Research Literature AUG 2003

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MND INFORMATION UPDATE - JULY 2003

These clinical journal articles are retrieved from a Medline/Premedline search of published Research within the last month. If any of these papers are particularly relevant to your work and you cannot obtain copies from your nearest clinical library please contact the Librarian ( If you are employed by NHS Scotland you may be able to retrieve the full-text of many of them using the NHS Scotland e-library. Contact your nearest clinical library for an Athens password) The MND library also has access to the NHS Scotland e-library.

1.  Yim MB. Yim HS. Chock PB. Stadtman ER.
 Enhanced free radical generation of FALSs-associated Cu,Zn-SOD mutants.
 Neurotoxicity Research.  1(2):91-7, 1999 December. 
Abstract
  Familial amyotrophic lateral sclerosis (FALS) is an inherited disorder of
  motor neurons, which is associated with missense mutations in the Cu,Zn-superoxide dismutase (Cu,Zn-SOD) gene. Mice from the G93A transgenic
  line were reported to develop a syndrome of FALS. The fact that the
  symptoms occurred against a background of normal mouse Cu,Zn-SOD activity  suggests that dominant, gain-of-function mutations in SOD play a role in the pathogenesis of FALS. We investigated the nature of this
  gain-of-function of FALS mutants. We have previously reported that
  Cu,Zn-SOD has the free radical-generating function in addition to normal
  dismutation activity. These two enzymic activities were compared by using
  mutants (G93A and A4V) and the wild-type Cu,Zn-SOD prepared by recombinant method. Our results showed that the wild-type, G93A, and A4V enzymes have identical dismutation activity. However, the free radical-generating function of the G93A and A4V mutants, as measured by the spin trapping and EPR method, is enhanced relative to that of the wild-type enzyme (wild type &lt; G93A &lt; A4V), particularly at lower H(2)O(2) concentrations. This is due to the decrease in the K(m) value for H(2)O(2), wild-type &gt; G93A &gt; A4V. The catalytic activity to generate free radicals is correlated to the clinical severity of the disorder induced by these
  mutant enzymes. Furthermore, we found that intact FALS mutants failed to
  enhance tyrosine nitration. Together our results indicate that the
  amyotrophic lateral sclerosis symptoms are not caused by the reduction of
  Cu,Zn-SOD dismutation activity with the mutant enzymes; rather, it is
  induced in part by enhancement of the free radical-generating function.

2. Kato S. Funakoshi H. Nakamura T. Kato M. Nakano I. Hirano A. Ohama E.
Expression of hepatocyte growth factor and c-Met in the anterior horn
cells of the spinal cord in the patients with amyotrophic lateral
sclerosis (ALS): immunohistochemical studies on sporadic ALS and familial
ALS with superoxide dismutase 1 gene mutation.
Acta Neuropathologica. 106(2):112-20, 2003 August.
Abstract
To clarify the trophic mechanism of residual anterior horn cells affected
by sporadic amyotrophic lateral sclerosis (SALS) and familial ALS (FALS)
with superoxide dismutase 1 (SOD1) mutations, we investigated the
immunohistochemical expression of hepatocyte growth factor (HGF), a novel neurotrophic factor, and its receptor, c-Met. In normal subjects,
immunoreactivity to both anti-HGF and anti-c-Met antibodies was observed
in almost all anterior horn cells, whereas no significant immunoreactivity
was observed in astrocytes and oligodendrocytes. Histologically, the
number of spinal anterior horn cells in ALS patients decreased along with
disease progression. Immunohistochemically, the number of neurons negative for HGF and c-Met increased with ALS disease progression. However, throughout the course of the disease, certain residual anterior horn cells co-expressed both HGF and c-Met with the same, or even stronger intensity in comparison with those of normal subjects, irrespective of the reduction in the number of immunopositive cells. Western blot analysis revealed that c-Met was induced in the spinal cord of a patient with SALS after a clinical course of 2.5 years, whereas the level decreased in a SALS
patient after a clinical course of 11 years 5 months. These results
suggest that the autocrine and/or paracrine trophic support of the
HGF-c-Met system contributes to the attenuation of the degeneration of
residual anterior horn cells in ALS, while disruption of the neuronal
HGF-c-Met system at an advanced disease stage accelerates cellular
degeneration and/or the process of cell death. In SOD1-mutated FALS
patients, Lewy body-like hyaline inclusions (LBHIs) in some residual
anterior horn cells exhibited co-aggregation of both HGF and c-Met,
although the cytoplasmic staining intensity for HGF and c-Met in the
LBHI-bearing neurons was either weak or negative. Such sequestration of
HGF and c-Met in LBHIs may suggest partial disruption of the HGF-c-Met
system, thereby contributing to the acceleration of neuronal degeneration
in FALS patients.

3. Ilecka J. Stelmasiak Z. Solski J. Wawrzycki S. Szpetnar M.
Plasma amino acids concentration in amyotrophic lateral sclerosis
patients.
Amino Acids. 25(1):69-73, 2003 July.
Abstract
Previous investigations showed an impairment of amino acids (AA)
metabolism in amyotrophic lateral sclerosis (ALS). It was hypothesized
that excitatory AA may play an important role in the etiopathogenesis of
this disease. The aim of the study was to determine plasma AA
concentrations in ALS patients, and to examine the relationship between AA and the clinical state of ALS patients, the type of ALS onset and the
duration of the disease. The study involved 20 ALS patients and 30 control
group people. The AA analysis was performed by ion - exchange
chromatography on an automatic AA analyser. The results showed
significantly decreased concentrations of valine, isoleucine, leucine,
tyrosine and aspartate in the plasma of the whole group of ALS patients
compared to the control group, and a significantly decreased concentration
of arginine in the patients with a long duration of ALS compared to the
patients with a short duration. The clinical state of ALS patients
significantly influenced only plasma alanine concentration. Other plasma
AA concentrations were not significantly associated with clinical
parameters of the disease. Our study confirms that metabolic abnormalities
concerning AA exist in ALS patients. However, the normal plasma glutamate concentration observed in this study in the whole group of ALS patients compared to the controls does not exclude that this excitatory AA may play a role in neurodegeneration in ALS.

4. Vercelletto M. Belliard S. Wiertlewski S. Venisse T. Magne C. Duyckaerts C. Damier P.
Clinique Neurologique, HA'pital R. et G. LaA[left point guillemet]nnec,
[Neuropsychological and scintigraphic aspects of frontotemporal dementia
preceding amyotrophic lateral sclerosis].
Revue Neurologique. 159(5 Pt 1):529-42, 2003 May.
Abstract
Between 1993 and 2001, we observed fifteen patients (ten men and five
women, mean age 63 years) with frontotemporal dementia (FTD) which
preceded signs of amyotrophic lateral sclerosis (ALS) which developed 21
months later. Mean disease duration in the fourteen deceased patients was
38 months. FTD associated with ALS is characterized by rapid course,
predominance of disinhibited forms (orbito-basal), presence of aphasia
with neologisms, and semantic memory disorders. Performed in all patients,
single-photon emission computed tomography demonstrated a bifrontal
pattern of low uptake, sometimes associated with low uptake in the
anterior temporal region. In one patient, neuropathology revealed neuron
atrophy and loss in the frontotemporal region, the anterior horns, and the
hypoglossal nucleus. Ubiquitin-positive inclusions were visible in the
dentate gyrus of the hippocampus and in the anterior horns. The
dementia/ALS association is classically described is uncommon. It belongs
to the FTD group since the Lund and Manchester consensus. Approximately 15 p.100 of patient with FTD can be expected to develop ALS. About 250 cases have been reported in the literature, half of them in the Pacific area
where the incidence of ALS is high (55/100,000 inhabitants versus
1/100,000 in the rest of the world). Intermediary forms of FTD, semantic
dementia, and progressive non-fluent aphasia are discussed since several
cases of non-fluent progressive aphasia associated with ALS are reported
in the literature. The links between these two degenerative diseases are
discussed.

5.  Kerr DA. LladA[superscript digit three] J. Shamblott MJ. Maragakis NJ. Irani DN. Crawford TO. Krishnan C. Dike S. Gearhart JD. Rothstein JD.
Human embryonic germ cell derivatives facilitate motor recovery of rats
with diffuse motor neuron injury.
Journal of Neuroscience.  23(12):5131-40, 2003 June 15. 
Abstract
  We have investigated the potential of human pluripotent cells to restore
  function in rats paralyzed with a virus-induced motor neuronopathy. Cells
  derived from embryonic germ cells, termed embryoid body-derived (EBD)
  cells, introduced into the CSF were distributed extensively over the
  rostrocaudal length of the spinal cord and migrated into the spinal cord
  parenchyma in paralyzed, but not uninjured, animals. Some of the
  transplanted human cells expressed the neuroglial progenitor marker
  nestin, whereas others expressed immunohistochemical markers
  characteristic of astrocytes or mature neurons. Rare transplanted cells
  developed immunoreactivity to choline acetyltransferase (ChAT) and sent
  axons into the sciatic nerve as detected by retrograde labeling. Paralyzed
  animals transplanted with EBD cells partially recovered motor function 12
  and 24 weeks after transplantation, whereas control animals remained
  paralyzed. Semi-quantitative analysis revealed that the efficiency of
  neuronal differentiation and extension of neurites could not account for
  the functional recovery. Rather, transplanted EBD cells protected host
  neurons from death and facilitated reafferentation of motor neuron cell
  bodies. In vitro, EBD cells secrete transforming growth factor-alpha
  (TGF-alpha) and brain-derived neurotrophic factor (BDNF). Neutralizing
  antibodies to TGF-alpha and to BDNF abrogated the ability of
  EBD-conditioned media to sustain motor neuron survival in culture, whereas neutralizing antibodies to BDNF eliminated the axonal outgrowth from spinal organotypics observed with direct coculture of EBD cells. We
  conclude that cells derived from human pluripotent stem cells have the
  capacity to restore neurologic function in animals with diffuse motor
  neuron disease via enhancement of host neuron survival and function.

6. Zhang H. Andrekopoulos C. Joseph J. Chandran K. Karoui H. Crow JP. Kalyanaraman B.
Bicarbonate-dependent peroxidase activity of human Cu,Zn-superoxide
dismutase induces covalent aggregation of protein: intermediacy of
tryptophan-derived oxidation products.
Journal of Biological Chemistry. 278(26):24078-89, 2003 June 27.
Abstract
This study addresses the mechanism of covalent aggregation of human
Cu,Zn-superoxide dismutase (hSOD1WT) induced by bicarbonate
(HCO3-)-mediated peroxidase activity. Higher molecular weight species
(apparent dimers and trimers) of hSOD1WT were formed from incubation
mixtures containing hSOD1WT, H2O2, and HCO3-. HCO3--dependent peroxidase activity and covalent aggregation of hSOD1WT were mimicked by UV photolysis of hSOD1-WT in the presence of a [Co(NH3)5CO3]+ complex that generates the carbonate radical anion (CO3.). Human SOD1WT has but one aromatic residue, a tryptophan residue (Trp-32) on the surface of the protein. Substitution of Trp-32 with phenylalanine produced a mutant
(hSOD1W32F) that exhibits HCO3--dependent peroxidase activity similar to wild-type enzyme. However, unlike hSOD1WT, incubations containing
hSOD1W32F,H2O2, and HCO3-did not result in covalent aggregation of SOD1. These findings indicate that Trp-32 is crucial for CO3.-induced covalent aggregation of hSOD1WT. Spin-trapping results revealed the formation of the Trp-32 radical from hSOD1WT, but not from hSOD1W32F. Spin traps also inhibited the covalent aggregation of hSOD1WT. Fluorescence experiments revealed that Trp-32 was further oxidized by CO3., forming kynurenine-type products in the presence of oxygen. Molecular oxygen was needed for HCO3-/H2O2-dependent aggregation of hSOD1WT, implicating a role for a Trp-32-dependent peroxidative reaction in the covalent aggregation of hSOD1WT. Taken together, these results indicate that Trp-32 oxidation is crucial for covalent aggregation of hSOD1. Implications of HCO3--dependent SOD1 peroxidase activity in amyotrophic lateral sclerosis disease are discussed.

7. Al-Chalabi A. Scheffler MD. Smith BN. Parton MJ. Cudkowicz ME. Andersen PM. Hayden DL. Hansen VK. Turner MR. Shaw CE. Leigh PN. Brown RH Jr.
Ciliary neurotrophic factor genotype does not influence clinical phenotype
 in amyotrophic lateral sclerosis.
Annals of Neurology.  54(1):130-4, 2003 July. 
Abstract
Ciliary neurotrophic factor (CNTF) maintains survival of adult motor
neurons. Mice lacking the CNTF gene develop mild, progressive motor neuron loss. In the normal human population, 1 to 2.3% are homozygous for a null allele, and reports suggest this mutant is associated with a younger onset of amyotrophic lateral sclerosis (ALS). We have tested this hypothesis in  a study of 400 subjects with ALS and 236 controls. There was no difference in age of onset, clinical presentation, rate of progression, or disease  duration for those with one or two copies of the null allele, excluding
CNTF as a major disease modifier in ALS. Ann Neurol 2003;54:130-134

8. Wilson JM. Khabazian I. Pow DV. Craig UK. Shaw CA.
Decrease in glial glutamate transporter variants and excitatory amino acid
receptor down-regulation in a murine model of ALS-PDC.
Neuromolecular Medicine. 3(2):105-18, 2003.
Abstract
Glutamate transporter proteins appear crucial to controlling levels of
glutamate in the central nervous system (CNS). Abnormal and/or decreased
levels of various transporters have been observed in amyotrophic lateral
sclerosis (ALS) and Alzheimer&apos;s disease (AD) and in other
neurological disorders. We have assessed glutamate transporter
(GLT-1/EAAT2) levels in mice fed washed cycad flour containing a suspected neurotoxin that induces features resembling the Guamanian disorder, ALS-PDC. Down-regulation of glutamate transporter subtypes was detected by immunohistology using antibodies specific for two glial glutamate transporter splice variants (GLT-1alpha and GLT-1B). Immunohistology showed a &quot;patchy&quot; loss of antibody label with the patches centered on blood vessels. Computer densitometry showed significantly decreased GLT-1alpha levels in the spinal cord and primary somatosensory cortex of cycad-fed mice. GLT-1B levels were significantly decreased in the spinal cord, in the motor, somatosensory, and piriform cortices, and in the striatum. Western blots showed a 40% decrease in frontal motor cortex and lumbar spinal cord of cycad-fed mice that appeared to be
phosphorylation-dependent. Receptor-binding assays showed decreased NMDA and AMPA receptor levels and increased GABAA receptor levels in cycad-fed mice cortex. These receptor data are consistent with an increased level of extracellular glutamate. The generalized decrease in GLT-1, decreased excitatory amino acid receptor levels, and increased GABAA receptor levels may reflect an early glutamate-mediated excitotoxicity following cycad exposure. Deciphering the series of events leading to neurodegeneration in cycad-fed animals may provide clues leading to therapeutic approaches to halt the early stages of disease progression.

9. Mattson MP.
Excitotoxic and excitoprotective mechanisms: abundant targets for the
prevention and treatment of neurodegenerative disorders.
Neuromolecular Medicine. 3(2):65-94, 2003.
Abstract
Activation of glutamate receptors can trigger the death of neurons and
some types of glial cells, particularly when the cells are coincidentally
subjected to adverse conditions such as reduced levels of oxygen or
glucose, increased levels of oxidative stress, exposure to toxins or other
pathogenic agents, or a disease-causing genetic mutation. Such excitotoxic
cell death involves excessive calcium influx and release from internal
organelles, oxyradical production, and engagement of programmed cell death (apoptosis) cascades. Apoptotic proteins such as p53, Bax, and Par-4
induce mitochondrial membrane permeability changes resulting in the
release of cytochrome c and the activation of proteases, such as
caspase-3. Events occurring at several subcellular sites, including the
plasma membrane, endoplasmic reticulum, mitochondria and nucleus play
important roles in excitotoxicity. Excitotoxic cascades are initiated in
postsynaptic dendrites and may either cause local degeneration or
plasticity of those synapses, or may propagate the signals to the cell
body resulting in cell death. Cells possess an array of antiexcitotoxic
mechanisms including neurotrophic signaling pathways, intrinsic
stress-response pathways, and survival proteins such as protein
chaperones, calcium-binding proteins, and inhibitor of apoptosis proteins.
Considerable evidence supports roles for excitotoxicity in acute disorders
such as epileptic seizures, stroke and traumatic brain and spinal cord
injury, as well as in chronic age-related disorders such as
Alzheimer&apos;s, Parkinson&apos;s, and Huntington&apos;s disease and
amyotrophic lateral sclerosis. A better understanding of the excitotoxic
process is not only leading to the development of novel therapeutic
approaches for neurodegenerative disorders, but also to unexpected insight
into mechanisms of synaptic plasticity.

10.  Kent RD. Vorperian HK. Kent JF. Duffy JR.
Voice dysfunction in dysarthria: application of the Multi-Dimensional
Voice Program.
Journal of Communication Disorders.  36(4):281-306, 2003 Jul-Aug. 
Abstract
  Phonatory dysfunction is a frequent component of dysarthria and often is a
  primary feature noted in clinical assessment. But the vocal impairment can
  be difficult to assess because (a) the analysis of voice disorder of any
  kind can be challenging, and (b) the voice disorder in dysarthria often
  occurs along with other impairments affecting articulation, resonance, and
  respiration. A promising assessment tool is multi-parameter acoustic
  analysis, such as the Multi-Dimensional Voice Program (MDVP). Part 1 of
  this paper recommends procedures and standards for the acoustic analysis
  of voice, including (1) selection of the sample to be analyzed, (2) signal
  quality requirements, (3) availability of normative data for both genders
  and different ages of speakers, (4) reliability of analysis, and (5)
  correlation of acoustic results with results from other methods of
  analysis. In Part 2, acoustic data are reviewed for the dysarthria
  associated with Parkinson disease (PD), cerebellar disease, amyotrophic
  lateral sclerosis (ALS), traumatic brain injury (TBI), unilateral
  hemispheric stroke, and essential tremor. Tentative profiles of voice
  disorder are described for these conditions. These profiles may serve as
  hypotheses for future research. Although several issues remain to be
  resolved in the acoustic analysis of voice disorder in dysarthria, steps
  can be taken now to promote the reliability, validity, and clinical
  utility of such analyses.(1) As a result of this activity, the participant
  will be able to describe ways in which an optimal multi-dimensional
  analysis of voice can be performed with modern acoustic analysis systems.
  (2) As a result of this activity, the participant will be able to apply
  multi-dimensional acoustic analysis of voice to individuals who have a
  dysarthria-related voice disorder. (3) As a result of this activity, the
  participant will be able to identify major sources of normative data on
  the Multi-Dimensional Voice Program.

11. Aksoy H. Dean G. Elian M. Deng HX. Deng G. Juneja T. Storey E. McKinlay Gardner RJ. Jacob RL. Laing NG. Siddique T.
A4T mutation in the SOD1 gene causing familial amyotrophic lateral
sclerosis.
Neuroepidemiology.  22(4):235-8, 2003 Jul-Aug. 
Abstract
  We report the clinical and laboratory findings in the largest kindred so
  far recorded with familial amyotrophic lateral sclerosis due to an A4T
  mutation in the SOD1 gene. The age of onset ranged from 32 to 60 years,
  with a mean of 46 years. Weakness in the legs was the most frequent early
  symptom and there was a predominance of lower motor neuron signs. The mean time from onset of symptoms to death was 14 months. One man with onset at the age of 37 has shown a slowly developing form and is currently alive 76 months after diagnosis (October 2002), although severely affected. The A4T mutation, with one exception, was of similar severity to the A4V mutation. Copyright 2003 S. Karger AG, Basel

12.  Armon C.
  An evidence-based medicine approach to the evaluation of the role of
  exogenous risk factors in sporadic amyotrophic lateral sclerosis.
  Neuroepidemiology.  22(4):217-28, 2003 Jul-Aug. 
Abstract
  An evidence-based medicine approach was applied to evaluate analytic
  studies of exogenous risk factors for amyotrophic lateral sclerosis (ALS)
  published since 1991. Classification systems for evaluating the literature
  and for drawing conclusions based on the class of available evidence were
  developed, modeled on those used by national societies. Considerations
  regarding the impact on the general public of confirming a role for
  putative risk factors were made explicit. There was evidence in support of
  smoking being a probable (&apos;more likely than not&apos;) risk factor
  for ALS. Smoking has broad public health impact, no redeeming features,
  and is a modifiable risk factor. Evidence supported the conclusion that
  the following were probably not risk factors for ALS: trauma, physical
  activity, residence in rural areas and alcohol consumption. Evidence-based
  medicine methodology does not permit calculation of the magnitude of type
  I or type II errors in drawing these conclusions. New evidence may change
  these conclusions. Recommendations for future research include: draw on
  clinical trial methodology in designing future, confirmatory, case-control
  studies; consider utilizing cohort studies, recognizing the longer
  timelines for these to come to fruition; accord priority to investigating
  putative risk factors with greatest public health impact. Advances in
  study methodology may lead to development of finite research cycles for
  individual putative risk factors for sporadic ALS. Copyright 2003 S.
  Karger AG, Basel

13. Govoni V. Granieri E. Capone J. Manconi M. Casetta I.
Incidence of amyotrophic lateral sclerosis in the local health district of
Ferrara, Italy, 1964-1998.
Neuroepidemiology. 22(4):229-34, 2003 Jul-Aug.
Abstract
One of the epidemiologic characteristics of amyotrophic lateral sclerosis
(ALS) still under discussion is whether the incidence of ALS is increasing
over time. We performed a new investigation expanding our previous study
of ALS in the local health district (LHD) of Ferrara, northern Italy, to
determine whether there have been any changes in the incidence of ALS in
the years 1964-1998. We used a complete enumeration approach by reviewing all possible sources of case collection available in the study area. We selected all patients with definite and probable ALS according to the
World Federation of Neurology criteria. The mean annual crude incidence
rate for 1964-1998 was 1.63 per 100,000 population (95% CI 1.31-2.00). An
increase in incidence from 1.07 to 2.19 per 100,000 population was
observed during the study period. It was greater in women and in
individuals of 70 years old and over. Substantial population ageing
occurred in the LHD of Ferrara during the study period and it was more
prominent in women. This increase in incidence seems to be explained
mainly by the ageing of the population. Moreover, greater precision in
diagnosis of ALS in elderly women, rather than better case ascertainment
of diagnosed patients, may have contributed to the increase. The role of
environmental factors cannot be excluded, but based on the present
findings, it seems to be of little importance. Copyright 2003 S. Karger
AG, Basel

14.  Kang SJ. Sanchez I. Jing N. Yuan J.
 Dissociation between Neurodegeneration and Caspase-11-Mediated Activation of Caspase-1 and Caspase-3 in a Mouse Model of Amyotrophic Lateral  Sclerosis.
Journal of Neuroscience.  23(13):5455-60, 2003 July 2. 
Abstract
  Caspase-11 is a key regulator of caspase-1 and caspase-3 activation under
  pathological conditions. We show here that the expression of caspase-11 is
  upregulated in the spinal cord of superoxide dismutase 1 (SOD1) G93A
  transgenic mice, a mouse model of amyotrophic lateral sclerosis (ALS),
  before the onset of motor dysfunction and remains at the high levels
  throughout the course of disease. The caspase-1- and caspase-3-like
  activities, as well as the level of interleukin-1beta, were significantly
  reduced in the spinal cord of symptomatic caspase-11-/-;SOD1 G93A mice
  compared with that of caspase-11+/-; SOD1 G93A mice. However,
  neurodegeneration, inflammatory responses, and the disease onset and
  progression in SOD1 G93A transgenic mice were not altered by the ablation
  of caspase-11 gene. Thus, although caspases may contribute to certain
  aspects of pathology in this mouse model of ALS, their inhibition is not
  sufficient to prevent neurodegeneration. Our study urges caution when
  considering the inhibition of caspases as a direct therapeutic method for
  the treatment of chronic neurodegenerative diseases.

15.  Andersen J.
Defects in Dynein linked to motor neuron degeneration in mice.
Science of Aging Knowledge Environment.  2003(18):PE10, 2003 May 7. 
Abstract
  Although the causative genetic mutations for a subset of some of the most
  prevalent human motor neurodegenerative diseases have been identified, the
  exact molecular mechanisms behind motor neuron and associated muscular
  loss in these disorders remain an unsolved mystery. In a recent issue of
  Science, two mutagenesis-derived mouse mutants are described that contain
  missense mutations in the gene encoding the cytoplasmic dynein heavy-chain  protein, which is part of a major cellular motor complex involved in
  retrograde axonal transport. These mutations result in progressive motor
  neuron degeneration in heterozygous animals and Lewy-like inclusion bodies  in the homozygotes resembling those that occur in related human
  pathologies such as amyotrophic lateral sclerosis, spinal muscular
  atrophy, and spinal-bulbar muscular atrophy. This discovery opens up the
  exciting possibility that similar mutations may be involved in these human
  disease states.

16. Cox PR. Siddique T. Zoghbi HY.
Genomic organization of Tropomodulins 2 and 4 and unusual intergenic and
intraexonic splicing of YL-1 and Tropomodulin 4.
BMC Genomics. 2(1):7, 2001.
Abstract
BACKGROUND: The tropomodulins (TMODs) are a family of proteins that cap the pointed ends of actin filaments. Four TMODs have been identified in humans, with orthologs in mice. Mutations in actin or actin-binding proteins have been found to cause several human diseases, ranging from hypertrophic cardiomyopathy to immunodefiencies such as Wiskott-Aldrich syndrome. We had previously mapped Tropomodulin 2 (TMOD2) to the genomic region containing the gene for amyotrophic lateral sclerosis 5 (ALS5). We determined the genomic structure of Tmod2 in order to better analyze patient DNA for mutations; we also determined the genomic structure of Tropomodulin 4 (TMOD4). RESULTS: In this study, we determined the genomic structure of TMOD2 and TMOD4 and found the organization of both genes to be similar. Sequence analysis of TMOD2 revealed no mutations or polymorphisms in ALS5 patients or controls. Interestingly, we discovered that another gene, YL-1, intergenically splices into TMOD4. YL-1 encodes six exons, the last of which is 291 bp from a 5&apos; untranslated exon of TMOD4. We used 5&apos; RACE and RT-PCR from TMOD4 to identify several intergenic RACE products. YL-1 was also found to undergo unconventional splicing using non-canonical splice sites within exons (intraexonic splicing) to produce several alternative transcripts. CONCLUSIONS: The genomic structure of TMOD2 and TMOD4 have been delineated. This should facilitate future mutational analysis of these genes. In addition, intergenic splicing at TMOD4/YL-1 was discovered, demonstrating yet another level of complexity of gene organization and regulation.

17. Katsuno M. Adachi H. Doyu M. Minamiyama M. Sang C. Kobayashi Y. Inukai A. Sobue G.
Leuprorelin rescues polyglutamine-dependent phenotypes in a transgenic
mouse model of spinal and bulbar muscular atrophy.
Nature Medicine.  9(6):768-73, 2003 June. 
Abstract
  Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron
  disease that affects males. It is caused by the expansion of a
  polyglutamine (polyQ) tract in androgen receptors. Female carriers are
  usually asymptomatic. No specific treatment has been established. Our
  transgenic mouse model carrying a full-length human androgen receptor with expanded polyQ has considerable gender-related motor impairment. This phenotype was abrogated by castration, which prevented nuclear
  translocation of mutant androgen receptors. We examined the effect of
  androgen-blockade drugs on our mouse model. Leuprorelin, a lutenizing
  hormone-releasing hormone (LHRH) agonist that reduces testosterone release from the testis, rescued motor dysfunction and nuclear accumulation of mutant androgen receptors in male transgenic mice. Moreover, leuprorelin
  treatment reversed the behavioral and histopathological phenotypes that
  were once caused by transient increases in serum testosterone. Flutamide,
  an androgen antagonist promoting nuclear translocation of androgen
  receptors, yielded no therapeutic effect. Leuprorelin thus seems to be a
  promising candidate for the treatment of SBMA.

18.   Mayoralas Alises S. GA[superscript digit three]mez Mendieta MA.
 DA-az Lobato S.
 The progression of amyotrophic lateral sclerosis: respiratory function.
 Archivos de Bronconeumologia.  39(7):327-8, 2003 July.

19.  Kang SJ. Sanchez I. Jing N. Yuan J.
Dissociation between neurodegeneration and caspase-11-mediated activation
of caspase-1 and caspase-3 in a mouse model of amyotrophic lateral
sclerosis.
Journal of Neuroscience.  23(13):5455-60, 2003 July 2. 
Abstract
  Caspase-11 is a key regulator of caspase-1 and caspase-3 activation under
  pathological conditions. We show here that the expression of caspase-11 is
  upregulated in the spinal cord of superoxide dismutase 1 (SOD1) G93A
  transgenic mice, a mouse model of amyotrophic lateral sclerosis (ALS),
  before the onset of motor dysfunction and remains at the high levels
  throughout the course of disease. The caspase-1- and caspase-3-like
  activities, as well as the level of interleukin-1beta, were significantly
  reduced in the spinal cord of symptomatic caspase-11-/-;SOD1 G93A mice
  compared with that of caspase-11+/-; SOD1 G93A mice. However,
  neurodegeneration, inflammatory responses, and the disease onset and
  progression in SOD1 G93A transgenic mice were not altered by the ablation
  of caspase-11 gene. Thus, although caspases may contribute to certain
  aspects of pathology in this mouse model of ALS, their inhibition is not
  sufficient to prevent neurodegeneration. Our study urges caution when
  considering the inhibition of caspases as a direct therapeutic method for
  the treatment of chronic neurodegenerative diseases.

20. Batulan Z. Shinder GA. Minotti S. He BP. Doroudchi MM.
Nalbantoglu J. Strong MJ. Durham HD.
High threshold for induction of the stress response in motor neurons is
associated with failure to activate HSF1.
Journal of Neuroscience. 23(13):5789-98, 2003 July 2.
Abstract
Heat shock protein 70 (Hsp70) protects cultured motor neurons from the
toxic effects of mutations in Cu/Zn-superoxide dismutase (SOD-1), which is
responsible for a familial form of the disease, amyotrophic lateral
sclerosis (ALS). Here, the endogenous heat shock response of motor neurons was investigated to determine whether a high threshold for activating this protective mechanism contributes to their vulnerability to stresses
associated with ALS. When heat shocked, cultured motor neurons failed to
express Hsp70 or transactivate a green fluorescent protein reporter gene
driven by the Hsp70 promoter, although Hsp70 was induced in glial cells.
No increase in Hsp70 occurred in motor neurons after exposure to
excitotoxic glutamate or expression of mutant SOD-1 with a glycine--&gt;
alanine substitution at residue 93 (G93A), nor was Hsp70 increased in
spinal cords of G93A SOD-1 transgenic mice or sporadic or familial ALS
patients. In contrast, strong Hsp70 induction occurred in motor neurons
with expression of a constitutively active form of heat shock
transcription factor (HSF)-1 or when proteasome activity was sufficiently
inhibited to induce accumulation of an alternative transcription factor
HSF2. These results indicate that the high threshold for induction of the
stress response in motor neurons stems from an impaired ability to
activate the main heat shock-stress sensor, HSF1.

21.    Vasconcelos OM. Harter DH. Duffy C. McDonough B. Seidman JG. Seidman CE.  Campbell WW.
 Adult Hallervorden-Spatz syndrome simulating amyotrophic lateral
 sclerosis.
 Muscle & Nerve.  28(1):118-22, 2003 July. 
Abstract
  Hallervorden-Spatz syndrome (HSS) is a neurodegenerative disorder
  characterized by progressive dementia, dystonia, ataxia, and rigidity. An
  atypical form of adult-onset HSS was observed in a 36-year-old man
  presenting with progressive dysarthria. Markedly dysarthric speech and a
  weak atrophic tongue associated with a neurogenic pattern of motor unit
  recruitment in bulbar-supplied muscles on electromyography led to an
  initial impression of bulbar amyotrophic lateral sclerosis (ALS). Lack of
  expected progression of symptoms, however, prompted reinvestigation.
  Repeat brain magnetic resonance imaging demonstrated an
  &quot;eye-of-the-tiger&quot; pattern in the basal ganglia, characteristic
  of HSS, thus requiring genetic studies. DNA analyses of the pantothenate
  kinase gene (PANK2) was conducted and revealed two novel, disease-causing exon 3 missense mutations (Cys231Ser and Tyr251Cys). This case broadens the genotypic and phenotypic spectrum of HSS to include a late-onset syndrome resembling bulbar-onset ALS. Copyright 2003 Wiley Periodicals,  Inc.

22.  PitkA[currency sign]nen A.
Clinical trials in neuroprotection. 23-25 January 2003, Key Biscayne, FL,
Idrugs.  6(3):200-2, 2003 March. 
Abstract
  The basis for this meeting ras the fact that many neurological and
  psychiatric disorders are accompanied by neuronal loss, either acutely or
  chronically. Furthermore, many of the underlying mechanisms of neural
  tissue damage are similar across a wide variety of neurodegenerative
  conditions, including stroke, central nervous system damage secondary to
  cardiac surgery,epilepsy, traumatic brain and spinal cord injury,
  Alzheimer&apos;s disease (AD), Parkinson&apos;s disease (PD), amyotrophic lateral sclerosis (ALS), and even some psychiatric diseases. Despite a large number of animal studies with promising neuroprotective agents, no successful strategy for neuroprotection from any of these conditions has  been successfully demonstrated. The aim of the meeting was to review the  current status of neuroprotection and provide new ideas on how to get  further in research, preclinical and clinical study designs, and perhaps  to generate &apos;out of the box&apos; ideas for future progress by
bringing together experts from different fields of neuroprotection.

23.  Kleopa KA. Zamba-Papanicolaou E. Kyriakides T.
Compressive lumbar myelopathy presenting as segmental motor neuron
disease.
Muscle & Nerve.  28(1):69-73, 2003 July. 
Abstract
  Four patients presented with slowly progressive, bilateral, asymmetric
  weakness and muscle atrophy in the lower extremities, accompanied by
  cramps and fasciculations. Sensory symptoms were insignificant. There was
  no bladder or bowel disturbance. Upper extremities and cranial nerves were
  normal. Weakness was found in lumbosacral myotomes, ranging from L2 to S1. The tendon reflexes varied, and extensor plantar responses were found in
  one case with proximal leg involvement. Nerve conduction studies were
  normal, but segmental chronic and often active denervation confined to the
  weak myotomes in the lower extremities was found in the electromyogram.
  Magnetic resonance imaging showed evidence of spondylotic lumbosacral
  myelopathy associated with disc herniation or osteophytic arthropathy at
  the T11/T12 spinal level in all patients, with increased signal within the
  adjacent cord. This unusual purely motor presentation may result from
  ischemic myelopathy secondary to compression of the anterior spinal
  artery. Copyright 2003 Wiley Periodicals, Inc.

24. Drory VE. Birnbaum M. Peleg L. Goldman B. Korczyn AD.
Hexosaminidase A deficiency is an uncommon cause of a syndrome mimicking amyotrophic lateral sclerosis.
Muscle & Nerve.  28(1):109-12, 2003 July. 
Abstract
  Patients with adult hexosaminidase A (Hex A) deficiency may have clinical
  manifestations similar to amyotrophic lateral sclerosis (ALS). Mutations
  in the hexosaminidase A (HEXA) gene are common in the Jewish Ashkenazi population in Israel. Serum samples of 115 Israeli patients with sporadic ALS were screened for enzymatic activity to detect &quot;enzyme-based carriers.&quot; Fifteen samples with low (&lt; 50%) enzymatic activity
were subjected to mutation analysis, which included the two common
mutations in the HEXA gene among Ashkenazi Jews (+1278TATC and
IVS12+1G--&gt;C). Three &quot;enzymatic carrier&quot; patients of Moroccan origin were checked for two additional mutations (DeltaF304/305 and  Arg170--&gt;Gln), specific to this ethnic group. Two &quot;enzymatic
carrier&quot; patients of Iraqi origin were analyzed for the mutation
Gly250--&gt;Val, specific to this population. The mutation Gly
269--&gt;Ser was screened in carriers of Ashkenazi origin only (n = 10).
The only abnormalities found were heterozygous +1278TATC mutations in two Ashkenazi patients. Their clinical presentation was not different from
  that usually encountered in ALS. The frequency of mutations in the HEXA
  gene among Israeli ALS patients was not higher than in the healthy Israeli
  population. Therefore, Hex A deficiency seems to be a very unlikely cause
  of an ALS-mimic syndrome. Copyright 2003 Wiley Periodicals, Inc.

25.  Dave KR. Prado R. Busto R. Raval AP. Bradley WG. Torbati D.
PA(C)rez-pinzA[superscript digit three]n MA.
Hyperbaric oxygen therapy protects against mitochondrial dysfunction and
delays onset of motor neuron disease in wobbler mice.
Neuroscience.  120(1):113-20, 2003. 
Abstract
 The Wobbler mouse is a model of human motor neuron disease. Recently we
reported the impairment of mitochondrial complex IV in Wobbler mouse CNS,  including motor cortex and spinal cord. The present study was designed to  test the effect of hyperbaric oxygen therapy (HBOT) on (1) mitochondrial  functions in young Wobbler mice, and (2) the onset and progression of the  disease with aging. HBOT was carried out at 2 atmospheres absolute (2 ATA)  oxygen for 1 h/day for 30 days. Control groups consisted of both untreated  Wobbler mice and non-diseased Wobbler mice. The rate of respiration for  complex IV in mitochondria isolated from motor cortex was improved by 40%  (P&lt;0.05) after HBOT. The onset and progression of the disease in the  Wobbler mice was studied using litters of pups from proven heterozygous  breeding pairs, which were treated from birth with 2 ATA HBOT for 1 h/day  6 days a week for the animals&apos; lifetime. A &quot;blinded&quot;  observer examined the onset and progression of the Wobbler phenotype,  including walking capabilities ranging from normal walking to jaw walking  (unable to use forepaws), and the paw condition (from normal to curled  wrists and forelimb fixed to the chest). These data indicate that the  onset of disease in untreated Wobbler mice averaged 36+/-4.3 days in terms  of walking and 40+/-5.7 days in terms of paw condition. HBOT significantly  delayed (P&lt;0.001 for both paw condition and walking) the onset of  disease to 59+/-8.2 days (in terms of walking) and 63+/-7.6 days (in terms  of paw condition). Our data suggest that HBOT significantly ameliorates  mitochondrial dysfunction in the motor cortex and spinal cord and greatly  delays the onset of the disease in an animal model of motor neuron  disease.

26.  de Visser M.
 Motor neuron disease.
 Lancet. Neurology.  2(3):196, 2003 March.

27. Toyohima Y. Piao YS. Tan CF. Morita M. Tanaka M. Oyanagi K. Okamoto K. Takahashi H.
Pathological involvement of the motor neuron system and hippocampal
formation in motor neuron disease-inclusion dementia.
Acta Neuropathologica.  106(1):50-6, 2003 July. 
Abstract
  We report two patients with motor neuron disease-inclusion dementia, with
  special reference to the pathology of the motor neuron system and
  hippocampal formation. The ages of the patients at death were 55 and 62
  years, and the disease durations were 8 and 3 years, respectively. The two
  patients exhibited progressive frontotemporal dementia in the absence of
  motor neuron signs. At autopsy, both cases exhibited frontotemporal lobar
  atrophy with ubiquitin-positive, and tau- and alpha-synuclein-negative
  neuronal inclusions. As expected from the clinical signs, in both cases,
  the upper and lower motor neuron systems were well preserved: no Bunina
  bodies or ubiquitinated inclusions were detected in the motor neurons.
  However, of great importance was that when visualized
  immunohistochemically, the Golgi apparatus and trans-Golgi network often
  exhibited fragmentation in the lower motor neurons (the spinal anterior
  horn cells). In one of the cases, a decrease in the amount of Golgi
  apparatus was also a frequent feature in the upper motor neurons (Betz
  cells in the motor cortex). Moreover, in both cases, circumscribed
  degeneration affecting the CA1-subiculum border zone was evident in the
  hippocampal formation. These findings further strengthen the idea that,
  pathologically, motor neuron disease-inclusion dementia is a rare
  phenotype of amyotrophic lateral sclerosis.

28.  Turner MR. Parton MJ. Shaw CE. Leigh PN. Al-Chalabi A.
 Prolonged survival in motor neuron disease: a descriptive study of the
 King's database 1990-2002.
Journal of Neurology, Neurosurgery & Psychiatry.  74(7):995-7, 2003 July. 
Abstract
  Motor neuron disease is a clinically heterogeneous disease with
  significant differences in survival. The authors have characterised a
  subset of long term survivors seen in a tertiary clinic over a 12 year
  period in terms of clinical variables and demographics, comparing them
  with short term survivors and the remaining population. Thirty of 769
  patients survived more than 10 years, corresponding to 4% of the total
  population. Significantly younger onset of disease symptoms and a
  predominance of pure upper motor neuron signs at presentation
  characterised the long term survivors, but factors traditionally regarded
  as being associated with poor prognosis were also well represented. For a
  few people with motor neuron disease there remains the hope, whatever the
  initial presentation, that their subsequent survival will be longer than
  expected.

29.  Oransky I.
Protective autoimmunity in amyotrophic lateral sclerosis.
Lancet. Neurology.  2(5):267, 2003 May.

30. CzapliA[undefined]ski A. Strobel W. Gobbi C. Steck AJ. Fuhr P. 
Leppert D.
Respiratory failure due to bilateral diaphragm palsy as an early
manifestation of ALS.
Medical Science Monitor.  9(5):CS34-6, 2003 May. 
Abstract
  BACKGROUND: Diaphragm palsy is common in the advanced stages of motor neuron disease and is a primary cause of fatal outcome However,
  respiratory failure is a presenting symptom of motor neuron disease in
  only a small number of patients. CASE REPORT: We present the case of a
  patient with dyspnea and orthopnea followed by subacute respiratory
  failure due to bilateral diaphragm paralysis as the first manifestation of
  amyotrophic lateral sclerosis. CONCLUSIONS: Failure of respiratory muscle function can be the first symptom of motor neuron disease, and may precede clinical manifestation in voluntary motor units in ALS. Therefore, in
  cases of unexplained acute respiratory failure or when respiratory support
  must be continued for no clear reason, a motor neuron disease such as
  amyotrophic lateral sclerosis, which leads to respiratory muscle weakness
  and diaphragm paralysis, should be taken into consideration.

31.   Isacson O.
The production and use of cells as therapeutic agents in neurodegenerative
diseases.
Lancet. Neurology.  2(7):417-24, 2003 July. 
Abstract
  Although progressive neurodegenerative diseases have very different and
  highly specific causes, the dysfunction or loss of a vulnerable group of
  neurons is common to all these disorders and may allow the development of
  similar therapeutic approaches to the treatment of diseases such as
  amyotrophic lateral sclerosis, Parkinson&apos;s disease, and
  Huntington&apos;s disease. When a disease is diagnosed, the first step is
  to instigate protective measures to prevent further degeneration. However,
  most patients are symptom-free until almost all of the vulnerable cells
  have become dysfunctional or have died. There are known molecular
  mechanisms and processes in stem cells and progenitor cells that may be of
  use in the future design and selection of cell-based replacement therapies
  for neurological diseases. This review provides examples of conceptual and
  clinical problems that have been encountered in the development of
  cell-based treatments, and specific criteria for the effective use of
  cells in the future treatment of neurodegenerative diseases.

32.  Butcher J.
Woman with motor-neuron disease denied right to die.
Lancet. Neurology.  1(2):77, 2002 June 1.

33.  Marquard R. Bergida R. MA1/4ller R. Becker I. Wada M. Kurz A.
Dementia accompanying motor neuron disease--7 cases.
Dementia & Geriatric Cognitive Disorders.  16(2):98-102, 2003. 
Abstract
  Seven typical cases of dementia with motor neuron disease (D-MND) are
  reported. Among 1,000 dementia cases, D-MND was more frequent than
  Pick&apos;s disease, Lewy body disease or Creutzfeldt-Jakob disease. D-MND accounted for 30.4% of all forms of frontal lobe dementia (FLD) including FLD and Pick&apos;s disease. These data support that this combined syndrome may be more frequent than previously reported. As the subcortical  neuropathology of D-MND is identical with MND, D-MND is rather the  cortical manifestation of MND than a new disease entity. Copyright 2003 S.  Karger AG, Basel

34. Tortarolo M. Veglianese P. Calvaresi N. Botturi A. Rossi C. Giorgini A. Migheli A. Bendotti C.
Persistent activation of p38 mitogen-activated protein kinase in a mouse
model of familial amyotrophic lateral sclerosis correlates with disease
progression.
Molecular & Cellular Neurosciences. 23(2):180-92, 2003 June.
Abstract
The p38 mitogen-activated protein kinase (p38MAPK) is activated via
phosphorylation in neurones and glial cells by a variety of stimuli
including oxidative stress, excitotoxicity, and inflammatory cytokines.
Activated p38MAPK can in turn induce phosphorylation of cytoskeletal
proteins and activation of cytokines and nitric oxide, thus contributing
to neurodegeneration. We investigated the expression and distribution of
p38MAPK in the spinal cord of transgenic mice expressing a superoxide
dismutase 1 mutation (SOD1G93A), a model of familial amyotrophic lateral
sclerosis (ALS). Accumulation of p38MAPK was found by immunoblotting in the spinal cord of G93A mice during the progression of disease, but no
changes were detected in its mRNA levels. Immunostaining for
phosphorylated p38MAPK in lumbar spinal cord sections of SOD1G93A mice at the presymptomatic and early stages of disease showed an increased
labeling in motor neurones that colocalized with phosphorylated
neurofilaments in vacuolized perikarya and neurites, as detected by
confocal microscopy. As the disease progressed, activated p38MAPK also
accumulated in hypertrophic astrocytes and reactive microglia, as
demonstrated by colocalization with GFAP and CD11b immunostaining,
respectively. These data suggest that activation of p38MAPK in motor
neurons and then in reactive glial cells may contribute, respectively, to
the development and progression of motor neuron pathology in SOD1G93A
mice.

35. Garbuzova-Davis S. Willing AE. Zigova T. Saporta S. Justen EB. Lane JC. Hudson JE. Chen N. Davis CD. Sanberg PR.
Intravenous administration of human umbilical cord blood cells in a mouse
model of amyotrophic lateral sclerosis: distribution, migration, and
differentiation.
Journal of Hematotherapy & Stem Cell Research. 12(3):255-70, 2003 June.
Abstract
Amyotrophic lateral sclerosis (ALS), a multifactorial disease
characterized by diffuse motor neuron degeneration, has proven to be a
difficult target for stem cell therapy. The primary aim of this study was
to determine the long-term effects of intravenous mononuclear human
umbilical cord blood cells on disease progression in a well-defined mouse
model of ALS. In addition, we rigorously examined the distribution of
transplanted cells inside and outside the central nervous system (CNS),
migration of transplanted cells to degenerating areas in the brain and
spinal cord, and their immunophenotype. Human umbilical cord blood (hUCB) cells (10(6)) were delivered intravenously into presymptomatic G93A mice. The major findings in our study were that cord blood transfusion into the systemic circulation of G93A mice delayed disease progression at least 2-3 weeks and increased lifespan of diseased mice. In addition, transplanted cells survived 10-12 weeks after infusion while they entered regions of motor neuron degeneration in the brain and spinal cord. There, the cells migrated into the parenchyma of the brain and spinal cord and expressed neural markers [Nestin, III Beta-Tubulin (TuJ1), and glial fibrillary acidic protein (GFAP)]. Infused cord blood cells were also widely
distributed in peripheral organs, mainly the spleen. Transplanted cells
also were recovered in the peripheral circulation, possibly providing an
additional cell supply. Our results indicate that cord blood may have
therapeutic potential in this noninvasive cell-based treatment of ALS by
providing cell replacement and protection of motor neurons. Replacement of
damaged neurons by progeny of cord blood stem cells is probably not the
only mechanism by which hUCB exert their effect, since low numbers of
cells expressed neural antigens. Most likely, cord blood efficacy is
partially due to neuroprotection by modulation of the autoimmune process.

36. HA[yen]kansson N. Gustavsson P. Johansen C. Floderus B.
Neurodegenerative diseases in welders and other workers exposed to high
levels of magnetic fields.
Epidemiology. 14(4):420-6; discussion 427-8, 2003 July.
Abstract
BACKGROUND: Previous work has suggested an increase in risk of amyotrophic lateral sclerosis (ALS) and Alzheimer&apos;s disease among workers exposed to extremely low-frequency magnetic fields (ELF-MF). We evaluated the relation between ELF-MF from occupational exposures and mortality from neurodegenerative diseases. METHODS: The study was based on a cohort of Swedish engineering industry workers, comprising 537,692 men and 180,529 women. The cohort was matched against the 3 most recent censuses and The Causes of Death Registry. Levels of ELF-MF exposure were obtained by linking occupation according to the censuses to a job exposure matrix. We used 4 levels of exposure and considered both the primary and contributing causes of death, 1985-96. RESULTS: The risk of Alzheimer&apos;s disease as primary or contributing cause of death increased with increasing exposure to ELF-MF among both men and women, with a relative risk (RR) of 4.0 and a 95% confidence interval (95% CI) of 1.4-11.7 in the highest exposure group for both sexes combined. There was a RR of 2.2 (95% CI: 1.0-4.7) for ALS in the highest exposure group with the suggestion of an exposure-response relationship. No evidence of increased risk was seen for Parkinson&apos;s disease or multiple sclerosis. CONCLUSIONS: The findings support previous observations of an increased risk of Alzheimer&apos;s disease and ALS among employees occupationally exposed to ELF-MF. Further studies based on morbidity data are warranted.

37.  Feychting M. Jonsson F. Pedersen NL. Ahlbom A.
Occupational magnetic field exposure and neurodegenerative disease.
Epidemiology.  14(4):413-9; discussion 427-8, 2003 July. 
Abstract
  BACKGROUND: Several studies have identified occupational exposure to
  extremely low-frequency electromagnetic fields (EMF) as a potential risk
  factor for neurodegenerative disease, but the evidence is contradictory
  and inconclusive. METHODS: We conducted a cohort study to explore these associations. We studied all economically active individuals in the
Swedish 1980 census (4,812,646 subjects), and followed them for
  neurodegenerative disease mortality from 1981 through 1995. Information
  about occupation was available for 1970 and 1980. A job-exposure matrix
  based on magnetic field measurements was used to assess EMF exposure.
  RESULTS: An increased risk of Alzheimer&apos;s disease mortality was
  observed among men exposed both in 1970 and 1980 (relative risk = 2.3; 95% confidence interval = 1.6-3.3 for exposure &gt;/=0.5 microT). The
  associations were most pronounced for early-onset Alzheimer&apos;s disease mortality or with follow-up limited to 10 years after the last known
  occupation. Amyotrophic lateral sclerosis was not associated with EMF
  exposure, but the risk estimate with &quot;electrical and electronics
  work&quot; was 1.4 (95% confidence interval = 1.1-1.9). CONCLUSIONS: Our study gives some support to the hypothesis that EMF exposure increases the risk of early-onset Alzheimer&apos;s disease, and suggests that magnetic
  field exposure may represent a late-acting influence in the disease
  process. Electric shock is an unlikely explanation for the increased risk
  of amyotrophic lateral sclerosis in &quot;electrical and electronics
  work&quot; in this study.

38. Shi L. Tang GP. Gao SJ. Ma YX. Liu BH. Li Y. Zeng JM. Ng YK. Leong KW. Wang S.
Repeated intrathecal administration of plasmid DNA complexed with
polyethylene glycol-grafted polyethylenimine led to prolonged transgene
expression in the spinal cord.
Gene Therapy. 10(14):1179-88, 2003 July.
Abstract
Gene delivery into the spinal cord provides a potential approach to the
treatment of spinal cord traumatic injury, amyotrophic lateral sclerosis,
and spinal muscular atrophy. These disorders progress over long periods of
time, necessitating a stable expression of functional genes at therapeutic
levels for months or years. We investigated in this study the feasibility
of achieving prolonged transgene expression in the rat spinal cord through
repeated intrathecal administration of plasmid DNA complexed with 25 kDa
polyethylenimine (PEI) into the lumbar subarachnoid space. With a single
injection, DNA/PEI complexes could provide transgene expression in the
spinal cord 40-fold higher than naked plasmid DNA. The transgene
expression at the initial level persisted for about 5 days, with a
low-level expression being detectable for at least 8 weeks. When repeated
dosing was tested, a 70% attenuation of gene expression was observed
following reinjection at a 2-week interval. This attenuation was
associated with apoptotic cell death and detected even using complexes
containing a noncoding DNA that did not mediate any gene expression. When each component of the complexes, PEI polymer or naked DNA alone, were tested in the first dosing, no reduction was found. Using polyethylene
glycol (PEG)-grafted PEI for DNA complexes, no attenuation of gene
expression was detected after repeated intrathecal injections, even in
those rats receiving three doses, administered 2 weeks apart. Lumbar
puncture is a routine and relatively nontraumatic clinical procedure.
Repeated administration of DNA complexed with PEG-grafted PEI through this less invasive route may prolong the time span of transgene expression when needed, providing a viable strategy for the gene therapy of spinal cord
disorders.

39. Ge WW. Leystra-Lantz C. Wen W. Strong MJ.
Selective Loss of trans-Acting Instability Determinants of Neurofilament
mRNA in Amyotrophic Lateral Sclerosis Spinal Cord.
Journal of Biological Chemistry. 278(29):26558-63, 2003 July 18.
Abstract
Neurofilament (NF) aggregates in motor neurons are a key neuropathological
feature of amyotrophic lateral sclerosis (ALS). We have previously
observed an alteration in the stoichiometry of NF subunit steady state
mRNA levels in ALS spinal motor neurons using in situ hybridization and
proposed that this led to aggregate formation. We have now examined the
levels of NF mRNA in whole tissue homogenates of spinal cord using the
RNase protection assay and real time reverse transcriptase-PCR and
observed significant elevations of NF mRNA level in ALS. Compared with
age-matched control, we observed a greater stability of heterogeneously
expressed NFL mRNA in the presence of ALS spinal cord homogenates. Heat denaturing or protease K digestion of the control homogenates increased the stability of the NFL mRNA to levels observed in ALS homogenate. Increased NFL mRNA stability was also induced by increasing the percentage of ALS homogenate in an admixture of control and ALS homogenates. These observations suggest the presence of trans-acting NFL mRNA-destabilizing elements in control but not in ALS spinal cord homogenates. This was confirmed in gel retardation assays. We also observed that the destabilizing elements interact with the 3&apos;-untranslated region of NFL mRNA. These findings suggest that the trans-acting NFL-destabilizing elements are selectively suppressed in ALS homogenates, resulting in an increased stability and level of NFL mRNA.

40.   Farbu E. Rekand T. Tysnes OB. Aarli JA. Gilhus NE. Vedeler CA.
GM1 antibodies in post-polio syndrome and previous paralytic polio.
Journal of Neuroimmunology.  139(1-2):141-4, 2003 June. 
Abstract
We studied the relationship between post-polio syndrome (PPS) and GM1
antibodies, since such antibodies have been associated with PPS and motor
 neuron disorders. Sera from 144 patients with previous poliomyelitis (105
paralytic, 22 nonparalytic and 17 PPS), 60 with previous Guillain-BarrA(C)
syndrome, 44 with amyotrophic lateral sclerosis (ALS) and 22 healthy blood
donors were analyzed with ELISA for GM1 IgM, IgG and IgA antibodies. GM1 antibodies were present in 14% of the PPS patients, but the prevalence did not differ significantly from that of the other groups. Our study does not
support the hypothesis that GM1 antibodies are involved in the pathogenesis of PPS.

41. Garbuzova-Davis S. Willing AE. Zigova T. Saporta S. Justen EB. Lane Hudson JE. Chen N. Davis CD. Sanberg PR.
Intravenous administration of human umbilical cord blood cells in a mouse
model of amyotrophic lateral sclerosis: distribution, migration, and
differentiation.
Journal of Hematotherapy & Stem Cell Research. 12(3):255-70, 2003 June.
Abstract
Amyotrophic lateral sclerosis (ALS), a multifactorial disease
characterized by diffuse motor neuron degeneration, has proven to be a
difficult target for stem cell therapy. The primary aim of this study was
to determine the long-term effects of intravenous mononuclear human
umbilical cord blood cells on disease progression in a well-defined mouse
model of ALS. In addition, we rigorously examined the distribution of
transplanted cells inside and outside the central nervous system (CNS),
migration of transplanted cells to degenerating areas in the brain and
spinal cord, and their immunophenotype. Human umbilical cord blood (hUCB) cells (10(6)) were delivered intravenously into presymptomatic G93A mice. The major findings in our study were that cord blood transfusion into the systemic circulation of G93A mice delayed disease progression at least 2-3 weeks and increased lifespan of diseased mice. In addition, transplanted cells survived 10-12 weeks after infusion while they entered regions of motor neuron degeneration in the brain and spinal cord. There, the cells migrated into the parenchyma of the brain and spinal cord and expressed neural markers [Nestin, III Beta-Tubulin (TuJ1), and glial fibrillary acidic protein (GFAP)]. Infused cord blood cells were also widely
distributed in peripheral organs, mainly the spleen. Transplanted cells
also were recovered in the peripheral circulation, possibly providing an
additional cell supply. Our results indicate that cord blood may have
therapeutic potential in this noninvasive cell-based treatment of ALS by
providing cell replacement and protection of motor neurons. Replacement of
damaged neurons by progeny of cord blood stem cells is probably not the
only mechanism by which hUCB exert their effect, since low numbers of
cells expressed neural antigens. Most likely, cord blood efficacy is
partially due to neuroprotection by modulation of the autoimmune process.

42. IA[undefined]zecka J.
Prostaglandin E2 is increased in amyotrophic lateral sclerosis patients.
Acta Neurologica Scandinavica. 108(2):125-9, 2003 August.
Abstract
OBJECTIVES -: Oxidative stress and glutamate-mediated excitotoxicity may
play an important role in the etiopathogenesis of amyotrophic lateral
sclerosis (ALS). Prostaglandin E2 (PGE2) activity can be associated with
motor neuron death by inducing free radical formation and glutamate
release from astrocytes. The aim of this study was to determine PGE2
concentration in the serum and cerebrospinal fluid (CSF) of ALS patients.
MATERIAL AND METHODS -: PGE2 concentration was measured by the
enzyme-linked immunosorbent method in the serum and CSF from ALS and
control group patients. RESULTS -: Serum and CSF PGE2 concentration was significantly higher in the whole group of ALS patients compared with the control group patients (P &lt; 0.05). There was no relationship between
PGE2 concentration and clinical parameters of the disease, such as
clinical state, type of ALS onset, and duration of the disease (P &gt;
0.05). A significant correlation between CSF PGE2 concentration and age of control group patients was found (P &lt; 0.05). CONCLUSIONS -: A
significant increase in serum and CSF PGE2 concentration, in ALS patients
observed in this study, indicates that PGE2 may play a role in
neurodegeneration of ALS through oxidative damage of neurons and
glutamate-mediated excitotoxicity. It suggests that inhibition of PGE2
synthesis could prevent motor neuron death. However, serum and CSF PGE2 cannot be a marker of the type of ALS onset, clinical state of patients,
or the duration of the disease.

43. Ajit GT. Corse AM. Coccia CF. Bilak MM. Rothstein JD. Slusher BS.
NAALADase inhibition protects motor neurons against chronic glutamate
toxicity.
European Journal of Pharmacology. 471(3):177-84, 2003 June 27.
Abstract
Glutamate toxicity is implicated in the pathogenesis of amyotrophic
lateral sclerosis. The neuropeptide N-acetyl-aspartyl glutamate (NAAG)
appears to function both as a storage form for glutamate and as a
neuromodulator at glutamatergic synapses. N-acetylated-alpha-linked acidic
dipeptidase (NAALADase; also termed glutamate carboxypeptidase II) yields N-acetyl aspartate (NAA) and glutamate. Prior studies have demonstrated NAALADase upregulation in motor cortex and increased NAAG, NAA and glutamate in cerebrospinal fluid from amyotrophic lateral sclerosis patients. The potent NAALADase inhibitor, 2-(phosphonomethyl)-pentanedioic acid (2-PMPA), was tested in an in vitro model of chronic
glutamate-mediated motor neuron degeneration. Neuroprotection was
determined (1) biochemically, by measuring choline acetyltransferase
activity, (2) immunohistochemically, by counting neurofilament-H-positive
motor neurons and (3) morphologically, with phase contrast microscopy.
2-PMPA (10 microM) had significant neuroprotective effects on motor
neurons as evidenced by increased choline acetyltransferase activity,
decreased motor neuron loss and improved gross morphology. Results suggest that NAALADase inhibitors protect against chronic glutamate-mediated motor neuron degeneration and may prove therapeutic towards amyotrophic lateral sclerosis.

44.  Abalkhail H. Mitchell J. Habgood J. Orrell R. De Belleroche J.
A new familial amyotrophic lateral sclerosis locus on chromosome
16q12.1-16q12.2.
American Journal of Human Genetics.  73(2):383-9, 2003 August. 
Abstract
  Familial amyotrophic lateral sclerosis (FALS) affects 5%-10% of cases of
  amyotrophic lateral sclerosis (ALS) and is inherited as an autosomal
  dominant condition with incomplete penetrance. One-fifth of these cases of
  FALS are associated with mutations in copper/zinc-dependent superoxide
  dismutase (SOD1), but the gene defect in the remaining 80% of familial
  cases is, as yet, unknown. We have carried out a preliminary genome
  screen, using a U.K. resource of families lacking SOD1 mutations, to
  identify other potential disease loci and have identified a putative locus
  on chromosome 16q12.1-q12.2. The region associated with disease was
  further refined in the major family that contributed to this result and
  was localized to D16S409-D16S3032, a 14.74-cM genetic interval that
  corresponds to a physical distance of 6.6 Mb, which coincides with a
  region independently identified by two further research groups in the
  United States and the United Kingdom.

45. Sapp PC. Hosler BA. McKenna-Yasek D. Chin W. Gann A. Genise H. Gorenstein J. Huang M. Sailer W. Scheffler M. Valesky M. Haines JL. Pericak-Vance M.  Siddique T. Horvitz HR. Brown RH Jr.
Identification of two novel Loci for dominantly inherited familial
amyotrophic lateral sclerosis.
American Journal of Human Genetics.  73(2):397-403, 2003 August. 
Abstract
  Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, adult-onset
  motor neuron disease that arises as a dominantly inherited trait in
  approximately 10% of ALS cases. Mutations in one gene, cytosolic Cu/Zn
  superoxide dismutase (SOD1), account for approximately 25% of familial ALS  (FALS) cases. We have performed a genetic linkage screen in 16 pedigrees with FALS with no evidence for mutations in the SOD1 gene and have identified novel ALS loci on chromosomes 16 and 20. The analysis of these genes will delineate pathways implicated as determinants of motor-neuron viability and provide insights into possible therapies for ALS.

46. Nagano I. Murakami T. Shiote M. Manabe Y. Hadano S. Yanagisawa Y. Ikeda  JE. Abe K.
Single-nucleotide polymorphisms in uncoding regions of ALS2 gene of
Japanese patients with autosomal-recessive amyotrophic lateral sclerosis.
Neurological Research.  25(5):505-9, 2003 July. 
Abstract
  ALS2 is an autosomal recessive form of amyotrophic lateral sclerosis
  (AR-ALS) with juvenile onset, and has been mostly found in North African
  and Middle Eastern countries. Deletion mutations in the coding exons of a
  new gene ALS2, encoding a protein with guanine-nucleotide exchange factor (GEF) domains, have recently been identified in ALS2 patients. These
  mutations are predicted to cause a loss of protein function, indicating
  that ALS2 is the causative gene underlying ALS2. To examine whether ALS2  is mutated in Japanese ALS patients sharing some characteristics of ALS2,  we analyzed ALS2 gene from three patients with AR-ALS. While no deletion  mutation was detected in the coding regions of ALS2 gene, several
  single-nucleotide polymorphisms (SNPs) that have been found in healthy
  controls as well as in Tunisian ALS2 patients were found mostly in
  intronic regions of the gene. These results suggest that deletion
  mutations in ALS2 gene detected in ALS2 patients seem to be uncommon in
  Japanese AR-ALS, and that SNPs in uncoding regions might possibly be
  relevant to predisposition to ALS.

47. Ruddy DM. Parton MJ. Al-Chalabi A. Lewis CM. Vance C. Smith BN. Leigh PN. Powell JF. Siddique T. Postumus Meyjes E. Baas F. De Jong V. Shaw CE.
Two families with familial amyotrophic lateral sclerosis are linked to a
novel locus on chromosome 16q.
American Journal of Human Genetics. 73(2):390-6, 2003 August.
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset disease in
which motor neurons in the brain and spinal cord degenerate by largely
unknown mechanisms. ALS is familial (FALS) in 10% of cases, and the
inheritance is usually dominant, with variable penetrance. Mutations in
copper/zinc super oxide dismutase (SOD1) are found in 20% of familial and
3% of sporadic ALS cases. Five families with ALS and frontotemporal
dementia (ALS-FTD) are linked to 9q21, whereas one family with pure ALS is linked to 18q21. We identified two large European families with ALS
without SOD1 mutations or linkage to known FALS loci and conducted a
genomewide linkage screen using 400 microsatellite markers. In both
families, two-point LOD scores &gt;1 and a haplotype segregating with
disease were demonstrated only across regions of chromosome 16. Subsequent fine mapping in family 1 gave a maximum two-point LOD score of 3.62 at D16S3137 and a three-point LOD score of 3.85 for markers D16S415 and D16S3137. Haplotype analysis revealed no recombination &gt; approximately 30 cM, (flanking markers at D16S3075 and D16S3112). The maximum two-point LOD score for family 2 was 1.84 at D16S415, and the three-point LOD scorewas 2.10 for markers D16S419 and D16S415. Definite recombination occurred in several individuals, which narrowed the shared haplotype in affected individuals to a 10.1-cM region (flanking markers: D16S3396 and D16S3112). The region shared by both families on chromosome 16q12 corresponds to approximately 4.5 Mb on the Marshfield map. Bioinformatic analysis of the region has identified 18 known genes and 70 predicted genes in this region, and sequencing of candidate genes has now begun.

48.   Ryberg H. Askmark H. Persson LI.
A double-blind randomized clinical trial in amyotrophic lateral sclerosis
using lamotrigine: effects on CSF glutamate, aspartate, branched-chain
amino acid levels and clinical parameters.
Acta Neurologica Scandinavica.  108(1):1-8, 2003 July. 
Abstract
  OBJECTIVES: A study was conducted to examine the effect of lamotrigine
  (LTG) in amyotrophic lateral sclerosis (ALS). MATERIAL AND METHODS:
  Patients were entered in a double-blind, placebo-controlled, crossover
  study. None of the patients were treated with riluzole, which was not
  approved for treatment of ALS in Sweden when the study started. After
  randomization, each patient was treated with placebo or LTG 300 mg daily,
  followed by a washout period and a second treatment period. RESULTS:
  Thirty patients completed the study and were included in the analysis of
  the primary outcome, which was measured with clinical scales. The
  cerebrospinal fluid (CSF) levels of glutamate, aspartate, branched-chain
  amino acids and LTG were also measured. Changes for glutamate, valine and  LTG were found during the progression of the disease. The clinical
  parameters and the levels of CSF amino acids were similar for the two
  treatment groups. CONCLUSION: No clinical effect of LTG on ALS progression  could be found.

49.   Al-Chalabi A. Scheffler MD. Smith BN. Parton MJ. Cudkowicz ME. Andersen  PM. Hayden DL. Hansen VK. Turner MR. Shaw CE. Leigh PN. Brown RH Jr.
Ciliary neurotrophic factor genotype does not influence clinical phenotype
in amyotrophic lateral sclerosis.
Annals of Neurology.  54(1):130-4, 2003 July. 
Abstract
  Ciliary neurotrophic factor (CNTF) maintains survival of adult motor
  neurons. Mice lacking the CNTF gene develop mild, progressive motor neuron loss. In the normal human population, 1 to 2.3% are homozygous for a null allele, and reports suggest this mutant is associated with a younger onset of amyotrophic lateral sclerosis (ALS). We have tested this hypothesis in a study of 400 subjects with ALS and 236 controls. There was no difference in age of onset, clinical presentation, rate of progression, or disease  duration for those with one or two copies of the null allele, excluding
CNTF as a major disease modifier in ALS.

50.  Finsterer J.
Mitochondriopathy mimicking amyotrophic lateral sclerosis.
 Neurologist.  9(1):45-8, 2003 January. 
Abstract
BACKGROUND: Mitochondriopathy has been rarely reported to imitate motor neuron disease. REVIEW SUMMARY: A 57-year-old, 157-cm-tall woman with clinical and electrophysiological features of motor neuron disease since 1993 is reported. She also had increased liver function parameters, hypothyroidism, and sinus tachycardia. Because her mother and sister had both died from assumed amyotrophic lateral sclerosis, familial ALS was  diagnosed. On reevaluation, screening for superoxide-dismutase gene  mutations was negative, but lactate stress testing was abnormal and muscle  biopsy revealed patchy COX deficiency and abnormal mitochondria. Analysis  of the muscle mtDNA revealed substitutions in the isoleucine tRNA, in the  ATPase-6, and in the cytochrome-b gene, respectively. Based on these data,  the diagnosis of ALS was changed to mitochondriopathy. CONCLUSIONS:  Mitochondriopathy may mimic ALS, phenotypically and
electrophysiologically. In patients with an ALS phenotype, slow
progression, and multisystem involvement, mitochondriopathy should be
considered a diagnostic possibility.

51.  LariviA[spacing diaeresis]re RC. Beaulieu JM. Nguyen MD.
 Julien JP.
Peripherin is not a contributing factor to motor neuron disease in a mouse
model of amyotrophic lateral sclerosis caused by mutant superoxide
dismutase.
Neurobiology of Disease.  13(2):158-66, 2003 July. 
Abstract
  Peripherin is a type III intermediate filament protein detected in axonal
  spheroids associated with amyotrophic lateral sclerosis (ALS). The
  overexpression of peripherin induces degeneration of spinal motor neurons
  during aging in transgenic mice and in cultured neuronal cells derived
  from peripherin transgenic embryos. Here, we investigated whether
  peripherin is a contributor of pathogenesis in mice overexpressing a
  mutant superoxide dismutase 1 (SOD1(G37R)) gene linked to familial ALS.
  This was done by the generation and analysis of SOD1(G37R) mice that
  either overexpress a peripherin transgene (G37R;TgPer mice) or lack the
  endogenous peripherin gene (G37R;Per-/- mice). Surprisingly, upregulation
  or suppression of peripherin expression had no effects on disease onset,
  mortality, and loss of motor neurons in SOD1(G37R) mice. These results
  provide compelling evidence that peripherin is not a key contributor of
  motor neuron degeneration associated with toxicity of mutant SOD1.

52.  Gelinas DF.
Pulmonary function screening.
Seminars in Neurology.  23(1):89-96, 2003 March. 
Abstract
  Patients who suffer from neuromuscular diseases often have complications
  from respiratory insufficiencies. Some neuromuscular diseases, for example
  Landry Guillain-BarrA(C) syndrome, may only require temporary tracheal
  intubation; patients with other neuromuscular diseases, such as
  amyotrophic lateral sclerosis, may decide with the assistance of their
  doctor and family to opt for lifelong noninvasive ventilatory support.
  Other patients may only opt for noninvasive positive pressure ventilation.
  Respiratory dysfunction is caused by weakness of the upper airway muscles,
  which can lead to sleep apnea, abnormal swallow, and decreased respiratory
  muscle strength, as well as a decrease in total lung volume. Early
  respiratory changes in patients with neuromuscular disease are often best
  detected during sleep. During rapid eye movement sleep, there is a
  reduction in respiratory drive predisposing to hypopneas and apneas. The
  majority of neuromuscular patients with respiratory insufficiency may be
  monitored and treated in the outpatient setting, thus allowing them to
  remain in their homes.

53. Strong MJ.
The basic aspects of therapeutics in amyotrophic lateral sclerosis.
Pharmacology & Therapeutics. 98(3):379-414, 2003 June.
Abstract
Once thought to be a single pathological disease state, amyotrophic
lateral sclerosis (ALS) is now recognized to be the limited phenotypic
expression of a complex, heterogeneous group of biological processes,
resulting in an unrelenting loss of motor neurons. On average, individuals
affected with the disease live &lt;5 years. In this article, the complex
nature of the pathogenesis of ALS, including features of age dependency,
environmental associations, and genetics, is reviewed. Once held to be
uncommon, it is now clear that ALS is associated with a frontotemporal
dementia and that this process may reflect disturbances in the
microtubule-associated tau protein metabolism. The motor neuron ultimately succumbs in a state where significant disruptions in neurofilament
metabolism, mitochondrial function, and management of oxidative stress
exist. The microenvironment of the neuron becomes a complex milieu in
which high levels of glutamate provide a source of chronic excitatory
neurotoxicity, and the contributions of activated microglial cells lead to
further cascades of motor neuron death, perhaps serving to propagate the
disease once established. The final process of motor neuron death
encompasses many features of apoptosis, but it is clear that this alone
cannot account for all features of motor neuron loss and that aspects of a
necrosis-apoptosis continuum are at play. Designing pharmacological
strategies to mitigate against this process thus becomes an increasingly
complex issue, which is reviewed in this article.

54.  Cheah IK. Cheema SS. Langford SJ. Lopes EC. Macfarlane KJ. Petratos S.  Turner BJ.
Design and application of a peptide nucleic acid sequence targeting the
 p75 neurotrophin receptor.
Bioorganic & Medicinal Chemistry Letters.  13(14):2377-80, 2003 July 21. 
Abstract
  Novel antisense peptide nucleic acid (PNA) constructs targeting p75NTR as
  a potential therapeutic strategy for amyotrophic lateral sclerosis (ALS)
  were designed, synthesised and evaluated against phosphorothioate
  oligonucleotide sequences (PS-ODN). An 11-mer antisense PNA directed at
  the initiation codon dose-dependently inhibited p75NTR expression and
  death signalling by nerve growth factor in Schwann cell cultures.
  Inhibition of p75NTR production was not detected in cultures treated with
  the nonsense PNA or antisense PNA directed at the 3&apos;-terminus
  sequence. The 19-mer PS-ODN sequences also failed to confer any activity
  against p75NTR but, unlike the PNA sequences, were toxic in vitro at
  comparable doses.

55.   Kent RD. Vorperian HK. Kent JF. Duffy JR.
Voice dysfunction in dysarthria: application of the Multi-Dimensional
Voice Program.
Journal of Communication Disorders.  36(4):281-306, 2003 Jul-Aug. 
Abstract
  Phonatory dysfunction is a frequent component of dysarthria and often is a
  primary feature noted in clinical assessment. But the vocal impairment can
  be difficult to assess because (a). the analysis of voice disorder of any
  kind can be challenging, and (b). the voice disorder in dysarthria often
  occurs along with other impairments affecting articulation, resonance, and
  respiration. A promising assessment tool is multi-parameter acoustic
  analysis, such as the Multi-Dimensional Voice Program (MDVP). Part 1 of
  this paper recommends procedures and standards for the acoustic analysis
  of voice, including (1). selection of the sample to be analyzed, (2).
  signal quality requirements, (3). availability of normative data for both
  genders and different ages of speakers, (4). reliability of analysis, and
  (5). correlation of acoustic results with results from other methods of
  analysis. In Part 2, acoustic data are reviewed for the dysarthria
  associated with Parkinson disease (PD), cerebellar disease, amyotrophic
  lateral sclerosis (ALS), traumatic brain injury (TBI), unilateral
  hemispheric stroke, and essential tremor. Tentative profiles of voice
  disorder are described for these conditions. These profiles may serve as
  hypotheses for future research. Although several issues remain to be
  resolved in the acoustic analysis of voice disorder in dysarthria, steps
  can be taken now to promote the reliability, validity, and clinical
  utility of such analyses. (1). As a result of this activity, the
  participant will be able to describe ways in which an optimal
  multi-dimensional analysis of voice can be performed with modern acoustic
  analysis systems. (2). As a result of this activity, the participant will
  be able to apply multi-dimensional acoustic analysis of voice to
  individuals who have a dysarthria-related voice disorder. (3). As a result
  of this activity, the participant will be able to identify major sources
  of normative data on the Multi-Dimensional Voice Program.

56.  Yagi K.
[An autopsy case of amyotrophic lateral sclerosis with 22-years duration].
No to Shinkei - Brain & Nerve.  55(6):549-57, 2003 June.

57. Otomo A. Hadano S. Okada T. Mizumura H. Kunita R. Nishijima H. Showguchi-Miyata J. Yanagisawa Y. Kohiki E. Suga E. Yasuda M. Osuga H. Nishimoto T. Narumiya S. Ikeda JE.
ALS2, a novel guanine nucleotide exchange factor for the small GTPase
Rab5, is implicated in endosomal dynamics.
Human Molecular Genetics. 12(14):1671-87, 2003 July 15.
Abstract
ALS2 mutations account for a number of recessive motor neuron diseases
including forms of amyotrophic lateral sclerosis, primary lateral
sclerosis and hereditary spastic paraplegia. Although computational
predictions suggest that ALS2 encodes a protein containing multiple
guanine nucleotide exchange factor (GEF) domains [RCC1-like domain (RLD), the Dbl homology and pleckstrin homology (DH/PH), and the vacuolar protein sorting 9 (VPS9)], the functions of the ALS2 protein have not been revealed as yet. Here we show that the ALS2 protein specifically binds to small GTPase Rab5 and functions as a GEF for Rab5. Ectopically expressed ALS2 protein localizes with Rab5 and early endosome antigen-1 (EEA1) onto early endosomal compartments and stimulates the enlargement of endosomes in cultured cortical neurons. The carboxy-terminus of ALS2 protein carrying a VPS9 domain mediates not only the activation of Rab5 via a guanine-nucleotide exchanging reaction but also the endosomal localization of the ALS2 protein, while the amino-terminal half containing RLD acts suppressive in its membranous localization. Further, the DH/PH domain in the middle portion of ALS2 protein enhances the VPS9 domain-mediated endosome fusions. Taken together, the ALS2 protein as a novel Rab5-GEF, ALS2rab5GEF seems to be implicated in the endosomal dynamics in vivo. Notably, a feature common to eight reported ALS2 mutations among motor neuron diseases is the loss of VPS9 domain, resulting in the failure of Rab5 activation. Thus, a perturbation of endosomal dynamics caused by loss of ALS2 rab5GEF activity might underlie neuronal dysfunction and degeneration in a number of motor neuron diseases.

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