Publications by authors named "Asaff Harel"

21 Publications

  • Page 1 of 1

Outcomes of COVID-19 infection in multiple sclerosis and related conditions: One-year pandemic experience of the multicenter New York COVID-19 Neuroimmunology Consortium (NYCNIC).

Mult Scler Relat Disord 2021 Oct 19;55:103153. Epub 2021 Jul 19.

NYU Multiple Sclerosis Comprehensive Care Center, NYU Langone Health, New York, New York, USA.

Objective: To determine outcomes of COVID-19 in patients with Multiple Sclerosis (MS) and related conditions, and to determine predictors of these outcomes.

Methods: This was a multicenter, observational cohort study of patients with MS or related CNS autoimmune disorders who developed confirmed or highly suspected COVID-19 infection from 2/1/2020 to 12/31/2020.

Main Outcome And Measure: The primary outcome measure was hospitalization status due to COVID-19. Severity of infection was measured using a 4-point ordinal scale: 1. home care; 2. hospitalization without mechanical ventilation; 3. hospitalization and mechanical ventilation, and 4. death.

Results: Of 474 patients in the study, 63.3% had confirmed COVID-19 infection and 93.9% were diagnosed with an MS phenotype. Mean age was 45 ± 13 (mean±SD) years, 72% were female, and 86% were treated with a DMT at the time of infection. 58 patients (12.2%) were hospitalized. 24 patients (5.1%) were critically ill (requiring ICU care or outcome of death), of which 15 patients (3.2%) died. Higher neurological disability and older age independently predicted hospitalization. 85% (102/120) of patients with known antibody results not treated with anti-CD20 therapies were seropositive while only 39.5% (17/43) of patients treated with anti-CD20 demonstrated seropositivity (p < 0.0001). Only 25% (2/8) of patients with PCR-confirmed COVID-19 being treated with anti-CD20 therapies demonstrated seropositivity.

Conclusions: Neurological disability and older age independently predicted hospitalization due to COVID-19. Additionally, the results demonstrate that anti-CD20 therapies significantly blunt humoral responses post-infection, a finding that carries implications with regards to natural or vaccine-mediated immunity.
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http://dx.doi.org/10.1016/j.msard.2021.103153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286899PMC
October 2021

A patient with concurrent multiple sclerosis and moyamoya disease.

Mult Scler Relat Disord 2021 Sep 16;54:103151. Epub 2021 Jul 16.

Division of Neuro-Immunology, Department of Neurology, Lenox Hill Hospital, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY. Electronic address:

Background: Moyamoya disease (MMD) is a rare vasculopathy and Multiple Sclerosis (MS) is an autoimmune disease which causes CNS demyelination. While most literature has focused on misdiagnosis of MMD as an "MS-mimic", we present a patient in which both co-existed.

Methods: Case Report RESULTS: A 57-year-old woman presented with gait dysfunction and paresthesias in both feet. MRI revealed brain and spinal cord lesions consistent with MS. Vessel imaging revealed multivessel stenosis consistent with MMD. Lumbar puncture demonstrated oligoclonal bands, leading to two diagnoses, MS and MMD.

Conclusions: MS can exist concurrently with MMD, potentially due to underlying propensity for autoimmunity.
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http://dx.doi.org/10.1016/j.msard.2021.103151DOI Listing
September 2021

Large Adult Spinal Diffuse Midline Histone H3 Lysine27-to-Methionine-Mutant Glioma With Intramedullary and Extramedullary Components Presenting With Progressive Hydrocephalus: A Case Report Highlighting Unique Imaging Findings and Treatment.

Cureus 2021 May 30;13(5):e15333. Epub 2021 May 30.

Neurosurgery, Lenox Hill Hospital, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New York, USA.

Diffuse midline glioma with histone H3 lysine27-to-methionine mutation (H3 K27M mutation) is a rare, aggressive tumor that is designated as World Health Organization (WHO) grade IV regardless of histologic features. Preoperative diagnosis remains challenging due to limited evidence regarding distinctive clinical and imaging characteristics. We describe the case of a young woman who presented with progressively worsening headaches due to communicating hydrocephalus. MR imaging with contrast of the cervical and thoracic spine revealed diffuse leptomeningeal enhancement with focal areas of intramedullary and subarachnoid T2 hyperintensity and enhancement, suggestive of a potential infectious process. Intraoperatively, no epidural pathology was identified, and with the differential diagnosis remaining broad, a second procedure was conducted involving intradural exploration and biopsy of a lesion. This was then identified as a diffuse midline glioma with H3 K27M mutation. The nonfocal clinical presentation in the setting of communicating hydrocephalus as well as the significant exophytic tumor growth and imaging findings made the initial diagnosis unique and challenging. This case, therefore, emphasizes the rare presentation of this tumor, and the need for further understanding of the clinical and imaging characteristics of this disease as well as the need for effective therapeutics.
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http://dx.doi.org/10.7759/cureus.15333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240764PMC
May 2021

Wallerian degeneration as a mimic of recurrence of myelitis.

Pract Neurol 2021 Jun 18;21(3):235-236. Epub 2021 Mar 18.

Neurology, North Shore University Hospital, Manhasset, New York, USA

A middle-aged woman with idiopathic longitudinally extensive myelitis underwent repeat MR scan of cervical spine at 5-month follow-up, which showed new non-enhancing T2 hyperintensities, initially reported as myelitis recurrence. However, the hyperintensities involved both lateral corticospinal tracts caudal to the initial lesion and both dorsal columns rostral to the initial lesion and were therefore compatible with Wallerian degeneration. This radiological mimic should be considered in the differential of recurrence of myelitis.
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http://dx.doi.org/10.1136/practneurol-2020-002911DOI Listing
June 2021

Progressive Multifocal Leukoencephalopathy in a Patient With Progressive Multiple Sclerosis Treated With Ocrelizumab Monotherapy.

JAMA Neurol 2021 Jun;78(6):736-740

Division of Neuro-Immunology, Department of Neurology, Lenox Hill Hospital, North Shore University Hospital, Zucker School of Medicine at Hofstra/Northwell, New York, New York.

Importance: Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection caused by the JC virus that has no proven effective treatment. Although rare cases of PML have occurred with other anti-CD20 therapies, there had been no prior cases associated with ocrelizumab.

Objective: To report the first ever case of PML occurring with ocrelizumab monotherapy in a patient with progressive multiple sclerosis without prior immunomodulation.

Design, Setting, And Participant: This case was reported from an academic medical center. The patient had multiple sclerosis while receiving ocrelizumab monotherapy.

Exposures: Ocrelizumab monotherapy.

Results: A 78-year-old man with progressive multiple sclerosis treated with ocrelizumab monotherapy for 2 years presented with 2 weeks of progressive visual disturbance and confusion. Examination demonstrated a right homonymous hemianopia, and magnetic resonance imaging revealed an enlarging nonenhancing left parietal lesion without mass effect. Cerebrospinal fluid revealed 1000 copies/mL of JC virus, confirming the diagnosis of PML. Blood work on diagnosis revealed grade 2 lymphopenia, with absolute lymphocyte count of 710/μL, CD4 of 294/μL (reference range, 325-1251/μL), CD8 of 85/μL (reference range, 90-775/μL), CD19 of 1/μL, preserved CD4/CD8 ratio (3.45), and negative HIV serology. Retrospective absolute lymphocyte count revealed intermittent grade 1 lymphopenia that preceded ocrelizumab (absolute lymphocyte count range, 800-1200/μL). The patient's symptoms progressed over weeks to involve bilateral visual loss, right-sided facial droop, and dysphasia. Ocrelizumab was discontinued and off-label pembrolizumab treatment was initiated. The patient nevertheless declined rapidly and ultimately died. PML was confirmed at autopsy.

Conclusions And Relevance: In this case report, PML occurrence was likely a result of the immunomodulatory function of ocrelizumab as well as age-related immunosenescence. This case report emphasizes the importance of a thorough discussion of the risks and benefits of ocrelizumab, especially in patients at higher risk for infections such as elderly patients.
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http://dx.doi.org/10.1001/jamaneurol.2021.0627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967248PMC
June 2021

Isolated Asymmetric Progressive Optic Neuropathy as a First Presentation of Charcot-Marie-Tooth Disease Type 2A.

J Neuroophthalmol 2020 Nov 18. Epub 2020 Nov 18.

Medical School for International Health (MG), Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er Sheva, Israel; Department of Ophthalmology (JM) Manhattan Eye and Ear Hospital, Northwell Health, New York, New York; Zucker School of Medicine at Hofstra/Northwell (JM, BP, AG, AH), Hempstead, New York; Department of Radiology (BP), Lenox Hill Hospital, New York, New York; Department of Neurology (AG, AH), North Shore University Hospital, Manhasset, New York; and Department of Neurology (AH), Lenox Hill Hospital, New York, New York.

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http://dx.doi.org/10.1097/WNO.0000000000001100DOI Listing
November 2020

Defining the role of T lymphocytes in the immunopathogenesis of neuromyelitis optica spectrum disorder.

Discov Med 2020 Mar-Apr;29(157):91-102

Departments of Neurology, Molecular Medicine, Science Education, and Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA.

Auto-reactive T cells are fundamental to many autoimmune processes, including neuromyelitis optica spectrum disorder (NMOSD). Several lines of evidence indicate that an antibody against aquaporin-4 (AQP4) is present in NMOSD patients. Further, this AQP4 antibody is pathogenic and can cause profound neurological damage. T cells are fundamental to many autoimmune processes, including NMOSD. Here we review work from animal models to discuss mechanisms by which auto-reactive T cells modulate the process by which antibodies cross the blood-brain barrier and orchestrate the local inflammatory milieu underlying NMOSD pathophysiology. We also examine clinical studies that document the presence of AQP4-specific T cells and the unique cytokine profile of NMOSD patients. This work encourages a renewed and broadened attention to the fundamental role of T cells in neuroautoimmune conditions which will hopefully lead to new therapies and better patients' outcomes.
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September 2021

Negative SARS-CoV-2 antibody testing following COVID-19 infection in Two MS patients treated with ocrelizumab.

Mult Scler Relat Disord 2020 Sep 26;44:102341. Epub 2020 Jun 26.

Department of Neurology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 500 Hofstra Blvd, Hempstead, New York, USA; Department of Neurology, North Shore University Hospital, Manhasset, NY, USA; Department of Neurology, Lenox Hill Hospital, New York, NY, USA. Electronic address:

Background: It is unknown whether MS disease modifying therapies impact ability to mount an antibody response to SARS-CoV-2.

Methods: Case series and literature review. We report a series of two MS patients who developed COVID-19 while on Ocrelizumab therapy and subsequently exhibited negative SARS-CoV-2 serology.

Results: A 42-year-old man and 39-year-old woman with MS developed COVID-19 while on Ocrelizumab therapy. Neither patient required hospitalization. The man exhibited negative serology at 7- and 9-weeks post-infection. The woman exhibited negative serology at 6- and 12-weeks post-infection.

Conclusions: Large studies are essential to determine whether certain DMTs may blunt SARS-CoV-2 antibody production.
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http://dx.doi.org/10.1016/j.msard.2020.102341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318946PMC
September 2020

Dietary factors in experimental autoimmune encephalomyelitis and multiple sclerosis: A comprehensive review.

Mult Scler 2021 04 14;27(4):494-502. Epub 2020 May 14.

Department of Neurology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New York, NY, USA/Institute of Molecular Medicine, The Feinstein Institute for Medical Research, Manhasset, NY, USA/Department of Neurology, Lenox Hill Hospital, New York, NY, USA.

Background: Dietary intervention in multiple sclerosis carries potential therapeutic implications. While studies utilizing animal models of multiple sclerosis (MS) have demonstrated intriguing findings, well-designed clinical trials are few in number.

Objective: The objective of this study is to review the animal model and clinical literature regarding dietary factors in experimental autoimmune encephalitis (EAE) and MS.

Methods: This manuscript provides a comprehensive review of current animal model and clinical knowledge related to dietary factors in MS.

Results: While there is currently little data for any specific diet in MS, there is growing evidence that certain dietary factors may influence the disease.

Conclusions: Definitive information regarding dietary factors as a modifiable risk factor in MS will require larger randomized clinical trials.
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http://dx.doi.org/10.1177/1352458520923955DOI Listing
April 2021

Retinal vasculopathy with cerebral leukoencephalopathy (RVCL): A rare mimic of tumefactive MS.

Neurology 2018 10 7;91(15):e1423-e1428. Epub 2018 Sep 7.

From the Department of Internal Medicine (J.R.), Division of Neuro-Immunology, Department of Neurology (D.P.M., A.H.), Division of Neuroradiology, Department of Radiology (B.P.), Division of Neuropathology, Department of Pathology (S.A., T.A.), Department of Neurosurgery (J.B.), and Department of Neurology (S.N.), Lenox Hill Hospital, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New York, NY.

Objective: We report a series of 2 brothers who each developed tumefactive brain lesions, initially thought to have brain tumors or tumefactive multiple sclerosis (MS), but who were ultimately diagnosed with a rare autosomal dominant condition known as retinal vasculopathy with cerebral leukoencephalopathy (RVCL).

Methods: Case series and literature review.

Results: We present 2 brothers who developed tumefactive right frontal brain lesions leading to gait disturbances and cognitive changes. Both brothers also had nonspecific brain calcifications and T2-hyperintense lesions, and both had ophthalmic and liver disease of unclear etiology. The first brother had been extensively evaluated by various specialists, underwent inconclusive brain and liver biopsies, and was ultimately unsuccessfully treated for a diagnosis of tumefactive MS. The second brother also underwent unrevealing evaluation with CSF analysis and brain biopsy. Further family history revealed that the patients' father developed a tumefactive brain lesion in the 1980s and had been diagnosed with CNS vasculitis. Given the familial link, RVCL was suspected, and genetic analysis confirmed the diagnosis with a 3-prime repair exonuclease 1 () C-terminal mutation.

Conclusion: The presence of tumefactive brain lesions, nonspecific brain calcifications, liver disease, and retinal vasculopathy, coupled with suggestive family history, led to the RVCL diagnosis. This report contributes to the limited understanding of RVCL, which can cause brain lesions that mimic gliomas or tumefactive MS. Recognition of this entity may prevent unnecessary invasive procedures and inappropriate therapeutic interventions, and would allow for proper counseling of family members.
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http://dx.doi.org/10.1212/WNL.0000000000006329DOI Listing
October 2018

Successful treatment of progressive multifocal leukoencephalopathy with recombinant interleukin-7 and maraviroc in a patient with idiopathic CD4 lymphocytopenia.

J Neurovirol 2018 10 9;24(5):652-655. Epub 2018 Jul 9.

Mount Sinai Hospital, 5 East 98th Street, Suite 1138, New York, NY, 10029, USA.

Progressive multifocal leukoencephalopathy (PML) is a rapidly progressive, often fatal viral infection of the brain without a known treatment. Recently, case reports have demonstrated survival from PML with therapies that improve cell-mediated immunity, including interleukin-7 (IL-7) or the chemokine receptor type 5 (CCR5) antagonist, maraviroc (MVC). We present the first known case of a patient with PML successfully treated with both IL-7 and MVC. A 63-year-old woman presented to our center with a 6-month history of progressive left hemiparesis. Extensive laboratory testing was negative except for a severe CD4 lymphocytopenia (140/μL). Serial brain MRIs done prior to presentation revealed an enlarging, non-enhancing T2-hyperintense lesion in the right fronto-parietal white matter. PML was confirmed through detection of the JC virus by PCR in the cerebrospinal fluid and by brain biopsy, and she was started on mirtazapine and mefloquine. She continued to deteriorate and was then given a course of recombinant IL-7. Though she remained clinically stable after IL-7 treatment and serum JCV PCR decreased from 1000 copies/mL to a nadir of 238 copies/mL, a repeat MRI 3 months later showed lesion enlargement. MVC was then initiated. Now, more than 2 years after initial presentation, she remains stable and serum JCV PCR is undetectable. This case demonstrates successful treatment of PML in a patient with idiopathic CD4 lymphocytopenia and highlights the potential benefits of IL-7 and MVC in the treatment of PML. Treatment with IL-7 and MVC led to clinical stability and improvement in JC virus titers.
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http://dx.doi.org/10.1007/s13365-018-0657-xDOI Listing
October 2018

Brain microstructural injury occurs in patients with RRMS despite 'no evidence of disease activity'.

J Neurol Neurosurg Psychiatry 2018 09 16;89(9):977-982. Epub 2018 Mar 16.

Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Objectives: The accuracy of 'no evidence of disease activity' (NEDA) in predicting long-term clinical outcome in patients with relapsing remitting multiple sclerosis (RRMS) is unproven, and there is growing evidence that NEDA does not rule out disease worsening. We used diffusion tensor imaging (DTI) to investigate whether ongoing brain microstructural injury occurs in patients with RRMS meeting NEDA criteria.

Methods: We performed a retrospective study to identify patients with RRMS visiting our centre over a 3-month period who had undergone prior longitudinal DTI evaluation at our facility spanning ≥2 years. Patients meeting NEDA criteria throughout the evaluation period were included in the NEDA group, and those not meeting NEDA criteria were included in an 'evidence of disease activity' (EDA) group. Fractional anisotropy (FA) and mean diffusivity (MD) maps were created, and annual rates of change were calculated.

Results: We enrolled 85 patients, 39 meeting NEDA criteria. Both NEDA and EDA groups showed longitudinal DTI worsening. Yearly FA decrease was lower in the NEDA group (0.5%, p<0.0001) than in the EDA group (1.2%, p=0.003), while yearly MD increase was similar in both groups (0.8% for NEDA and EDA, both p<0.01). There was no statistical difference in deterioration within and outside of T2 lesions. DTI parameters correlated with disability scores and fatigue complaints.

Conclusions: White matter microstructural deterioration occurs in patients with RRMS over short-term follow-up in patients with NEDA, providing further evidence of the limitations of conventional measures and arguing for DTI in monitoring of the disease process.
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http://dx.doi.org/10.1136/jnnp-2017-317606DOI Listing
September 2018

Cerebellar lobule atrophy and disability in progressive MS.

J Neurol Neurosurg Psychiatry 2017 12 26;88(12):1065-1072. Epub 2017 Aug 26.

Departments of Neurology, Radiology and Neuroscience, Icahn School of Medicine, New York, USA.

Objective: To investigate global and lobular cerebellar volumetries in patients with progressive multiple sclerosis (MS), testing the contribution of cerebellar lobular atrophy to both motor and cognitive performances.

Methods: Eighty-two patients with progressive MS and 46 healthy controls (HC) were enrolled in this cross-sectional study. Clinical evaluation included motor and cognitive testing: Expanded Disability Status Scale, cerebellar Functional System score, Timed 25-Foot Walk Test, 9-Hole Peg Test (9-HPT), Symbol Digit Modalities Test (SDMT), Brief Visuospatial Memory Test-Revised (BVMT) and California Verbal Learning Test II (CVLT). Cerebellar volumes were automatically obtained using the Spatially Unbiased Infratentorial Toolbox. A hierarchical multiple linear regression analysis was performed to assess the relationship between MRI variables of supratentorial and cerebellar damage (grey matter fraction, T2 lesion volume, metrics of cerebellar atrophy and cerebellar lesion volume) and motor/cognitive scores.

Results: Patients with MS exhibited lower cerebellar volumes compared with HC. Regression analysis showed that cerebellar metrics accounted for extra variance in both motor and cognitive performances, with cerebellar lesion volume, cerebellar Lobules VI, Crus I and VIIIa atrophy being independent predictors of 9-HPT, SDMT, BVMT and CVLT performances.

Conclusions: Atrophy of specific cerebellar lobules explains different aspects of motor and cognitive disability in patients with progressive MS. Investigation of cerebellar involvement provides further insight into the pathophysiological basis of clinical disability in progressive MS.
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http://dx.doi.org/10.1136/jnnp-2017-316448DOI Listing
December 2017

The relationship between cortical lesions and periventricular NAWM abnormalities suggests a shared mechanism of injury in primary-progressive MS.

Neuroimage Clin 2017 4;16:111-115. Epub 2017 Jul 4.

Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, USA.

In subjects with multiple sclerosis (MS), pathology is more frequent near the inner and outer surfaces of the brain. Here, we sought to explore if in subjects with primary progressive MS (PPMS) cortical lesion load is selectively associated with the severity of periventricular normal appearing white matter (NAWM) damage, as assessed with diffusion weighted imaging. To this aim, twenty-four subjects with PPMS and twenty healthy controls were included in the study. Using diffusion data, skeletonized mean diffusivity (MD) NAWM maps were computed excluding WM lesions and a 2 mm-thick peri-lesional rim. The supra-tentorial voxels between 2 and 6 mm of distance from the lateral ventricles were included in the periventricular NAWM mask while the voxels between 6 and 10 mm from the lateral ventricles were included in the deep NAWM mask; mean MD values were then computed separately for these two masks. Lastly, cortical lesions were assessed on phase-sensitive inversion recovery (PSIR) images and cortical thickness was quantified on volumetric T1 images. Our main result was the observation in the PPMS group of a significant correlation between periventricular NAWM MD values and cortical lesion load, with a greater cortical lesion burden being associated with more abnormal periventricular NAWM MD. Conversely, there was no correlation between cortical lesion load and deep NAWM MD values or periventricular WM lesions. Our data thus suggest that a common - and relatively selective - factor plays a role in the development of both cortical lesion and periventricular NAWM abnormalities in PPMS.
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http://dx.doi.org/10.1016/j.nicl.2017.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537392PMC
April 2018

An HSV-based library screen identifies PP1α as a negative TRPV1 regulator with analgesic activity in models of pain.

Mol Ther Methods Clin Dev 2016 22;3:16040. Epub 2016 Jun 22.

Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania, USA.

Transient receptor potential vanilloid 1 (TRPV1) is a pronociceptive cation channel involved in persistent inflammatory and neuropathic pain. Herpes simplex virus (HSV) vector expression of TRPV1 causes cell death in the presence of capsaicin, thereby completely blocking virus replication. Here we describe a selection system for negative regulators of TRPV1 based on rescue of virus replication. HSV-based coexpression of TRPV1 and a PC12 cell-derived cDNA library identified protein phosphatase 1α (PP1α) as a negative regulator of TRPV1, mimicking the activity of "poreless" (PL), a dominant-negative mutant of TRPV1. Vectors expressing PP1α or PL reduced thermal sensitivity following virus injection into rat footpads, but failed to reduce the nocifensive responses to menthol/icilin-activated cold pain or formalin, demonstrating that the activity identified in vitro is functional in vivo with a degree of specificity. This system should prove powerful for identifying other cellular factors that can inhibit ion channel activity.
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http://dx.doi.org/10.1038/mtm.2016.40DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916946PMC
July 2016

Phase-Sensitive Inversion-Recovery MRI Improves Longitudinal Cortical Lesion Detection in Progressive MS.

PLoS One 2016 22;11(3):e0152180. Epub 2016 Mar 22.

Department of Neurology, Mount Sinai Hospital, New York, New York, United States of America.

Previous studies comparing phase sensitive inversion recovery (PSIR) to double inversion recovery (DIR) have demonstrated that use of PSIR improves cross-sectional in vivo detection of cortical lesions (CL) in multiple sclerosis. We studied the utility of PSIR in detection/characterization of accrual of CL over time in a 1-year longitudinal study in primary progressive multiple sclerosis (PPMS) compared to DIR. PSIR and DIR images were acquired with 3T magnetic resonance imaging (MRI) in 25 patients with PPMS and 19 healthy controls at baseline, and after 1 year in 20 patients with PPMS. CL were classified as intracortical, leucocortical or juxtacortical. Lesion counts and volumes were calculated for both time points from both sequences and compared. Correlations with measures of physical and cognitive disability were determined as well as new CL counts and volumes. Compared to DIR, PSIR led to detection of a higher number of CL involving a larger proportion of patients with PPMS both cross-sectionally (p = 0.006, 88%) and longitudinally (p = 0.007, 95%), and led to the reclassification of a third of CL seen on DIR at each time point. Interestingly, PSIR was more sensitive to new CL accumulation over time compared to DIR. PSIR is a promising technique to monitor cortical damage and disease progression in patients with PPMS over a short-term follow-up.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0152180PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4803340PMC
August 2016

Novel Agents for Relapsing Forms of Multiple Sclerosis.

Annu Rev Med 2016 17;67:309-21. Epub 2015 Sep 17.

Icahn School of Medicine at Mount Sinai, New York, NY 10029; email: , ,

Since 2004, five drugs with new mechanisms of action have been approved by the US Food and Drug Administration for the treatment of relapsing forms of multiple sclerosis (MS). The expanded armamentarium of treatment options offers new opportunities for improved disease control and increased tolerability of medications, and also presents new safety concerns and monitoring requirements with which physicians must familiarize themselves. We review each of the newly approved agents-natalizumab, fingolimod, teriflunomide, dimethyl fumarate, and alemtuzumab-with regard to their mechanism of action, clinical trial data, safety and tolerability concerns, and monitoring requirements. We also review available data for promising agents that are currently in late-phase clinical trials, including daclizumab, ocrelizumab, and ofatumumab.
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http://dx.doi.org/10.1146/annurev-med-052814-023415DOI Listing
October 2016

CALM, a clathrin assembly protein, influences cell surface GluR2 abundance.

Neuromolecular Med 2011 Mar 8;13(1):88-90. Epub 2011 Jan 8.

Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, NIH, 251 Bayview Boulevard, Baltimore, MD 21224, USA.

The clathrin assembly protein, CALM, promotes the assembly of clathrin-coated vesicles. In a previous study, we showed that CALM controls the level of the synaptic vesicle protein VAMP2 at the plasma membrane by regulating VAMP2 endocytosis. Here, we provide evidence that CALM also influences the cell surface level of the AMPA receptor subunit GluR2. Although mechanistic details as well as the physiological relevance of CALM and GluR2 in the neuron have yet to be established, CALM-mediated trafficking could function as a component of a dedicated system for controlling postsynaptic abundance of GluR2.
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http://dx.doi.org/10.1007/s12017-010-8142-6DOI Listing
March 2011

Clathrin assembly protein AP180 and CALM differentially control axogenesis and dendrite outgrowth in embryonic hippocampal neurons.

J Neurosci 2008 Oct;28(41):10257-71

Laboratory of Neurosciences, National Institute on Aging-National Institutes of Health, Baltimore, Maryland 21224, USA.

Emerging data suggest that, much like epithelial cells, the polarized growth of neurons requires both the secretory and endocytic pathways. The clathrin assembly proteins AP180 and CALM (clathrin assembly lymphoid myeloid protein) are known to be involved in clathrin-mediated endocytosis, but their roles in mammalian neurons and, in particular, in developmental processes before synaptogenesis are unknown. Here we provide evidence that AP180 and CALM play critical roles in establishing the polarity and controlling the growth of axons and dendrites in embryonic hippocampal neurons. Knockdown of AP180 primarily impairs axonal development, whereas reducing CALM levels results in dendritic dystrophy. Conversely, neurons that overexpress AP180 or CALM generate multiple axons. Ultrastructural analysis shows that CALM affiliates with a wider range of intracellular trafficking organelles than does AP180. Functional analysis shows that endocytosis is reduced in both AP180-deficient and CALM-deficient neurons. Additionally, CALM-deficient neurons show disrupted secretory transport. Our data demonstrate previously unknown functions for AP180 and CALM in intracellular trafficking that are essential in the growth of neurons.
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http://dx.doi.org/10.1523/JNEUROSCI.2471-08.2008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2581865PMC
October 2008

Evidence for CALM in directing VAMP2 trafficking.

Traffic 2008 Mar 21;9(3):417-29. Epub 2007 Dec 21.

Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.

Clathrin assembly lymphoid myeloid leukemia protein (CALM) is a clathrin assembly protein with a domain structure similar to the neuron-specific assembly protein AP180. We have previously found that CALM is expressed in neurons and present in synapses. We now report that CALM has a neuron-related function: it facilitates the endocytosis of the synaptic vesicle protein VAMP2 from the plasma membrane. Overexpression of CALM leads to the reduction of cell surface VAMP2, whereas knockdown of CALM by RNA interference results in the accumulation of surface VAMP2. The AP180 N-terminal homology (ANTH) domain of CALM is required for its effect on VAMP2 trafficking, and the ANTH domain itself acts as a dominant-negative mutant. Thus, our results reveal a role for CALM in directing VAMP2 trafficking during endocytosis.
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http://dx.doi.org/10.1111/j.1600-0854.2007.00694.xDOI Listing
March 2008

Adolescents and genetic testing: what do they think about it?

J Adolesc Health 2003 Dec;33(6):489-94

Brandeis University, Waltham, Massachusetts, USA.

Purpose: To examine adolescents' attitudes toward screening for hereditary disorders.

Methods: A survey was distributed among 672 students in grades 10 to 12 attending a public suburban high school. The first part of the survey consisted of information about three diseases: familial breast cancer, Tay-Sachs disease, and hypercholesterolemia. The second part was a questionnaire developed by the authors, which explored students' attitudes toward testing for these diseases. Comparisons between and within groups were performed using X2 analysis.

Results: Out of the 672 surveys distributed, 361 were returned (54% response rate). Mean age of participants was 17 +/- 1 years. Most girls (67%) wanted to be tested for familial breast cancer. Girls were significantly more willing than boys to be tested for Tay-Sachs disease (23% vs. 13%, p <.002) and for hypercholesterolemia (54% vs. 39%, p <.001). Girls who had a relative with breast cancer were significantly more willing to be tested than other girls (p <.05). Individuals in the ethnic risk groups for Tay-Sachs disease were significantly more willing to be tested than those not in the ethnic risk groups (p <.001). However, only 33% of those in the ethnic risk groups for Tay-Sachs disease stated that they would either "definitely" or "probably" wish to be tested. Students who had a family history of high cholesterol were significantly more willing to be tested than those without a family history (70% vs. 34%, p <.0001). About 81% of the students with a family history of high cholesterol had never been referred for cholesterol testing. Only about 25% of participants stated that their attitude toward genetic testing was affected by concerns that genetic information might be misused by insurance companies/employers.

Conclusions: The main motivator for genetic testing is having someone in the family affected by the disease in question. Adolescent girls are more willing to be tested for genetic diseases than are boys.
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http://dx.doi.org/10.1016/s1054-139x(03)00135-6DOI Listing
December 2003
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