bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular genetic studies of muscle lactate dehydrogenase deficiency in white patients
Authors: Tsujino Seiichi , Shanske Sara , Brownell A. Keith W. , Haller Ronald G. , DiMauro Salvatore 
Published: January 2005

AbstractWe identified two new mutations in 2 white patients with muscle lactate dehydrogenase deficiency. Both patients had exercise intolerance, cramps, and recurrent myoglobinuria. One patient was homozygous for a 2‐bp deletion in exon 5, resulting in a frameshift with premature termination of translation. The second patient was homozygous for a G → A substitution at the 3′ end of exon 2, leading to exon skipping and splicing of exon 1 to exon 3; the aberrantly spliced messenger RNA contains a frameshift, resulting in premature termination of translation. The present report provides evidence of molecular genetic heterogeneity in white patients with muscle lactate dehydrogenase deficiency.
Positron emission tomographic evidence for progression of human MPTP‐induced dopaminergic lesions
Authors: Vingerhoets F. J. G. , Snow B. J. , Tetrud J. W. , Langston J. W. , Schulzer M. , Calne D. B. 
Published: January 2005

AbstractTransient exposure to the toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) produces a syndrome resembling idiopathic parkinsonism (IP). While IP inevitably progresses, the long‐term evolution of MPTP‐parkinsonism is unknown. Fluorodopa positron emission tomography (FD‐PET) is a reliable tool for assessing nigrostriatal dopaminergic function. We performed FD‐PET and clinical assessments on two occasions, 7 years apart, on 10 human subjects exposed to MPTP (age at the first scan, 32.7 ± 6.9 yr [mean ± SD], and on 10 normal individuals age, 53 ± 16 yr). At the time of their first scan, 5 of the subjects exposed to MPTP were clinically normal and 5 had limited signs of parkinsonism; 5 had new clinical deficits 7 years later. In the subjects exposed to MPTP, the PET index [(striatal – occipital)/occipital ratio] dropped by 2.3% per year from 0.70 ± 0.10 (mean ± SD) to 0.58 ± 0.10 (p < 0.001). This was significantly faster than normal aging (p < 0.01) and similar to the progression observed in IP (p = 0.06). The findings suggest that short‐term exposure to MPTP leads to a protracted decline in nigrostriatal dopaminergic function more rapid than occurs in normal aging and similar to IP progression. This is the first evidence that transient exposure to a toxin can cause progressive nigral pathology. At present, the mechanism leading to this progression is unknown. Our findings support the hypothesis that some neurodegenerative disorders may result from transient exposure to an environmental agent.
Amyloid β protein levels in cerebrospinal fluid are elevated in early‐onset Alzheimer's disease
Authors: Nakamura Tamiko , Shoji Mikio , Harigaya Yasuo , Watanabe Mitsunori , Hosoda Kenji , Cheung Tobun T. , Shaffer Lillian M. , Golde Todd E. , Younkin Linda H. , Younkin Steven G. , Hirai Shunsaku 
Published: January 2005

AbstractThe 4‐kd amyloid β prrotein (Aβ) deposited as amyloid in Alzheimer's disease (AD) is produced and released by normal proteolytic processing of the amyloid β protein precursor (βAPP) and is readily detected in cerebrospinal fluid (CSF). Here, we present the levels of Aβ in CSF from a total of 95 subjects, including 38 patients with AD, 14 with early‐onset AD and 24 with late‐onset AD, 25 normal control subjects, and 32 patients with other neurological diseases. The level of Aβ decreased with normal aging, and there was a significant elevation in the level of Aβ in the CSF of early‐onset AD patients (4.14 ±1.37 pmol/ml, p < 0.01). Neither Mini‐Mental State nor Functional Assessment Staging were correlated with the amount of Aβ in the CSF. The Aβ/secreted form of βAPP ration was elevated, but the level of α;1‐antichymotrypsin in the CSF did not correlate with the level of CSF Aβ in early‐onset AD patients. Thus, the level of Aβ in the CSF is elevated in early‐onset AD patients and is suggested to be correlated with the pathology in the brain that characterizes AD.
Pelizaeus‐Merzbacher disease presenting as spinal muscular atrophy: Clinical and molecular studies
Authors: Kaye Edward M. , Doll Rhonda F. , Natowicz Marvin R. , Smith Frances I. 
Published: January 2005

AbstractTwo brothers with profound neonatal hypotonia and hyporeflexia and electrodiagnostic testing consistent with lower motor neuron pathology were found to have a leukodystrophy. Using single‐strand conformational polymorphism analysis and direct sequencing, a mutation within exon 3 of the gene encoding proteolipid protein (Gly73 Arg substitution) was previously detected in both brothers and their mother, establishing the diagnosis of Pelizaeus‐Merzbacher disease. Despite reported sparing of the peripheral nervous system in Pelizaeus‐Merzbacher disease, we suggest that proteolipid protein gene products may influence the development of anterior horn cells or peripheral nervous system myelin and that some individuals affected with this disease may present with clinical and electromyographic features suggestive of neonatal spinal muscular atrophy.
Plasticity of nerve afferents to nigrostriatal neurons in parkinson's disease
Authors: Anglade Philippe , Javoy‐Agid France , AgidM Yves , Hirsch Etienne C. , Tsuji Shigeru 
Published: January 2005

AbstractClinical symptoms in Parkinson's disease do not appear until almost total depletion of dopamine has occurred in the striatum, suggesting the existence of compensatory mechanisms to offset the loss of nigrostriatal dopaminergic neurons. This compensation has been attributed mainly to an increased turnover of dopamine in the remaining dopaminergic neurons. Besides this biochemical phenomenon intrinsic to dopaminergic neurons, we tested whether morphological changes in the nerve afferents to the dopaminergic neurons could participate in these compensatory mechanisms. The afferents to the dendrites of dopaminergic neurons were analyzed ultrastructurally in the substantia nigra of parkinsonian patients and matched controls, using simultaneous histochemical detection of acetylcholine‐like cation and tyrosine hydroxylase. The size of acetycholine‐like cation‐containing terminals in contact with dopaminergic dendrites increased significantly by 38% in the substania nigra of parkinsonian patients; whereas their number per section of dopaminergic dendrite showed an increase of 60%, although not reaching statistical significance. The number of the terminals devoid of acetylcholine‐like cation per section of dopaminergic dendrite decreased significantly by 52% in the substantia nigra of parkinsonian patients. These results suggest (1) a plasticity of excitatory cholinergic neurons targeting nigral dopaminergic neurons and (2) an involution of noncholinergic nerve terminals, mostly originating from inhibitory nigral, pallidal, and striatal GABAergic neurons. The findings provide evidence of a capacity for neuronal plasticity in the elderly human brain, even in the presence of neurodegenerative disorders.
Neurotrophin‐3 reverses experimental cisplatin‐induced peripheral sensory neuropathy
Authors: Gao Wei‐Qiang , Dybdal Noel , Shinsky Natasha , Murnane Amy , Schmelzer Charles , Siegel Mark , Keller Gilbert , Hefti Franz , Phillips Heidi S. , Winslow John W. 
Published: January 2005

AbstractCisplatin, a widely used chemotherapeutic agent, induces a sensory neuropathy with selective loss of vibration sense and proprioception. Here we demonstrate that neurotrophin‐3 (NT‐3), a member of the nerve growth factor family of neurotrophic factors, restored to normal levels the reduced H‐reflex‐related sensory nerve conduction velocity induced by cisplatin in rats. NT‐3 treatment corrected an abnormal cytoplasmic distribution of neurofilament protein in large sensory neurons in dorsal root ganglia and the reduction in the numbers of myelinated fibers in sural nerves caused by cisplatin. The NT‐3–dependent reversal of cisplatin neurotoxicity thus suggests the possible use of NT‐3 in the treatment of peripheral sensory neuropathy.
Apolipoprotein E genotype in patients with alzheimer's disease: Implications for the risk of dementia among relatives
Authors: Farrer Lindsay A. , Adrienne Cupples L. , Van Duijn Cornelia M. , Kurz Alexander , Zimmer Reinhilde , Müller Ulrich , Green Robert C. , Clarke Valerie , Shoffner John , Wallace Douglas C. , Chui Helena , Flanagan Steven D. , Duara Ranjan , George‐Hyslop Peter St. , Auerbach Sanford A. , Volicer Ladislav , Wells John M. , Van Broeckhoven Christine , Growdon John H. , Haines Jonathan L. 
Published: January 2005

AbstractNumerous studies have shown that the risk of Alzheimer's disease (AD) is associated with the dose of the ϵ4 allele of apolipoprotein E (ApoE). However, more than one third of AD patients lack ϵ4 and many persons having ϵ4 survive cognitively intact to old age. We evaluated the lifetime risk of disease in 3,999 first‐degree relatives of 549 probands who met the criteria for probable or definite AD and whose ApoE genotypes were known. ApoE genotypes for relatives were not determined. After age 65 the risk among relatives was proportional, as much as 7 to 10% at age 85, to the number of ϵ4 alleles present in the proband. Risks to relatives of ApoE 2/2 and 2/3 probands were nearly identical at all ages to risks for relatives of ApoE 3/3 probands. The expected proportion of relatives having at least one ϵ4 allele was calculated for each genotype group based on the distribution of parents, sibs, and offspring in the sample. Among relatives in the ApoE 3/3 group, the lifetime risk for AD by age 90 was three times greater than the expected proportion of ϵ4 carriers, suggesting that factors other than ApoE contribute to AD susceptibility. Furthermore, the 44% risk of AD by age 93 among relatives of ApoE 4/4 probands indicates that as many as 50% of people having at least one ϵ4 allele do not develop AD. We also found that among male relatives, risk of AD in the ApoE 3/4 group was similar to that for the ApoE 3/3 group but significantly less than the risk for the ApoE 4/4 group. In contrast, among female relatives the risk for the ApoE 3/4 group was nearly twice that for the ApoE 3/3 group and identical to the risk for the ApoE 4/4 group. These findings are consistent with a sex‐modification effect of the E4 isoform on disease susceptibility.
Striatal dopaminergic denervation in Pallidopyramidal disease demonstrated by positron emission tomography
Authors: Remy Philippe , Hosseini Hassan , Degos Jean‐Denis , Samson Yves , Agid Yves , Warter Jean‐Marie , Vidailhet Marie 
Published: January 2005

AbstractPallidopyramidal disease is a rare disease of young patients in which they manifest a parkinsonian syndrome and pyramidal signs. Pallidopyramidal disease has been attributed to a degeneration of the pallidum and the pyramidal tract, although only 1 patient has been studied postmortem. In the present report, [18F]fluorodopa positron emission tomography in 2 patients showed a marked dopaminergic denervation of the striatum, suggesting that this disease corresponds more to a nigropallidopyramidal dysfunction.
Nerve growth factor protects the neonatal brain against hypoxic–ischemic injury
Authors: Holtzman David M. , Sheldon R. Ann , Jaffe Wyatt , Cheng Yu , Ferriero Donna M. 
Published: January 2005

AbstractNerve growth factor (NGF) has been shown to protect specific neurons that express its signaling receptor, trkA, from a variety of insults. There are some data, in particular in the developing brain, indicating that NGF has neuroprotective actions that extend beyond cells expressing trkA. In this study, we asked whether NGF would protect against brain injury in a neonatal model of hypoxia–ischemia. Postnatal day (PD) 7 rat pups received a right carotid ligation and were then exposed to hypoxic conditions. Prior to carotid ligation and 48 hours later, pups received an intracerebroventricular injection of NGF or denatured NGF dissolved in vehicle or vehicle alone. Brains were then assessed at PD21. In vehicle‐ and denatured NGF‐treated animals, there was significant damage (30–40% volume loss) to both the striatum and cortex ipsilateral to the carotid ligation. In contrast, little damage (10% volume loss) was observed in most NGF‐treated animals. NGF injection studies revealed that NGF stimulated tyrosine phosphorylation of trkA in multiple brain regions. These results show that NGF appears globally neuroprotective to the developing brain in a neonatal model of hypoxia‐ischemia and that there may be novel mechanisms in vivo through which NGF exerts its protective actions.
Relationship between trinucliotide repeats and neuropathological changes in Huntington's diease
Authors: Furtado Sarah , Suchowersky Oksana , Rewcastle N. Barry , Graham Lisa , Klimek Mary Lou , Garber Anthony 
Published: January 2005

AbstractThe discovery of the Huntington's disease (HD) gene has provided the impetus to determine the association between the triplet repeat sequences and clinical manifestations of the disease. The present study is directed toward determining the relationship between the triplet repeat sequences and severity of the neurodegenerative process. Nineteen HD postmortem cases were evaluated for neuropathological changes as well as for the number of trinucleotide repeat sequences, each in a blinded fashion. Each case was assigned a gross grade according to the scale of Vonsattel and colleagues (1985); neuronal counts were then performed on both the caudate and the putamen. For 7 of the postmortem cases, blood had been collected prior to death and was analyzed for the HD gene. For the 12 remaining cases for which blood was unavailable, DNA from the frontal neocortex and striatum was extracted from frozen or formalin‐fixed paraffinized tissue and subsequently analyzed for the HD gene. When correlation was made for age at death, greater numbers of trinucleotide repeats were associated with greater neuronal loss, in both the caudate (r = 0.9641, p < 0.001) and the putamen (r = 0.9652, p < 0.001). When correction was made for disease duration, the correlation was again significant, for both the caudate (r = 0.6396, p < 0.01) and the putamen (r equals; 0.6710, p < 0.001). This suggests that in HD, longer trinucleotide repeat length is associated with a faster rate of deterioration and greater pathological severity. A comparison of trinucleotide repeat length in different brain regions in 4 of the HD postmortem cases associated with greater numbers of repeats consistently demonstrated fewer repeats in the cerebellum than in the frontal cortex, striatum or blood.
Developmental dyslexia: A motor‐articulatory feedback hypothesis
Authors: Heilman Kenneth M. , Voeller Kytja , Alexander Ann W. 
Published: January 2005

AbstractReading is mediated by parallel and widely distributed modular systems. There are, therefore, multiple loci in these systems where dysfunction may lead to developmental dyslexia. However, most normal children learn to read using the alphabetic system. Learning to use this system requires awareness that words are comprised of a series of speech sounds (phonological awareness) and the knowledge of how to conyert letters (graphemes) into these speech sounds (phonemes). Most dyslexic children have deficient phonological awareness and have difficulty converting graphemes into phonemes. Studies of patients with acquired lesions who are unable to convert graphemes into phonemes, as well as positron emission tomographic studies of normal subjects, suggest that the left inferior frontal lobe is important in phonologic reading. Phonetic gestures are represented in the brain as invariant motor commands that program the articulators. Phono‐ logic reading may activate the left inferior frontal lobe because grapheme‐to‐phoneme conversion requires activation of these motor‐articulatory gestures. Dyslexic children are unaware of the position of their articulators during speech. The inability to associate the position of their articulators with speech sounds may impair the development of phonological awareness and the ability to convert graphemes to phonemes. Unawareness of their articulators may be related to programming or feedback deficits.
Brain thiamine, its phosphate esters, and its metabolizing enzymes in alzheimer's disease
Authors: Mastrogiacomo Frank , Bettendorff Lucien , Grisar Thierry , Kish Stephen J. 
Published: January 2005

AbstractClinical data suggest that high‐dose thiamine (vitamin B,) may have a mild beneficial effect in some patients with Alzheimer's disease (AD). Since this action could be related to a brain thiamine deficiency, we measured directly levels of free (nonphosphorylated) thiamine and its phosphate esters, thiamine monophosphate and thiamine diphosphate (TDP), and activities of three TDP‐metabolizing enzymes (thiamine pyrophosphokinase, thiamine diphosphatase, and thiamine triphosphatase) in autopsied cerebral cortex of 18 patients with AD and 20 matched controls. In the AD group, mean levels of free thiamine and its monophosphate ester were normal, whereas levels of TDP were significantly reduced by 18 to 21% in all three cortical brain areas examined. Activities of the TDP‐metabolizing enzymes were normal in the AD group, suggesting that decreased TDP is not due to altered levels of these enzymes. The TDP decrease could be explained by a cerebral cortical deficiency in AD of ATP, which is needed for TDP synthesis. Although the magnitude of the TDP reduction is slight, a chronic subclinical TDP deficiency could contribute to impaired brain function in AD and might provide the basis for the modest improvement by thiamine in cognitive status of some patients with AD.
Trifunctional enzyme deficiency: Adult presentation of a usually fatal β‐oxidation defect
Authors: Schaefer Jochen , Jackson Sandra , Turnbull Douglass M. , Dick David J. 
Published: January 2005

AbstractDisorders of mitochondrial fatty acid oxidation are a common cause of exercise‐induced rhabdomyolysis and myoglobinuria. We report three adult patients from a family with symptoms of recurrent exercise‐induced rhabdomylysis. This presentation closely resembles adult‐type carnitine palmitoyltransferase II deficiency except that these patients had an associated peripheral neuropathy. Investigation of fatty acid oxidation in the patients revealed a deficiencyof the mitochondrial trifunctional enzyme of β‐oxidation, a newly described fatty acid oxidation disorder with multiorgan involvement and a usually fatal outcome in early childhood. Our cases therefore represent a new phenotype of the disease, which is characterized by recurrent rhabdomyolysis and peripheral neuropathy, but without involvement of other organs, and which is associated with prolonged survival beyond the fourth decade. A low‐fat/high‐carbohydrate diet proved bneficial in one of the patients, drastically reducing the frequency of rhabdomyloytic episodes. Our findings suggest that mitochondrial trifnctional enzyme deficiency should be considered in patients with recurrent eipsodes of myoglobinuria and peripheral neuropathy presenting in later life.
Interferon beta induces interleukin‐10 expression: Relevance to multiple sclerosis
Authors: Rudick Richard A. , Ransohoff Richard M. , Peppler Richard , Medendorp Sharon Vanderbrug , Lehmann Paul , Alam John 
Published: January 2005

AbstractInterferon‐β decreases the relapse rate, relapse severity, progression of neurological disability, and development of new brain lesions observed with brain magnetic resonance imaging in relapsing‐remitting multiple sclerosis patients. The mechanism of action of this effect is presently unknown. This study was based on the hypothesis that immunoregulatory effects of interferon‐β may underlie its demonstrated clinical efficacy. The objective of the study was to determine the effect of interferon‐β‐1a on the expression of interleukin‐10, a cytokine that strongly inhibits cell‐mediated immune responses. Interferon‐β‐1a induced accumulation of interleukin‐10 messenger RNA and protein secretion by cultured peripheral blood mononuclear cells. The observed in vitro effects were similar for healthy control subjects and multiple sclerosis patients. Intramuscular injections of interferon‐β‐1a increased serum levels of interleukin‐10 at 12 and 24 hours following the injection. Greater increases were induced with 12 × 106‐IU than 6 × 106‐IU injections. The effect of interferon‐β‐1a was relatively specific for interleukin‐10, as treatment with interferon‐β‐1a did not result in accumulation of transforming growth factor‐β messenger RNA. Upregulation of interleukin‐10 represents a possible mechanism of action of interferon‐β's therapeutic effect in relapsing‐remitting multiple sclerosis, and has implications for therapy of other autoimmune diseases.
Exercise fuel mobilization in mitochondrial myopathy: A metabolic dilemma
Authors: Vissing John , Galbo Henrik , Haller Ronald G. 
Published: January 2005

AbstractIn mitochondrial myopathy, severely impaired muscle oxidative capacity poses a dilemma for metabolic regulation in exercise. We inquired whether fuel mobilization during exercise in mitochondrial myopathy is adjusted to the reduced capacity to oxidize substrate, or if fuel is mobilized in excess of oxidative capacity. Hormonal and metabolic responses to 20 minutes of cycle exercise were studied in 4 patients with mitochondrial myopathy working at near maximal effort and in 4 healthy matched controls. On 2 separate days, controls were studied at the same absolute (A) workload (9 ± 3 W) and the same relative (R) workload (77 ± 9 W) as performed by the patients. During exercise, average glucose production was higher in patients (28 ± 5 μmol min−1 kg−1) than in controls at both workloads (A, 12 ± 1; R, 18 ± 2 μmol min−1 kg−1). Exercise‐induced increases in plasma glucose, growth hormone, epinephrine, norepinephrine, corticotropin, and lactate, and decreases in plasma insulin and pH were also larger in patients compared with findings in controls at both workloads. In conclusion, mitochondrial myopathies are associated with excessive neuroendocrine responses and mobilization of glucose during exercise. These responses augment ATP synthesis but result in proressive accumulation of nonoxidized substrates. Apparently, substrate mobilization and neuroendocrine responses in exercise are linked to oxidative demand rather than to oxidative capacity in working muscle.
Interferon β‐1b decreases the migration of T lymphocytes in vitro: Effects on matrix metalloproteinase‐9
Authors: Stüve Olaf , Dooley Nora P. , Uhm Joon H. , Antel Jack P. , Francis Gordon S. , Yong Voon Wee , Williams Gary 
Published: January 2005

AbstractIn multiple sclerosis (MS), the influx of activated T lymphocytes into the brain parenchyma leads to the subsequent damage of oligodendrocytes, the cells that produce central nervous system (CNS) myelin. We report here that interferon β‐1b (IFNβ‐1b), a drug shown to be efficacious in the treatment of patients with MS, decreases the in vitro migration of activated T lymphocytes through fibronectin (FN), a major component of the basement membrane that surrounds cerebral endothelium. At 1,000 IU/ml, IFNβ‐1b reduced the migratory rate to that of unactivated T cells. In contrast, IFNγ at 1,000 IU/ml, which caused a similar decrease (25%) in the proliferation rate of T lymphocytesas IFNβ‐1b, did not affect migration. All T‐lymphocyte subsets and natural killer (NK) cells were demonstrated by flow cytometry to be equally affected by IFNβ‐1b treatment. 125I‐Westernblot analyses revealed that IFNβ‐1b treatment resulted in a marked reduction of the ability of T cells to cleave FN. The substrate‐degrading capability of T lymphocytes was shown to be due predominantly to the activity of a 92‐kd matrix metalloproteinase, MMP‐9, whose levels were decreased by IFNβ‐1b. We suggest that the clinical benefits of IFNβ‐1b treatment in MS patients may be in part a result of the ability of this drug to significantly decrease MMP‐9 activity, leading to a reduction of T‐lymphocyte infiltration into the CNS.