bluuebunny/crossref_metadata_2025 huggingface dataset:
Neural degeneration and the transport of neurotransmitters
Authors: Edwards Robert H.
Published: January 2005

A number of neurodegenerative diseases selectively affect distinct neuronal populations, but the mechanisms responsible for selective cell vulnerability have generally remained unclear. The toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) reproduces the selective degeneration of dopaminergic neurons in the substantia nigra characteristic of Parkinson's disease. The plasma membrane dopamine transporter mediates this selective toxicity through accumulation of the active metabolite N‐methyl‐4‐phenylpyridinium (MPP+). In contrast, the vesicular amine transporter protects against this form of injury by sequestering the toxin from its primary site of action in mitochondria. Together with the identification of defects in glutamate transport from patients with amyotrophic lateral sclerosis, these observations suggest that neurotransmitter transport may have a major role in neurodegenerative disease. The recent cloning of cDNAs encoding these transport proteins will help to explore this hypothesis.
Inhibition of acute, experimental autoimmune encephalomyelitis by the synthetic immunomodulator linomide
Authors: Karussis D. M. , Lehmann D. , Slavin S. , Vourka‐Karussis U. , Mizrachi‐Koll R. , Ovadia H. , Ben‐Nun A. , Kalland T. , Abramsky O.
Published: January 2005

Linomide (LS‐2616, quinoline‐3‐carboxamide) is a synthetic immunomodulator that stimulates natural killer cell activity and activates several lymphocytic subpopulations in experimental animals and humans. In this study we determined the effect of oral treatment with linomide on the development of experimental autoimmune encephalomyelitis, an animal model for immune‐mediated human demyelinating disorders. Experimental autoimmune encephalomyelitis was induced in SJL/J mice and in an outbred strain of rats (Sabra) by subcutaneous injection of spinal cord homogenate in adjuvant followed by inoculation with Bordetella pertussis. Linomide was administered in drinking water, at an estimated dose of 50 to 100 mg/kg/day. None of the linomide‐treated mice (0/41) and Sabra rats (0/15) developed any clinical or pathological signs of experimental autoimmune encephalomyelitis, whereas almost all control animals (48/53 and 18/19, respectively) were severely paralyzed and 64.5% died from the disease. Lymphocytes obtained from linomide‐treated animals had reduced in vitro proliferative responses to guinea pig myelin basic protein, proteolipid protein of the myelin, and tuberculin‐purified protein derivative, unlike antigen‐independent proliferation which was rather unaffected. Natural killer cell activity (tested by a cytotoxic assay on radiolabeled YAC‐1 target cells) was significantly enhanced in mice treated with linomide. Our results indicate that modulation of the immune system with linomide leads to complete inhibition of experimental autoimmune encephalomyelitis in the absence of systemic immunosuppression. Linomide could therefore be of use in future clinical trials for the treatment of human autoimmune demyelinating disorders.
Correlation between magnetic resonance imaging findings and lesion development in chronic, active multiple sclerosis
Authors: Katz David , Taubenberger Jeffery K. , Cannella Barbara , McFarlin Dale E. , Raine Cedric S. , McFarland Henry F.
Published: January 2005

Magnetic resonance imaging is a highly sensitive method for the detection of the lesions of multiple sclerosis and renders possible the study and the evolution of early lesions. Previous reports on magnetic resonance imaging following gandolinium‐diethylenetriamine pentaacetic acid (Gd‐DTPA) injection demonstrated that new lesions can be recognized by contrast enhancement. The pathological basis of these observations is uncertain. We have had the opportunity to study at autopsy the brain of a patient with chronic progressive multiple sclerosis who suffered acute worsening leading to death. Magnetic resonance imaging performed 10 days and 4 weeks prior to death showed new Gd‐DTPA‐enhanced lesions in the posterior hemispheric white matter adjacent to the lateral ventricles. Light microscopic examination of these areas demonstrated them to be fresh lesions comprising intense inflammatory activity and dense perivascular cuffs within an edematous lesion center and a striking parenchymal mononuclear cell infiltration at the margins of the lesions. Lesions that were demonstrated by increased signal on T2‐weighted images, but were not enhanced following administration of Gd‐DTPA, were all of the chronic type, either inactive or active. None of these showed the intense inflammatory activity of the acute lesions and most displayed fibrous astrogliosis.
Evidence for a central cholinergic effect of high‐dose thiamine
Authors: Meador K. J. , Nichols M. E. , Franke P. , Durkin M. W. , Oberzan R. L. , Moore E. E. , Loring D. W.
Published: January 2005

In vitro animal studies have suggested that thiamine is involved in the presynaptic release of acetylcholine. Total thiamine content in cholinergic nerve terminals is comparable with that of acetylcholine, and the phosphorylation state of thiamine changes with release of acetycholine. Thiamine binds to nicotinic receptors and may exhibit anticholinesterase activity. Based on these observations, we investigated the effects of pharmacological doses of thiamine on the cognitive deficits induced by the anticholinergic scopolamine in healthy young adults using a randomized, double‐blind, placebo‐controlled, double‐crossover design. Drug effects were assessed by P3 event‐related potential, quantitated electroencephalography, and free recall memory. Conditions included (1) baseline, (2) thiamine 5 gm p.o. and scopolamine 0.007 mg/kg IM, and (3) lactose PO and scopolamine 0.007 mg/kg IM. Thiamine significantly reduced adverse effects of scopolamine on P3 latency, spectral components of electroencephalography, and memory recall. The results are consistent with a cholinomimetic effect of thiamine in the central nervous system. Additional studies are needed to delineate the basic mechanisms and possible therapeutic efficacy of thiamine at pharmacological dosages.
Molecular genetics in neurology
Authors: Martin Joseph B.
Published: January 2005

There has been remarkable progress in the identification of mutations in genes that cause inherited neurological disorders. Abnormalities in the genes for Huntington disease, neurofibromatosis types 1 and 2, one form of familial amyotrophic lateral sclerosis, fragile X syndrome, myotonic dystrophy, Kennedy syndrome, Menkes disease, and several forms of retinitis pigmentosa have been elucidated. Rare disorders of neuronal migration such as Kallmann syndrome, Miller‐Dieker syndrome, and Norrie disease have been shown to be due to specific gene defects. Several muscle disorders characterized by abnormal membrane excitability have been defined as mutations of the muscle sodium or chloride channels. These advances provide opportunity for accurate molecular diagnosis of at‐risk individuals and are the harbinger of new approaches to therapy of these diseases.
Atrophy of mesial structures in patients with temporal lobe epilepsy: Cause or consequence of repeated seizures?
Authors: Cendes F. , Andermann F. , Gloor P. , Lopes‐Cendes I. , Andermann E. , Melanson D. , Jones‐Gotman M. , Robitaille Y. , Evans A. , Peters T.
Published: January 2005

We studied 70 epileptic patients by using magnetic resonance imaging volumetric measurements of amygdala (AM) and hippocampal formation (HF). Fifty patients presented with intractable temporal lobe epilepsy (TLE), 10 patients had focal extratemporal lobe epilepsy, and 10 had generalized epilepsy. In 91% of the 45 TLE patients without foreign tissue lesions, there was significant smallness of the AM and/or HF coinciding with the side of electroencephalographic seizure onset. No significant smallness or asymmetry was demonstrated in patients with focal extratemporal or generalized epilepsy. We performed a linear regression analysis, plotting the number of years of recurrent seizures and the estimated seizure frequency against the volumes of the AM and HF. There was no correlation between either of these two parameters and AM or HF volume (p > 0.9). There was also no correlation between the patient's age and volumetric measurements of AM or HF, nor did these measurements correlate with the occurrence of generalized seizures. On the other hand, patients with antecedent prolonged febrile convulsions in early childhood had significantly smaller AM and HF, compared with those without such a history (p < 0.001). The findings indicate that repeated seizures or longer duration of epilepsy do not cause increased atrophy of AM or HF that is measurable by volumetric magnetic resonance imaging.
Serum antibodies to Purkinje cells and dorsal root ganglia neurons in sensory neuronopathy without malignancy
Authors: Nemni R. , Camerlingo M. , Fazio R. , Casto L. , Quattrini A. , Mamoli D. , Lorenzetti I. , Canal N. , Mamoli A.
Published: January 2005

Anti‐Purkinje cell antibodies (APCA), believed to be markers of paraneoplastic cerebellar degeneration in females, have been identified in the serum of 3 men with subacute sensory neuronopathies and no evidence of tumors 5 years after the onset of the neurological signs. By indirect immunohistochemistry on sections of rat cerebellum and dorsal root ganglia, the patients' IgG bound to the cytoplasms of both Purkinje cells and dorsal root ganglia neurons. By western blot analysis on whole human cerebellum and whole human dorsal root ganglia homogenates, the IgG from 2 patients bound to a 62‐kd protein in both homogenates and the IgG from 1 patient bound to a 110‐kd protein in the cerebellum homogenate only. Yo autoantibody test was negative in all patients. Our study provides evidence that non‐anti‐Yo APCA may be associated with subacute sensory neuronoopathies and are not necessarily markers of an underlying tumor. The previously described anti‐Yo APCA has only occurred in females with cancer.
The gp 120 glycoprotein of human immunodeficiency virus type 1 binds to sensory ganglion neurons
Authors: Apostolski Slobodan , McAlarney Terence , Quattrini Angelo , Levison Steven W. , Rosoklija Gorazd , Lugaressi Alessandra , Corbo Massimo , Sadiq Saud A. , Lederman Seth , Hays Arthur P. , Latov Norman
Published: January 2005

Using immunofluorescence microscopy we found that gp 120 binds to the surface of rat dorsal root ganglia neurons and human neuroblastoma cells but not to rat fibroblasts or glial cells. The binding of gp 120 to neurons was eliminated by pretreatment with trypsin, which removes cell‐surface proteins, but not with chloroform: methanol, which removes glycolipids. As control, neuronal staining by antisulfatide antibodies was eliminated by pretreatment with chloroform: methanol but not with trypsin. The gp 120 binding to neurons was also inhibited by the mouse monoclonal antibody 01, which binds to galactocerebroside and cross‐reactive glycoproteins. These studies suggest that the receptor for gp 120 on the surface of the dorsal root ganglia neurons is a glycoprotein. This interaction may mediate the effects of human immunodeficiency virus type 1 in sensory neuropathy.
Demonstration of human T‐cell lymphotrophic virus type I (HTLV‐I) from an HTLV‐I seronegative South Indian patient with chronic, progessive spastic paraparesis
Authors: Nishimura Masataka , Mingioli Elizabeth , McFarlin Dale E. , Jacobson Steven
Published: January 2005

Here we describe a human T‐cell lymphotopic virus type I (HTLV‐I) seronegative patient from South India with a chronic, progressive spastic paraparesis from which HTLV‐I has been isolated from peripheral blood lymphocytes. HTLV‐I pol and tax viral sequences were detected in DNA from fresh peripheal blood lymphocytes (PBL) by polymerase chain reaction (PCR) and liquid hybridization techniques. Southern blot analysis of the PCR products demonstrated a low copy number of HTLV‐I at the level of one viral copy per 10,000 fresh PBL. A long‐term CD4+ T‐cell line was established from PBL of this patient using recombinant interleukin‐2, OKT3, and feeder cells. DNA from these cultured lines was amplified and portions of the HTLV‐I long terminal repeat (U3), pol, env, and tax regions were sequenced (a total of 1,115 bp). The sequence data showed that the HTLV‐I associated with this patient was 98.8% homologous to prototype HTLV‐I. Southern blot analysis also confirmed the presence of full‐length HTLV‐I. These results indicate that HTLV‐I can be demonstrated in an HTLV‐I seronegative patient from south India with a chronic progressive neurological disorder.
Carotid endarterectomy: Trials and tribulations
Authors: Easton J. D. , Wilterdink J. L.
Published: January 2005

Since its introduction 40 years ago, the value of carotid endarterectomy has been controversial. In the early 1980s, several clinical trials were initiated to determine the efficacy of this operation in patients with carotid stenoses who were either symptomatic or asymptomatic for retinal or hemispheric ischemia. In 1991, interim results were published for the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the European Carotid Surgery Trial (ECST), both reporting efficacy for surgery in patients with symptomatic carotid artery stenosis of greater than 70%. Subgroup analyses revealed variable risk groups. The Veterans Administration (VA) Symptomatic Trial (Cooperative Studies Program 309 of the Department of Veterans Affairs) terminated early because of these results and its findings were consistent with the results of the larger trials. NASCET and ECST continue for symptomatic patients with carotid stenoses between 30% and 69%. The results of three trials in asymptomatic patients, the Mayo asymptomatic trial, the Carotid Artery Stenosis with Asymptomatic Narrowing: Operation Versus Aspirin trial, and the VA Asymptomatic Trial (Cooperative Studies Protocol 167 of the Department of Veterans Affairs), have been reported. None showed a statistically significant benefit for surgery in the prevention of stroke or death. However, none was sufficiently large to exclude such a benefit. The large Asymptomatic Carotid Atherosclerosis Study is in progress. Differences in the results and design of these trials are discussed as are restrictions in the applicability of their results.
Indices of oxidative stress and mitochondrial function in individuals with incidental Lewy body disease
Authors: Dexter D. T. , Sian J. , Rose S. , Hindmarsh J. G. , Mann V. M. , Cooper J. M. , Wells F. R. , Daniel S. E. , Lees A. J. , Schapira A. H. V. , Jenner P. , Marsden C. D.
Published: January 2005

Brain tissue from normal individuals with incidental Lewy bodies and cell loss in pigmented substantia nigra neurons (asymptomatic Parkinson's disease) and age‐matched control subjects without nigral Lewy bodies was examined biochemically. There was no difference in dopamine levels or dopamine turnover in the caudate and putamen of individuals with incidental Lewy body disease compared to control subjects. There were no differences in levels of iron, copper, manganese, or zinc in the substantia nigra or other brain regions from the individuals with incidental Lewy body disease compared to those from control subjects. Similarly, ferritin levels in the substantia nigra and other brain areas were unaltered. There was no difference in the activity of succinate cytochrome c reductase (complexes II and III) or cytochrome oxidase (complex IV) between incidental Lewy body subjects and control subjects. Rotenone‐sensitive NADH coenzyme Q1 reductase activity (complex I) was reduced to levels intermediate between those in control subjects and those in patients with overt Parkinson's disease, but this change did not reach statistical significance. The levels of reduced glutathione in substantia nigra were reduced by 35% in patients with incidental Lewy body disease compared to control subjects. Reduced glutathione levels in other brain regions were unaffected and there were no changes in oxidized glutathione levels in any brain region. Altered iron metabolism is not detectable in the early stages of nigral dopamine cell degeneration. There may be some impairment of mitochondrial complex I activity in the substantia nigra in Parkinson's disease. The marked reduction in nigral reduced glutathione levels suggests this to be an important early change in the process of oxidative stress underlying Parkinson's disease.
Oligodendrocytes in the early course of multiple sclerosis
Authors: Brück Wolfgang , Schmied Mascha , Suchanek Gerda , Brück Yvonne , Breitschopf Helene , Poser Sigrid , Piddlesden Sara , Lassmann Hans
Published: January 2005

The neuropathology of demyelinating lesions in multiple sclerosis was studied in specimens obtained by diagnostic needle biopsy during early stages of the disease. The lesions were characterized by a chronic inflammatory reaction dominated by lymphocytes and macrophages, plaque‐like demyelination, and astroglial sclerosis. Oligodendrocytes within the lesions were studied by immunocytochemistry using antibodies against various myelin and oligodendroglia components. The expression of messenger RNA for proteolipid protein was determined by in situ hybridization. Our studies revealed that myelin‐oligodendrocyte glycoprotein is a sensitive and reliable marker for identification of oligodendrocytes in demyelinated plaques. The results suggest that in the early course of the disease in some patients, oligodendrocytes may largely be preserved, whereas in others oligodendroglial loss is pronounced. Loss of oligodendrocytes was only marginally related to the stage of demyelinating activity within the lesions. These findings indicate that the pathogenesis of demyelination may vary within different multiple sclerosis patients.
Alzheimer's disease and Lewy body disease: A comparative clinicopathological study
Authors: Lippa C. F. , Smith T. W. , Swearer J. M.
Published: January 2005

The exact nature of the relationship between Lewy body disease and Alzheimer's disease (AD) is unknown. To investigate this, we compared cases of pure Lewy body disease, mixed Lewy body disease with AD, and pure AD to see what pathological features were shared and how they differed. We counted neurons, Lewy bodies, diffuse and neuritic senile plaques, neurofibrillary tangles, and neuropil threads in the frontal and medial temporal cortex and hippocampus from 5 autopsied cases of Lewy body disease (without AD histopathology), 7 with combined Lewy body disease and AD, 6 with AD, and 5 age‐matched normal control subjects. Average neuronal counts in the cases with Lewy body disease were indistinguishable from those of control subjects, but higher than those for AD and combined Lewy body disease and AD. Diffuse plaque densities were similar in all disease forms. Neuritic senile plaques, neurofibrillary tangles, and neuropil threads were numerous in AD and combined Lewy body disease and AD, but sparse or absent in Lewy body disease and controls. Pure Lewy body disease and AD appear to be distinct clinicopathological entities except for the common feature of diffuse plaques in both disorders.
Influence of visual information on cerebellar saccadic dysmetria
Authors: Gaymard B. , Rivaud S. , Amarenco P. , Pierrot‐Deseilligny C.
Published: January 2005

We compared the accuracy of saccades made to seen or remembered visual targets in 3 patients with saccadic dysmetria due to cerebellar lesions. Saccadic dysmetria was worse for saccades to remembered targets and for saccades to flashed targets visible for only 150 msec (i.e., invisible at the time of saccade). Furthermore, no corrective saccades were made if the target was not visible. These results have implications for testing saccadic dysmetria and suggest new hypotheses about the control of saccadic amplitude.
Inborn errors of urea synthesis
Authors: Batshaw Mark L.
Published: January 2005

Inborn errors of urea synthesis can present in the newborn period as a catastrophic illness or later in childhood or adulthood with an indolent course punctuated by hyperammonemic episodes. Because symptoms mimic other neuropsychiatric disorders, it is common for there to be a delay in diagnosis, often with dire consequences. Diagnosis relies on the combination of clinical suspicion and the measurement of ammonium, lactate, and amino acids in plasma and organic acids and orotic acid in urine. Treatment involves nitrogen restriction combined with the stimulation of alternate pathways of waste nitrogen excretion. More recently liver transplantation has been performed as enzyme replacement therapy. The outcome is poor in children who survive prolonged neonatal hyperammonemic coma, with most manifesting developmental disabilities. The etiology of neuronal injury in this disorder is unclear but may involve some combination of ammonia/amino acid accumulation, neurotransmitter alterations, and excitotoxic injury. Gene therapy holds the promise of improved treatment in the future.
An immunohistochemical study on α‐ketoglutarate dehydrogenase complex in Parkinson's disease
Authors: Mizuno Yoshikuni , Matuda Sadayuki , Yoshino Hiroyo , Mori Hideo , Hattori Nobutaka , Ikebe Shin‐Ichirou
Published: January 2005

We report an immunohistochemical study of the mitochondrial α‐ketoglutarate dehydrogenase complex (KGDHC) in the substantia nigra in Parkinson's disease. The KGDHC, the three enzyme complex catalyzing the oxidation of α‐ketoglutarate to succinate through succinic semialdehyde, is the rate‐regulating enzyme of the TCA cycle. The mitochondrial toxin, MPP+, inhibits not only complex I but also the KGDHC. Therefore, we investigated this enzyme complex in Parkinson's disease. In the control patients (n = 6), the immunostaining of the melanized nigral neurons was generally uniform; most of the melanized neurons showed good immunostaining with some neurons showing somewhat reduced staining. In Parkinson's disease (n = 9), many melanized neurons showed reduced immunostaining for the KGDHC, and those neurons were more frequently seen in the lateral one‐third of substantia nigra. The decrease in the immunostaining for the KGDHC correlated roughly with the severity of degeneration. The KGDHC is more vulnerable to degeneration than complex II, III, and IV as noted in our previous immunohistochemical study. Even if secondary, the loss may play a role in the progression of the disease.
Mechanism of action of the anticonvulsant felbamate: Opposing effects on N‐methyl‐D‐aspartate and γ‐aminobutyric acidA receptors
Authors: Rho Jong M. , Donevan Sean D. , Rogawski Michael A.
Published: January 2005

Felbamate is a promising new antiepileptic drug whose mechanism of action is unknown. In whole‐cell voltage clamp recordings from cultured rat hippocampal neurons, clinically relevant concentrations of felbamate (0.1–3 mM) inhibited N‐methyl‐D‐aspartate (NMDA) responses and potentiated γ‐aminobutyric acid (GABA) responses. Single‐channel recordings indicated that the effect on NMDA responses occurred via a channel blocking mechanism. Felbamate is the first anticonvulsant drug with dual actions on excitatory (NMDA) and inhibitory (GABA) brain mechanisms. This unique combination of effects could account for felbamate's broad spectrum of anticonvulsant activity in animal seizure models and its distinctive clinical efficacy and safety profile.
Childhood ataxia with diffuse central nervous system hypomyelination
Authors: Schiffmann Raphael , Moller Johanna R. , Trapp Bruce D. , Shih Henry H‐L. , Farrer Robert G. , Katz David A. , Alger Jeffry R. , Parker Colette C. , Hauer Peter E. , Kaneski Christine R. , Heiss John D. , Kaye Edward M. , Quarles Richard H. , Brady Roscoe O. , Barton Norman W.
Published: January 2005

A significant number of patients with progressive leukodystrophy do not have a definitive diagnosis. This report describes the clinical, morphological, and biochemical characteristics of 4 unrelated girls with progressive ataxic diplegia of unknown etiology. These patients had normal development until the ages of 1.5 to 5 years. A diffuse confluent abnormality of the white matter of the central nervous system was present on computed tomography and magnetic resonance scans obtained early in the course of the illness. Dementia was not present and peripheral nerves were normal. All patients were evaluated for known metabolic and degenerative diseases and no abnormalities were observed. Light and electron microscopy of open‐brain biopsy specimens from 2 girls showed selective white matter abnormalities including hypomyelination, demyelination, and gliosis. Myelin‐specific proteins in the subcortical white matter were examined immunocytochemically and by Western blot analysis. The were of normal molecular size but were markedly reduced in quantity in both patients compared to control subjects. Lipid analysis revealed decreased levels of characteristic myelin lipids. When examined by magnetic resonance spectroscopic imaging, all patients showed a marked decrease of N‐acetylaspartic acid, choline, and creatine in white matter only. The magnetic resonance spectroscopic imaging profile is a unique diagnostic feature of this clinicopathological syndrome.
A splice junction mutation in a new myopathic variant of phosphoglycerate kinase deficiency (PGK North Carolina)
Authors: Tsujino Seiichi , Tonin Paola , Shanske Sara , Nohria Virinder , Boustany Rose‐Mary , Lewis Darrell , Chen Yuan‐Tuong , DiMauro Salvatore
Published: January 2005

We report on a 12‐year‐old boy with the myopathic form of phosphoglycerate kinase (PGK) deficiency, and unique kinetic and physical characteristics of the mutant enzyme (PGK North Carolina). A G‐to‐T substitution at the 5′ end of intron 4 was identified in the PGK gene of this patient. The mutation destroys the consensus sequence GT at the 5′ splice junction of the intron. Activation of a cryptic splice site within intron 4 causes the insertion into the transcript of a 30‐bp fragment at the 5′ end of intron 4. This insertion results in ten additional amino acids within the “nose” of the PGK molecule, but does not generate a frameshift or a premature stop codon.
Posterior temporal epilepsy: Electroclinical features
Authors: Duchowny M. , Jayakar P. , Resnick T. , Levin B. , Alvarez L.
Published: January 2005

In the course of evaluating children with posterior temporal lobe epilepsy with subdural electrodes, we observed that their seizures commonly arose from basal rather than convexity foci and that they followed a stereotyped clinical sequence. Seizures characteristically began with behavioral arrest that coincided with basal temporal seizure discharges and progressed to motor signs as the seizure activity spread to the ipsilateral cortical convexity. Behavioral automatisms were observed in approximately half the patients, but were never the first or most prominent ictal manifestation. Focal lesions were identified preoperatively in 7 patients. We performed tailored temporal lobe resections in 14 patients, 10 (71%) of whom were seizure free (N = 9) or had occasional auras (N = 1) at a mean follow‐up of 2 years. These findings suggest that in childhood, posterior temporal seizures frequently arise from basal cortex and have a consistent and recognizable ictal and electrographic semiology. In medically refractory patients, tailored temporal resection is an effective therapy.
Pretreatment with intraventricular basic fibroblast growth factor decreases infarct size following focal cerebral ischemia in rats
Authors: Koketsu Naoki , Berlove David J. , Moskowitz Michael A. , Kowall Neil W. , Caday Cornelio G. , Finklestein Seth P.
Published: January 2005

Basic fibroblast growth factor is a polypeptide with potent multipotential trophic effects on central nervous system cells, including neurons, glia, and endothelial cells. In particular, it promotes the survival of a wide variety of brain neuron in vitro, and protects these neurons against the effects of several neurotoxins, including excitatory amino acids, hypoglycemia, and calcium ionophore. Since lack of substrate delivery, excitatory amino acid toxicity, and calcium entry into cells appear to be important processes in neuronal death after ischemia, we tested the hypothesis that pretreatment with basic fibroblast growth factor limits infarct size in a model of focal cerebral ischemia in vivo. Mature male Long‐Evans rats received either continuous intraventricular infusion of basic fibroblast growth factor (1.2μ/day; with or without heparin, added to stabilize the growth factor) or vehicle alone for 3 days before focal ischemic infarcts were made in the right lateral cerebral cortex by permanent distal middle cerebral artery occlusion and temporary (45‐minute) bilateral carotid occlusion. Intraoperative measurements of core temperarure, arterial blood pressure and blood gases, blood glucose concentration, and hematocrit, and postoperative measurements of temperature revealed no differences among vehicle‐ versus basic fibroblast growth factor–treated animals. Twenty‐four hours later, animals were killed, brains were removed and stained to visualize cortical infarcts, and infarct volume was determined by image analysis. Overall, we found a 25% reduction in infarct volume in basic fibroblast growth factor– (N = 25) versus vehicle‐treated (N = 23) animals (p < 0.01). This reduction was not enhanced by the addition of heparin. These data show that pretreatment with intraventricular basic fibroblast growth factor limits infarct size following focal cerebral ischemia in rats.
Anti‐CD11b monoclonal antibody reduces ischemic cell damage after transient focal cerebral ischemia in rat
Authors: Chen H. , Chopp M. , Zhang R. L. , Bodzin G. , Chen Q. , Rusche J. R. , Todd R. F.
Published: January 2005

We investigated the effect of an anti‐CD11b monoclonal antibody (1B6c) on ischemic cell damage after transient middle cerebral artery occlusion. We divided animals into three groups: MAb 1 group (n = 5)—rats were subjected to 2 hours of transient occlusion and 1B6c (1 mg/kg) was administered intravenously at 0 and 22 hours of reperfusion; MAb 2 group (n = 5)—same experimental protocol as MAb 1 group, except that the initial dose of 1B6c was increased to 2 mg/kg; and control group (n = 5)—same experimental protocol as MAb 2 group, except that an isotype‐matched control antibody was administered. Animals were weighed and tested for neurological function before and after occlusion of the middle cerebral artery. Forty‐six hours after reperfusion, brain sections were stained with hematoxylin and eosin for histology evaluation. We observed a significant reduction of weight loss and improvement in neurological function after ischemia in the MAb 2 animals compared to MAb 1 and vehicle‐treated animals (p < 0.05). The lesion volume was significantly smaller in the MAb 2 group (19.5 ± 1.9%) compared to MAb1 (29.9 ± 2.6%) and vehicletreated (34.2 ± 5.4%) group (p < 0.01). Tissue polymorphonuclear cell numbers were reduced in both 1B6c‐administered groups. Our data demonstrate that administration of anti‐CD11b antibody results in a dose‐dependent, significant functional improvement and reduction of ischemic cell damage after transient focal cerebral ischemia in the rat.
Elevated serum levels of endothelial leukocyte adhesion molecules in Guillain‐Barré syndrome and chronic inflammatory demyelinating polyneuropathy
Authors: Oka Nobuyuki , Akiguchi Ichiro , Kawasaki Teruaki , Ohnishi Katsunori , Kimura Jun
Published: January 2005

We determined the serum concentrations of the soluble form of endothelial leukocyte adhesion molecule‐1 (sELAM‐1) in 25 patients with Guillain‐Barré syndrome, 14 patients with chronic inflammatory demyelinating polyneuropathy, 15 patients with amyotrophic lateral sclerosis, 15 patients with other polyneuropathies, 10 patients with acute stroke, and 12 healthy control subjects. The patients with Guillain‐Barré syndrome in the acute stage had a higher sELAM‐1 serum level compared with the control subjects (p < 0.001). In 7 of the 9 patients the elevated level returned to normal by 14 days after the onset of neurological symptoms. In addition, a significantly elevated serum level of sELAM‐1 was found in patients with chronic inflammatory demyelinating polyneuropathy (p < 0.01). These findings suggest a role for ELAM‐1 in the inflammatory process of these disorders.
Antiparkinsonian effects of remacemide hydrochloride, a glutamate antagonist, in rodent and primate models of Parkinson's disease
Authors: Greenamyre J. Timothy , Eller Robert V. , Zhang Zhiming , Ovadia Aliza , Kurlan Roger , Gash Don M.
Published: January 2005

Loss of dopaminergic innervation of the striatum results in overactivity of the glutamatergic pathways from the subthalamic nucleus to the internal segment of the globus pallidus and the substantia nigra pars reticulata, the output nuclei of the basal ganglia. Previous work has shown that local blockade of glutamate receptors in the internal segment of the globus pallidus or substantia nigra pars reticulata leads to marked suppression of parkinsonian signs. We have now examined whether systemic administration of a glutamate receptor antagonist has antiparkinsonian effects in rodent and primate models of Parkinson's disease. Remacemide hydrochloride is an anticonvulsant, neuroprotective compound with antagonist activity at the N‐methyl‐D‐aspartate receptor ion channel. In normal rats and monoaminedepleted rats, remacemide hydrochloride did not cause locomotor hyperactivity, unlike MK‐801. When monoaminedepleted rats were treated with a subthreshold dose of levodopa methylester, remacemide hydrochloride (5–40mg/kg, orally) caused a dose‐dependent increase in locomotor activity. Moreover, remacemide hydrochloride (10 mg/kg, orally) potentiated the effects of each suprathreshold dose of levodopa methylester tested (100–200 mg/kg, intraperitoneally). Parkinsonian rhesus monkeys were tested with oral doses of vehicle plus vehicle, vehicle plus levodopa‐carbidopa, and remacemide hydrochloride (5 mg/kg) plus levodopa‐carbidopa. Blinded clinical scoring of videotapes revealed that treatment with remacemide hydrochloride plus levodopa‐carbidopa was substantially better than levodopa‐carbidopa plus vehicle or vehicle plus vehicle. The effects of remacemide hydrochloride lasted at least 5 hours. We conclude that certain N‐methyl‐D‐aspartate receptor antagonists have antiparkinsonian actions and low potential for side effects. Clinical trials of remacemide hydrochloride in patients with Parkinson's disease may be warranted.
Pyruvate dehydrogenase deficiency: Molecular basis for intrafamilial heterogeneity
Authors: Fujii Tatsuya , Van Coster Rudy N. , Old Susan E. , Medori Rosella , Winter Susan , Gubits Ruth M. , Matthews Paul M. , Brown Ruth M. , Brown Garry K. , Dahl Hans‐Henrik M. , De Vivo Darryl C.
Published: January 2005

Two half‐brothers and their mother had symptomatic pyruvate dehydrogenase complex deficiency. The infants had severe congenital lactic acidosis, seizures, and apneic spells and died at the ages of 3 and 4 months. The mother was less symptomatic with mental retardation, truncal ataxia, and dysarthria. The residual pyruvate dehydrogenase activities in cultured skin fibroblasts from the 2 infants and their mother were 7, 15, and 10% of control values. Immunoblot analysis showed negligible amounts of E1α and E1β subunits of the complex. Northern blot analysis for the E1α subunit showed normal results. In the 2 sons, complementary DNA sequence analysis reveled a cytosine to thymine mutation in exon 4, resulting in a change of arginine 127 to tryptophan in the E1α subunit. Restriction enzyme analysis of the polymerase chain reaction product representing exon 4 of the E1α gene revealed that the mother was a heterozygote. Complementary DNA restriction analysis and methylation analysis of the X chromosome DXS255 loci revealed skewed activation of the mutant allele, consistent with the deficient pyruvate dehydrogenase activity in the mother's fibroblasts. The milder maternal phenotype is consistent with variable X‐inactivation patterns in different organs of female heterozygotes.
Subacute sclerosing panencephalitis in an infant: Diagnostic role of viral genome analysis
Authors: Baram Tallie Z. , Gonzalez‐Gomez Ignacio , Xie Zong‐De , Yao Dapeng , Gilles Floyd H. , Nelson Marvin D. , Nguyen Hahn T. , Peters Julius
Published: January 2005

Subacute sclerosing panencephalitis (SSPE) is related to “defective” measles virus or vaccination, though an association with parainfluenza viruses has been reported. SSPE is characterized by a slow, erratic course and elevated cerebrospinal fluid measles titers. An immunocompetent, vaccinated infant, with onset of symptoms in parainfluenza virus season and a catastrophic course is described. Cerebrospinal fluid titers were negative, but postmortem brain had typical SSPE lesions. Patient brain‐derived RNA, subjected to reverse transcription followed by polymerase chain reaction yielded polymerase chain reaction products with measles virus but not parainfluenza virus genes. The sequenced fragment revealed multiple mutations, typical for SSPE. SSPE can thus present in infants, with short latency and no cerebrospinal fluid antibodies. Viral genomic analysis may be diagnostic, permitting early therapy.
Discordant twins with Parkinson's disease: Positron emission tomography and early signs of impaired cognitive circuits
Authors: Holthoff V. A. , Vieregge P. , Kessler J. , Pietrzyk U. , Herholz K. , Bönner J. , Wagner R. , Wienhard K. , Pawlik G. , Heiss W.‐D.
Published: January 2005

We evaluated 7 pairs of twins (2 monozygotic and 5 dizygotic) discordant for Parkinson's disease (PD), of whom the cotwins showed no signs of motor impairment on neurological examination. All subjects underwent positron emission tomographic measurements of cerebral glucose metabolism and dopaminergic, nigrostriatal function following injection of 2‐[18F]fluoro‐2‐deoxy‐D‐glucose and L‐6‐[18F]fluorodopa ([18F]dopa), respectively, as well as testing for anterograde, verbal episodic, and semantic memory performance. Statistical analysis demonstrated significant reduction of striatal [18F]dopa uptake not only in the twin patients with PD but also in all of the cotwins, who showed significantly (p < 0.05) impaired [18F]dopa metabolism in at least one of the striatal measures including caudate, putaminal, and the rostrocaudal putaminal gradient of [18F]dopa uptake. Compared with age‐matched controls, regional glucose metabolism was unchanged in all the twins. Neuropsychological testing showed significant (p < 0.05) 0.0(5) impairment in verbal memory processing in the twin patients with PD and in 6 of the cotwins. Semantic memory skills were affected in 2 twin patients only. A significant correlation was found between scores obtained in Buschke's Selective Reminding Test and striatal [18F]dopa uptake, further substantiating the role of dopaminergic pathways in memory processing. The present study is the first to reveal not only significant disturbance of nigrostriatal dopaminergic function in asymptomatic cotwins of twin patients with PD, but also significant impairment in the processing of anterograde, verbal episodic memory that is known to be affected in PD. Larger studies with a longitudinal design will be necessary to answer the question of whether cognitive changes found in the cotwin group are signs of incipient PD.
The effect of systemically administered recombinant human nerve growth factor in healthy human subjects
Authors: Petty Brent G. , Cornblath David R. , Adornato Bruce T. , Chaudhry Vinay , Flexner Charles , Wachsman Matthew , Sinicropi Dominick , Burton Louis E. , Peroutka Stephen J.
Published: January 2005

This phase I double‐masked, randomized, placebocontrolled study evaluated the safety of single intravenous or subcutaneous doses of recombinant human nerve growth factor (rhNGF) in healthy human volunteers at doses ranging from 0.03 to 1 μg/kg. No life‐threatening adverse events were seen at any dose. At doses above 0.1 μg/kg, subjects reported mild to moderate muscle pain, primarily in the bulbar and truncal musculature. The duration and severity of these myalgias varied in a dosedependent manner, and women appeared to be more susceptible than men. Intravenous rhNGF produced earlier and more pronounced systemic effects than did identical subcutaneous doses. Subjects receiving subcutaneous rhNGF noted hyperalgesia at the injection site, a local effect persisting up to 7 weeks, that also varied in a dose‐dependent manner. Antibodies to NGF were not detected in any subject. These results indicate that systemically administered rhNGF exerts a characteristic and reproducible biological effect in healthy subjects at very low doses and in a dose‐dependent manner.
Genetic linkage studies in autosomal dominant parkinsonism: Evaluation of seven candidate genes
Authors: Gasser T. , Wszolek Z. K. , Trofatter J. , Ozelius L. , Uitti R. J. , Lee C. S. , Gusella J. , Pfeiffer R. F. , Calne D. B. , Breakefield X. O.
Published: January 2005

Linkage studies were performed in three families (A, B, and C) with autosomal dominantly inherited parkinsonism affecting multiple members in three generations. Affected individuals exhibited the cardinal signs and symptoms of Parkinson's disease, with a mean age of onset of 51, 62, and 61 years in Families A, B, and C, respectively. Parkinsonian symptoms responded to L‐dopa treatment, and an [18F]6‐fluoro‐L‐dopa positron emission tomography scan in 1 affected member of Family B showed decreased striatal uptake typical of Parkinson's disease. Ancestors of all three families were traced to a small region in northern Germany and southern Denmark, suggesting the possibility of a common mutation. Linkage studies were performed with polymorphic markers associated with the following candidate genes: the genes for glutathione peroxidase (GPX1, 3q11), tyrosine hydroxylase (TH, 11p15.5), brain‐derived neurotrophic factor (BDNF, 11p14), catalase (CAT, 11p13), amyloid precursor protein (APP, 21q21), copper‐zinc superoxide dismutase (SODI, 21q21), and debrisoquin 4‐hydroxylase (CYP2D6, 22q13.1). Summed lod scores for all families excluded linkage to the genes GPX1, TH, APP, SODI, and CYP2D6, as well as to the chromosomal region containing the genes CAT and BDNF. If families were analyzed individually, exclusion was possible for two (Family A), six (Family B), and five (Family C) of the seven candidate genes. There was strong evidence against linkage for the remaining loci in all families analyzed individually, except for TH, which was uninformative in Families A and B, and CYP2D6, which gave slightly positive pairwise lod scores in Family A. Our results indicate that the candidate genes investigated are not involved in the etiology of parkinsonism in these families.
Band heterotopia: Correlation of outcome with magnetic resonance imaging parameters
Authors: Barkovich A. J. , Guerrini R. , Battaglia G. , Kalifa G. , N'Guyen T. , Parmeggiani A. , Santucci M. , Giovanardi‐Rossi P. , Granata T. , D'Incerti L.
Published: January 2005

The “band heterotopia” or “double cortex” is a brain anomaly that is presumed to result from a premature arrest of neuronal migration. Patients with this anomaly are reported to have a variable clinical course that has been, heretofore, unpredictable. The clinical records and magnetic resonance (MR) imaging studies of 27 patients with band heterotopia were retrospectively reviewed in an attempt to determine whether imaging findings are useful in predicting clinical outcome of affected patients. Statistical analyses revealed the following corelations: (1) severity of T2 prolongation in the brain with motor delay (p = 0.03); (2) degree of ventricular enlargement with the age of seizure onset (p = 0.04) and with development and intelligence (p = 0.04); (3) severity of pachygyria with the age of seizure onset (p = 0.01), seizure type (p = 0.03), and an abnormal neurologic examination (p = 0.002); (4) parietal involvement with delayed speech development (p = 0.05); (5) occipital involvement with age of seizure onset (p = 0.006); (6) age of seizure onset with development and intelligence (p = 0.03) and with an abnormal neurologic examination (p = 0.04); and (7) severity of the pachygyria and thickness of band with development of symptomatic generalized epilepsy (p = 0.002 and p = 0.02, respectively) and Lennox‐Gastaut syndrome (p = 0.002 and p = 0.01, respectively).
Red nuclear and cerebellar but no olivary activation associated with essential tremor: A positron emission tomoraphic study
Authors: Wills A. J. , Jenkins I. H. , Thompson P. D. , Findley L. J. , Brooks D. J.
Published: January 2005

There has been debate as to whether essential tremor has a central origin and over the possible role of the inferior olivary nucleus in its genesis. We use positron emission tomography with radioactve water (H215O) to detect abnormal patterns of cerebral activity associated with this condition, at rest, without tremor, and on posture when the tremor was present. At rest, cerebellar blood flow was significantly increased bilaterally in the group with essential tremor (30–40%) but no increased olivary activity was evident. Essential tremor during arem extension was associated with further abnormal increases in bilateral cerebellar and abnormal red nuclear activation. Again, no olivary overactivity was evident. Voluntary wrist oscillation in control subjects caused only ipsilateral cerebellar activation. We conclude that essential tremor is associated with abnormal bilateral overactivity of cerebellar and red nuclear connections but found no evidence of intrinsic overactivity of the inferior olivary nucleus, as evidenced by raised blood flow.
Cytokine expression in the muscle of HIV‐infected patients: Evidence for interleukin‐1α accumulation in mitochondria of AZT fibers
Authors: Gherardi R. K. , Florea‐Strat A. , Fromont G. , Poron F. , Sabourin J‐C. , Authier J.
Published: January 2005

To evaluate the possible role of cytokines in human immunodeficiency virus (HIV)–associated muscular disorders, we performed immunocytochemistry for interleukin‐1α, ‐1β, and ‐6 and tumor necrosis factor‐α on frozen muscle biopsy specimens from HIV‐infected patients with various myopathies (HIV polymyositis in 5, HIV‐wasting syndrome in 5, zidovudine myopathy in 10) and from seronegative individuals (normal muscle in 2, mitochondrial cytopathies in 10). The HIV‐infected patients showed positive reactivities in vessels (interleukin‐1) and in inflammatory cells (mainly interleukin‐1 and tumor necrosis factor‐α), including perivascular hemosiderin‐laden macrophages in 5 patients. In zidovudine myopathy, a majority of AZT fibers (i.e., ragged‐red fibers with marked myofibrillar changes) showed mild to marked expression of interleukin‐1. Expression of interleukin‐1 in the other mitochondrial myopathies was much weaker. Interleukin‐1β messenger RNA was demonstrated in muscle fibers by in situ hybridization, implying that interleukin‐1 was produced in muscle cells. Immunoelectron microscopy showed that interleukin‐1α was mainly bound to mitochondrial membranes in AZT fibers. Proinflammatory and destructive effects of the studied cytokines might be responsible for several myopathological changes observed in HIV‐infected patients, including inflammation and hemosiderin deposits in muscle tissue, and prominent myofibrillar breakdown in AZT fibers.