bluuebunny/crossref_metadata_2025 huggingface dataset:
Autoantibodies against the Hel‐N1 RNA‐binding protein among patients with lung carcinoma: An association with type I anti–neuronal nuclear antibodies
Authors: Dropcho Edward J. , King Peter H.
Published: January 2005

Hel‐N1 is a novel human complementary DNA encoding a neuronal RNA‐binding protein which shares considerable sequence homology with the HuD protein, a target of type I anti–neuronal nuclear antibodies in patients with paraneoplastic encephalomyelitis. The aim of the present study was to determine the prevalence of antibodies against the Hel‐N1 protein among patients with lung carcinoma, including those with paraneoplastic disorders. Sera from 45 patients with lung cancer (42 with small‐cell carcinoma) and from 28 control patients with other neurological diseases were studied by enzyme‐linked immunosorbent assay (ELISA) and by immunoblotting with recombinant Hel‐N1 protein. Sixteen of the 45 lung cancer patients (14 with small‐cell and 2 with undifferentiated carcinoma) had paraneoplastic encephalomyelitis and high‐titer type I anti–neuronal nuclear antibodies; sera from each of these 16 patients also showed strong reactivity with Hel‐N1 protein. The other 29 lung cancer patients, all of whom had neurological dysfunction and 24 of whom had known or suspected paraneoplastic disorders, lacked the type I antibody by standard testing. The mean anti–Hel‐N1 titer (by ELISA) of sera from patients negative for type I anti–neuronal nuclear antibody was significantly less than that of the patients positive for the type I antibody, but exceeded that of the control patients with other neurological diseases (p < 0.001). Fifteen (52%) of the 29 type I antibody–negative patients had positive serum anti–Hel‐N1 titers which did not overlap the high anti–Hel‐N1 titers of the 16 type I antibody–positive patients. These findings support the theory that type I anti–neuronal nuclear antibodies react with a family of neuronal RNA‐binding proteins, and suggest that these proteins share one or more epitopes. High titers of circulating anti–Hel‐N1 antibodies correlate with paraneoplastic encephalomyelitis, while lower anti–Hel‐N1 titers are present in a sizeable proportion of patients with small‐cell lung cancer without a clear association with their clinical condition.
Glutathione‐related enzymes in brain in Parkinson's disease
Authors: Sian J. , Dexter D. T. , Lees A. J. , Daniel S. , Jenner P. , Marsden C. D.
Published: January 2005

The activities of enzymes related to glutathione synthesis, degradation, and function were analyzed in various brain regions (cerebral cortex, caudate nucleus, putamen, globus pallidus, and substantia nigra) from patients dying with pathologically proven Parkinson's disease (PD) and multiple system atrophy (MSA), and from matched controls with no neurological disorder. The activity of the glutathione degradative enzyme, σ‐Glutamyltranspeptidase, was selectively elevated in substantia nigra (SN) in PD. In contrast, the activity of the synthetic enzyme, σ‐glutamylcysteine synthetase, was unaltered in SN and other brain areas in PD. Similarly, glutathione peroxidase and glutathione transferase activities were unaltered in SN or in other brain regions in PD. σ‐Glutamylcysteine synthetase, σ‐glutamyltranspeptidase, glutathione peroxidase, and glutathione transferase activities were normal in SN and most other brain areas in MSA. However, glutathione peroxidase activity was increased in the lateral globus pallidus and caudate nucleus in MSA. The depletion of reduced glutathione (GSH) in the SN in PD, with no change in oxidized glutathione (GSSG), may be due to efflux of GSH mainly out of glia promoted by σ‐glutamyltranspeptidase, perhaps with additional increased conversion of GSH to GSSG (which itself is transported out of cells by σ‐glutamyltranspeptidase), in response to increased hydrogen peroxide formation.
Increased transforming growth factor‐β, interleukin‐4, and interferon‐γ in multiple sclerosis
Authors: Link Joanne , Söderström Mats , Olsson Tomas , Höjeberg Bo , Ljungdahl Årke , Link Hans
Published: January 2005

The inflammatory nature of multiple sclerosis (MS) implicates the participation of immunoregulatory cytokines, including the T‐helper type 1 (Th1) cell–associated interferon‐σ (IFN‐σ), the Th2 cell–related interleukin‐4 (IL‐4), and the immune response–downregulating cytokine transforming growth factor‐β (TGF‐β), but proof for their involvement in MS has been lacking. By adopting in situ hybridization with complementary DNA oligonucleotide probes for human IFN‐ IL‐4, and TGF‐β, the expression of mRNA for these cytokines was detected in mononuclear cells (MNC) from blood and cerebrospinal fluids. Strongly elevated levels of MNC expressing all three cytokines were found in peripheral blood and at even higher frequencies in cerebrospinal fluid from untreated patients with MS and optic neuritis, i.e., a common first manifestation of MS, compared with patients with other neurological diseases and healthy subjects. In MS and optic neuritis, IL‐4 mRNA expressing cells predominated, followed by TGF‐β– and IFN‐σ–positive cells. Control patients with myasthenia gravis had similarly elevated levels of IFN‐σ and TGF‐β mRNA expressing blood MNC but lower numbers of IL‐4–positive cells. No or slight disability of MS was associated with high levels of TGF‐β mRNA expressing cells, while MS patients with moderate or severe disability had high levels of IFN‐σ–positive cells. IFN‐σ and TGF‐β may have opposing effects in MS, and treatments inhibiting IFN‐σ and/or promoting TGF‐β might ameliorate MS.
Decreased cerebrospinal fluid levels of β‐endorphin in Japanese patients with Joseph disease
Authors: Matsuishi Toyojiro , Sakai Tetsuo , Nagamitsu Shinichiro , Komori Hironori , Iwashita Hiroshi , Kato Hiroshisa
Published: January 2005

We measured the cerebrospinal fluid (CSF) levels of β‐endorphin in 7 Japanese patients with Joseph disease and compared them with control values. The 7 patients included 4 with type I and 3 with type II disease; their mean age was 45.7 ± 12.09 years. Diseased controls were matched in age to the patients studied. In these patients, CSF β‐endorphin level was significantly lower than in the controls (40% of normal values). An alteration in CSF β‐endorphin level may explain some of the neurological impairment found in Joseph disease.
Multislice proton magnetic resonance spectroscopic imaging in X‐linked adrenoleukodystrophy
Authors: Kruse Bernd , Barker Peter B. , van Zijl Peter C. M. , Duyn Jeff H. , Moonen Chrit T. W. , Moser Hugo W.
Published: January 2005

Multislice proton magnetic resonance spectroscopic imaging permits metabolic analysis of brain tissue in vivo by data acquisition in four oblique axial slices, each 15‐mm thick and divided into 0.8‐ml single‐volume elements. We applied this technique to the systematic study of 25 patients with adrenoleukodystrophy: 3 with the severe childhood or adult cerebral form of the disease, 5 with adrenomyeloneuropathy, 12 with no demonstrable neurological involvement, and 5 women heterozygous for adrenoleukodystrophy who had some degree of neurological disability. Abnormalities on magnetic resonance spectroscopic imaging included a reduction in N‐acetyl aspartate, an increase in cholin‐containing compounds, and at times, an increase in lactate. Five patients showed abnormalities in the presence of normal‐appearing magnetic resonance images, and in 8 other patients the alterations on spectroscopic images were more severe than those demonstrable by magnetic resonance imaging. Correlation with clinical course suggests that an increase in the choline‐containing compounds is associated with an active demyelinative process, whereas such compounds are not elevated in lesions that are stable. We conclude that magnetic resonance spectroscopic imaging is a more sensitive indicator of early neurological involvement thatn is magnetic resonance imaging, and that the character of abnormalities detected by the former technique may serve as a gauge of the degree of activity of the demyelinating process and as a guide to the selection and evaluation of therapeutic approaches.
Neurological complications of peripheral and cutaneous T‐cell lymphomas
Authors: Kaufman David K. , Habermann Thomas M. , Kurtin Paul J. , O'Neill B. P.
Published: January 2005

To determine the frequency and pattern of neurological complications of T‐cell lymphoma (TCL), we retrospectively reviewed the medical records of 316 patients with TCL diagnosed between January 1984 and May 1991. Disease entities not included in this study were lymphoblastic lymphoma, primary central nervous system lymphoma, CD30‐positive anaplastic large cell lymphoma, and lymphomas secondary to human immunodeficiency virus or human T‐cell lymphotropic virus type I. Cases were classified as having direct complications (parenchymal, leptomeningeal, epidural, or peripheral) or indirect complications (paraneoplastic, disease related, or treatment related). Preexisting neurological conditions were excluded. The overall rate of neurological complications was 7.9%. The frequency of neurological complications in peripheral TCL and cutaneous TCL was 17% and 3%, respectively, with at least half of the neurological complications in both conditions due to direct involvement of the nervous system. Direct neurological complications of TCL were primarily due to leptomeningeal and parenchymal involvement. There were no cases of epidural spinal cord disease.
Increased risk of Parkinson's disease in parents and siblings of patients
Authors: Payami Haydeh , Larsen Kimberly , Bernard Steven , Nutt John
Published: January 2005

We studied the incidence of Parkinson's disease in 586 first‐degree relatives (parents and siblings) of 114 randomly ascertained white patients with idiopathic Parkinson's disease and in 522 first‐degree relatives of 114 age‐matched unrelated white control subjects. Sixteen percent of patients had a family history as compared to 4% of control subjects (p < 0.01). The age‐specific cumulative incidence was higher in the first‐degree relatives of patients than in the first‐degree relatives of control subjects (p = 0.007). The age‐adjusted odds ratio was 3.5 (95% confidence interval: 1.3–9.4; p = 0.014). These results suggest that genes contribute to the etiology of Parkinson's disease.
Human immunodeficiency virus encephalitis is the pathological correlate of dementia in acquired immunodeficiency syndrome
Authors: Wiley Clayton A. , Achim Cristian
Published: January 2005

While dementia has been observed in approximately one‐fourth of terminally ill patients with acquired immunodeficiency syndrome, it has been difficult to attribute this clinical disorder to a single neuropathological substrate. We used a simple and readily reproducible scale for estimating the burden of human immunodeficiency virus (HIV) in the central nervous system (i.e., severity of HIV encephalitis) and compared this to autopsy neurological summaries of dementia. Like others, we found that multinucleated giant cells were present in only half of the dementia patients. However, all of the dementia patients had severe HIV encephalitis as assessed by measurements of intra–central nervous system viral burden. Additional patients had severe HIV encephalitis without clinical histories of dementia. We interpret these latter findings as evidence that HIV encephalitis exists for a period of time before the clinical symptomatology develops. Comparison of presence or absence of concurrent cytomegalovirus encephalitis showed no association with dementia.
Longitudinal fluorodopa positron emission tomographic studies of the evolution of idiopathic parkinsonism
Authors: Vingerhoets F. J. G. , Snow B. J. , Lee C. S. , Schulzer M. , Mak E. , Calne D. B.
Published: January 2005

Previous estimates of the rate of progression of the nigral pathology underlying idiopathic parkinsonism (IP) have been derived mainly from pathological studies that have an inherent selection bias. Fluorodopa positron emission tomography (PET) is a reliable tool for assessing nigrostriatal dopaminergic function in vivo. We performed fluorodopa PET on two occasions, 7 years apart, on 16 patients with IP (age at the time of the first scan, 51 ± 14 yr [mean ± SD]) and 10 normal controls (age, 54 ± 16 yr). For the patients with IP, the average duration of symptoms from the time of diagnosis to the first scan was 4.5 years (range, 1–12 yr); their PET index (striatal – occipital)/occipital ratio, dropped by 1.7% per year, from 0.49 ± 0.08 to 0.43 ± 0.08 (p < 0.001). The normals' ratio decreased by 0.3% per year from 0.77 ± 0.05 to 0.75 ± 0.10 (p = 0.33). The ratios in the IP group progressed significantly faster than the controls (p = 0.036). The rate of decline in IP represents 7.8% per decade, expressed as a fraction of the normals' initial mean value at 54 years of age. These results also permit power analysis for the design of future studies assessing the effect of treatment on the underlying pathology in IP.
An oxidative defect in metabolic myopathies: Diagnosis by noninvasive tissue oximetry
Authors: Bank William , Chance Britton
Published: January 2005

Metabolic myopathies due to a variety of enzymatic deficiencies are well recognized. The dynamics of oxygen delivery and utilization during exercise have not been observed previously in these disorders. We used a noninvasive optical technique to measure oxygen consumption in the exercising limb in normal subjects and patients with metabolic myopathies. We measured near‐infrared spectra of hemoglobin in the gastrocnemius muscle during treadmill exercise in 10 normal subjects, 1 patient with cytochromecoxidase deficiency, 2 patients with myophosphorylase deficiency, 3 patients with phosphofructokinase deficiency, and 2 patients with carnitine palmityl transferase deficiency. All normal subjects demonstrated a sustained deoxygenation during exercise, indicating an efficient utilization of delivered oxygen. The patient with cytochromecoxidase deficiency demonstrated consistent oxygenation during exercise, indicating an underutilization of delivered oxygen. In the patients with myophosphorylase or phosphofructokinase deficiency, abnormal oxgenation during exercise indicated an oxidative defect due to a lack of pyruvate production. In the patients with myophosphorylase deficiency, changes in oxidation coincident with glucose utilization and “the second wind phenomenon” were observed. Patients with carnitine palmityl transferase deficiency demonstrated a normal deoxygenation during exercise. Noninvasive tissue oximetry during exercise demonstrates specific abnormalities in a variety of metabolic myopathies, indicating abnormal oxygen utilization, and will be a useful addition to the clinical investigation of exercise intolerance.
Evidence for hypoxia‐induced, programmed cell death of cultured neurons
Authors: Rosenbaum Daniel M. , Michaelson Marc , Batter David K. , Doshi Pooja , Kessler John A.
Published: January 2005

Apoptosis, a form of cell death (“programmed” cell death) in which the nucleus and cytoplasm shrink and often fragment, serves to eliminate excessive or unwanted cells during remodeling of embryonic tissues, during organ involution, and in tumor regression. In acute pathological states, such as ischemia, the cells tend to swell and lyse—a process called necrosis. We hypothesize that the delayed neural death clinically associated with hypoxia may, in part, represent apoptosis. A tissue culture model of 24 hours of hypoxia was employed using sympathetic neurons. Pretreatment with an endonuclease inhibitor (aurintricarboxylic acid) decreased cell death by 53%, depolarizing conditions (55 mM potassium chloride) decreased cell death by 33%, and an RNA synthesis inhibitor (actinomycin D) by 26% (all have been shown to prevent apoptosis). Pretreatment with antisense c‐myc had no effect. Fluorescent staining with propidium iodide (a DNA marker) demonstrated chromatin condensation and agarose gel electrophoresis demonstrated a DNA “ladder.” These data suggest that apoptosis may play a role in hypoxic cell death and that in this paradigm, expression of c‐myc is unnecessary. This would suggest a new approach to our understanding of hypoxia and open new strategies to lessen neuronal damage secondary to this process.
Neuropathologic correlates of persistent neurologic deficit in lithium intoxication
Authors: Schneider Julie A. , Mirra Suzanne S.
Published: January 2005

While acute neurological symptoms complicating lithium therapy are well recognized, persistent neurologic dysfunction is uncommon. Regardless of the duration of symptoms, neuropathological correlates of lithium toxicity are few. We report the case of a 67‐year‐old man who developed lithium toxicity manifested by encephalopathy and coma followed by persistent dysarthria and ataxia. Autopsy revealed neuronal loss and gliosis in the cerebellar cortex and dentate nuclei; the cerebellar white matter exhibited prominent spongy change. Persistent cerebellar syndrome may occur with lithium intoxication and should be considered in the differential diagnosis of chronic cerebellar dysfunction.
Elevated mast cell tryptase in cerebrospinal fluid of multiple sclerosis patients
Authors: Rozniecki J. J. , Hauser S. L. , Stein M. , Lincoln R. , Theoharides T. C.
Published: January 2005

Multiple sclerosis (MS) lesions are associated with infiltration of T lymphocytes and macrophages that appear to mediate myelin destruction and gliosis (scarring). Mast cells are located perivascularly in the brain, are juxtaposed to neurons, and have been shown to secrete vasoactive and inflammatory mediators in response to neuropeptides and direct nerve stimulation. Mast cells have been previously identified in MS lesions, are activated by myelin basic protein, and can participate in the regulation of blood–brain barrier permeability, as well as in myelin destruction. Here, cerebrospinal fluid from MS patients and controls with other neurologic diseases was assayed for histamine, its major metabolite methylhistamine, and the specific mast cell marker tryptase. Histamine and methylhistamine were not elevated in MS. However, the mast cell specific proteolytic enzyme tryptase was significantly elevated in MS, suggesting that mast cell activation may be involved in the pathophysiology of this disease.
Tumor necrosis factor‐α messenger RNA expression in patients with relapsing‐remitting multiple sclerosis is associated with disease activity
Authors: Rieckmann P. , Albrecht M. , Kitze B. , Weber T. , Tumani H. , Broocks A. , Lüer W. , Helwig A. , Poser S.
Published: January 2005

We determined the cytokine messenger RNA (mRNA) expression pattern of blood mononuclear cells in 29 patients with relapsing‐remitting multiple sclerosis every 4 weeks over a period of 12 months. During this period 27 relapses occurred in 14 patients (48%). Progression of disease activity as assessed by the occurrence of new lesions on nonenhancing T2‐weighted magnetic resonance images of the head was detected in 12 (48%) of 25 patients. Using a semiquantitative polymerase chain reaction we demonstrated significant increases in tumor necrosis factor‐α mRNA expression in peripheral blood mononuclear cells prior to a relapse. In 24 (85%) of 27 relapses increased tumor necrosis factor‐α mRNA expression preceded clinical symptoms by 4 weeks. A similar pattern was observed for lymphotoxin mRNA expression. At the same time, transforming growth factor‐β and interleukin‐10 mRNA levels declined. Fluctuations in the mRNA expression of tumor necrosis factor‐αwere also observed in 6 patients with stable disease who had active magnetic resonance scans on follow‐up. No correlation of disease activity was observed with interleukin‐1β, ‐4, or ‐6, inferferon gamma or endothelin‐1 mRNA expression. From these data it can be concluded that variations in cytokine mRNA expression in blood mononuclear cells are correlated with disease activity in relapsing‐remitting multiple sclerosis. It may be a valuable parameter to monitor the immunological status of patients in future clinical trials.
Experimental ischemic neuropathy: Salvage with hyperbaric oxygenation
Authors: Kihara Mikihiro , McManis Philip G. , Schmelzer James D. , Kihara Yoriko , Low Phillip A.
Published: January 2005

Hyperbaric oxygenation is effective in augmenting the delivery of oxygen to tissue, but also causes oxidative stress. As part of our focus on improving peripheral nerve salvage from ischemic fiber degeneration, we evaluated whether hyperbaric oxygenation rescues peripheral nerve, rendered ischemic by microembolization, from ischemic fiber degeneration. The supplying arteries of rat sciatic nerve were embolized with microspheres of 14 μm diameter at moderate (2 × 106) and high (5.6 × 106) doses. Rats were randomized to receive hyperbaric oxygenation treatment (2.5 atm 100% oxygen for 2 hours/day for 7 days beginning within 30 minutes of ischemia), or room air. End points for the embolized limb were (1) behavioral scores (0–11 in increasing levels of limb function), (2) nerve action potential of sciatic‐tibial nerve, (3) nerve blood flow, and (4) histological grade as percentage of fibers undergoing ischemic fiber degeneration (0 = <5%; 1 = 5–25%; 2 = 26–50%; 3 = 51–75%; 4 = >76%). Nerve blood flow and nerve action potential were uniformly absent and more than 90% of fibers had degenerated in both control and treatment groups receiving high doses. Control and treatment groups receiving moderate doses were well matched by level of ischemia (8.5 ± 0.3 [N = 18] vs 7.7 ± 0.4 ml/100 gm/min [N = 18], P > 0.05) but were significantly different by behavior score (5.6 ± 0.7 vs 9.2 ± 0.5 [N = 19], p < 0.001), nerve action potential (1.4 ± 1.0 vs 3.9 ± 0.5 [N = 6], p < 0.05), and histology (2.4 ± 0.4 [N = 5] vs 0.8 ± 0.5 [N = 4], p < 0.05). On single teased fiber evaluation, the predominant abnormality was E (axonal degeneration). We conclude that hyperbaric oxygenation will effectively rescue fibers from ischemic fiber degeneration, providing the ischemia is not extreme.
Genetic identity of Fukuyama‐type congenital muscular dystrophy and Walker‐Warburg syndrome
Authors: Toda Tatsushi , Yoshioka Mieko , Nakahori Yutaka , Kanazawa Ichiro , Nakamura Yusuke , Nakagome Yasuo
Published: January 2005

Both Fukuyama‐type congenital muscular dystrophy (FCMD) and Walker‐Warburg syndrome (WWS) are unusual genetic syndromes consisting of congenital muscular dystrophy and complex malformations of the brain and eye. It has been intensively discussed whether FCMD and WWS belong to the same disease entity or not. We analyzed a family in which 3 siblings were affected with either FCMD or WWS by using polymorphic microsatellites flanking the FCMD locus on chromosome 9q31–33. The results suggested that both FCMD and WWS siblings shared the identical combination of mutations on either allele of the FCMD locus. FCMD and WWS could be “genetically” identical.
Topical lidocaine gel relieves postherpetic neuralgia
Authors: Rowbotham Michael C. , Davies Pamela S. , Fields Howard L.
Published: January 2005

Postherpetic neuralgia (PHN) following herpes zoster is a common and disabling neuropathic pain syndrome. In a double‐blind, three‐session study, 5% lidocaine gel or vehicle was applied simultaneously to both the area of pain and to the contralateral mirror‐image unaffected skin. In the local session, lidocaine gel was applied to the painful skin area. In the remote session, lidocaine gel was applied to mirror‐image skin. In the placebo session, vehicle was applied bilaterally. For cranial PHN, gel was applied without occlusion for 8 hours. For limb or torso PHN, gel was applied under occlusion for 24 hours. The 16 subjects with cranial PHN reported pain relief significantly favoring local drug application at 30 minutes, 2, 4, and 8 hours. The 23 subjects with torso or limb PHN reported significantly lower pain intensity with local drug application at 8 hours and both pain relief and reduced pain intensity at 24 hours. Remote lidocaine application to mirror‐image skin was no different from placebo. No systemic adverse effects were reported and blood levels did not exceed 0.6 μg/ml. Topical application of 5% lidocaine gel relieves PHN pain by a direct drug action on painful skin.
Concentrations of amyloid β protein in cerebrospinal fluid of patients with alzheimer's disease
Authors: Van Gool W. A. , Walstra G. J. M. , Bolhuis P. A. , Kuiper M. A. , Wolters E. Ch
Published: January 2005

Deposition of fibrillar amyloid β protein (Aβ) is increased in brains of patients with Alzheimer's disease. Concentrations of Aβ were measured in cerebrospinal fluid with an enzyme‐linked immunosorbent assay in 10 neurological patients free from neurodegenerative disease, 28 patients with Parkinson's disease, and 18 patients with probable Alzheimer's disease. Levels of Aβ in cerebrospinal fluid were not significantly different among these groups. This observation suggests that concentrations of soluble Aβ in cerebrospinal fluid as measured in this study do not reflect the amount of fibrillar, aggregated Aβ in the brain of patients with Alzheimer's disease.
Proton magnetic resonance spectroscopic imaging in patients with frontal lobe epilepsy
Authors: Garcia Paul A. , Laxer Kenneth D. , van der Grond Jeroen , Hugg James W. , Matson Gerald B. , Weiner Michael W.
Published: January 2005

Proton magnetic resonance spectroscopic imaging (1H MRSI) has demonstrated decreased N‐acetyl compounds (NA) in the epileptogenic hippocampus in patients with temporal lobe epilepsy. We studied 8 patients with frontal lobe epilepsy and found mean NA/creatine (Cr) in the epileptogenic frontal lobe decreased by 27% compared with that of the contralateral homologous region (1.81 ±0.36 vs 2.49 ± 0.60, p < 0.008). In every patient, NA/Cr was decreased in the epileptogenic region by at least 5%. These findings suggest that 1H MRSI may be useful in the presurgical evaluation of patients with frontal lobe epilepsy.
JC virus DNA in cerebrospinal fluid of human immunodeficiency virus—infected patients: Predictive value for progressive multifocal leukoencephalopathy
Authors: McGuire Dawn , Barhite Steven , Hollander Harry , Miles Michael
Published: January 2005

Progressive multifocal leukoencephalopathy (PML) is a lytic infection of oligodendrocytes by the human papovavirus JC. Patients with defects in cell‐mediated immunity are at risk for active disease: a usually lethal demyelination of the brain. PML develops in at least 4% of patients with the acquired immunodeficiency syndrome (AIDS). Definitive diagnosis currently requires brain biopsy. Previous attempts to detect JC virus DNA by polymerase chain reaction in cerebrospinal fluid of PML patients, particularly those with human immunodeficiency virus type 1 (HIV ‐ 1) infection, have been of low sensitivity. In the present study, cerebrospinal fluid was assayed by polymerase chain reaction from 26 HIV‐1‐positive patients with PML, 114 HIV‐1‐positive control subjects, and 16 control subjects who were HIVv1 negative or were without risk factors for HIV disease. Polymerase chain reaction conditions were optimized to detect a single copy of viral DNA in 50 μl of cerebrospinal fluid. Specificity of the polymerase chain reaction product was confirmed by size on gel electrophoresis and Southern blot hybridization. JC virus DNA was detected in 24 of 26 samples from patients with PML: 8 of 8 with tissue diagnosis and 16 of 18 with strong clinical and magnetic resonance imaging evidence of PML. Among control subjects, 11 of 130 samples were positive for JC virus: 10 of 114 samples from HIV‐infected patients and one from an HIVvnegative patient with risk factors for PML and an unexplained hemiparesis. Overall senstivity was 92% (24/26); specificity was, at minimum, 92% (119/130). Treatments for PML are now in clinical trials. This assay provides a safe, inexpensive means of establishing the diagnosis of a potentially treatable condition. Furthermore, our data suggest that a subgroup of presymptomatic patients who may be at high risk for PML can be identified. Such patients may be particularly suitable for prophylactic interventions.
Pontine ischemic rarefaction
Authors: Pullicino Patrick , Ostrow Peter , Miller Lucia , Snyder Wendy , Munschauer Frederick
Published: January 2005

To investigate apparently asymptomatic, bilateral symmetrical predominantly pontine hyperintensities (PHI) on magnetic resonance imaging (MRI) scans in elderly patients, we examined the pons histopathologically in two brains of elderly hypertensives with PHI, and in three without PHI, on postmortem MRI scans. We also reviewed 85 serial in vivo MRI scans of patients over 60 and compared scan findings, vascular risk factors, and clinical symptoms between patients with PHI and a control group. A subcortical arteriosclerotic encephalopathy (SAE)‐like pathology was present in the pons in only the two autopsy brains with PHI and corresponded with the location of PHI on the postmortem MRI scans and with the most frequent sites of PHI on in vivo scans. SAE also involved the hemispheric white matter in one of the autopsy brains. Five of 16 (31%) patients with, and 4 of 69 (6%) without, PHI on in vivo MRI scans had marked periventricular hyperintensity (PVHI) compatible with SAE (p = 0.01). We conclude that an SAE‐like pathology may be seen in the pons in elderly hypertensives and this pathology is probably the cause of PHI seen on MRI scans of patients over 60 years of age.
X‐linked vacuolated myopathy: Complement membrane attack complex on surface membrane of injured muscle fibers
Authors: Villanova Marcello , Louboutin Jean Pierre , Chateau Danielle , Eymard Bruno , Sagniez Marguerite , Toméa Fernando M. S. , Fardeau Michel
Published: January 2005

We describe a probable recessive X‐linked myopathy characterized by the presence of vacuolated muscle fibers. Four males and their shared maternal grandfather were affected. Clinical characteristics include juvenile onset, very slow progression, and predominant proximal muscle involvement. The clinical picture and the morphological findings are compared with those previously described in a family. By immunofluorescence, all histologically abnormal muscle fibers, in particular those vacuolated, showed a strong deposition of the complement C5b‐9 membrane attack complex over the whole muscle fiber surface. Weak immunostaining for membrane attack complex was also found in endomysial capillaries and perimysial vessel walls. Muscle fibers showed sarcolemmal immunolabeling with anti–major histocompatibility complex I, which was also present on the margins of many vacuoles. All vacuoles were stained by antidystrophin antibody, which colocalized in most of them with antilaminin immunostaining. Taken together, these results suggest that the deposition of membrane attack complex on the damaged cell surface membrane could be important in the pathogenesis of this muscle disorder, and that the membrane‐bounded vacuoles could be a consequence of sarcolemmal invagination.
Retinotopic and directional defects in motion discrimination in humans with cerebral lesions
Authors: Barton Jason J. S. , Sharpe James A. , Raymond Jane E.
Published: January 2005

We investigated the discrimination of motion direction in peripheral and central vision in 23 patients with unilateral cerebral hemispheric lesions on computed tomography or magnetic resonance imaging. We used random dot cinematograms that determined a percent coherence motion threshold for 16 points in the peripheral field and for four directions separately in central vision. We measured asymmetry of right‐ versus left‐field peripheral discrimination (retinotopic defects) and asymmetry of central discrimination for rightward versus leftward motion (directional defects), compared with normal subjects. Five patients had directional asymmetries of foveal motion perception, all worse for motion toward the side of their lesions. One patient had a bidirectional defect for the perception of horizontal motion. For 3 of these 6, the average of all horizontal and vertical motion discrimination thresholds was also elevated. Two had contralateral retinotopic defects. One of these also had an ipsidirectional foveal defect, but the other did not. The remaining 5 patients with ipsidirectional foveal defects had hemianopias that precluded testing for coexistent retinotopic defects. The lesions of the 6 patients with ipsidirectional defects overlapped in white matter underlying the lateral temporo‐occipital cortex, at the junction of Brodmann areas 19 and 37. In contrast, lesions of patients without directional defects spared this region.
Studies of the coding region of the neuronal glutamate transporter gene in amyotrophic lateral sclerosis
Authors: Meyer T. , Lenk U. , Küther G. , Weindl A. , Speer A. , Ludolph A. C.
Published: January 2005

Studies of the coding region of the neuronal glutamate transporter of 6 amyotrophic lateral sclerosis (ALS) patients and 10 controls show an identical pattern of four reported amino acid variations. No mutations and polymorphisms were detected in 5 sporadic ALS patients and a single patient with the familial form of the disease.
Neuroimaging and cerebrospinal fluid cytology in the diagnosis of leptomeningeal metastasis
Authors: Freilich Ronnie J. , Krol George , Deangelis Lisa M.
Published: January 2005

The diagnosis of leptomeningeal metastasis is often difficult and usually requires the demonstration of malignant cells in the cerebrospinal fluid. Neuroimaging, however, may establish or support the diagnosis in some patients. Radiographic abnormalities consistent with or suggestive of leptomeningeal metastasis include leptomeningeal, subependymal, dural, or cranial nerve enhancement; superficial cerebral lesions; and communicating hydrocephalus. We evaluated 137 cancer patients with clinical symptoms suspicious for leptomeningeal metastasis with neuroimaging or cerebrospinal fluid cytology or both. Neuroimaging findings were abnormal in 70 of 128 tested patients; cytology was performed in 58 of these 70 and the results were positive in 37. Conversely, cytological findings were positive in 53 of 115 tested patients; neuroimaging was performed in 49 of these 53 and the findings were abnormal in 37 (26/29 solid tumors and 11/20 hematological tumors). Of the total series of 137 patients, leptomeningeal metastasis was diagnosed in 77; in 24 (31%) the diagnosis was made on the basis of clinical picture and abnormal neuroimaging alone. Neuroimaging is a valuable tool in the investigation of leptomeningeal metastasis in the cancer population, and the presence of typical clinical features together with appropriate neuroimaging abnormalities is adequate to make the diagnosis of leptomeningeal metastasis even if cerebrospinal fluid cytological results are negative.
Molecular and clinical correlations in spinocerebellar ataxia type 3 and Machado‐Joseph disease
Authors: Matilla Toni , McCall Alanna , Subramony S. H. , Zoghbi Huda Y.
Published: January 2005

The autosomal dominant spinocerebellar ataxias are clinically and genetically a heterogeneous group of neurodegenerative disorders. Genetic studies have classified some of these disorders based on the mapping of their respective genes. The gene for Machado‐Joseph disease, one type of spinocerebellar ataxia, has been mapped to the long arm of chromosome 14q24.3‐ter. The gene for another spinocerebellar ataxia, which is clinically distinct from Machado‐Joseph disease, has been also localized to the same region on 14q and has been named type 3 spinocerebellar ataxia. Recently, expansions of a CAG trinculeotide repeat in a novel gene on chromosome 14q32.1 were shown in 11 patients affected with Machado‐Joseph disease. In this study, we analyzed the DNA samples from 103 individuals representing 42 independent families with dominantly inherited ataxia to determine whether any had the Machado‐Joseph disease mutation. The Machado‐Joseph disease CAG expansion was detected in 5 of these 42 families. Sixteen affected individuals displayed a normal allele containing 14 to 31 CAG repeats and an expanded allele ranging between 66 and 79 CAG repeats. Seven asymptomatic individuals showed an allele ranging between 67 and 80 CAG repeats. Two of these families had a phenotype consistent with Machado‐Joseph disease while the other 3 had clinical features of type 3 spinocerebellar ataxia. These data suggest that a single locus at 14q32.1 is responsible for two forms of spinocerebellar ataxia, spinocerebellar ataxia type 3 and Machado‐Joseph disease, and that this locus may account for approximately 11% of this group of dominantly inherited ataxias.
Oligodendroglial development in human fetal cerebrum
Authors: Rivkin Michael J. , Flax Jonathan , Mozell Robin , Osathanondh Rapin , Volpe Joseph J. , Villa‐Komaroff Lydia
Published: January 2005

We have successfully established mixed glial cell primary cultures prepared from individual fetal human brains (15–18 weeks' gestation in age). Cultures were maintained for as long as 3 months in either 10% fetal calf serum (FCS) or serum‐free chemically defined medium (CDM). By morphological and immunohistochemical criteria, the precursor cell for human oligodendrocytes (O‐2A cell) was identified. This cell exhibited the bipolar morphology and A2B5‐positive (A2B5+) immunoreactivity typical of the O‐2A precursor cell. With time in culture, cells possessing a stellate morphology appeared, some of which stained with the O4 antibody, indicative of cell differentiation in the oligodendroglial lineage. At yet older culture age, arborized cells bearing the O1 (galactocerebroside, GC) immunohistochemical marker and displaying the morphological characteristics typical of more mature oligodendrocytes were found, confirming their oligodendroglial identity. Oligodendroglial differentiation was supported best by CDM rather than FCS. To complement these observations, double immunofluorescent studies were performed on parietal sections from human fetal brains at 20 to 22 weeks of gestation. Bipolar A2B5+, multipolar A2B5+/O4+, and arborized A2B5−/O1+ cells were found, thus confirming the presence of oligodendrocytes in human fetal brain at this stage of prenatal development and consistent with the observations made in cell culture.
A case—control study of apolipoprotein E genotypes in Alzheimer's disease associated with Down's syndrome
Authors: van Gool W. A. , Evenhuis H. M. , van Duijn C. M. ,   Behalf of the Dutch Study Group on Down's Syndrome and Ageing
Published: January 2005

The prevalence of clinical signs and neuropathological findings of Alzheimer's disease (AD) is high in Down's syndrome (DS). In the general population, the apolipoprotein E (ApoE) ϵ4 isoform is an important risk Marchker for AD. We studied the allelic frequencies of ApoE in 26 DS cases fulfilling clinical diagnostic criteria for AD and in 26 DS controls matched for age, sex, and premorbid level of mental retardation. A meta‐analysis of data available in the literature was used for comparison with allele frequencies in other AD and control populations. ApoE type 2, 3, or 4 allele freqeuencies were not significantly different in AD–DS cases and DS controls. The ApoE ϵ4 frequency in DS cases with AD (0.14; CI, 0.06–0.26) was significantly lower than in any other AD population studied so far and it is within the range of nondemented controls from the general population. These findings suggest that ApoE ϵ4 does not significantly affect the pathogenesis of AD in DS patients.
Intracerebral distribution of infectious amyloid protein in spongiform encephalopathy
Authors: Brown P. , Kenney K. , Little B. , Ironside J. , Will R. , Cervenáková L. , Bjork R. J. , San Marchtin R. A. , Safr J. , Roos R. , Haltia M. , Gibbs C. J. , Gajdusek D. C.
Published: January 2005

We studied the regional distribution of infectious amyloid protein by western immunoblots of brain tissue extracts from 37 patients with different forms of spongiform encephalopathy, i.e., 16 sporadic cases, 18 familial cases with a variety of mutations, and 3 iatrogenic cases. In sporadic and familial Creutzfeldt‐Jakob disease, amyloid protein concentrations were usually highest in the frontotemporal regions of the cerebral cortex, whereas iatrogenic Creutzfeldt‐Jakob disease and Gerstmann‐Sträussler‐Scheinker syndrome had as high or higher concentrations in the deep cerebral nuclei and cerebellum. As a group, familial cases had lower amyloid protein concentrations than either sporadic or iatrogenic cases, and fatal familial insomnia patients had the lowest concentrations found in any form of disease. This hierarchy of amyloid protein concentrations corresponds to the experimental transmission rates observed for each form of disease and is consistent with the concept that the protein molecule is an integral component of the infectious agent. Regional amyloid protein pattern analysis of brain and spinal cord may help to distinguish sporadic from environmentally acquired infections, as for example, cases of human disease suspected to have arisen from exposure to sheep or cows infected with scrapie or bovine spongiform encephalopathy.
Enhanced endothelial cell adhesion of human cerebrospinal fluid lymphocytes
Authors: Elfont Robert M. , Griffin Diane E. , Goldstein Gary W.
Published: January 2005

Lymphocyte migration into a tissue depends on properties of both the lymphocyte and the tissue's vascular endothelium. The central nervous system (CNS) possesses a specialized microvasculature and lymphocytes appear to enter the CNS less readily than peripheral tissues. We investigated whether those lymphocytes that interact with the CNS, as represented by cerebrospinal fluid (CSF)‐derived lymphocytes, express adhesive properties distinct from peripheral blood lymphocytes (PBLs). Adhesion of human lymphocytes to bovine endothelial cell monolayers was quantitated microscopically. A greater number of PBLs adhered to aortic than to retinal endothelial cell cultures (e.g., 10.9 ± 0.6 and 4.5 ± 0.2, respectively; p = 0.0023). Preincubation of either endothelial cell type with tumor necrosis factor‐α (TNF‐α) enhanced lymphocyte adhesion. Activation of PBLs with concanavalin A or phytohemagglutinin increased endothelial cell adhesion and the effect was additive with that of TNF‐7alpha;. The number of CSF lymphocytes adhering to endothelial cell cultures (retinal, 67.5 ± 9.0; aortic, 83.7 ± 10.6) was more than 10 times the number of PBLs (retinal, 5.4 ± 0.8; aortic, 8.0 ± 1.3; p < 0.0001). CSF lymphocytes did not, however, adhere preferentially to CNS‐derived endothelial cell cultures. These results suggest that CSF may be enriched, compared with peripheral blood, in its content of surveillance lymphocytes, but that these cells might enter target tissues nonspecifically.
An adenoviral vector can transfer lacZ expression into schwann cells in culture and in sciatic nerve
Authors: Shy Michael E. , Tani Mari , Shi Yi‐Jun , Whyatt Shelley A. , Chbihi Taibi , Scherer Steven S. , Kamholz John
Published: January 2005

Although a number of genetic defects in the P0, peripheral myelin protein‐22, and connexin‐32 genes recently were shown to cause the demyelinating forms of Charcot‐Marie‐Tooth disease, there is yet no effective treatment for these patients. Recent studies showed that replication defective adenoviral vectors can efficiently introduce genes into muscle, brain, lung, and other tissues, suggesting that this vector system may be useful for the treatment of a number of genetic diseases. In this work, we demonstrated that a replication deficient adenovirus expressing the Escherichia coli β‐galactosidase gene (AdCMVLacZ) can introduce genes into Schwann cells, in culture as well as in sciatic nerve. Schwann cells cultured at a multiplicity of infection of 250:1 did not demonstrate cytopathic effects. Following injection of AdCMVLacZ into sciatic nerve of rats, lacZ‐expressing, myelinating Schwann cells could be detected for at least 45 days. These data suggest that in the future, these vectors may be useful both in perturbing Schwann cell gene expression and in designing therapies for the treatment of Charcot‐Marie‐Tooth disease.
Deficiency of brain synaptic dystrophin in human duchenne muscular dystrophy
Authors: Kim Tae‐Wan , Wu Kuo , Black Ira B.
Published: January 2005

Duchenne muscular dystrophy (DMD) is characterized by a defect in dystrophin, a high molecular weight protein that is located predominantly in muscle, but which has been detected in brain. Brain dystrophin has been localized to the synapse, in the postsynaptic density (PSD), and is absent in the mdx mouse, an animal model of human DMD. To define the potential pathogenic role of dystrophin deficiency in cognitive impairment, we examined the protein in human DMD brain. The 427‐kd dystrophin was absent in the PSD from DMD brain, but was normally expressed in the brain from an age‐matched control subject. Our findings indicate that dystrophin is deficient in human DMD cortical synapses and provide a potential pathogenic mechanism for cognitive impairment.
AIDS dementia complex and HIV‐1 brain infection: Clinical‐virological correlations
Authors: Brew Bruce J. , Rosenblum Marc , Cronin Kathy , Price Richard W.
Published: January 2005

To evaluate the presence and distribution of central nervous system infection by human immunodeficiency virus type 1 (HIV‐1), we used immunohistochemical methods to map the HIV‐1 p24 core protein in the brains of 55 autopsied patients with acquired immunodeficiency syndrome (AIDS). In a subset of 40 of these patients who had undergone antemortem neurological evaluation of the AIDS dementia complex (ADC), we analyzed the relation between the severities of the viral infection and clinical dysfunction. Viral antigen was detected in macrophages and cells with morphological and immunohistochemical characteristics of microglia as well as multinucleated cells. The distribution of antigen‐positive cells preferentially involved certain deep brain structures, especially the globus pallidus, other basal ganglia nuclei, and the central white matter. Overall, the presence and frequency of infected cells were highly correlated with the histological findings of multinucleated‐cell encephalitis and in general with the clinical ADC stage. However, infection was often more limited than might be “anticipated” from the severity of patients' clinical dysfunction: Only 61% of patients with at least ADC stage 1 had detectable antigen and of these only approximately 30% of the brain sections were antigen positive. These results suggest a pathogenetic model of ADC where virus‐ or cell‐coded toxins amplify the effect of limited brain infection.
Autosomal dominant rolandic epilepsy and speech dyspraxia: A new syndrome with anticipation
Authors: Scheffer Ingrid E. , Jones Loretta , Pozzebon Marchgaret , Anne Howell R. , Saling Michael M. , Berkovic Samuel F.
Published: January 2005

We describe a family of 9 affected individuals in three generations with nocturnal oro‐facio‐brachial partial seizures, secondarily generalized partial seizures, and centro‐temporal epileptiform discharges, associated with oral and speech dyspraxia and cognitive impairment. The speech disorder was prominent, but differed from that of Landau‐Kleffner syndrome and of epilepsy with continuous spike and wave during slow‐wave sleep. The electroclinical features of this new syndrome of autosomal dominant rolandic epilepsy resemble those of benign rolandic epilepsy, a common inherited epilepsy of childhood. This family shows clinical anticipation of the seizure disorder, the oral and speech dyspraxia, and cognitive dysfunction, suggesting that the genetic mechanism could be expansion of an unstable triplet repeat. Molecular studies on this syndrome, where the inheritance pattern is clear, could also be relevant to identifying a gene for benign rolandic epilepsy where anticipation does not occur and the mode of inheritance is uncertain.