This study evaluated the use of an Accutome AccuPach VI pachymetry system to measure corneal thickness in cynomolgus monkeys. The system showed good intra-run precision between 5.3-6.9% and inter-run precision between 1.5-1.9%. Measurements also showed high concordance between technicians of 97.9-98.3%. The mean corneal thickness measurements of 411.3-418.7 μm were within the normal expected range for cynomolgus monkeys using ultrasound pachymetry. The pachymetry system was determined to be valid for measuring corneal thickness in cynomolgus monkeys based on the precision and accuracy of the measurements obtained.
1. CONTEMPORARY REVIEW
Safety Evaluation of CNS Administered Biologics—
Study Design, Data Interpretation, and Translation to
the Clinic
Brian R. Vuillemenot,*,1
Sven Korte,†
Teresa L. Wright,‡
Eric L. Adams,§
Robert B. Boyd,§
and Mark T. Butt¶
*Genentech, Inc, South San Francisco, California; †
Covance Laboratories GmbH, Mu¨ nster, Germany;
‡
Dimension Therapeutics, Cambridge, Massachusetts; §
Northern Biomedical Research, Muskegon, Michigan;
and ¶
Tox Path Specialists, Frederick, Maryland
1
To whom correspondence should be addressed at Genentech, Inc., 1 DNA Way, South San Francisco, California 94080. Fax: 650-866-2621.
E-mail: vuillemb@gene.com.
ABSTRACT
Many central nervous system (CNS) diseases are inadequately treated by systemically administered therapies due to the
blood brain barrier (BBB), which prevents achieving adequate drug concentrations at sites of action. Due to the increasing
prevalence of neurodegenerative diseases and the inability of most systemically administered therapies to cross the BBB,
direct CNS delivery will likely play an increasing role in treatment. Administration of large molecules, cells, viral vectors,
oligonucleotides, and other novel therapies directly to the CNS via the subarachnoid space, ventricular system, or
parenchyma overcomes this obstacle. Clinical experience with direct CNS administration of small molecule therapies
suggests that this approach may be efficacious for the treatment of neurodegenerative disorders using biological therapies.
Risks of administration into the brain tissue or cerebrospinal fluid include local damage from implantation of the delivery
system and/or administration of the therapeutic and reactions affecting the CNS. Preclinical safety studies on CNS
administered compounds must differentiate between the effects of the test article, the delivery device, and/or the vehicle,
and assess exacerbations of reactions due to combinations of effects. Animal models characterized for safety assessment of
CNS administered therapeutics have enabled human trials, but interpretation can be challenging. This manuscript outlines
the challenges of preclinical intrathecal/intracerebroventricular/intraparenchymal studies, evaluation of results,
considerations for special endpoints, and translation of preclinical findings to enable first-in-human trials.
Recommendations will be made based on the authors’ collective experience with conducting these studies to enable clinical
development of CNS-administered biologics.
Key words: CNS administration; intrathecal; intracerebroventricular; neurodegeneration; enzyme replacement therapy.
Neurodegenerative diseases represent a major health burden
and inadequately met medical need. This burden includes
Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral
sclerosis, Huntingdon’s disease, lysosomal storage diseases
(LSDs), and other diseases. Systemically administered biologics
have not yet been effective in treating these diseases, largely
due to the challenges in achieving adequate concentrations at
key sites of action in the central nervous system (CNS). Direct
CNS administration circumvents the barriers that keep large
molecules out of the CNS and introduces potential therapies
VC The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.
For Permissions, please e-mail: journals.permissions@oup.com
3
TOXICOLOGICAL SCIENCES, 152(1), 2016, 3–9
doi: 10.1093/toxsci/kfw072
Contemporary Review
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2. close to sites of action, and is likely to play an increasingly large
role in addressing these unmet medical needs. Preclinical devel-
opment of CNS-administered therapeutics faces a number of
challenges not typically encountered with systemically admin-
istered therapeutics. The objective of this article is to review the
main challenges of preclinical safety assessment of CNS admin-
istered molecules. Recommendations for the translation of
these studies to enable first-in-human trials will also be made.
Current experience with protein-based therapeutics ad-
ministered directly to the CNS is limited. CNS-administered
biologics have been evaluated preclinically and/or clinically
to treat pain, cancer, neurodegenerative diseases, and lyso-
somal storage diseases (LSDs)]. A summary is presented in
Table 1.
The only currently marketed biologic developed specifically
for direct CNS administration is Ziconitide, a cone snail derived
peptide to treat pain (Williams et al., 2008). Baclofen, a marketed
small molecule therapy approved for treatment of muscle
spasms, was also developed for intrathecal (IT) administration
(Richard and Menei, 2007). Several monoclonal antibodies have
been administered to the cerebrospinal fluid (CSF) off label with
evidence of efficacy in different cancers. In contrast, attempts
to develop therapies for neurodegenerative diseases using CNS
administration of growth and neurotrophic factors have so far
been unsuccessful. LSDs may be caused by genetic deficiency of
lysosomal enzymes, with over two-thirds involving CNS disease
(Schultz et al., 2011). Systemically administered enzyme replace-
ment therapies (ERTs) have been successful in treating nonCNS
symptoms of these diseases, but not the neurological compo-
nents (Hollak and Wijburg, 2014). Several of the approved ERTs
have been used off label for direct CNS administration (Mu~noz-
Rojas et al., 2008, 2010). Several clinical trials are in progress for
CNS-administered ERTs to treat neurodegenerative LSDs (Katz
et al., 2014; Muenzer et al., 2016). Gene therapy strategies using
IT administration have been described in Beutler et al. (2005)
and Hirai et al. (2014). Direct CNS delivery of antisense oligonu-
cleotides (ASOs), used to regulate target mRNA, is also in devel-
opment (Miller et al., 2013). Intracerebroventricular (ICV) and IT
administration of ASOs has resulted in neuronal uptake in mon-
eys and dogs.
BREACHING THE BLOOD BRAIN BARRIER
The blood brain barrier (BBB) represents the primary obstacle to
achieving CNS distribution of large molecule therapeutics ad-
ministered systemically. The BBB consists of tight junctions be-
tween capillary endothelial cells that provide a physical barrier
to the entry of large molecules (Bauer et al., 2014; Tajes et al.,
2014). Numerous transporters in the BBB tightly regulate move-
ment of molecules from the bloodstream to the CNS (Fricker
and Miller, 2004). Through the physical barrier provided by the
tight junctions and the transport barrier, virtually all large mol-
ecules are excluded from the CNS when administered into the
systemic circulation.
Physically breaching the BBB by administering a therapy into
the CSF is one means of achieving CNS distribution. CSF plays
multiple roles including providing brain buoyancy, protecting
the brain from sudden impacts, regulation of solute concentra-
tions and pressure, and elimination of wastes (Sakka et al.,
2011). CSF is secreted continuously at a rate of approximately
0.3 ml/min in adults primarily by choroid plexus ependymal
cells in the ventricles (Oreskovic and Klarica, 2010). It flows out
through the ventricular system into the subarachnoid space,
and around the external surfaces of the brain and spinal cord
(Greitz, 1993). CSF circulates through the brain parenchyma
along perivascular spaces surrounding arteries via the glym-
phatic pathway; this brain-wide perivascular network facilitates
solute exchange between the CSF and interstitial fluid (Iliff et al.,
2012; Yang et al., 2013). The continuous movement of CSF can
distribute therapeutics in the CNS after IT or ICV administra-
tion. The total CSF volume in an adult human is approximately
150 ml, with a total of approximately 500 ml of CSF secreted per
day. Drainage into the systemic circulation via the arachnoid
granulations and lymphatics (Bulat and Klarica, 2011) allows for
maintenance of a stable volume.
TABLE 1. Representative Biological Therapies that Have Been Used for Direct CNS Administration
Indication Molecule Route Development
Phase/Results
References
Pain Ziconitide (Prialt) IT-L Approved Williams et al. (2008)
Breast cancer brain metastasis Trastuzumab (Herceptin) IT-L Off label/P1/2 Oliveira et al. (2011)
Leukemia Rituximab (Rituxan) IT-L P1/2 Jaime-Perez et al. (2009)
Non-Hodgkins lymphoma ICV Off label/P1/2 Rubenstein et al. (2007)
Multiple sclerosis IT-L P2 Bonnan et al. (2014)
Alzheimer’s disease Nerve growth factor (NGF) ICV Off label Eriksdotter Jonhagen et al. (1998)
Parkinson’s disease Glial derived neurotrophic factor
(GDNF)
ICV, IP Clinical trials
stopped after P2
Nutt et al. (2003), Patel et al. (2005)
Amyotrophic lateral sclerosis Brain derived neurotrophic factor
(BDNF)
IT-L No efficacy in P3 Beck et al. (2005)
Vascular endothelial growth factor
(VEGF)
ICV P1/2 Storkebaum et al. (2005)
Mucopolysaccharidosis I Laronidase (Aldurazyme) IT-L Off label Munoz-Rojas et al. (2008)
Mucopolysaccharidosis II Idursulfase-IT IT-L P2/3 Felice et al. (2011), Muenzer et al. (2016)
Mucopolysaccharidosis IIIA Heparan-N-sulfatase IT-L P1/2 Pfeifer et al. (2012)
Mucopolysaccharidosis IIIB Alpha-N-acetylglucosaminidase ICV Preclinical Kan et al. (2014)
Mucopolysaccharidosis VI Galsulfase (Naglazyme) IT-L Off label Mu~noz-Rojas et al. (2010)
Metachromatic leukodystrophy Arylsulfatase A IT-L P1/2 Patil and Maegawa (2013)
CLN2 disease (a form of Batten Disease) Tripeptidyl peptidase I ICV P1/2 Katz et al. (2014), Vuillemenot et al. (2015)
ICV, intracerebroventricular; IP, intrapanenchymal; IT-L, intrathecal lumbar.
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3. ROUTES OF DIRECT ADMINISTRATION
TO THE CNS
There are several routes of direct CNS administration, either via
the CSF or directly to tissue. IT administration introduces the
therapeutic into the CSF in the subarachnoid space, between
the arachnoid and pia mater. This is most frequently accom-
plished via the implantation of a catheter into the IT lumbar
(IT-L) space. IT-L administration has a potential disadvantage
that the administered biologic needs to travel a longer distance
to reach the brain than via other direct routes to the CNS.
However, IT-L administration studies in multiple nonclinical
species have demonstrated adequate brain distribution to
achieve pharmacological activity of the therapeutic when ad-
ministered in a large dose volume or with a subsequent catheter
flush with buffer (Dickson et al., 2007; Felice et al., 2011; Xu et al.,
2011). With test articles more dense than CSF, body posture dur-
ing IT-L dose administration (supine vs upright) may lead to dif-
ferences in brain distribution, particularly in semi-bipedal
species, such as monkeys. Delivering test articles to the CSF in
closer proximity to the brain can also be achieved by adminis-
tering into the cisterna magna within the cerebromedullary cis-
tern (IT-cisternal, IT-C). IT-C administration is not often used
clinically because of safety risks but is sometimes used in pre-
clinical studies. Catheters and dosing ports have been im-
planted to the lumbar spine to enable repeat IT-L infusion
administration in multiple animal models. IT-C administration
is typically conducted as a bolus injection. In rodents, IT cathe-
ters terminating in the lumbar space may be introduced
through the cerebromedullary cistern.
ICV administration introduces the therapeutic into the lat-
eral ventricle, in close proximity to the primary CSF production.
The outward flow of CSF from the ventricles may result in wider
CNS distribution than that achieved by IT-L administration
(Vuillemenot et al., 2014). ICV administration is usually accom-
plished by infusion via an implanted catheter and dosing port.
Intraparenchymal (IP) administration introduces the therapy di-
rectly to the brain tissues. Convection enhanced delivery can be
used to increase the distribution achieved with IP administra-
tion through increased pressures (Barua et al., 2014). As com-
pared with IP administration, introducing the therapeutic to the
CSF by IT or ICV administration may produce a broader distribu-
tion pattern.
Both bolus and continuous administration may be utilized
with these different routes. Infusions lasting from several hours
to continuous may be preferable to bolus injection to achieve
the required concentration of therapeutic in the brain safely. If
the rate of infusion is less than the normal turnover of CSF,
then no appreciable changes in CSF volume will result, and
safety concerns due to excessive intracranial pressure can be
minimized. When selecting an appropriate clinical route, it is
important to consider the optimal CNS distribution in the in-
tended patient population. Whenever possible, the intended
clinical route of administration should be used for any pivotal
preclinical safety studies, although alternate routes are often
employed for preliminary studies, and occasionally for pivotal
toxicology studies.
CONSIDERATIONS FOR DESIGN OF
NONCLINICAL CNS ADMINISTRATION
STUDIES
Nonclinical studies involving direct CNS administration are fun-
damentally different than studies with more conventional routes
and several important points should be considered. Adverse ef-
fects in CNS delivery studies are generally not due to the biologic
per se, but changes due to the delivery device alone or with an ad-
ditive effect related to the therapeutic may occur. Inclusion of ve-
hicle and/or device-only control groups is critical to sort out the
causes of any findings. Due to the often limited group size of
these studies, a thorough review of historical control data may be
the only accurate means of assessing study findings.
Recently, the Society of Toxicologic Pathologists published
updated recommendations for sampling the CNS for general
toxicity studies (Bolon et al., 2012). Although possibly sufficient
for general toxicity studies where there is no reason to suspect
an effect on the nervous system, these schemes are not ade-
quate for a study involving direct CNS delivery. The trimming/
embedding/staining scheme for a direct CNS delivery study
should be customized to allow for a thorough assessment of the
local effects on the various structures/cell types of the brain and
spinal cord that may be due to the placement/presence of the
drug and/or the delivery device, as well as more distant effects
that may be due to the device, or distribution of the drug.
Assessment of pharmacokinetics (PK), exposure, and immu-
nogenicity are important for evaluating the dose response of
any pharmacology or toxicity of a CNS administered biologic.
A significant fraction of the test article that is not distributed
into the CNS will enter the systemic circulation within a few
hours via the arachnoid granulations and/or lymphatics. This
occurs through natural CSF turnover and via outflow caused by
increased pressure (Bulat and Klarica, 2011). CSF also drains to
cervical lymph nodes via the glymphatic system, a dural lym-
phatic network (Aspelund et al., 2015). Systemic exposure to
CNS-administered biologics can lead to an immune response.
Anti-drug antibody (ADA) formation may occur when adminis-
tering a human protein to animals. This response may result in
decreased exposure and/or activity or hypersensitivity
reactions. Administering a biologic to the CNS via slow infusion
may reduce the maximal systemic concentrations and reduce
the likelihood of immunogenicity. In addition, pretreatment
with antihistamines has been efficacious in reducing the
incidence of hypersensitivity (Kim et al., 2008; Vuillemenot et al.,
2011).
Sufficient sampling of both plasma and CSF should be in-
cluded to characterize standard PK parameters, while ADAs
may be monitored in serum and/or CSF. To enable collection of
serial samples, a dual catheter/access port setup may be useful,
with one catheter used for dose administration and the other
catheter for CSF collection (Figure 1). CSF samples collected
from the ventricles versus the lumbar region have been shown
to differ in composition and cellularity (Provencio et al, 2005;
Rubalcava and Sotelo, 1995; Torres-Corzo et al., 2009), which
should be considered when interpreting CSF data and compar-
ing between studies. As a backup to lumbar sampling, direct cis-
terna magna sampling may be used to obtain CSF for analysis,
although this is a technically challenging procedure in nonclini-
cal species due to the small volume of this space and close prox-
imity to the spinal cord.
The CNS distribution should be also evaluated to guide the
clinical dose regimen. This can be accomplished through dedi-
cated biodistribution studies or by sampling CNS tissues in
pharmacology and/or toxicology studies to analyze for drug
concentrations. Understanding the relationship between CSF/
systemic PK and CNS exposure is important when designing the
clinical dosing regimen. This is best assessed in animal models,
as serial CSF sampling is generally not possible in clinical
studies.
VUILLEMENOT ET AL. | 5
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4. A very important final consideration is the selection of ap-
propriate in vivo models to assess the safety, PK, and pharmaco-
logical activity. The species selected should express a similar
target as that in human patients. When administering a human
protein to animals, the molecule should display activity against
the homologous target in the animals. Differences in the activ-
ity or receptor density in the species tested should be consid-
ered when interpreting the results. When developing therapies
for neurodegenerative diseases where the CNS is undergoing
changes that may affect the safety, distribution, and/or activity
of the molecule, it may be informative to conduct safety assess-
ments in an animal disease model undergoing similar changes.
Non-affected controls of the same species can be assessed
alongside to get an idea of the toxicity on a non-diseased CNS
background.
NONCLINICAL SPECIES SELECTION/
INTERPRETATION
When interpreting in vivo data, the relevance of the CNS in the
nonclinical species to the human should be carefully consid-
ered. Biologics have been administered directly to the CNS in all
of the common lab animal species, including mice, rats, dogs,
monkeys, sheep, and pigs. CNS differences between these spe-
cies and human must be considered when designing and inter-
preting direct CNS administration studies. A summary of
different parameters affecting the pharmacology and safety of
CNS-administered molecules is presented in Table 2.
Differences in brain mass are an important limitation of ani-
mal models. The nonclinical species have a significantly
smaller brain than humans. Smaller brains have a higher sur-
face area to volume ratio, potentially increasing relative uptake
from CSF. In addition, the smaller the brain, the less distance a
therapeutic is required to travel to reach all sites of activity
within the CNS. Smaller brains may also display a more severe
reaction to CNS delivery devices, and there is less area in which
to implant these devices. Achieving precise targets within the
smaller brains of animals is more challenging because of the
smaller relative size of these targets. For example, the lateral
ventricle has a mean volume of approximately 25 ml in hu-
mans, but only 0.25 ml in monkeys (Akdogan et al., 2010). Total
CSF volume is also less in the nonclinical species than human.
However, the rate of CSF turnover is similar between dog, mon-
key, and human, but several-fold higher in rodents. Differences
in CSF volume and turnover must be taken into account when
interpreting PK data and scaling to human patients.
MORPHOLOGIC ASSESSMENT OF CNS TISSUES
Morphologic assessment of the nervous system in a study uti-
lizing a direct delivery device requires particular scrutiny in the
areas traversed by the device and the site of deposition of the
therapeutic. Synergy may be observed between the test article
and the delivery system. Complications of surgery or the device
are common, and even in vehicle/device only control animals
there may be numerous microscopic changes (Butt, 2011a).
These changes must be differentiated from what is caused by
the test article.
When evaluating nervous system tissues from a direct CNS
deliver study, the timing of the necropsy, tissue processing, and
staining must be carefully considered. Timing of tissue collec-
tion must capture the full spectrum of potential changes occur-
ring. It is important to assess effects acutely, as early toxicities
may be completely resolved at later times (Switzer, 2011).
Single-dose pilot studies should include multiple tissue collec-
tion times. Morphological assessment is complicated because
there must be sufficient time between device implantation and
dosing to allow for the changes from surgery to resolve. It is
common to observe neuronal necrosis at the site of catheter in-
sertion into the brain, but this should not be confused with an
effect of the tested therapeutic.
Design of the CNS morphological evaluation should be based
on the study objectives, delivery methods, and any knowledge
of the effects of the test article. In addition to brain and spinal
cord, nerves and ganglia may warrant evaluation. Changes to
one part of the nervous system may manifest as changes in
other parts, and all may need to be examined. The brain and
spinal cord should be sectioned to allow for an evaluation that
provides sufficient confidence that any effects on the CNS have
FIG. 1. Dual port catheter system in the cynomolgus monkey. In this setup, the
animal was surgically implanted with access ports and catheters terminating in
the lumbar spine and the cisterna magna. The lumbar catheter/access port,
which has a dosing needle inserted in this picture, was used for dose adminis-
tration, while the cisternal device enabled repeat CSF sampling for toxicokinetic
and other analyses.
TABLE 2. CNS Parameters of Nonclinical Species Compared with Human
Species Mouse Rat Dog Monkey Human
Brain mass (fold human) 0.4 g (0.0004) 2 g (0.002) 72 g (0.072) 100 g (0.1) 1000–1500 g
CSF volume (fold human) 0.04 ml (0.0004) 0.15 ml (0.0015) 12 ml (0.12) 15 ml (0.15) 100–150 ml
CSF turnovers/day (fold human) 12.5 Â (2.5) 28.8 Â (5.76) 5.75 Â (1.15) 4 Â (0.8) 5Â
Posture Quadrupedal Quadrupedal Quadrupedal Semi-bipedal Bipedal
From Pardridge (1991).
6 | TOXICOLOGICAL SCIENCES, 2016, Vol. 152, No. 1
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5. been determined. For the brain, that involves at least 3 trans-
verse or sagittal sections through the site of administration and
the region traversed by the device, with sufficient additional
sections to characterize any distant effects. It is useful to pro-
duce full transverse sections including both hemispheres in
studies where a device traverses the brain. In general, at least
8–10 full transverse sections are required to evaluate the main
brain regions in any species. For IT studies, multiple sections
near the catheter tip will allow for a complete evaluation of
changes. Inspection of the spinal cord for IT granuloma (Allen
et al., 2006; Butt, 2011a) should be performed. Evaluating trans-
verse and oblique sections of spinal cord increase the sensitivity
for detecting changes. Typically, the spinal cord should be sec-
tioned to include cervical, thoracic, catheter tip, and spinal
cord/cauda equina caudal to the catheter tip regions.
The objectives of the histological evaluation should be taken
into account when determining the choices of tissue preserva-
tion and staining reagents. Intravascular perfusion is
recommended to minimize artifactual changes that often com-
plicate microscopic interpretation (Garman, 2011). Peripheral
nerves are best immediately fixed with a fixative containing
glutaraldehyde to preserve myelin. Tissue sections may be em-
bedded in paraffin or resin or frozen. Although paraffin allows
for more detail than frozen, frozen sectioning may allow for im-
proved immunohistochemistry and use of specialized stains
(Switzer, 2000). Resin embedding is useful for optimal cross sec-
tioning to preserve myelin.
For all studies, paraffin embedded or frozen sections should
be stained with hematoxylin and eosin (H&E) for general evalu-
ation. In the brain and spinal cord, immunohistochemical
stains to reveal astrocyte and microglial reactions can demon-
strate glial cell changes not detectable by H&E. In acute studies,
a stain that increases the sensitivity of detection of neuronal
necrosis should be used, such as Fluoro-Jade (Schmued et al.,
2005) or Cupric silver (Switzer, 2000). Other potentially useful
stains include non-selective silver stains for axons, Luxol fast
blue for myelin, neurofilament protein immunohistochemistry,
and stains for specific neuronal populations. The combination
of a longitudinal section in paraffin (H&E stain) and a cross sec-
tion that has been osmicated, resin embedded, and stained
with toluidine blue provides assessment of axonal degenera-
tion, regeneration, and myelin alterations (Butt, 2011b).
It is virtually impossible to prevent local damage when im-
planting a CNS catheter. Inflammation, haemorrhage, and glio-
sis are frequently encountered adjacent to the delivery device.
Accumulation of fluid around the catheter track may be due to
edema, and/or excess test article. Microscopic changes due to
the delivery device are seldom associated with clinical signs
and are not necessarily adverse, as they may be an unavoidable
consequence of the mode of administration in the animal
model and irrelevant to the intended clinical population. It can
be challenging to differentiate the relative contributions of the
test article and each component of the delivery system, even in
properly controlled studies.
USING NONCLINICAL STUDIES TO ENABLE
FIRST IN HUMAN TRIALS
The intended clinical regimen should guide the nonclinical pro-
gram, with pivotal nonclinical studies should use the same
route as that in the first in human trial. Distribution of the bio-
logic to the target tissues/cells at pharmacologically active con-
centrations should be demonstrated if possible. In addition,
disposition of drug into the systemic compartment, and the re-
lationship between CNS and systemic PK, should be character-
ized. Toxicities revealed in the nonclinical studies should be
monitored for in the clinic. For example, the presence of CNS in-
flammation and elevated CSF white blood cells in nonclinical
studies may lead to monitoring CSF cell counts clinically. The
nonclinical studies should provide information about the ef-
fects of the administration procedure, delivery device, vehicle,
and test article, alone and in combination. It is expected that
there will be a local reaction to CNS administered biologics, so
consideration of the risk/benefit profile in the context of the pa-
tient population is important.
A safe starting dose can be determined using an appropriate
safety factor and the pivotal nonclinical no observed adverse ef-
fect level (NOAEL). For CNS administered biologics, brain mass
or CSF volume can be used to normalize doses between species.
If CSF volume is used, differences in the rates of turnover be-
tween the different species should be considered (Table 2). An
example of clinical safety factors determined based on a mon-
key NOAEL scaled for differences in brain mass is illustrated in
Table 3 (Felice et al., 2011; USFDA, 2005).
Additional nonclinical studies may be needed to support the
use of a delivery device in combination with the therapeutic.
Utilizing the same or similar device in the nonclinical and clini-
cal studies is desirable to demonstrate the safety of the drug-
device combination. For developmental and reproductive
toxicology studies, if warranted, the IV route should be used
(Skov et al., 2007).
FUTURE DIRECTIONS
CNS administration of biologics is likely to play an increasing
role in treating neurodegenerative disease in the future. Careful
consideration of nonclinical program design will insure the suc-
cess of these efforts. Nonclinical studies to enable clinical trials
of CNS administered drugs must consider the clinical regimen,
assessment of exposure in CSF, plasma, and/or CNS tissue, CNS
effects, and the relevance of animal models to human patients.
Nonclinical programs should be designed on a case-by-case ba-
sis, carefully considering the clinical plan and the risk/benefit
profile in the intended patient population. Interpretation of di-
rect CNS administration studies is complicated by the histologi-
cal changes attributable to the route of administration and
presence of delivery devices in the CNS. Therefore, inclusion of
applicable control groups is essential. CNS sampling for histo-
pathological evaluation must be extensive, and may involve
TABLE 3. Calculation of Clinical Safety Factors based on NOAEL from Pivotal Monkey Study
Human (Pediatric; Brain 5 1 kg) Monkey (Brain 5 0.1 kg) Safety margin
Clinical dose, mg mg/kg brain weight Nonclinical NOAEL, mg mg/kg brain weight
10 10 100 1000 100-fold
100 100 100 1000 10-fold
VUILLEMENOT ET AL. | 7
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6. serial sectioning of the entire brain as well as thorough sam-
pling of spinal cord, dorsal nerve roots, and ganglia. In addition,
use of multiple stains to illuminate specific neuronal changes is
recommended. Prior to entry into first in human trials, a non-
clinical program should describe the safety findings of the bio-
logic in conjunction with the delivery device and vehicle,
support the likely efficacy in the patient population, character-
ize the PK and distribution, and provide rationale for inclusion
of clinical endpoints of safety and efficacy. Therefore, a strong
nonclinical data package is required to support these challeng-
ing but increasingly worthwhile clinical trials.
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