ABSTRACT
Spinocerebellar ataxia type 34 (SCA34) is an autosomal dominant inherited ataxia due to mutations in ELOVL4, which encodes one of the very long-chain fatty acid elongases. SCA38, another spinocerebellar ataxia, is caused by mutations in ELOVL5, a gene encoding another elongase. However, there have been no previous studies describing the neuropathology of either SCA34 or 38. This report describes the neuropathological findings of an 83-year-old man with SCA34 carrying a pathological ELOVL4 mutation (NM_022726, c.736T>G, p.W246G). Macroscopic findings include atrophies in the pontine base, cerebellum, and cerebral cortices. Microscopically, marked neuronal and pontocerebellar fiber loss was observed in the pontine base. In addition, in the pontine base, accumulation of CD68-positive macrophages laden with periodic acid-Schiff (PAS)-positive material was observed. Many vacuolar lesions were found in the white matter of the cerebral hemispheres and, to a lesser extent, in the brainstem and spinal cord white matter. Immunohistological examination and ultrastructural observations with an electron microscope suggest that these vacuolar lesions are remnants of degenerated oligodendrocytes. Electron microscopy also revealed myelin sheath destruction. Unexpectedly, aggregation of the four-repeat tau was observed in a spatial pattern reminiscent of progressive supranuclear palsy. The tau lesions included glial fibrillary tangles resembling tuft-shaped astrocytes and neurofibrillary tangles and pretangles. This is the first report to illustrate that a heterozygous missense mutation in ELOVL4 leads to neuronal loss accompanied by macrophages laden with PAS-positive material in the pontine base and oligodendroglial degeneration leading to widespread vacuoles in the white matter in SCA34.
Subject(s)
Brain/pathology , Nerve Degeneration/pathology , Oligodendroglia/pathology , Spinocerebellar Ataxias/pathology , White Matter/pathology , Aged, 80 and over , Eye Proteins/genetics , Humans , Male , Membrane Proteins/genetics , Mutation, Missense , Nerve Degeneration/genetics , Spinocerebellar Ataxias/genetics , Vacuoles/pathologyABSTRACT
Neuromyelitis optica spectrum disorder (NMOSD) is an immune-mediated disorder. It often develops acute myelopathy due to longitudinally extensive transverse myelitis (LETM), although other disorders can cause an LETM-like lesion. Here, we report a 76-year-old patient presenting with acute-onset, progressive myelopathy, which proved to be caused by an intracranial dural arteriovenus fistula (dAVF). Magnetic resonance imaging (MRI) revealed a longitudinally extensive spinal cord lesion, which was further extended rostrally to the medulla. Although cord surface flow voids were absent on T2-weighted MRI, abnormally congested peri-spinal veins showed up with gadolinium contrast. Angiography confirmed dAVF in the posterior fossa, which drained into the peri-spinal veins. Intracranial dAVF should be considered as a differential diagnosis of NMOSD, because it is not immunologically but is surgically treatable.
Subject(s)
Angiography, Digital Subtraction , Central Nervous System Vascular Malformations/diagnostic imaging , Magnetic Resonance Imaging , Neuromyelitis Optica/diagnostic imaging , Spinal Cord Diseases/diagnostic imaging , Spinal Cord/diagnostic imaging , Aged , Central Nervous System Vascular Malformations/complications , Central Nervous System Vascular Malformations/therapy , Diagnosis, Differential , Embolization, Therapeutic , Humans , Intracranial Arteriovenous Malformations , Male , Predictive Value of Tests , Spinal Cord Diseases/etiology , Spinal Cord Diseases/therapy , Treatment Outcome , Vascular Surgical ProceduresABSTRACT
A 22-year-old woman acutely developed recurrent convulsive seizures followed by fever and headache. Cerebrospinal fluid study showed leukocytosis without hypoglycorrhachia. These clinical features suggested acute viral or aseptic encephalitis. The patient was treated only with an antiviral agent and improved immediately with good prognosis. Afterwards, the characteristic brain MRI findings required us to check the patient's serum, and the final diagnosis of myelin oligodendrocyte glycoprotein (MOG) antibody-positive cerebral cortical encephalitis (CCE) was confirmed. Most previously reported cases with MOG antibody-positive CCE clinically showed fever and/or headache, and some were initially misdiagnosed of having central nervous system infection. All previously reported cases were treated with immunotherapy. However, our case showed the very benign clinical course and improved rapidly without any immunotherapy. We should be reminded that MOG-antibody-positive CCE could be self-remitting and mimic acute viral or aseptic encephalitis. In addition, the characteristic neuroradiological findings could be an important clue to the correct diagnosis of CCE.
Subject(s)
Autoimmune Diseases of the Nervous System/diagnosis , Autoimmune Diseases of the Nervous System/immunology , Cerebral Cortex/pathology , Encephalitis/diagnosis , Encephalitis/immunology , Myelin-Oligodendrocyte Glycoprotein/immunology , Cerebral Cortex/diagnostic imaging , Encephalitis, Viral/diagnosis , Female , Humans , Young AdultABSTRACT
Starting with a series of CC chemokine receptor-4 (CCR4) antagonists developed in a previous study, the potency was improved by replacing the pyrrolidine moiety of N-(4-chlorophenyl)-6,7-dimethoxy-2-(4-pyrrolidin-1-ylpiperidin-1-yl)quinazolin-4-amine 2 with a 3-(hydroxymethyl)piperidine. The resulting compound (1'-{4-[(4-chlorophenyl)amino]-6,7-dimethoxyquinazolin-2-yl}-1,4'-bipiperidin-3-yl)methanol 8ic was a strong inhibitor of human/mouse chemotaxis. Oral administration of 8ic showed anti-inflammatory activity in a murine model of acute dermatitis (oxazolone-induced contact hypersensitivity test) in a dose-dependent manner.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Quinazolines/pharmacokinetics , Receptors, CCR4/antagonists & inhibitors , Administration, Oral , Amines , Animals , Anti-Inflammatory Agents/pharmacokinetics , Chemotaxis/drug effects , Dermatitis/drug therapy , Disease Models, Animal , Humans , Mice , Piperidines , Quinazolines/pharmacology , Structure-Activity RelationshipABSTRACT
A series of CC chemokine receptor-4 (CCR4) antagonists were examined in a previous report in an attempt to improve metabolic stability in human liver microsomes. In this study, the cycloheptylamine moiety of N-cycloheptyl-6,7-dimethoxy-2-(4-pyrrolidin-1-ylpiperidin-1-yl)quinazolin-4-amine 1 was replaced with the p-chloroaniline moiety, and the resulting compound, N-(4-chlorophenyl)-6,7-dimethoxy-2-(4-pyrrolidin-1-ylpiperidin-1-yl)quinazolin-4-amine (8c), retained its potency ([(35)S]GTPgammaS-binding inhibition and CCL22-induced chemotaxis in humans/mice). Based on the structure-activity relationships (SAR), a homology model was constructed for CCR4 to explain the binding mode of 8c. Overall, there was good agreement between the docking pose of the CCR4 homology model and the human [(35)S]GTPgammaS assay results. Administration of 8c in a murine model of acute dermatitis showed anti-inflammatory activity (oxazolone-induced contact hypersensitivity test).
Subject(s)
Computer Simulation , Models, Chemical , Quinazolines/chemistry , Quinazolines/pharmacology , Receptors, CCR4/antagonists & inhibitors , Animals , Binding Sites , Cell Line , Drug Evaluation, Preclinical , Humans , Injections, Subcutaneous , Mice , Models, Molecular , Molecular Structure , Oxazolone , Quinazolines/chemical synthesis , Receptors, CCR4/chemistry , Skin Diseases/chemically induced , Skin Diseases/drug therapy , Skin Diseases/pathology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A new series of quinazolines that function as CCR4 antagonists were discovered during the screening of our corporate compound libraries. Subsequent compound optimization elucidated the structure-activity relationships and led the identification of 2-(1,4'-bipiperidine-1'-yl)-N-cycloheptyl-6,7-dimethoxyquinazolin-4-amine 14a, which showed potent inhibition in the [(35)S]GTPgammaS-binding assay (IC(50)=18nM). This compound also inhibited the chemotaxis of human and mouse CCR4-expressing cells (IC(50)=140nM, 39nM).
Subject(s)
Quinazolines/chemical synthesis , Quinazolines/pharmacology , Receptors, CCR4/antagonists & inhibitors , Animals , Chemotaxis/drug effects , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Humans , Mice , Structure-Activity RelationshipABSTRACT
A single rf bunch in the KEK proton synchrotron was accelerated with an induction acceleration method from the injection energy of 500 MeV to 5 GeV.
