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Purpose We previously demonstrated that passive transfer of lymphocytes from glaucomatous mice induces retinal ganglion cell (RGC) damage in recipient animals, suggesting a role for immune responses in the multifactorial pathophysiology of glaucoma. Here we evaluate whether absence of an adaptive immune response reduces RGC loss in glaucoma. Methods Elevated intraocular pressure (IOP) was induced in one eye of C57BL/6J (B6) or T- and B-cell-deficient Rag1-/- knockout mice. After 16 weeks RGC density was determined in both the induced and the normotensive contralateral eyes. Data were compared to mice having received injections of "empty" vector (controls). The number of extravascular CD3+ cells in the retinas was determined using FACS. Results Retinas of eyes with elevated IOP contain significantly more extravasated CD3+ cells than control retinas (46.0 vs. 27.1, P = 0.025). After 16 weeks of elevated IOP the average RGC density in B6 mice decreased by 20.7% (P = 1.9 × 10-4). In contrast, RGC loss in Rag1-/- eyes with elevated IOP was significantly lower (10.3%, P = 0.006 vs. B6). RGC loss was also observed in the contralateral eyes of B6 mice, despite the absence of elevated IOP in those eyes (10.1%; P = 0.008). In RAG1-/- loss in the contralateral eyes was minimal (3.1%) and significantly below that detected in B6 (P = 0.02). Conclusions Our findings demonstrate that T Rag1-/- mice are significantly protected from glaucomatous RGC loss. In this model, lymphocyte activity contributes to approximately half of all RGC loss in eyes with elevated IOP and to essentially all loss observed in normotensive contralateral eyes.

Dermatomyositis and vasculitic neuropathies are disorders with immune mediated ischemic injuries. Cellular responses to hypoxia include the hypoxia-inducible factor-1 (HIF-1)-induced transcription of genes involved in angiogenesis. To study their possible roles in those disorders, the immunohistochemical expression of HIF-1alpha, HIF-1beta, HIF-2alpha, vascular endothelial growth factor (VEGF), VEGF-receptor (VEGF-R) and erythropoietin-receptor was investigated. Cases of normal nerves, diabetic neuropathy, normal muscles, polymyositis and inclusion-body-myositis served as controls. The latter were chosen because they represent comparable inflammatory disorders, however, in these ischemia/hypoxia is not supposed to play such a prominent pathogenetic role. Hypoxia-related proteins were not detected in normal controls. In polymyositis and inclusion-body-myositis, there was VEGF-R-expression in muscle fibers and HIF-2alpha reactivity in endothelial cells. In dermatomyositis, HIF-1alpha and HIF-1beta were found in endothelial cells, whereas HIF-2alpha, erythropoietin-receptor, VEGF and VEGF-R additionally were observed in muscle fibers. In vasculitic and diabetic neuropathies, a variable focal expression of hypoxia-inducible factors, VEGF, VEGF-R and erythropoietin-receptor was seen in vessels. These observations suggest that the upregulation of hypoxia-related proteins may represent an adaptation mechanism of neuromuscular tissues to immune mediated deprivation of the blood supply.

Objective: To describe the clinical, electrophysiologic and morphologic features of a Costa Rican family with an autosomal dominant inherited Charcot–Marie–Tooth (CMT) neuropathy. Methods: The field study took place in Costa Rica, Central America. Seven patients underwent neurological examinations and standard electrodiagnostic tests, and a sural nerve biopsy was taken from one patient. Fifteen family members were screened for gene defects associated with CMT disease. Results: Characteristic features of this family were a late age of onset (35–56 years), positive sensory symptoms and muscle cramps. Based on electrodiagnostic and morphologic data, the patients were classified as having a CMT2 neuropathy. The CMT1A duplication/HNPP deletion and point mutations in genes PMP22, MPZ, Cx32 and EGR2 implicated in the most common types of CMT disease were excluded. Subsequently, almost all known CMT loci were excluded by linkage analysis. Discussion: Features of this family were a late age of onset and positive sensory symptoms. This new autosomal dominant CMT neuropathy is associated with an unknown gene defect. [Neurol Res 2009; 31: 283–288] Objetivo: Describir las características clínicas, electrofisiológicas y morfológicas de una familia costarricense con una neuropatía de Charcot-Marie-Tooth (CMT) hereditaria autosómica dominante. Métodos: El estudio de campo se llevó a cabo en Costa Rica, Centroamérica. Siete pacientes se sometieron a exámenes neurológicos y pruebas de electrodiagnóstico estándar, ya un paciente se le tomó una biopsia del nervio sural. Quince miembros de la familia fueron evaluados por defectos genéticos asociados con la enfermedad de CMT. Resultados: Los rasgos característicos de esta familia fueron una edad de inicio tardía (35-56 años), síntomas sensoriales positivos y calambres musculares. Sobre la base de los datos morfológicos y de electrodiagnóstico, los pacientes se clasificaron con una neuropatía CMT2. Se excluyeron la duplicación de CMT1A/deleción HNPP y las mutaciones puntuales en los genes PMP22, MPZ, Cx32 y EGR2 implicados en los tipos más comunes de enfermedad de CMT. Posteriormente, casi todos los loci CMT conocidos fueron excluidos por análisis de ligamiento. Discusión: Las características de esta familia fueron una edad de inicio tardía y síntomas sensoriales positivos. Esta nueva neuropatía de CMT autosómica dominante está asociada con un defecto genético desconocido. [NeurolRes 2009; 31: 283–288] Universidad Nacional, Costa Rica. Escuela de Ciencias Biológicas

Motoneurons release the heparansulfate proteoglycan agrin and thereby activate the muscle-specific receptor tyrosine kinase (MuSK), which is the main organizer of subsynaptic specializations at the neuromuscular junction. Recently, we showed that (1) the protein kinase CK2 interacts with the intracellular region of MuSK; (2) the CK2 protein is enriched and co-localized with MuSK at postsynaptic specializations; (3) CK2-mediated phosphorylation of serine residues within a specific MuSK epitope, named the kinase insert, regulates acetylcholine receptor (AChR) clustering; (4) muscle-specific CK2beta knockout mice develop a myasthenic phenotype due to impaired muscle endplate structure and function (see Genes Dev 20(13):1800-1816, 2006). Here, we investigated for the first time if CK2 is modulated in biopsies from human patients. To this end, we measured transcript amounts of the subunits CK2alpha and CK2beta and determined holoenzyme CK2 activity in 34 muscle biopsies of human patients with different muscle pathologies.

Prostaglandins (PGs) are critical mediators of physiologic processes and inflammation. They are produced by two different isoforms of the cyclooxygenase (COX) enzyme, namely COX-1 and COX-2. In particular COX-2 was demonstrated to be crucial for PG-synthesis in inflammation. Recently, inhibition of COX-2 was shown to prevent the loss of motor neurons in a model of amyotrophic lateral sclerosis (ALS). Furthermore, spinal COX-2 expression was shown to be increased in transgenic mice that produce an ALS-like syndrome. Therefore, we investigated the expression of COX-1 and COX-2 in the spinal cord of seven human sporadic ALS patients by means of immunohistochemistry. Specimens from seven patients without any neurological disease served as controls. COX-2 expression was dramatically increased in the spinal cord of patients with ALS. Its protein was found in motor neurons, interneurons and glial cells. Statistical analysis showed a significantly higher expression of COX-2 in ALS for both neurons and glia. In contrast, COX-1 expression was predominantly confined to microglia and no apparent difference was detected between controls and ALS. In addition, we studied the concentration of prostaglandin E2 (PG E2) as a marker for COX activity in the cerebrospinal fluid of nine patients diagnosed for ALS and compared the results with those from nine patients without motor neuron disease. PG E2 levels were markedly increased in ALS cases (45.8 +/- 35.1 pg/mL) compared to the non-ALS specimens (15.8 +/- 3.7 pg/mL). The results of our study corroborate a potential role for COX-2 in the pathogenesis of motor neuron death in ALS. Selective COX-2 inhibition might therefore offer a new possibility in the treatment of human ALS. However, to determine the exact role of COX-2 in human ALS will require further research.

In amyotrophic lateral sclerosis (ALS) patients, hyperintense signals at the subcortical precentral gyrus in brain fluid attenuated inversion recovery (FLAIR) MR images have been found more frequently than in controls. Quantitative analysis has revealed a significant increase of the FLAIR-magnetic resonance imaging (MRI) signal at the subcortical precentral gyrus of ALS patients compared to healthy controls. In addition, hypointense signals at the rim of the precentral gyrus in FLAIR and T2-weighted images have been shown in ALS patients. In 17 ALS patients, we evaluated hyperintense signals in T2-, T1-, proton density-weighted and FLAIR MR images, and hypointense signals in T2-weighted and FLAIR images 15.7+/-3.0 months after the initial examination by visual scoring. In FLAIR images, a quantitative analysis was added. The visual scores of hyperintense signals along the corticospinal tract did not change significantly in all sequences. However, the quantitative evaluation of FLAIR images revealed a significant increase of the signal intensity at the subcortical precentral gyrus (p

Amyotrophic lateral sclerosis is a rapidly progressive and fatal disease which has no known cure and limited symptomatic treatment. While coping strategies in more common diseases are widely assessed, coping is poorly understood in ALS.We examined 41 ALS patients using a standardised interview, a validated coping self-rating questionnaire and a self-rating depression scale. The evaluation was repeated after six months."Loss of speech", "loss of mobility" and "the poor prognosis" were the most frequent answers in the standardised interview to questions regarding the worst aspect of the disease. Pain was seldom mentioned. "Family members" were most helpful in coping with the disease, followed by "unspecific mechanisms" and "technical aids". None of our patients expressed a wish for assisted suicide. In comparison with other fatal diseases, patients with ALS had similar rankings in the coping mechanism of "rumination", but lower rankings in "search for social integration", "defence of fear", "search for information and communication". In contrast,* "search for hold in the religion" was of high importance for our ALS patients. In the follow-up examination the importance of "search for information and communication" increased.The results emphasise the importance of "loss of speech" and the importance of the caring family as well as the availability of technical aids in ALS. Coping in ALS seems to be based mainly on "rumination" and *"hold in the religion", but the increasing importance of "search for information" indicates that the sustained offer of information is essential.

Artículo científico -- Universidad de Costa Rica. Instituto de Investigaciones en Salud, 2001. Este documento es privado debido a limitaciones de derechos de autor. Autosomal recessive Charcot-Marie-Tooth disease (CMT) represents a heterogeneous group of disorders affecting the peripheral nervous system. The axonal form of the disease is designated as "CMT type 2" (CMT2), and one locus (1q21.2-q21.3) has been reported for the autosomal recessive form. Here we report the results of a genomewide search in an inbred Costa Rican family (CR-1) affected with autosomal recessive CMT2. By analyzing three branches of the family we detected linkage to the 19q13.3 region, and subsequent homozygosity mapping defined shared haplotypes between markers D195902 and D19S907 in a 5.5-cM range. A maximum two-point LOD score of 9.08 was obtained for marker 019S867, at a recombination fraction of .00, which strongly supports linkage to this locus. The epithelial membrane protein 3 gene, encoding a PMP22 homologous protein and located on 19q13.3, was ruled out as being responsible for this form of CMT. The age at onset of chronic symmetric sensory-motor polyneuropathy was 28-42 years (mean 33.8 years); the electrophysiological data clearly reflect an axonal degenerative process. The phenotype and locus are different from those of demyelinating CMT4F, recently mapped to 19q13.1-13.3; hence, the disease affecting the Costa Rican family constitutes an axonal, autosomal recessive CMT subtype (ARCMT2B). Universidad de Costa Rica. Instituto de Investigaciones en Salud UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA)

Hepatitis C virus (HCV) infection is often associated with abnormal immunological responses. We describe four patients with vasculitic neurological signs and symptoms following HCV infection. A 56-year-old woman with HCV infection developed peripheral neuropathy characterized by asymmetric distal painful hypesthesia, dysesthesia and moderate motor weakness of the lower limbs. Serological examinations revealed cryoglobulinemia and low levels of complement C4. A biopsy of the sural nerve revealed vasculitic neuropathy. HCV infection associated immunomediated vasculitis was diagnosed. While steroid therapy was ineffective, treatment with interferon-alpha improved the neuropathy considerably without, however, eliminating HCV infection. A 62-year-old man with HCV infection developed peripheral sensory neuropathy. Complement C3 was slightly diminished. Nerve biopsy revealed vasculitic neuropathy. A 71-year-old woman developed chronic symmetric sensomotor polyneuropathy. HCV hepatitis followed blood transfusions. Cryoglobulins tested positive, consistent with type II cryoglobulinemia. Complements C3 and C4 were diminished. Inflammatory infiltrates in the sural nerve biopsy specimen led to the diagnosis of chronic vasculitic disorder. A 55-year-old woman with HCV infection developed vasculitis of the skin, connective tissue, visceral organs, and kidney, leading to hemodialysis. Neurologically she developed severe apathy and drowsiness, myoclonic jerks, exaggerated deep tendon reflexes, and positive pyramidal signs. Magnetic resonance imaging of the brain showed diffuse increased signal abnormalities involving supra- and infratentorial white matter suggesting cerebral vasculitis. Cryoglobulins were positive, complements C3 and C4 slightly diminished (54 mg/dl, 4.3 mg/dl). Supportive therapy resulted in neurological improvement. Treatment with interferon-alpha was discontinued because of agranulocytosis. In patients with peripheral neuropathy or signs of leucencephalopathy, a hepatitis C associated vasculitis should be considered in the differential diagnosis.

Bartonella henselae, the causative agent of cat scratch disease and bacillary angiomatosis, is associated with an expanding spectrum of diseases. Here, we report on a 40-year-old patient suffering from chronic recurrent painful ulcers of the toes, distal axonal sensomotor polyneuropathy and Raynaud's phenomenon. Biopsy of the sural nerve demonstrated an axonal neuropathy with a neurogenic muscular atrophy. Treatment with high dose corticosteroids had no beneficial effect. A biopsy taken from a recurring ulcer 7 years after the beginning of the disease revealed superficial ulcerated hyperkeratosis with subepithelial proliferation of small vessels compatible with a diagnosis of verruca peruana, however, without detection of microorganism. Serologic analysis revealed an elevated IFT titer of 1:1,024 against B. henselae. Treatment with erythromycin induced healing of the ulcer, remission of the vasculitis and the polyneuropathy, and a decline of the IFT titer. This case illustrates that B. henselae infection should be considered in patients with vasculitis and polyneuropathic syndromes.

A multicenter test was conducted to investigate the effectiveness of the selective serotonin agonist sumatriptan in patients with the computerized headache diagnosis of migraine. A computer program was used for diagnostic evaluation of patients attending a general practice because of headache. The results of the analysis were taken as a direct decision on therapy. If the patients satisfied the criteria for migraine, they were given subcutaneous sumatriptan for treating three migraine attacks. The patients were able to use the study medication under outpatient conditions. The therapeutic efficacy of the medicine was recorded in a headache diary. A total of 91 patients were included in the study at 22 practices in Germany. An average of four patients per practice were recruited. In the first migraine attack treated, headache improvement was experienced by 77.7% of the patients treated. In the second and third attacks an improvement was experienced by 93.5% and 89.8%, respectively. The results show that by optimizing diagnostic reliability with the aid of the computer program a high response rate can be achieved under practice conditions using the selective serotonin agonist sumatriptan. Since the computer program described permits a specific diagnosis, it improves the prospects of effective headache therapy in the individual patient. Thus treatment based on this approach can reduce inputs of time and money in migraine therapy.

We report on a patient with an interstitial myositis in type II polyendocrine autoimmune disease (Schmidt's syndrome) showing an immunohistochemical demonstrated perifascicular expression of Leu 19 indicating perifascicular denervation, which could not be detected with classical histological methods. In neurogenic muscular atrophy, idiopathic polymyositis and normal muscle we could not find such an exclusive perifascicular expression of the Leu 19 antigen. We conclude that perifascicular denervation is a characteristic feature in IM and thus might have diagnostic value. Furthermore the interstitial myositis is characterized by a complement-mediated angiopathy (vascular deposition of the membranolytic attack complex C5b-9). This pattern is comparable to well-known changes in dermatomyositis. Interstitial myositis and dermatomyositis are evidently pathogenetically similar according to myopathological criteria, but show phenotypic differences. Additional in interstitial myositis and idiopathic polymyositis inflammatory infiltrates surrounding Leu 19 expressing myocytes are regarded as the cause of disseminated intrafascicular muscle fibre denervation.

The growth-associated protein B-50, also termed GAP-43, is a membrane-bound phosphoprotein that is expressed in neurons. It is particularly abundant during periods of axonal outgrowth in development and regeneration of the central and peripheral nervous system. In this paper we study the expression of B-50 in inflammatory and dystrophic myopathies. To investigate the state of regeneration, N-CAM and vimentin serial sections were performed, because N-CAM and cytoskeletal protein vimentin are excellent markers for regenerating muscle. Light-microscopic evaluation showed that muscle fiber regeneration in myopathies corresponds closely to B-50 immunoreactivity in satellite cells, myoblasts, myotubes and small regenerating myocytes in cytoplasmatic distribution. In normal muscle and in biopsies of neurogenic muscular atrophy, however, no light-microscopically demonstrable B-50 staining was found. B-50 in muscles apparently plays a role in the growth morphology of regenerating myocytes, and the phosphoprotein B-50 can no longer be regarded as a neuron-specific molecule.

OBJECTIVE Annexin-1 is a calcium-binding protein with anti-inflammatory properties, which has previously been described in MS plaque tissue. We investigated the feasibility and specificity of annexin-1-immuncytochemistry of CSF cells to test its potential as a surrogate marker for MS. MATERIALS AND METHODS CSF-specimens of 49 MS cases with different courses and 94 control cases were immunocytochemically studied with a monoclonal antibody to annexin-1. RESULTS The highest level of cytoplasmic immunoreaction was seen in the most acute inflammatory disorders, such as bacterial meningitis and neuroborreliosis. CIS-, RR-MS-, and viral meningoencephalitis cases came next. The lowest annexin-1 expression was observed in neurosyphilis and SP-MS. In PP-MS and non-inflammatory control cases, annexin-1 expression was entirely lacking. CONCLUSION Immunocytochemical staining of CSF cells with an antibody to annexin-1 is feasible. This may be helpful in further study of its role in the pathophysiology of inflammatory CNS diseases. The expression pattern seems to rather reflect the acuteness of the inflammatory process than specifying a certain underlying pathology. Although differences were observed between diverse disease groups, because of considerable overlap, a certain diagnosis of an individual case cannot be achieved. Thus, at present, we cannot recommend annexin-1 as a reliable surrogate marker of MS.

The immunoproteasome is upregulated by disease, oxidative stress, and inflammatory cytokines, suggesting an expanded role for the immunoproteasome in stress signaling that goes beyond its canonical role in generating peptides for antigen presentation. The signaling pathways that are regulated by the immunoproteasome remain elusive. However, previous studies suggest a role for the immunoproteasome in the regulation of PTEN and NF-κB signaling. One well-known pathway upstream of NF-κB and downstream of PTEN is the Akt signaling pathway, which is responsible for mediating cellular survival and is modulated after optic nerve crush (ONC). This study investigated the role of retinal immunoproteasome after injury induced by ONC, focusing on the Akt cell survival pathway. Retinas or retinal pigment epithelial (RPE) cells from wild type (WT) and knockout (KO) mice lacking either one (LMP2) or two (LMP7 and MECL-1) catalytic subunits of the immunoproteasome were utilized in this study. We show that mRNA and protein levels of the immunoproteasome subunits are significantly upregulated in WT retinas following ONC. Mice lacking the immunoproteasome subunits show either a delayed or dampened apoptotic response as well as altered Akt signaling, compared to WT mice after ONC. Treatment of the RPE cells with insulin growth factor-1 (IGF-1) to stimulate Akt signaling confirmed that the immunoproteasome modulates this pathway, and most likely modulates parallel pathways as well. This study links the inducible expression of the immunoproteasome following retinal injury to Akt signaling, which is important in many disease pathways.

La mutación p.thr124Met en la proteína mielina cero (MPZ) causa la enfermedad de Charcot-Marie-Tooth tipo 2J, una neuropatía periférica con síntomas adicionales como alteraciones pupilares y sordera. Se ha observado en varias familias alrededor del mundo, originarias de Alemania, Bélgica, Japón, Italia y Norteamérica, entre otras. Aquí reportamos a pacientes centroamericanos provenientes de Costa Rica que acarrean esta mutación. Se realizaron análisis clínico, electrofisiológico y molecular de pacientes y controles, incluyendo secuenciación del gen y de marcadores ligados a éste. Estos pacientes comparten casi por completo el haplotipo con dos pacientes belgas no emparentados. Como resultado del análisis de los haplotipos, basado en diez marcadores (siete SNPs, dos microsatélites y un elemento poli-A intrónico), se sugiere que se ha dado un efecto fundador en la migración de este alelo.

Recently we showed that donor-specific tolerance to MHC-matched islet allografts in diabetic NOD mice could be induced by simultaneous islet and bone marrow transplantation. Mononuclear cell infiltration surrounding the islets was also found in tolerated grafts. In this study, we compared gene expression in the tolerated and rejected islet grafts by using Affymetrix Murine U74A oligonucleotide arrays. To confirm the results of microarray analysis, we performed real-time PCR and RNase protection assay on selected genes. Of over 12,000 genes studied, 57 genes were expressed at consistently higher levels in tolerated islet grafts, and 524 genes in rejected islet grafts. Genes from a variety of functional clusters were found to be different between rejected and tolerated grafts. In the rejected islet grafts, a number of T-cell surface markers and of cytotoxicity-related genes were highly expressed. Also in the rejected grafts, a number of cytokines and chemokines and their receptors were highly expressed. The differential expression of selected genes found by microarray analysis was also confirmed by real-time PCR and RNase protection assay. Our results indicated that gene microarray analysis can help us to detect gene expression differences representative of the biologic mechanisms of tolerance and rejection.

Clinically, amyotrophic lateral sclerosis (ALS) usually presents as a pure motor system disorder, whereas oculomotor and sphincter muscle control of the anus and the bladder appear to be spared. Previously, a lacking expression of calcium binding proteins (CBPs) was demonstrated in vulnerable motor neurons in contrast to spared neuronal populations, e.g., the motor neurons of the cranial nerve III (NO) and the Onufrowicz nucleus (ON), suggesting a potential role of CBPs in the selective motoneuronal vulnerability in ALS. The annexins comprise a multigene family of CBPs, constituting a significant amount of total cellular protein and presumably involved in calcium-homeostasis and intracellular calcium-regulated pathways. We immunohistochemically investigated the expression patterns of annexins A1, A2, A4, A5, A6, and A7 in spinal cord and midbrain tissues from 24 ALS patients and 5 age-matched controls to test the hypothesis that annexins also contribute to the selective vulnerability in ALS. There was no difference in the expression patterns of ALS cases and normal controls. Annexin A1 was expressed in ependymal cells and motor neurons. Annexin A2 could be detected in ependymal and endothelial cells and motor neurons. Annexins A4 and A5 were found in both ependymal and glial cells, whereas annexin A6 was strongly expressed in motor neurons. Annexin A7 was totally absent from central nervous system tissue. A contribution of annexins to the selective vulnerability in ALS could not be derived from our results.

Glial cell cytoplasmic inclusions were identified in a case of spinocerebellar ataxia type 2. These have not been reported before. The inclusions were found in low frequency in the dentate nucleus, cerebellar white matter, pontine transverse fibres, and the inferior olivary nucleus. They were of variable size and shape and expressed ubiquitin, thus resembling glial cytoplasmic inclusions in multiple system atrophy. However, their immunohistochemical profile was different as they did not show immunoreactivity for either tau protein or alpha-synuclein. There was no evidence of expanded polyglutamine tracts in these inclusions, which also failed to label with silver stains. As in many other neurodegenerative diseases, in spinocerebellar ataxia type 2 there may be pathogenic contributions of glial cells other than the common astrogliotic response to neuronal damage.

Charcot-Marie-Tooth disease (CMT) comprises a heterogeneous group of hereditary motor and sensory peripheral neuropathies. The autosomal recessive axonal form of CMT (ARCMT2) is rare. Eight patients of a large consanguineous family of Spanish ancestry in Costa Rica were diagnosed with ARCMT2B; previous genetic studies of this family revealed linkage to chromosome 19q13.3. The clinical and electrophysiological features of these patients are reported. All patients presented with a symmetric motor and sensory neuropathy, which was more pronounced in the lower limbs. Further, distal muscle wasting and impaired deep tendon reflexes were found. Age at onset was between 26 and 42 years, and the disease duration ranged from 2 to 19 years. Electrophysiological studies revealed a primary axonal degenerative process. The clinical characteristics of this family differed in several aspects from previously reported families with ARCMT2.

Objectives : There is evidence of impaired cardiovascular autonomic control and reduced baroreflex sensitivity in patients with amyotrophic lateral sclerosis (ALS). A compromised baroreflex–chemoreflex interaction might result in inadequate responses to chemoreflex activation with progressive hypercapnia and hypoxia and contribute to early fatalities. This study was performed to assess cardiovascular and ventilatory responses to hypercapnic and hypoxic stimulation in ALS patients with impaired baroreflex function. Patients and methods : In 15 ALS patients with previously demonstrated baroreflex dysfunction and in 15 age-matched controls, we compared electrocardiographic RR-interval (RRI), systolic blood pressure (SBP) and minute ventilation (VE) during normal ventilation and during selective progressive hypoxia and hypercapnia. Results : Ventilatory and RRI responses to hypoxic and hypercapnic stimulation as well as SBP responses to hypercapnia did not differ between patients and controls. In contrast, hypoxia induced a significant SBP increase in patients only. Conclusions : The normal ventilatory and RRI responses to chemoreflex activation suggest intact afferent chemoreflex function. The hypertensive response to hypoxia might be due to a compromised interaction with the baroreflex. Avoiding hypoxic episodes might reduce the risk of cardiovascular crisis in ALS patients.

Objectives: Amyotrophic lateral sclerosis (ALS) is a fatal disease with unique demands on patients and carers. Patients and methods: The total burden of care and burden components in 37 ALS carers were measured using validated questionnaires. Furthermore, influencing factors (functional impairment of the patient, additional carers, participation in support groups) were assessed. Results: The mean total burden of care for ALS was low compared with dementia, mixed neuropsychiatric and internal diseases, but was correlated with functional impairment ( P = 0.003). The main burden components were 'personal and social restrictionsfland ’physical and emotional problems‘. Problem behaviour of the patients was low in general, but was higher in carers participating in support groups ( P = 0.002). Carers supported by additional carers had higher strain. Conclusion: The low burden of ALS carers may be caused by the low incidence of problem behaviour in ALS patients. However, if problem behaviour exists, carers participate more often in support groups, indicating the need for assistance. The burden of care increases with the functional impairment. Support for the carers has to start sooner.

artículo -- Universidad de Costa Rica. Instituto de Investigaciones en Salud, 2003 Abstract. Charcot-Marie-Tooth disease type IB (CMT 1B) is caused by mutations in the gene coding for peripheral myelin protein zero (MPZ, P0) that plays a fundamental role in adhesion and compaction of peripheral myelin. Here we report a Costa Rican family with a hereditary peripheral neuropathy due to a novel Tyr145Ser MPZ mutation. Four family members were heterozygously affected; two siblings of two heterozygous carriers were homozygous for this mutation. On neurological examination the heterozygous parents and their homozygous children both showed distal sensory deficits. The mother and the siblings displayed impaired deep tendon reflexes and mild sensory ataxia. The homozygous individuals were more severely affected with an earlier age of onset, distal motor weakness, and pupillary abnormalities. Electrophysiological studies revealed both signs of demyelination and axonal nerve degeneration. The sural nerve biopsy of one sibling showed thinly myelinated nerve fibers, onion bulb formation, and clusters of regenerating fibers. On electron microscopy axonal degeneration and decompaction of inner myelin layers were found. This Costa Rican family shows phenotypic variability depending on the homozygous or heterozygous state of the Tyr145Ser mutation carriers. info:eu-repo/grantAgreement/Universidad de Costa Rica/Instituto de Investigaciones Psicológicas //// UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA)

This study describes the distribution and identity of annexin-1 positive cells in the central nervous system in patients with multiple sclerosis (MS). Glucocorticoid-inducible, anti-inflammatory properties have been ascribed to annexin-1, a member of a family of calcium-binding proteins that are referred to collectively as annexins. We have found annexin-1 to be spatially associated with active MS lesions and demonstrated a stage-dependent expression of annexin-1 in MS plaques. All of the most important pathogenetically involved cells of MS lesions showed a strong annexin-1 reactivity. Both correlation analysis and double staining procedures suggested annexin-1 expression in macrophages and perivascular lymphocytes, where a cytoplasmic reactivity was displayed, whereas in activated, gemistocytic astrocytes it was also concentrated close to the plasma membrane. Although the exact roles of annexin-1 in this setting are still to be determined, a possible contribution to anti-inflammatory processes might be suggested.

Background. Human type 1 diabetes is associated with defects in the hematopoietic stem cells. Simultaneous donor islet and bone marrow transplantation may be an ideal therapeutic approach for inducing tolerance to islet allogeneic antigens and restoring self-tolerance to islet autoimmune antigens. Methods. Using a nonobese diabetic (NOD) mouse model of human type 1 diabetes, we investigated whether tolerance to MHC-matched allogeneic islet grafts from male nonobese diabetes-resistant (NOR) donors can be induced in female NOD recipients by simultaneous islet and bone marrow transplantation under fludarabine phosphate-based nonmyeloablative and irradiation-free conditioning therapy. Donor-specific chimerism in the peripheral blood of tolerant mice (n=7) was measured by semiquantitative polymerase chain reaction for a male-specific marker (SRY). Results. Donor-specific tolerance to NOR islet grafts was induced in all diabetic NOD mice after simultaneous islet and bone marrow transplantation and treated with fludarabine phosphate, cyclophosphamide, anti-mouse lymphocyte serum, and rapamycin. At 100 days and 200 days after transplantation, the average percentage of male NOR marker in DNA derived from the peripheral blood of NOD recipients that had long-term islet graft survival was over 10%. Conclusion. Our data suggest that this approach may induce donor-specific tolerance in clinical islet transplantation and living-related donor solid organ transplantation.

Hematopoietic macrochimerism, established by bone marrow transplantation, can be used as an approach for treating autoimmune disease and inducing transplant tolerance. In this study, we investigated whether a stable, high level of fully MHC-mismatched hematopoietic macrochimerism can be induced by using irradiation-free protocols, and whether rapamycin and T cell costimulatory blockades (anti-CD40L monoclonal antibody (mAb) and CTLA4Ig) as post-transplant treatment promote bone marrow engraftment. Donor-specific blood transfusion (DST), anti-lymphocyte serum (ALS), busulfan, and cyclophosphamide were given pretransplantation. Balb/c (H-2(d)) bone marrow cells, at a dose of 4 x 10(7), were infused into each C57BL/6 mouse (H-2(b)). Rapamycin, anti-CD40L mAb, and CTLA4Ig were then administered, either alone or in combination. Without ALS or busulfan and cyclophosphamide, macrochimerism can only rarely be induced. Donor-specific transfusion (DST) enhances induction of hematopoietic macrochimerism. Rapamycin, anti-CD40L mAb and CTLA4Ig, alone or in combination, induce a stable and high level of hematopoietic macrochimerism. In the chimeric mice, donor-derived cells were detected in all lymphohematopoietic tissues and donor-specific tolerance was induced in vitro. We conclude that a stable and high level of fully MHC-mismatched hematopoietic macrochimerism can be induced in mice after transplanting a single modest dose of bone marrow cells without irradiation. Rapamycin and T cell costimulatory blockade as post-transplant treatment promote bone marrow engraftment.

This is the case of a 41 year old man, suffering general weakness and elevated liver enzymes, sensitive to a treatment with riboflavin and coenzyme Q 10 . Tandem mass spectroscopy and molecular analysis reveal a multiple acyl-CoA-dehydrogenase deficiency (MADD) with two novel heterozygote missense mutations of the EFTDH gene.

In some patients with amyotrophic lateral sclerosis (ALS), T2-weighted and proton-density-weighted magnetic resonance imaging (MRI) shows hyperintense or hypointense signals at the corticospinal tract. Fluid-attenuated inversion recovery (FLAIR) sequences increase the sensitivity of MRI to detect cortical and subcortical tissue changes. In 31 ALS patients and 33 controls, we studied the frequency and the extent of signal abnormalities in FLAIR images compared to T2-, T1- and proton-density-weighted images. Hyperintense signals at the corticospinal tract were significantly more frequent in FLAIR images than in all other tested sequences. In FLAIR images of ALS patients only, distinct hyperintense signals at the subcortical precentral gyrus (five patients), the centrum semiovale (eight patients), the crus cerebri (nine patients) and the pons (four patients) as well as mild hyperintense signals in the medulla oblongata (three patients) were seen. More frequently, but not exclusively in ALS patients, FLAIR images showed mild hyperintense signals at the subcortical precentral gyrus (15 patients vs. 1 control). Quantitative analysis confirmed the significant difference between ALS patients and controls at the subcortical precentral gyrus in FLAIR images. In T1-weighted images, the corticospinal tract at the capsula interna was hypointense in significantly more controls than ALS patients. Also this difference was confirmed in the quantitative analysis. Similar to previous results, MR image alterations did correlate poorly to clinical data of upper motor neuron affliction.MR images of the head, including FLAIR images, provide additional information regarding corticospinal tract involvement in ALS patients. Because of an overlap with physiological findings, they have to be interpreted cautiously, with the exception of hyperintense signals at the subcortical precentral gyrus.

Increased oxidative stress and advanced glycosylation are important factors in the development of diabetic neuropathy. In non-diabetic neuropathies their influence has not been investigated in detail so far. We studied the localisation of N(epsilon)-carboxymethyllysine (CML) - a biomarker for oxidative stress - by immunohistochemistry in sural nerve biopsies of 31 patients with different polyneuropathies [diabetic polyneuropathy (n=5), alcohol-associated polyneuropathy (n=4), vitamin B12-deficient polyneuropathy (n=6), chronic inflammatory demyelinating polyneuropathy (CIDP) (n=6), vasculitic neuropathy (n=6), Charcot-Marie-Tooth disease type I (CMT I) (n=4)] and 4 normal controls. CML was detected in the perineurium of patients with diabetic, alcohol-associated, vitamin B12-deficient and vasculitic polyneuropathies. Epineurial, perineurial and endoneurial vessels were CML positive in diabetic, vitamin B12-deficient and vasculitic polyneuropathies. CML was also found in mononuclear inflammatory cells in vasculitic neuropathy. In CIDP and normal controls there was only marginal perineurial CML deposition in 2/6 and 1/4 cases. In CMT I no CML was detected. Immunohistochemical results were confirmed by immunoblot. Our data suggest a role of oxidative stress in the pathogenesis not only of diabetic but also of alcohol-associated, vitamin B12-deficient and vasculitic polyneuropathies. It may be a minor pathogenetic factor in CIDP and may not be involved in CMT I. Underlying causes for increased oxidative stress may be an elevated production of reactive oxygen species and an impairment of antioxidative defences. Therefore, an antioxidative treatment should be considered in alcohol-associated, vitamin B12-deficient and vasculitic polyneuropathy.

A growing number of patients with neuromuscular disease have been treated with home mechanical ventilation during the past 15 years. We prospectively examined the long-term effects and complications of this method, particularly with regard to noninvasive positive pressure ventilation (NPPV). Thirty-one patients with amyotrophic lateral sclerosis (ALS, n = 20) or other slowly progressive neuromuscular diseases (NMD, n = 11) were observed for 17,517 home ventilation days (almost 48 ventilation years). The mean observed ventilation time was 565 days (min/max: 30/2930). Twenty-five patients were ventilated noninvasively with different masks. The calculated mean survival with NPPV ventilation (criteria: death, tracheostomy, or patient deciding to break off) was 2052 (SE: +/- 317.8) days in the NMD group, 248 days (+/- 35.7) for ALS patients without bulbar symptoms, and 82 days (+/- 27.4) with bulbar paralysis. Complications with the need for intervention were observed six times more frequently with ALS than with NMD. NPPV is effective for years in patients with slowly progressing NMD. Those ALS patients without bulbar symptoms can profit for up to a year from NPPV, while those with bulbar paralysis can have some symptom relief. Complications of every kind are much more frequent in ALS patients.

Segmental muscle enlargement occurs in a variety of neurogenic conditions. We present a patient with calf hypertrophy, likely produced by continuous neuromuscular irritability and compensatory type 1 and type 2 muscle fiber hypertrophy. The underlying lesion of the S1 nerve root was caused by scarring, which could be demonstrated by Gadolinum enhanced, fat saturated magnetic resonance imaging. Thus, the application of this technique is recommended in otherwise etiologically unclear cases of neurogenic muscular lesions in order to detect chronic nerve root pathology.

Chronic venous insufficiency (CVI) of the lower legs may cause tissue damage, but involvement of peripheral nerves is uncertain. We examined 30 patients with CVI and 20 healthy controls using motor and sensory nerve conduction studies, vibration testing and thermotesting, quantitative sudomotor axon-reflex test, and laser Doppler flowmetry. Subjects with possible confounding factors for peripheral neuropathies were excluded. Prolongation of distal motor latency of the peroneal nerve (median, 5.4 versus 4.5 ms; P = 0.02), increased limits for warm (9.60 degrees C versus 5.20 degrees C; P = 0.016) and cold detection (3.45 degrees C versus 1.55 degrees C; P = 0.016) and reduced vibration sense (2.8925 versus 1.1075; P0.008) were found. The results demonstrate a disturbance of A-alpha fibers, A-beta fibers, A-delta fibers, and thermoafferent-C fibers, possibly induced by ischemia due to venous microangiopathy and increased endoneurial pressure. Analogous to neuropathic ulcers in diabetes, the CVI-associated neuropathy may also be a cofactor in the development of venous ulcers.

Tay-Sachs disease is caused by Hexosaminidase A deficiency. Symptoms of the enzyme deficiency rarely become clinically manifest in adult age; then the course of the disease differs in a wide range. We report on a patient with cerebellar ataxia and lower motor neuron disease. Neurophysiological investigations, neuro-imaging (CT, MRI), and muscle biopsy reveal pathological but nonspecific findings. Determination of hexosaminidase A and B activities leads to the diagnosis. In patients with spinocerebellar ataxia hexosaminidase deficiency has to be considered as a differential diagnosis.

In the presented study we attempted to demonstrate a correlation between muscle regeneration and fibrillations in electromyography in dystrophic myopathies. Especially in Emery-Dreifuss muscular dystrophy there is much abnormal spontaneous activity, and NCAM (neural cell adhesion molecule)and cytoskeletal protein vimentin expressing myocytes are predominantly seen. Therefore, definitely regenerating fibers are identified apart from only a few remnants of previous necrosis. Moreover, in the other biopsies of dystrophic myopathies there are also scattered and clustered NCAM and vimentin expressing regenerating myofibers. Here, regressive fiber changes, like necrosis, are more prominent. Furthermore, most regenerating fibers show pseudo-cholinesterase activity indicating innervation. Interestingly, motor end-plate changes in regeneration and in disuse atrophy are very similar. They predominantly consist of terminal sprouting and pseudo-cholinesterase spread. However, in disuse atrophy there is no abnormal spontaneous spread in electromyography. Therefore, in regenerating muscle not innervation, but regeneration itself is likely to be the cause of fibrillations. In conclusion, a correlation is evident between regenerating muscle and fibrillations in electromyography.

The aim of the open prospective study was to investigate the efficacy, safety and tolerability of subcutaneous sumatriptan in acute migraine treatment. Patient self-treatment was monitored over a time period of 6-18 months with 6 mg of sumatriptan administered subcutaneously by an autoinjector. In total, 2,263 patients participated in the study. Headache intensity was documented by the patient in a headache diary before and 1 and 2 h after application. During the study period from October 1991 to June 1993, 43,691 migraine attacks were investigated. Treatment with sumatriptan was efficient in 89.5% of the attacks. Headache relief was achieved in 71%. Headache reoccurred in 22.7% of the attacks, and therefore a second injection was administered. An intraindividual treatment efficacy of 80-100% was achieved in 82.9% of the patients. During long-term treatment the ratio of effective treatment and headache frequency was constant; 4.9% of the patients withdrew from the study because of adverse events and because they felt the treatment was not effective. A total of 44.5% of the patients reported adverse events that were serious in 1.7%. Subcutaneous self-treatment with sumatriptan in the acute treatment of migraine is effective and well tolerated by the patients.

In muscle, the neural cell adhesion molecule (NCAM) is known to be expressed in denervated and regenerating fibers. Our present study, performed with immunohistochemical detection procedures, attempts to demonstrate the expression of NCAM in mitochondrial myopathy. Biopsy specimens from 29 patients were investigated. The following conditions were represented: nonweak control subjects (8 cases), chronic progressive external ophthalmoplegia (7 cases), Kearns-Sayre syndrome (5 cases), unclassified mitochondrial myopathy (2 cases), idiopathic polymyositis (7 cases). We demonstrate the expression of NCAM in mitochondrial myopathy. But NCAM is expressed in ragged-red fibers both in mitochondrial and idiopathic inflammatory myopathy. Furthermore, NCAM-immunoreactive fibers are more abundant than ragged-red and cytochrome-c-deficient fibers. Thus, we conclude that NCAM expression precedes histochemical and enzyme-histochemical demonstrable mitochondrial abnormalities. NCAM expression may reflect compensatory regenerating tendency of ragged-red fibers. Vimentin expression in mitochondrial myopathy favors this view. Probably, NCAM plays a role in the enrichment of abnormal mitochondria as a compensatory process for the biochemical deficit. The expression of NCAM in mitochondrial myopathies suggests that NCAM is related to the pathophysiology of these diseases and can be a helpful clue in the diagnosis of mitochondrial myopathy. But NCAM expression is not a specific phenomenon in mitochondrial myopathy, because in secondary mitochondrial changes like in idiopathic polymyositis NCAM expression is observed, too.

In a double-blind, placebo-controlled trial, the effect of 75 mg of a slow-release formulation of amitriptyline on the clinical severity of chronic tension-type headache and on headache-associated neurophysiological parameters (EMG activity, exteroceptive suppression of temporal muscle activity, contingent negative variation (CNV) and experimental pain sensitivity) was investigated. All of the patients treated had a history of headaches of many years standing, and numerous failed attempts at treatment. In the amitriptyline group, a significant reduction in daily headache duration was already found in the third week of treatment, while in the placebo group no significant changes in headache duration were to be seen. In week 6 the amitriptyline group had a significantly shorter daily duration of headache than the placebo group. Treatment did not result in any significant effects on EMG recording of pericranial muscle activity either during relaxation or contraction, on exteroceptive suppression of the temporal muscle and on CNV. The sensitivity to suprathreshold experimental pain, however, was significantly reduced. The data show a statistically relevant reduction of daily headache duration in chronic tension-type headache. However, they also show that amitriptyline can only partly alleviate chronic headaches but cannot cure them.

We report on the expression of growth associated protein (GAP)43 and neural cell adhesion molecule (NCAM) in congenital fibre type disproportion (CFTD) with myopathological additional signs of interstitial myositis. We assume that sarcolemmal GAP43 in developmental disordered myocytes plays a role in maintenance of growth morphology. In muscular dystrophy light microscopical evaluation reveals no GAP43 immunoreactivity in regenerating fibres. The expression of GAP43 seems to be a characteristic feature of CFTD. The expression of NCAM, particularly in the sarcolemma of small muscle fibres of CFTD, indicates a functional state of permanent partial denervation. Whether the steroid-responsive interstitial myositis is pathogenetically related to CFTD or a coincidental inflammation is not known. Because of the clinical and myopathological data the differential diagnosis of Emery-Dreifuss muscular dystrophy is considered.

Entrapment of the suprascapular nerve with shoulder pain and atrophic paresis of both the supraspinatus and infraspinatus muscles has been known since the fifties. So far a bilateral entrapment of the suprascapular nerve has rarely been described. We present a report of an endogenous bilateral entrapment neuropathy of the suprascapular nerve and discuss the differential diagnoses in relation to therapeutic and prognostic consequences.