bluuebunny/crossref_metadata_2025 huggingface dataset:
Selective expansion and long‐term culture of human schwann cells from sural nerve biopsies
Authors: Van den Berg Leonard H. , Bär Peter R. , Sodaar Peter , Mollee Isabel , Wokke John J. H. , Logtenberg Ton
Published: January 2005

Fragments of sural nerve biopsy specimens were cultured in the presence of the supernatant of lymphokine‐activated killer cells, resulting in the selective outgrowth of cells with bipolar or tripolar morphology, reminiscent of that of Schwann cells. Immunofluorescent staining with antibodies to the S‐100 protein, the low‐affinity nerve growth factor receptor, and the surface Thy‐1 antigen confirmed that these cultures contained more than 99% Schwann cells and no detectable fibroblasts. The mitotic activity of Schwann cells was measured by bromodeoxyuridine labeling, and was increased when the cells were grown in medium with lymphokine‐activated killer cell supernatant compared with medium without this supernatant. In the presence of lymphokine‐activated killer cell supernatant, Schwann cells could be maintained in continuous culture for a minimum of 8 months.
Acquired neuromyotonia: Evidence for autoantibodies directed against K+channels of peripheral nerves
Authors: Shillito Paul , Molenaar Peter C. , Vincent Angela , Leys Katherine , Zheng Wang , van den Berg Rutgeris J. , Plomp Jaap J. , Van Kempen Gertrudis Th. H. , Chauplannaz Guy , Wintzen Axel R. , van Dijk J. Gert , Newsom‐Davis John
Published: January 2005

Acquired neuromyotonia is characterized by hyperexcitability of motor nerves leading to muscle twitching, cramps, and weakness. The symptoms may improve following plasma exchange, and injection of immunoglobulin G (IgG) from 1 neuromyotonia patient into mice increased the resistance of neuromuscular transmission tod‐tubocurarine. Here we examine nerves and muscle in vitro from mice injected with plasma or purified IgG from 6 neuromyotonia patients or pooled control subjects, and cultured dorsal root ganglion cells after treatment with IgG. Three of the patients had antibodies against human voltage‐gated potassium channels labeled with125I‐α‐dendrotoxin. The quantal release of acetylcholine (quantal content) at end‐plates in diaphragms from mice treated with neuromyotonia IgG preparations was increased by 21% relative to control values (p= 0.0053). With one IgG preparation, the duration of the superficial peroneal nerve compound action currents was increased by 93%. The dorsal root ganglion cells treated with this IgG showed a Marchked increase in repetitive firing of action potentials. All effects were similar to those obtained with aminopyridines. We conclude that at least some patients with acquired neuromyotonia have antibodies directed against aminopyridine‐ or α‐dendrotoxin‐sensitive K+channels in motor and sensory neurons, and they are likely to be implicated in the disease process.
Cortical control of double‐step saccades: Implications for spatial orientation
Authors: Heide W. , Blankenburg M. , Zimmermann E. , Kömpf D.
Published: January 2005

To accurately localize a visual target in space despite eye movement‐induced shifts of its retinal image, the brain must take into account both its retinal location and information about current eye position or at least the preceding eye displacement. We examined this ability with respect to saccadic eye movements by applying “double‐step” stimuli, where the locations of two sequentially flashed target lights have to be fixated by two successive saccades performed after their disappearance. As the 2nd saccade will not start at the spatial location from which the 2nd target was seen, a dissonance arises between its retinal coordinates and the motor coordinates of the required 2nd saccade. Nevertheless, these saccades were performed quite accurately by 32 healthy human adults. To investigate the contribution of the cerebral cortex, we recorded horizontal double‐step saccades in 35 patients with focal unilateral hemispheric lesions. Whereas frontal lesions impaired temporal properties, posterior parietal lesions caused spatial dysmetria or failure of even ipsiversive 2nd saccades following contraversive 1st saccades. This reflects an inability to compensate for retino‐spatial dissonance by using nonretinal information (corollary discharge) about eye displacement associated with a previous saccade into the contralesional hemifield. In conclusion, the parietal cortex is crucial for spatial constancy across saccades.
Effect of intensive diabetes treatment on nerve conduction in the diabetes control and complications trial
Authors:   DCCT Research Group, Box NDIC/DCCT, Bethesda, MD 20892.
Published: January 2005

The Diabetes Control and Complications Trial demonstrated that intensive diabetes therapy effectively delays the onset of clinically apparent neuropathy in patients with insulin‐dependent diabetes mellitus. A total of 1,441 patients with insulin‐dependent diabetes mellitus were randomly assigned to receive intensive treatment or conventional treatment. Of these, 1,290 were randomized at least 41/2 years or more prior to study termination. Nerve conduction studies were performed at baseline and repeated after approximately 5 years for 1,243 of these patients, 96% of the eligible population. After 5 years of treatment, significant nerve conduction differences were observed between the intensive and conventional treatment groups, all favoring better performance (faster sensory and motor conduction velocities and shorter F‐wave latencies) in the intensive treatment group. Moreover, while performance generally deteriorated among the conventionally treated patients, most attributes remained stable or showed modest improvement in the intensively treated group. Treatment group differences were consistent across strata defined by duration of diabetes and the presence of neuropathy at baseline. A nonparametric multivariate test of all ten nerve conduction measures established a strong effect in favor of intensive treatment. These data confirm that the electrophysiological abnormalities associated with diabetic neuropathy are delayed or prevented by intensive diabetes treatment.
Impact of deprenyl and tocopherol treatment on Parkinson's disease in DATATOP subjects not requiring levodopa
Authors:   Parkinson Study Group
Published: January 2005

In the controlled trial Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP), 310 of the 800 enrolled subjects did not reach the primary end point of disability requiring levodopa therapy during 21 ± 4 (mean ± SD) months of observation or need early initiation of deprenyl (selegiline) during a 2‐month withdrawal of experimental treatments. While maintaining the blindness of their original deprenyl and tocopherol treatment assignments, these 310 subjects were administered deprenyl 10 mglday (open label) and were monitored systematically at 1‐ to 3‐month intervals for up to 18 months (12 ±5 mo). During this extended trial, the 189 subjects who had been assigned originally to active deprenyl tended to reach the end point of disability faster than the 121 subjects who had not been assigned originally to deprenyl (hazard ratio, 1.43; 95% CI, 0.98, 2.09; p = 0.065). However, the differential rates of reaching the end point may have been due in part to the more severe baseline impairment of deprenyl‐assigned subjects, who benefited originally from deprenyl but who were more likely to require levodopa during this extended period of observation. Prior treatment with deprenyl did not lead to superior survival with respect to the end point of disability requiring levodopa, suggesting that the initial advantages of deprenyl were not sustained.
Functional imaging of human right hemispheric activation for exploratory movements
Authors: Gitelman Darren R. , Alpert Nathaniel M. , Kosslyn Stephen , Daffner Kirk , Scinto Leonard , Thompson William , Mesulam M‐Marsel
Published: January 2005

We employed positron emission tomography to examine the functional anatomy of the exploratory‐motor aspect of spatial attention. Subjects moved their right hand under nonexploratory (control) versus exploratory (active) conditions. Movement architecture and eye movements were matched across conditions. Statistical parametric maps of the exploratory (active) minus nonexploratory (control) tasks in subjects using their right hand in the right hemispace demonstrated activation in right cingulate, premotor and posterior parietal areas. The net activation of multiple right hemisphere cortical areas ipsilateral to the active limb and hemispace strongly supports the predicted, distributed network anatomy and is consistent with possible right hemispheric dominance for exploratory attentional movements.
Deletions of chromosome 17p11.2 in multifocal neuropathies
Authors: Tyson J. , Malcolm S. , Thomas P. K. , Harding A. E.
Published: January 2005

We investigated 51 patients with multifocal neuropathies for the deletion of chromosome 17p11.2 described in families with hereditary neuropathy with liability to pressure palsies (HNPP). The deletion was detected in 24 patients, including 19 patients from 14 of 15 families in whom HNPP had been considered likely on clinical, neurophysiological, and/or pathological grounds. One patient with a deletion had rather unusual clinical features for HNPP, presenting with a progressive scapuloperoneal syndrome. Overall, 7 (37%) of the 19 index patients with the deletion had no affected relatives, and less than half had evidence of a generalized neuropathy on examination. Peripheral nerve lesions were related to pressure in only 15 (62%) of the patients with the deletion. Nerve conduction studies in 23 of 25 patients and relatives studied showed a fairly uniform pattern of moderate prolongation of distal sensory and motor latencies and slowing of conduction velocities, and variable reduction of sensory or evoked muscle action potential amplitudes. The patients investigated who did not have a deletion of 17p11.2 were heterogeneous and included those with recurrent and/or familial neuralgic amyotrophy, two or more peripheral nerve lesions at common sites of entrapment, or a patchy axonal neuropathy of unknown etiology. In 1 patient a diagnosis of HNPP remains most likely. DNA analysis for the deletion of 17p11.2 is clearly useful in establishing the diagnosis of HNPP, which should be considered regardless of family history or clinical evidence of a generalized neuropathy, and in patients with multifocal neuropathies that do not conform to the classic clinical picture of HNPP.
Use of anti‐neurofilament antibody to identify paired‐helical filaments in inclusion‐body myositis
Authors: Askanas Valerie , Alvarez Renate B. , Mirabella Massimiliano , Engel W. King
Published: January 2005

Paired‐helical filaments (PHFs) are an important diagnostic criterion of the inclusion‐body myositis (IBM) muscle biopsy; but, until now, their presence could be identified only by electronmicroscopy. In this report, we describe an easy immunocytochemical procedure, utilizing commercially available antibody, that enables reliable identification of muscle PHFs by light microscopy. This procedure greatly facilitates diagnosis of IBM.
Levodopa ethylester : A novel rescue therapy for response fluctuations in parkinson's disease
Authors: Djaldetti Ruth , Melamed Eldad
Published: January 2005

In Parkinson's disease (PD), response fluctuations may be due, in part, to pharmacokinetic problems including poor solubility of levodopa and difficulties in its absorption. We administered levodopa ethylester (LDEE), a new highly soluble prodrug of levodopa, by subcutaneous and intramuscular injections to PD patients with response fluctuations, in an open trial to examine its safety and efficacy. Various doses of LDEE (150–400 mg) turned patients “on” with a high success rate (43 of 45 injections). Latencies to “turning on” decreased and duration of on responses increased in a dose‐dependent manner. LDEE, given either subcutaneously or intramuscularly, produced similar beneficial effects and induced rapid and sustained elevations in plasma levodopa levels. The drug was well tolerated with only minor and negligible side effects. Study suggests that subcutaneous and intramuscular administration of LDEE may be advantageous as a novel therapeutic strategy for response fluctuations. It may be particularly useful to rapidly and predictably rescue patients from a variety of disabling “off” situations.
Spinocerebellar ataxia 3 and machado‐joseph disease: Clinical, molecular, and neuropathological features
Authors: Durr Alexandra , Stevanin Giovanni , Cancel Geraldine , Duyckaerts Charles , Abbas Nacer , Didierjean Olivier , Chneiweiss Herve , Benomar Ali , Lyon‐Caen Olivier , Julien Jean , Serdaru Michel , Penet Christiane , Agid Yves , Brice Alexis
Published: January 2005

Patients with spinocerebellar ataxia 3 (SCA3) and Machado‐Joseph disease (MJD) carry an expanded CAG repeat in the MJDl gene. One hundred twenty families of different geographic origin with autosomal dominant cerebellar ataxia (ADCA) type I were tested. Thirty‐four families (126 patients) carried an expanded CAG repeat. The expanded and the normal allele did not overlap and the repeat was unstable during transmission, with variation in the size of the CAG length ranging from −8 to +5 and a mean expansion of 0.86 repeats without differences according to the parental sex. There was a combined effect of the number of CAG repeats of the expanded and normal allele on the age at onset, which accounted for 70% of its variability. The length of the CAG repeat influenced the frequency of clinical signs associated with cerebellar ataxia, such as abnormal tendon reflexes or decreased vibration sense, whereas the interindividual variation of supranuclear ophthalmoplegia, sphincter and swallowing difficulties, and amyotrophy was mostly determined by different disease durations. We compared the clinical profile of 91 SCA3/MJD patients with 51 SCAl and 32 SCA2 patients. There were striking differences between the SCA3/MJD and SCA2 but not with SCAl groups of patients. Despite their clinical similarities, distinct neuropathological features were observed in 2 SCA3/MJD and SCAl patients.
The response to levodopa in parkinson's disease: Imposing pharmacological law and order
Authors: Nutt John G. , Holford Nicholas H. G.
Published: January 2005

The seemingly unpredictable response to levodopa in patients with Parkinson's disease can be understood as an interaction between several distinct pharmacological effects of levodopa. The most important are a short‐duration response with a half‐life of minutes to hours and a long‐duration response with a half‐life of days, superimposed on diurnal motor variation. A negative response characterized by brief worsening before and after the short‐duration response and dyskinesia accentuate the short‐duration response. These various responses are modified by disease progression and long‐term levodopa therapy. Pharmacodynamic modeling of the short‐duration response indicates that with time, the response becomes less graded and small changes in levodopa concentrations can produce big changes in response. In this setting, unpredictability arises from the variation in absorption and distribution of levodopa.
Paramyotonia congenita: The R1448P Na+ channel mutation in adult human skeletal muscle
Authors: Lerche H. , Mitrovic N. , Dubowitz V. , Lehmann‐Horn F.
Published: January 2005

Twitch force and Na+ currents were investigated in a muscle biopsy specimen from a patient with paramyotonia congenita carrying the dominant Arg‐1448‐Pro mutation in the skeletal muscle sodium channel. Cooling of the muscle fibers caused sustained membrane depolarization that resulted in reduced twitch force. Membrane repolarization, produced by a K+ channel opener, partly prevented and antagonized the drop in twitch force. Patch‐clamp recordings on sarcolemmal blebs revealed a distinctly slower Na+ current decay on paramyotonia congenita muscle compared to control muscle. In addition, patches with mutant Na+ channels showed a significantly higher frequency of steady‐state openings, which increased with cooling. Activation of mutant channels was not affected, whereas the steady‐state inactivation curve was shifted by −5 mV and showed less voltage dependence. We suggest that the weakness of cooled muscle can be explained by a combination of the increased steady‐state Na+ current and the left‐shifted inactivation curve.
Intercellular adhesion molecule‐1‐deficient mice are less susceptible to cerebral ischemia‐reperfusion lnjury
Authors: Soriano Sulpicio G. , Lipton Stuart A. , Wang Yanming F. , Xaio Min , Springer Timothy A. , Gutierrez‐Ramos Jose‐Carlos , Hickey Paul R.
Published: January 2005

Neutrophil emigration is mediated by adhesion proteins that are highly expressed on the endothelial surface during inflammatory processes in the brain. Intercellular adhesion molecule‐1 (ICAM‐1) is an inducible adhesion molecule that binds to leukocyte integrins and facilitates neutrophil adhesion and transendothelial migration. To study the role of ICAM‐1 during ischemia and reperfusion in the brain, we analyzed the effect of transient focal cerebral ischemia in ICAM‐1‐deficient mice generated by gene targeting in embryonic stem cells. Transient focal ischemia was induced by occluding the left middle cerebral artery for 3 hours followed by a 21‐ or 45‐hour reperfusion period. When compared with their wild‐type littermates, ICAM‐1‐deficient mice were less susceptible to cerebral injury as demonstrated by a 5.6‐ or 7.8‐fold reduction in infarction volume, respectively. These data support the premise that neutrophil adhesion in ischemic areas may be deleterious and that ICAM‐1 deficiency reduces neurological damage after transient focal cerebral ischemia.
A β‐subunit mutation in the acetylcholine receptor channel gate causes severe slow‐channel syndrome
Authors: Gomez Christopher M. , Maselli Ricardo , Gammack Jason , Lasalde Jose , Tamamizu Shiori , Cornblath David R. , Lehar Mohamed , McNamee Mark , Kuncl Ralph W.
Published: January 2005

Point mutations in the genes encoding the acetylcholine receptor (AChR) subunits have been recognized in some patients with slow‐channel congenital myasthenic syndromes (CMS). Clinical, electrophysiological, and pathological differences between these patients may be due to the distinct effects of individual mutations. We report that a spontaneous mutation of the β subunit that interrupts the leucine ring of the AChR channel gate causes an eightfold increase in channel open time and a severe CMS characterized by severe endplate myopathy and extensive remodeling of the postsynaptic membrane. The pronounced abnormalities in neuromuscular synaptic architecture and function, muscle fiber damage and weakness, resulting from a single point mutation are a dramatic example of a mutation having a dominant gain of function and of hereditary excitotoxicity.
The neuropathology of chromosome 17‐linked dementia
Authors: Sima A. A. F. , Defendini R. , Keohane C. , D'Amato C. , Foster N. L. , Parchi P. , Gambetti P. , Lynch T. , Wilhelmsen K. C.
Published: January 2005

We recently described a family with chromosome 17‐linked dementia, characterized clinically by disinhibition‐dementia parkinsonism‐amyotrophy complex. We report now the neuropathology of 6 affected family members. This included semiquantitative scoring of neuronal loss, gliosis, and spongiosis and immunocytochemical and ultrastructural characterization of neuronal and glial inclusions. The changes consisted of circumscribed neuronal loss, gliosis, and spongiosis of limbic neocortical areas and frontal, temporal, and occipital association areas. Similar changes were present in subcortical nuclei, most severe in the substantia nigra, but also involved the ventral striatum and amygdala. The hippocampus was spared except for degeneration of the afferent perforant tract, secondary to entorhinal nerve cell loss. Hgyrophilic neuronal inclusions, with a characteristic immunocytochemical profile, were found in brainstem nuclei, hypothalamus, and basal ganglia. Ultrastructurally, in 3 patients these inclusions showed hitherto undescribed abnormally assembled filaments. Glial cytoplasmic inclusions were widespread in white matter structures. Immunocytochemistry failed to demonstrate the protease‐resistant prion protein. The pathology appears to be unique, involving various cortical and subcortical structures, and is consistent with the clinical findings of Kliiver‐Bucy‐like syndrome, parkinsonism, and frontal lobe dementia. For this entity we suggest the term “chromosome 17‐ linked dementia”.
Evidence for anticipation and association of deletion size with severity in facioscapulohumerd muscular dystrophy
Authors: Tawil Rabi , Forrester James , Griggs Robert C. , Mendell Jerry , Kissel John , McDermott Michael , King Wendy , Weiffenbach Barbara , Figlewicz Denise ,   The FSH‐DY Group
Published: January 2005

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by marked inter and intrafamilial heterogeneity in its clinical expression. The contribution of genetic factors to this variability is not well characterized. We examined the relationship of phenotype to genotype in a clinically and genetically well‐defined FSHD population. Quantitative isometric myometry (QMT) scores, normalized for age, gender, and height, were used to quantify disease severity. We found a significant (r = 0.92, p < 0.004) correlation between disease severity and the size of the 4q35‐associated deletion. In addition, when relative disease severity of parent‐offspring pairs was compared, the offspring were found to be significantly more severely affected (p = 0.01 1). This generational effect suggests the presence of anticipation in FSHD and raises the possibility of an underlying dynamic mutation.
Multiple mitochondrial DNA deletions in sporadic inclusion body myositis: A study of 56 patients
Authors: Santorelli F. M. , Sciacco M. , Tanji K. , Shanske S. , Vu T. H. , Golzi V. , Griggs R. C. , Mendell J. R. , Hays A. P. , Bertorini T. E. , Pestronk A. , Bonilla E. , Dimauro S.
Published: January 2005

Inclusion body myositis, a chronic inflammatory disorder, is the most common cause of myopathy in adults over the age of 50. Diagnosis is based on clinical features and distinctive morphological findings by both light and electron microscopy. The causes of inclusion body myositis are still unknown. Ultrastructural mitochondrial changes and ragged‐ red fibers are common in patients with sporadic inclusion body myositis, and mutiple mitochondrial DNA (mtDNA) deletions have been reported in 3 such patients, suggesting that mtDNA mutations may have a pathogenetic role. We studied 56 patients with sporadic inclusion body myositis, using a combination of clinical, morphological, biochemical, and molecular genetic analyses to determine the frequency and the distribution of mtDNA deletions. Using the polymerase chain reaction, we found multiple mtDNA deletions in 73% of patients, compared to 40% of normal age‐matched control subjects and 47% of disease control subjects. The presence of deletions correlated with morphological evidence of ragged‐red, cytochrome c oxidase‐negative fibers, and with defects of complexes I and IV of the electron transport chain. Although aging may account for a proportion of mtDNA deletions in patients with sporadic inclusion body myositis and control subjects, mtDNA alterations may be accelerated in sporadic inclusion body myositis.
Familial cerebral cavernous angioma: A gene localized to a 15‐cm interval on chromosome 7q
Authors: Gil‐Nagel A. , Dubovsky J. , Wilcox K. J. , Stewart J. M. , Anderson V. E , Leppik I. E , Orr H. T , Johnson E. W , Weber J. L. , Rich S. S.
Published: January 2005

Cerebral cavernous angiomas are collections of closely clustered vessels without intervening normal brain parenchyma, with microscopic evidence of hemorrhage, frequently multiple; they are best visualized with magnetic resonance imaging. Familial cerebral cavernous angioma occurs as an autosomal dominant disorder, although carriers of the gene are often asymptomatic. Recently, a gene responsible for familial cerebral cavernous angioma in a large Hispanic kindred was mapped to human chromosome 7qll‐22, representing a large segment of DNA containing approximately 33 CM (about 33 million base pairs). This distance did not allow more restricted isolation of the region containing the familial cerebral cavernous angioma gene. In this report, we present a large white kindred with familial cerebral cavernous angioma and confirm the mapping to 7qll‐22, including the genetic markers D7S558/D7S1789 and D7S804. Recombination between several markers in the region suggests that the candidate region is distal to D7S804. Combining our results with those previously published, we suggest that the gene is likely to reside within a 15‐cM region bounded by markers D7S660 and D7S55WD7S1789. These results should assist the further refinement of the candidate region for familial cerebral cavernous angioma and facilitate the search for the gene.
Apolipoprotein E and cognitive change in an elderly population
Authors: Hyman B. T. , Gomez‐Isla T. , Briggs M. , Chung H. , Nichols S. , Kohout F. , Wallace R.
Published: January 2005

The apolipoprotein E (apoE) ε4 allele is overrepresented, and the apoE ε2 allele underrepresented, in Alzheimer's disease. To assess the risk of cognitive impairment in individuals with these genotypes in the general population, we studied a population‐based sample of 1,899 individuals 65 years and older as a follow‐up to the Iowa 65+ Rural Health Study. Multiple regression and logistic regression analyses demonstrated significant effects of apoE ε4 and apoE ε2 in predicting performance on a delayed recall task over a 4‐ to 7‐year period. The magnitude of this effect was, however, fairly modest, with odds ratios for developing impairment of approximately 1.37 (95% confidence interval: 1.007, 1.850; p = 0.045) for apoE ε4 and 0.53 (95% confidence interval: 0.368, 0.777; p = 0.001) for apoE ε2. These effects were more pronounced in women than men. Importantly, 85% of elderly apoE ε4/4 individuals (average age, 81) scored in the unimpaired range on a screening mental status test. Thus, many individuals reach old age without cognitive impairment despite inheritance of one or two apoE ε4 alleles. This suggests that apoE genotyping will have limited utility as a diagnostic or prognostic indicator of cognitive decline in individuals.
Recovery of sympathetic skin responses after digit‐to‐digit replantation and toe‐to‐digit transplantation in humans
Authors: Chu Nai‐Shin
Published: January 2005

Sympathetic skin response was utilized to study recovery of sudomotor function in 8 patients who had digit‐to‐digit replantation and 9 patients who had toe‐to‐digit transplantation. Sympathetic skin responses evoked by median nerve stimulation or magnetic stimulation of the neck were recorded from the tip of the replanted digits or transplanted toes. The contralateral normal fingers served as controls. The mean intervals between surgery and study were 33 and 37 months, respectively, for digit replantation and toe transplantation. In normal subjects, the sympathetic skin responses recorded from the fingertip were abolished by local anesthesia or cooling of the finger, while those recorded from the palm were not affected. Ischemia of the finger only transiently affected the digit sympathetic skin responses. These data indicate that the digit responses were locally generated and mediated by unmyelinated fibers. After digit replantation, the palm and digit sympathetic skin responses were not different between replanted and normal sides. After toe transplantation, palm sympathetic skin responses were normal, but digit ones had prolonged latency and reduced amplitude. The present findings suggest that recovery of sympathetic sudomotor activity can be nearly complete in digit replantation but less satisfactory in toe transplanatation.
Deficient expression in multiple sclerosis of the inhibitory transcription factor SP3 in mononuclear blood cells
Authors: Grekova Maria C. , Robinson Eve D. , Faerber Marc A. , Richert John R. , Katz Paul , McFarland Henry F.
Published: January 2005

To evaluate differential gene expression in multiple sclerosis (MS) patients and control subjects, we used differential display to screen for messenger RNAs that are differentially expressed in peripheral blood mononuclear cells from monozygotic twins who are discordant for MS. We identified a 232‐bp complementary DNA fragment, present only in material from the normal twin, that exhibited 100% identity with the inhibitory transcription factor Sp3. Oligonucleotide primers corresponding to Sp3 messenger RNA sequences amplified complementary DNA of appropriate size from 83% of control subjects but from only 21% of MS patients (p < 0.001). These results suggest that Sp3 gene transcription is suppressed in peripheral blood mononuclear cells from most MS patients and that other genes whose expression is normally suppressed by Sp3 in immune cells may consequently be overexpressed.
Impaired visual word processing in dyslexia revealed with magnetoencephalography
Authors: Salmelin R. , Kiesilä P. , Uutela K. , Service E. , Salonen O.
Published: January 2005

Dyslexia is most often atributed to phonological impairments, manifested in abnormal activation of the left temporal and temporoparietal cortex in response to auditorily presented language and possibly associated with anomalies in the cytoarchitecture and hemispheric symmetry of the plana temporale. The immediate cortical correlate of the severely impaired reading process has, however, remained obscure. Here we report on the distinct time courses of cortical activation in dyslexic and control subjects during passive viewing of single words, tracked with whole‐head magnetoencephalography. A striking difference was found in the left inferior temporo‐occipital region where intracranial recordings have recently identified word‐specific responses within 200 msec after stimulus onset: controls showed a sharp activation at about 180 msec after word presentation, whereas dyslexics failed to activate this area entirely, or showed a slowly increasing late response. Pereception of words as specific units thus seems to be imparied in dyslexics.
Genetic studies in Alzheimer's disease with an NACP/α‐synuclein polymorphism
Authors: Xia Yu , de Silva H. A. Rohan , Rosi Barbara L. , Yamaoka Larry H. , Rimmler Jacqueline B. , Pericak‐Vance Margaret A. , Roses Allen D. , Chen Xiaohua , Masliah Eliezer , Deteresa Richard , Iwai Akihiko , Sundsmo Mary , Thomas Ronald G. , Hofstetter C. Richard , Gregory Ethan , Hansen Lawrence A. , Katzman Robert , Thal Leon J. , Saitoh Tsunao
Published: January 2005

The non‐Aß component of Alzheimer's disease amyloid (NAC) is copurified with amyloid from the brain tissue of Alzheimer's disease victims and is immunohistochemically localized to amyloid fibrils. NAC is a hydrophobic peptide fragment from the NAC precursor protein (NACP/α‐synuclein) that is localized to presynaptic terminals. We used a polymorphic dinucleotide repeat sequence in a genomic clone of NACP for genetic association and linkage studies. Screening of Alzheimer's disease families failed to establish linkage between NACP and Alzheimer's disease. Nevertheless, one of the NACP polymorphisms (NACP allele 2) was shown to have significant association with healthy elderly control individuals with apolipoprotein E risk. This may indicate a possible protective function of the allele.
Genetic variability of the CYP 2D6 gene is not a risk factor for sporadic Parkinson's disease
Authors: Diederich Nico , Hilger Christiane , Hentges Francois , Metz Henri , Goetz Christopher G. , Keipes Marc , Vieregge Peter
Published: January 2005

Genetic studies of the frequencies of mutant alleles for coding cytochrome P‐450 monooxygenase (CYP 2D6) in Parkinson's disease (PD) patients have been inconsistent. We studied the mutants A and B in 80 strictly defined sporadic PD patients divided into young age onset of the disease (<40 years, N = 20), mid age onset (40‐50 years, N = 12), and older age onset (>50 years, N = 48). They were compared with 108 controls from the same geographic area. There were no significant differences in allele or genotype frequencies between PD patients and controls. Future genetic studies in PD should focus on other alleles or other areas of the genome.
Bilateral ptosis and upgaze palsy with right hemispheric lesions
Authors: Averbuch‐Heller Lea , Stahl John S. , Remler Bernd F. , Leigh R. John
Published: January 2005

Bilateral ptosis is reported with unilateral hemispheric lesions, suggesting partial lateralization of the control of the levator palpebrae superioris. There is a tight synkinesis between vertical eye and eyelid movements, but a similar, lateralized control of vertical gaze has not been previously described. We report 3 patients with right hemispheric infarctions, in whom bilateral ptosis was accompanied by impaired upward gaze. We postulate that this laterlization of ocular motor function reflects the special contribution that the nondominant hemisphere makes to attention.
Diagnostic guidelines in central nervous system Whipple's disease
Authors: Louis E. D. , Lynch T. , Kaufmann P. , Fahn S. , Odel J.
Published: January 2005

Many cases of central nervous system (CNS) Whipple's disease are not diagnosed until postmortem. Few reviews of CNS Whipple's disease have delineated the frequencies of abnormalities on neurological examination, cerebrospinal fluid studies, neuroimaging, and intestinal biopsy studies. Guidelines for diagnosis and treatment have not been proposed. In this review we present 3 new cases of CNS Whipple's disease and summarize the literature to determine the frequencies of neurological signs and abnormalities on diagnostic testing. We propose guidelines for diagnostic screening, selection for biopsy, and treatment. Review of the 84 cases of CNS Whipple's disease (81 in the literature, 3 new) revealed that 80% of the patients had systemic signs. Cognitive changes were frequent (71%), and 47% with cognitive changes also had psychiatric signs. Oculomasticatory myorhythmia and oculo‐facial‐skeletal myorhythmia, pathognomic for CNS Whipple's disease, were present in 20% of patients, and were always accompanied by a supranuclear vertical gaze palsy. Tissue biopsy was a sensitive technique; 89% of those who had biopsies had positive biopsy results. Diagnosis and treatment of definite CNS Whipple's disease should be based on the presence of pathognomic signs (oculomasticatory myorhythmia or oculo‐facial‐skeletal myorhythmia) or positive biopsy or polymerase chain reaction results. Possible CNS Whipple's disease should be diagnosed in the setting of unexplained systemic symptoms and neurological signs (supranuclear vertical gaze palsy, rhythmic myoclonus, dementia with psychiatric symptoms, or hypothalamic manifestations). Those with possible CNS Whipple's diseae should undergo small‐bowel biopsy.
Regional and cellular expression of the machado‐joseph disease gene in brains of normal and affected individuals
Authors: Nishiyama K. , Murayama S. , Goto J. , Watanabe M. , Hashida H. , Kanazawa I. , Katayama S. , Nakamura S. , Nomura Y.
Published: January 2005

Machado‐Joseph disease (MJD) is an autosomal dominant disorder characterized pathologicallly by spincoerebellar degeneration. Recently, an expansion of CAG repeat in a gene located at the chromosome 14q32.1 was found to be responsible for the disease. Here, we investigated in situ the expression of the MJD gene (MJD1) in the central nervous system of normal and affected individuals and in rat brains. This gene was expressed in all regions of rat and human normal brains with certain regional variations. MJD1 was transcribed preferentially in neurons, although low levels of MJD1 mRNA were also observed in glial cells. Neurons suspectible to degeneration in MJD expressed MJD1 but not selectively. In the affected brains, the MJD1 mRNA distribution and amount in all the areas examined were similar in patients and controls. In addition, the cellular MJD1 mRNA level correlated neither with clinical severity nor expanded length. Our study showed that the expression levels of trinucleotide repeats in MJD patients and normal controls did not differ, indicating that the pathogenesis of MJD may involve direct toxicity to vulnerable subsets and/or region‐specific cofactors of MJD proteins.
Congenital muscular dystrophy with primary laminin α2 (merosin) deficiency presenting as inflammatory myopathy
Authors: Pegoraro Elena , Cianno Brad Di , Hoffman Eric P. , Mancias Pedro , Swerdlow Steven H. , Raikow Radmila B. , Garcia Carlos , Marks Harold , Crawford Thomas , Carver Virginia
Published: January 2005

Ten laminin α2‐deficient patients were identified by both immunofluorescence and immunoblotting (30% of congenital muscular dystrophy patients tested). Three of the laminin α2‐deficient patients were carrying a diagnonsis of infantile polymyositis prior to immunostaining studies. The clinical features in the 10 merosin‐deficient patients were homogeneous, with severe floppiness at birth, delay in achievement of motor milestones, and magnetic resonance imaging findings of white matter changes with normal intelligence. The 10‐kb laminin α2‐coding sequence was screened for causative mutations by reverse transcriptase‐polymerase chain reaction/single‐stranded confronmational polymorphism analysis in muscle biopys specimens from 5 patients, followed by automatic sequencing of aberrant conformers. Clear loss‐of‐function deletion mutations were identified in both alleles of 1 patient. Muscle histopahtology in this patient showed a striking inflammatory infiltrate of T cells and B cells. REexaminatin of biopys specimens from other laminin α2‐deficient patients showed minor signs of inflammation in each. Based on these findings and the histological and clinical picture suggesting failure of muscle regeneration, a pathogenesis model for this major subswt of congenital muscular dystrophy is proposed. Our data show that muscle histopatholgoy showing a neonatal inflammatory process shold be considered consistent with congenital muscular dystrophy.
Skew deviation following vestibular nerve surgery
Authors: Riordan‐Eva P. , Harcourt J. P. , Faldon M. , Brookes G. B. , Gresty M. A.
Published: January 2005

Eighteen consecutive patients undergoing vestibular nerve surgery underwent pre‐ and postoperative examination of ocular motility. Five patients developed a skew deviation following surgery, with the lower eye on the operated side and an incomitant pattern of deviation in all cases. Three patients experienced diplopia lasting from 1 day to 6 months. The magnitude of skew deviation was increased by head tilt away from the operated side in only 1 case. The development of skew deviation was not determined by preoperative ocular alignment or binocular function, or any particular type or pattern of vestibular disease. There was an association with large changes in ocular torsion and subjective visual vertical, which correlated with lesser degrees of canal paresis to preoperative caloric testing on the operated side. No patient developed a head tilt postoperatively. There is a gradation of responses to surgical vestibular deafferentation in humans, skew deviation only occurring in patients suffering marked changes in subjective visual vertical and ocular torsion.
Mitochondrial function in muscle from elderly athletes
Authors: Brierley Elizabeth J. , Johnson Margaret A. , Bowman Andrew , Ford Gary A. , Subhan Feisel , Reed James W. , James OliverF. W. , Turnbull Douglass M.
Published: January 2005

The extent to which mitochondria are involved in the aging process is conttroversial; much of the reported decline in mitochondrial oxidations in human skeletal muscle may be due to disease and inactivity rather than age. To study true aging, mitochondrial respiratory chain function was studied in 9 young and 12 elderly athletes. No significant deterioration with age was observed. If mitochondria are involved in aging, it must be through a more subtle mechanism than a global decline in respiratory chain activity.
Maternal inheritance in Parkinson's disease
Authors: Wooten G. Frederick , Currie Lillian J. , Bennett James P. , Harrison Madaline B. , Trugman Joel M. , Parker W. Davis
Published: January 2005

To evaluate possible matrilineal factors in the inheritance of Parkinson's disease, we prospectively identified families in which a parent and multiple siblings had Parkinson's disease. In each of the 5 families identified, the affected parent was the mother (p < 0.03). The age at onset in the offspring generation in these 5 families was younger than the age at onset in the parental generation (p < 0.001). In addition, the age at onset in all patients with an affected mother (n = 18) was younger than the age at onset in the affected mothers (p > 0.001). No difference was found between the age at onset in patients with an affected father (n = 14) and the age at onset in the affected fathers. These results are consistent with a role for inherited abnormalities of mitochondrial DNA in the pathogenesis of at least some cases of Parkinson's disease.
Plasma Levels of amyloid β proteins Aβ1–40 and Aβ1–42(43) are elevated in Down's syndrome
Authors: Tokuda Takahiko , Fukushima Tetsuro , Ikeda Shu‐Ich , Sekijima Yoshiki , Shoji Shin'Ichi , Yanagisawa Nobuo , Tamaoka Akira
Published: January 2005

To investigate the effect of the overexpression of β‐amyloid precursor protein (APP) on the production of two major amyloid β protein (Aβ) species, Aβ40 and Aβ42(43), we measured amounts of Aβ1–40 and Aβ1–42(43) in the plasma from 44 patients with Down's syndrome (DS) (age, 19–61 years) and 66 age‐matched normal controls using enzyme‐linked immunosorbent assays. Plasma concentrations of both Aβ1–40 and Aβ1–42(43) were increased about 3‐fold and 2‐fold, respectively, in DS patients compared with normal controls. Especially, the increases in plasma Aβ1–40 in DS Patients were statistically higher than the 1.5‐fold increase one might predict based on the gene dose of APP in DS. These findings showed that both Aβ1–40 and Aβ1–42(43) are increased in plasma in DS patients, the former more than the latter, suggesting that overexpression of APP and/or other genes may have different effects on the production of these two Aβ species in DS.
Pathological correlates of extrapyramidal signs in Alzheimer's disease
Authors: Liu Yan , Stern Yaakov , Chun Michael R. , Jacobs Diane M. , Yau Patricia , Goldman James E.
Published: January 2005

Extrapyramidal signs frequently accompany Alzheimer's disease (AD), but the pathological substrate remains unknown. Clinical and postmortem information from patients with AD, Parkinson's disease, or progressive supranuclear palsy and control subjects seen at a large tertiary medical center between 1989 and 1994 was examined. AD patients who had taken neuroleptics and AD brains that also contained Lewy bodies were excluded. The presence of extrapyramidal signs was determined using the Unified Parkinson's Disease Rating Scale. Sections of basal ganglia, subthalamic nucleus, and substantia nigra were examined for neurofibrillary tangles and neuropil threads and the nigra for neuronal numbers. Patients with AD (with or without extrapyramidal signs) did not show neuronal loss in the nigra compared to control subjects, while both Parkinson's disease and progressive supranuclear palsy brains showed marked depletion. The number of neurofibrillary tangles and neuropil threads was increased in AD (with or without extrapyramidal signs) nigra compared to control tissue, and also in progressive supranuclear palsy nigra, but not Parkinson's disease nigra. The numbers of nigral neurofibrillary tangles and neuropil threads were positively related to extrapyramidal signs in AD. There were no correlations between tangles and threads in the basal ganglia or subthalamic nucleus and extrapyramidal signs in AD. Thus, extrapyramidal signs in AD correlate best with tangle pathology in the nigra and do not require the concomitant presence of Lewy bodies.
Machado‐joseph disease: Clinical, molecular, and metabolic characterization in chinese kindreds
Authors: Soon Bing‐wen , Cheng Chung‐Hui , Liu Ren‐Shyan , Shan Din‐E
Published: January 2005

Machado‐Joseph disease, an autosomal dominant multisystem motor degeneration, has been described mainly in people of Portuguese descent. Our report documents the presence of Machado‐Joseph disease in the Chinese population, based on the specific molecular marker of a CAG repeat array in the 3′ end of the MJD gene. We screened 21 Chinese families with dominant spinocerebellar ataxia. The results showed that Machado‐Joseph disease with CAG expansion accounted for 52% of families with autosomal dominant cerebellar ataxia in this series. The clinical characteristics, besides the well‐documented cerebellar ataxia, dysarthria, nystagmus, corticospinal dysfunctions, a variable degree of facial muscle fasciculation, and proprioceptive loss, included loss of optokinetic nystagmus and autonomic nervous system dysfunction. The CAG repeat number in the MJD gene ranged from 14 to 39 among normal alleles, and from 63 to 81 among MJD alleles. There was a strong inverse correlation (γ = –0.77) between number of CAG repeats and age at symptom onset, accounting for 60% of the variance of age at onset. A strong clinical anticipation of age at onset existed in successive generations. Mild instabilities of expanded CAG repeat numbers during meiotic transmission occurred, with no significant difference according to the gender of the transmitting parent. Finally, brain metabolism in Machado‐Joseph disease, studied with positron emission tomography, was characterized by significant progressive regional hypometabolism in the occipital cortex, as well as the cerebellar hemispheres, vermis, and brainstem.
Expression of the copper‐zinc superoxide dismutase gene in amyotrophic lateral sclerosis
Authors: Nishiyama Kazutoshi , Murayama Shigeo , Kwak Shin , Kanazawa Ichiro
Published: January 2005

The demonstration of a genetic linkage between the copper‐zinc superoxide dismutase (SOD1) gene and familial amyotrophic lateral sclerosis has aroused interest in the role of SOD1 in motoneuronal death. We investigated the expression of the human SOD1 gene at a cellular level in the motoneurons of patints with sporadic amytrophic lateral sclerosis, patients with familial amyotrophic lateral sclerosis, and normal control subjects, using a quantitative insitu hybridization technique. There were no significant differences between the amountf os SOD1 messenger RNA observed in patints wtih sporadic disease, patients with familial disease, and normal control subjects. However, many of the atrophic motoneurons from patients with sporadic or familial disease had significantly lower levls of SOD1 messenger RNA, compared to morphologically intact motoneurons. Moreover, motoneurons in the normal spinal ventral horn and precentral motor cortex exhibited significantly higher levels of SOD1 messenger RNA than did other neurons. Our study indicated that vulnerable neurons in amyotrophic lateral sclerosis exhibit high levels of SOD1 messenger RNA, suggesting a close relatioship between the SOD1 gene and the pathogenesisof amyotrophic lateral sclerosis.