Publications by authors named "Ricardo Fadic"

21 Publications

  • Page 1 of 1

Clinical Subtypes of Medication Overuse Headache - Findings From a Large Cohort.

Headache 2019 10 3;59(9):1481-1491. Epub 2019 Oct 3.

Headache Science Center, IRCCS Mondino Foundation, Pavia, Italy.

Background: The International Classification of Headache Disorders lists different subtypes of medication overuse headache (MOH), according to the medication overused. The aim of this study is to evaluate whether the different subtypes correspond to clinically distinguishable phenotypes in a large population.

Method: This descriptive cross-sectional observational study included 660 patients with MOH referred to headache centers in Europe and Latin America as a part of the COMOESTAS project. Information about clinical features was collected with structured patient interviews and with self-administered questionnaires for measuring disability, anxiety, and depression.

Results: Female/male ratio, body mass index, marital status, and level of education were similar among in subjects enrolled in the 5 centers. The mean age was higher among subjects overusing triptans (T-MOH) with respect to subjects overusing simple analgesic (A-MOH). Duration of headache before chronification was longer in T-MOH (19.2 ± 11.9 years) and in subjects overusing ergotamines (E-MOH, 17.8 ± 11.7 years) with respect to the A-MOH group (13.1 ± 10.9; P < .001 and P = .017, respectively) and in T-MOH with respect multiple drug classes (M-MOH, 14.9 ± 11.7; P = .030). Migraine Disability Assessment (MIDAS) score was significantly lower in E-MOH group (33.6 ± 41.6), while T-MOH group (56.8 ± 40.6) had a significant lower MIDAS score with respect to M-MOH (67.2 ± 62.5; P = .016 and P = .037, respectively). Prevalence of depression and anxiety was lower in patients overusing T with respect to other groups of patients (χ  = 10.953, P = .027 and χ  = 25.725, P < .001, respectively).

Conclusion: In this study on a large and very well characterized population of MOH, we describe the distinctive clinical characteristics of MOH subtypes. These findings contribute to more clearly define the clinical picture of a poorly delineated headache disorder. They also provide some insights in the possible trajectories leading to this highly disabling chronic headache, that is classified as a secondary form, but whose occurrence is entirely dependent on an underlying primary headache.
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http://dx.doi.org/10.1111/head.13641DOI Listing
October 2019

Economic benefits of treating medication-overuse headache - results from the multicenter COMOESTAS project.

Cephalalgia 2019 02 8;39(2):274-285. Epub 2018 Jul 8.

7 Headache Science Centre, C. Mondino National Neurological Institute, Pavia, Italy.

Background: Medication-overuse headache is a costly disease for individuals and society.

Objective: To estimate the impact of medication-overuse headache treatment on direct and indirect headache-related health care costs.

Methods: This prospective longitudinal study was part of the COMOESTAS project (COntinuous MOnitoring of Medication Overuse Headache in Europe and Latin America: development and STAndardization of an Alert and decision support System). Patients with medication-overuse headache were included from four European and two Latin American headache centers. Costs of acute medication, costs of health care services, and measurements of productivity were calculated at baseline and at 6-month follow-up Treatment consisted of overused drug withdrawal with optional preventive medication.

Results: A total of 475 patients (71%) completed treatment and were followed up for 6 months. Direct health care costs were on average reduced significantly by 52% ( p < 0.001) for the total study population. Significant reductions were seen in both number of consumed tablets (-71%, p < 0.001) and number of visits to physicians (-43%, p < 0.001). Fifty percent of patients reduced their number of consumed tablets ≥ 80%. Headache-related productivity loss, calculated either as absence from work or ≥ 50% reduction of productivity during the workday, were reduced by 21% and 34%, respectively ( p < 0.001).

Conclusion: Standardized treatment of medication-overuse headache in six countries significantly reduced direct health care costs and increased productivity. This emphasizes the importance of increasing awareness of the value of treating medication-overuse headache.

Trial Registration: The trial was registered at ClinicalTrials.gov (no. NCT02435056).
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http://dx.doi.org/10.1177/0333102418786265DOI Listing
February 2019

Psychological, clinical, and therapeutic predictors of the outcome of detoxification in a large clinical population of medication-overuse headache: A six-month follow-up of the COMOESTAS Project.

Cephalalgia 2019 01 27;39(1):135-147. Epub 2018 Jun 27.

1 Headache Science Centre, IRCCS Mondino Foundation, Pavia, Italy.

Aim: To identify factors that may be predictors of the outcome of a detoxification treatment in medication-overuse headache.

Methods: Consecutive patients entering a detoxification program in six centres in Europe and Latin America were evaluated and followed up for 6 months. We evaluated anxious and depressive symptomatology (though patients with severe psychiatric comorbidity were excluded), quality of life, headache-related disability, headache characteristics, and prophylaxis upon discharge.

Results: Of the 492 patients who completed the six-month follow up, 407 ceased overuse following the detoxification (non overusers), another 23 ceased overuse following detoxification but relapsed during the follow-up. In the 407 non-overusers, headache acquired an episodic pattern in 287 subjects (responders). At the multivariate analyses, lower depression scores (odds ratio = 0.891; p = 0.001) predicted ceasing overuse. The primary headache diagnosis - migraine with respect to tension-type headache (odds ratio = 0.224; p = 0.001) or migraine plus tension-type headache (odds ratio = 0.467; p = 0.002) - and the preventive treatment with flunarizine (compared to no such treatment) (odds ratio = 0.891; p = 0.001) predicted being a responder. A longer duration of chronic headache (odds ratio = 1.053; p = 0.032) predicted relapse into overuse. Quality of life and disability were not associated with any of the outcomes.

Conclusions: Though exploratory in nature, these findings point to specific factors that are associated with a positive outcome of medication-overuse headache management, while identifying others that may be associated with a negative outcome. Evaluation of the presence/absence of these factors may help to optimize the management of this challenging groups of chronic headache sufferers.
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http://dx.doi.org/10.1177/0333102418783317DOI Listing
January 2019

Changes in anxiety and depression symptoms associated to the outcome of MOH: A post-hoc analysis of the Comoestas Project.

Cephalalgia 2018 04 11;38(4):646-654. Epub 2017 Apr 11.

1 Headache Science Centre, C. Mondino National Neurological Institute, Pavia, Italy.

Aims To evaluate the impact of treatment success on depression and anxiety symptoms in medication-overuse headache (MOH) and whether depression and anxiety can be predictors of treatment outcome. Methods All consecutive patients entering the detoxification program were analysed in a prospective, non-randomised fashion over a six-month period. Depression and anxiety were assessed using the Hospital Anxiety and Depression Scale. Results A total of 663 MOH patients were evaluated, and 492 completed the entire protocol. Of these, 287 ceased overuse and reverted to an episodic pattern (responders) and 23 relapsed into overuse. At the final evaluation, the number of patients with depressive symptoms was reduced by 63.2% among responders ( p < 0.001) and did not change in relapsers ( p = 0.13). Anxious symptomatology was reduced by 43.1% in responders ( ps < 0.001) and did not change in relapsers ( p = 0.69). At the multivariate analysis, intake of a prophylactic drug and absence of symptoms of depression at six months emerged as prognostic factors for being a responder (OR 2.406; p = 0.002 and OR 1.989; p = 0.019 respectively), while lack of antidepressant drugs and presence of symptoms of depression at six months were prognostic factors for relapse into overuse (OR 3.745; p = 0.004 and OR 3.439; p = 0.031 respectively). Conclusions Symptomatology referred to affective state and anxiety can be significantly reduced by the treatment of MOH. Baseline levels of depression and anxiety do not generally predict the outcome at six months. Their persistence may represent a trait of patients with a negative outcome, rather than the consequence of a treatment failure.
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http://dx.doi.org/10.1177/0333102417704415DOI Listing
April 2018

The added value of an electronic monitoring and alerting system in the management of medication-overuse headache: A controlled multicentre study.

Cephalalgia 2017 Oct 20;37(12):1115-1125. Epub 2016 Jul 20.

1 Headache Science Centre, C. Mondino National Neurological Institute, Pavia, Italy.

Background Medication-overuse headache (MOH) is a chronic disabling condition associated with a high rate of relapse. Methods We evaluated whether the adoption of electronic-assisted monitoring, advice and communication would improve the outcome over a follow-up of 6 months in a controlled, multicentre, multinational study conducted in six headache centres located in Europe and Latin America. A total of 663 MOH subjects were enrolled and divided into two groups: the Comoestas group was monitored with an electronic diary associated with an alert system and a facilitated communication option, and the Classic group with a paper headache diary. Results We observed a significantly higher percentage of overuse-free subjects in the Comoestas group compared with the Classic group: 73.1 vs 64.1% (odds ratio 1.45, 95% confidence interval 1.07-2.09, p = 0.046). The Comoestas group performed better also regarding the number of days/month with intake of acute drugs and the level of disability [Migraine Disability Assessment Score: Comoestas group - 42.5 ± 53.6 (35.5-49.3) and Classic group - 27.5 ± 56.1 (20.6-34.3) ( p < 0.003)]. Conclusion The adoption of the electronic tool improved the outcome of patients suffering from MOH after withdrawal from overused drugs. Information and communication technology represents a valid aid for optimizing the management of chronic conditions at risk of worsening or of relapsing. Trial registration The trial was registered at ClinicalTrials.gov (no. NCT02435056).
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http://dx.doi.org/10.1177/0333102416660549DOI Listing
October 2017

Medication overuse headache in Europe and Latin America: general demographic and clinical characteristics, referral pathways and national distribution of painkillers in a descriptive, multinational, multicenter study.

J Headache Pain 2015 8;17:20. Epub 2016 Mar 8.

Danish Headache Center, Neurological Department, Glostrup Hospital, Glostrup, Denmark.

Background: Medication overuse headache (MOH) is a very disabling and costly disorder due to indirect costs, medication and healthcare utilization. The aim of the study was to describe general demographic and clinical characteristics of MOH, along with the national referral pathways and national painkillers distribution in several European and Latin American (LA) Countries.

Methods: This descriptive cross-sectional observational study included 669 patients with MOH referred to headache-centers in Europe and LA as a part of the COMOESTAS project. Information about acute medication and healthcare utilization were collected by extensive questionnaires, supplemented with structured patient interviews.

Results: Triptans were overused by 31 % European patients and by 6 % in LA (p < 0.001), whereas ergotamines were overused by 4 % in Europe and 72 % in LA (p < 0.001). Simple analgesics were overused by 54 % in Europe and by 33 % in LA (p < 0.001), while combination-analgesics were more equally overused (24 % in Europe and 29 % in LA). More European patients (57 %) compared with LA patients (27 %) visited general practitioners (p < 0.001), and 83 % of European patients compared to 38 % in LA consulted headache specialists (p < 0.001). A total of 20 % in Europe and 30 % in LA visited emergency rooms (p = 0.007).

Conclusion: There are marked variations between LA and Europe in healthcare pathways and in acute medication overuse regarding patients with MOH. This should be considered when planning prevention campaigns against MOH.
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http://dx.doi.org/10.1186/s10194-016-0612-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783306PMC
September 2016

Clinical and Demographical Characteristics of Patients with Medication Overuse Headache in Argentina and Chile: Analysis of the Latin American Section of COMOESTAS Project.

J Headache Pain 2015 18;16:83. Epub 2015 Sep 18.

Headache Science Centre, C. Mondino National Neurological Institute, Pavia, Italy.

Background: Data on the characteristics of Medication Overuse Headache (MOH) in Latin American (LA) are scarce. Here we report the demographic and clinical features of the MOH patients from Argentina and Chile enrolled in the multinational COMOESTAS project in the period 2008-2010.

Methods: The LA population was formed by 240 MOH subjects, 110 from Chile and 130 from Argentina, consecutively attending the local headache centres. In each centre, specifically trained neurologist interviewed and confirmed the diagnosis according to the ICHD-II criteria. A detailed history was collected on an electronic patient record form.

Results: The mean patient age was 38.6 years, with a female/male ratio of 8:2. The mean time since onset of the primary headache was 21 years, whereas duration of MOH was 3.9 years. The primary headache was migraine without aura in 77.5 % and migraine with aura in 18.8 %. Forty two % of the patients self-reported emotional stress associated with the chronification of headache; 43.8 % reported insomnia. The most overused medications were acute drug combinations containing ergotamine (70 %), NSAIDs (33.8 %) and triptans (5.4 %).

Conclusion: Though little described, MOH is present also in LA, where it affects mostly women, in the most active decades of life. Some differences emerge as regards the demographic and clinical characteristics of MOH in this population as compared to Europe or Northern America. What seems more worrying about MOH in Argentina and Chile is that most patients overuse ergotamine, a drug that may cause serious adverse events when used chronically. These findings once more underscore the importance of properly diagnose and treat MOH.
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http://dx.doi.org/10.1186/s10194-015-0561-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573742PMC
May 2016

Andrographolide attenuates skeletal muscle dystrophy in mdx mice and increases efficiency of cell therapy by reducing fibrosis.

Skelet Muscle 2014 21;4. Epub 2014 Mar 21.

Centro de Regulación Celular y Patología (CRCP), Centro de Regeneración y Envejecimiento (CARE), Laboratorio de Diferenciación Celular y Patología, Departamento de Biología Celular y Molecular, MIFAB, Pontificia Universidad Católica de Chile, Avenida Libertador Bernardo O'Higgins, 340, Santiago, Chile.

Background: Duchenne muscular dystrophy (DMD) is characterized by the absence of the cytoskeletal protein dystrophin, muscle wasting, increased transforming growth factor type beta (TGF-β) signaling, and fibrosis. At the present time, the only clinically validated treatments for DMD are glucocorticoids. These drugs prolong muscle strength and ambulation of patients for a short term only and have severe adverse effects. Andrographolide, a bicyclic diterpenoid lactone, has traditionally been used for the treatment of colds, fever, laryngitis, and other infections with no or minimal side effects. We determined whether andrographolide treatment of mdx mice, an animal model for DMD, affects muscle damage, physiology, fibrosis, and efficiency of cell therapy.

Methods: mdx mice were treated with andrographolide for three months and skeletal muscle histology, creatine kinase activity, and permeability of muscle fibers were evaluated. Fibrosis and TGF-β signaling were evaluated by indirect immunofluorescence and Western blot analyses. Muscle strength was determined in isolated skeletal muscles and by a running test. Efficiency of cell therapy was determined by grafting isolated skeletal muscle satellite cells onto the tibialis anterior of mdx mice.

Results: mdx mice treated with andrographolide exhibited less severe muscular dystrophy than untreated dystrophic mice. They performed better in an exercise endurance test and had improved muscle strength in isolated muscles, reduced skeletal muscle impairment, diminished fibrosis and a significant reduction in TGF-β signaling. Moreover, andrographolide treatment of mdx mice improved grafting efficiency upon intramuscular injection of dystrophin-positive satellite cells.

Conclusions: These results suggest that andrographolide could be used to improve quality of life in individuals with DMD.
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http://dx.doi.org/10.1186/2044-5040-4-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4021597PMC
May 2014

[Mitochondrial DNA heteroplasmy of the m.3243A>G mutation in maternally inherited diabetes and deafness].

Rev Med Chil 2013 Mar;141(3):305-12

Departamento de Nutrición, Diabetes y Metabolismo, Pontificia Universidad Católica de Chile, Chile.

Maternally Inherited Diabetes and Deafness (MIDD) is caused by mutations in mitochondrial DNA (mtDNA), mainly m.3243A>G. Severity, onset and clinical phenotype of MIDD patients are partially determined by the proportion of mutant mitochondrial DNA copies in each cell and tissue (heteroplasmy). The identification of MIDD allows a corred treatment with insulin avoiding drugs that may interfere with mitochondrial electrón chain transpon. We estimated the degree of heteroplasmy of the mutation m.3243A>G from blood, saliva, hair root and a muscle biopsy using quantitative PCR (qPCR) in a femóle adult patient. For this purpose, PCR producís were inserted in a vector creating plasmids with 3243A or G. Mutant and wild-type vectors were mixed in different proportions to créate a calibration curve used to interpólate heteroplasmy percentages with qPCR threshold cycles. The proportions of m.3243A>G heteroplasmy were 62% (muscle), 14% (saliva), 6% (blood leukocytes) and 3% in hair root. Quantitative analysis of heteroplasmy showed marked variations in different tissues (highest in muscle and lowest in blood). Given the relatively high heteroplasmy found in saliva, this type of biológical sample may represent an adequate non-invasive way for assessing the presence of m.3243A>G mutations in epidemiologic studies.
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http://dx.doi.org/10.4067/S0034-98872013000300004DOI Listing
March 2013

Pure autonomic failure with cold induced sweating.

Auton Neurosci 2013 Jun 16;176(1-2):98-100. Epub 2013 Mar 16.

Universidad de Valparaíso. School of Medicine, Valparaíso Chile.

Pure autonomic failure (PAF) is a progressive autonomic neurodegenerative disorder. Cold induced sweating occurred in syndromes with mutations in CRLF1 and CLCF1 genes and in a case of cervical dissection. A patient with PAF developed sweating induced by cool ambient temperatures. He had severe orthostatic hypotension, abnormal cardiovagal reflexes, and paradoxical sweating in the upper trunk at a room temperature of 18°C. Skin biopsy showed involvement of somatic epidermal unmyelinated nerve fibers. Quantitative sensory testing showed abnormal thresholds to all thermal modalities. Possible mechanisms include cold induced noradrenaline release in remaining autonomic innervation and a supersensitive sudomotor response.
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http://dx.doi.org/10.1016/j.autneu.2013.02.019DOI Listing
June 2013

Cervical disc herniation producing acute Brown-Sequard syndrome: dynamic changes documented by intraoperative neuromonitoring.

Eur Spine J 2012 Jun 16;21 Suppl 4:S418-21. Epub 2011 Jun 16.

Department of Orthopaedic Surgery, Pontificia Universidad Catolica de Chile, Marcoleta 352, Santiago, Chile.

Introduction: Brown-Sequard syndrome is an incomplete spinal cord lesion characterized by ipsilateral loss of motor function and contralateral loss of pain and temperature sensitivity, reflecting a hemi-compression or hemi-section of the spinal cord. Cervical disc herniation is an exceptional cause of this syndrome.

Material And Methods: We report a case of cervical disc herniation causing Brown-Sequard syndrome in a patient with an unusually rapid neurological deterioration associated to cervical extension, which was documented by neuromonitoring.

Conclusion: A prompt diagnosis, followed by spinal cord decompression should be warranted. Intraoperative neuromonitoring is a useful tool in preservation of neurologic function in these cases.
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http://dx.doi.org/10.1007/s00586-011-1881-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369036PMC
June 2012

[Stem cells therapy in amyotrophic lateral sclerosis treatment. A critical view].

Rev Neurol 2011 Apr;52(7):426-34

Departamento de Neurología, Laboratorio de Neurociencias, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.

Introduction: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. At present, there are not curative therapies for ALS. Pathogenic and progression mechanisms suggest the existence of oxidative stress, abnormal intracellular protein aggregation, mitochondrial dysfunction, axonal transport impairment, impairment of trophic support, altered glial cell function, and glutamate excitoxicity.

Aim: To evaluate therapeutic results with adult stem cell for ALS treatment.

Development: Stem cells represent a potential therapeutic strategy, because their biological mechanisms could act on several of the pathogenic mechanisms proposed for ALS. Bone marrow mesenchymal stem cells are especially interesting among adult stem cells. Mesenchymal stem cells can differentiate in all central nervous system cells and potentially replace them. Furthermore, they have immunomodulatory effects, secreting, especially in neuroinflammatory environments, neurotrophic and antiinflammatory factors. Studies in murine models of ALS show decrease of inflammation and disease progression, and increase on animal highly heterogeneous, suggest that mesenchymal stem cells transplant in ALS appears to be safe. However, they fail showing clinical improvement of patients.

Conclusion: Additional preclinical studies are necessary to refine this therapeutic approach, to assess long term survival and differentiation of mesenchymal stem cells, dosing, biological activity and safety should be conducted before any planning further human testing occurs.
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April 2011

[Orthostatic tremor causing postural instability in Parkinson disease: report of one case].

Rev Med Chil 2010 Nov 27;138(11):1410-3. Epub 2011 Jan 27.

Departamento de Neurología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Temuco, Chile.

Parkinson disease (PD) is a movement disorder characterized clinically by the variable combination of rigidity, bradykinesia, rest tremor and postural instability. Usually postural instability is a late-onset manifestation and is frequently associated with axial manifestations and with a poor prognosis. We report a 67-year-old female with orthostatic tremor as the etiology of her postural instability. The patient was treated with increasing doses of clonazepam, reaching 2 mg/day, and levodopa. There was an improvement of postural instability with a good response of parkinsonian symptoms.
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http://dx.doi.org//S0034-98872010001200010DOI Listing
November 2010

Transient orthostatic hypertension after partial cerebellar resection.

Clin Auton Res 2011 Feb 16;21(1):57-9. Epub 2010 Sep 16.

Universidad de Valparaíso, 22 Viña del Mar, Valparaíso, Chile.

An effective baroreflex and autonomic pathways normally ensure that blood pressure (BP) is satisfactorily maintained, despite various stimuli in daily life that include postural changes. We describe a 20-year-old man with a cerebellar hematoma and acute hydrocephalus, who had a vermian and partial right cerebellar hemisphere resection followed by orthostatic hypertension (OHT) and mutism. On standing his systolic BP rose over 60 mmHg with a fivefold increase in plasma noradrenaline. After a period of 8 weeks, postural BP regulation improved along with his ability to communicate. We conclude that transient impairment of cerebellar autonomic modulation or dysfunction of the baroreflex medullary circuit, may have resulted in OHT.
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http://dx.doi.org/10.1007/s10286-010-0085-3DOI Listing
February 2011

Intracellular amyloid formation in muscle cells of Abeta-transgenic Caenorhabditis elegans: determinants and physiological role in copper detoxification.

Mol Neurodegener 2009 Jan 6;4. Epub 2009 Jan 6.

Centro de Regulación Celular y Patología "Joaquín V, Luco" (CRCP), MIFAB, Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, 8331010 Santiago, Chile.

Background: The amyloid beta-peptide is a ubiquitous peptide, which is prone to aggregate forming soluble toxic oligomers and insoluble less-toxic aggregates. The intrinsic and external/environmental factors that determine Abeta aggregation in vivo are poorly understood, as well as the cellular meaning of this process itself. Genetic data as well as cell biological and biochemical evidence strongly support the hypothesis that Abeta is a major player in the onset and development of Alzheimer's disease. In addition, it is also known that Abeta is involved in Inclusion Body Myositis, a common myopathy of the elderly in which the peptide accumulates intracellularly.

Results: In the present work, we found that intracellular Abeta aggregation in muscle cells of Caenorhabditis elegans overexpressing Abeta peptide is affected by two single amino acid substitutions, E22G (Arctic) and V18A (NIC). Both variations show decrease intracellular amyloidogenesis compared to wild type Abeta. We show that intracellular amyloid aggregation of wild type Abeta is accelerated by Cu2+ and diminished by copper chelators. Moreover, we demonstrate through toxicity and behavioral assays that Abeta-transgenic worms display a higher tolerance to Cu2+ toxic effects and that this resistance may be linked to the formation of amyloid aggregates.

Conclusion: Our data show that intracellular Abeta amyloid aggregates may trap excess of free Cu2+ buffering its cytotoxic effects and that accelerated intracellular Abeta aggregation may be part of a cell protective mechanism.
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http://dx.doi.org/10.1186/1750-1326-4-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2632641PMC
January 2009

Inclusion body myositis: a view from the Caenorhabditis elegans muscle.

Mol Neurobiol 2008 Oct 5;38(2):178-98. Epub 2008 Sep 5.

Centro de Envejecimiento y Regeneración (CARE), Centro de Regulación Celular y Patología Joaquín V. Luco, MIFAB, Facultad de Ciencias Biológicas, P. Universidad Católica de Chile, Alameda 340, Santiago, Chile.

Inclusion body myositis (IBM) is the most common myopathy in people over 50 years of age. It involves an inflammatory process that, paradoxically, does not respond to anti-inflammatory drugs. A key feature of IBM is the presence of amyloid-beta-peptide aggregates called amyloid deposits, which are also characteristic of Alzheimer's disease. The use of animals that mimic at least some characteristics of a disease has become very important in the quest to elucidate the molecular mechanisms underlying this and other pathogeneses. Although there are some transgenic mouse strains that recreate some aspects of IBM, in this review, we hypothesize that the great degree of similarity between nematode and human genes known to be involved in IBM as well as the considerable conservation of biological mechanisms across species is an important feature that must be taken into consideration when deciding on the use of this nematode as a model. Straightforward laboratory techniques (culture, transformation, gene knockdown, genetic screenings, etc.) as well as anatomical, physiological, and behavioral characteristics add to the value of this model. In the present work, we review evidence that supports the use of Caenorhabditis elegans as a biological model for IBM.
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http://dx.doi.org/10.1007/s12035-008-8041-0DOI Listing
October 2008

Skeletal muscle cells express the profibrotic cytokine connective tissue growth factor (CTGF/CCN2), which induces their dedifferentiation.

J Cell Physiol 2008 May;215(2):410-21

Centro de Regulación y Patología Joaquín V. Luco, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, MIFAB, Santiago, Chile.

Fibrotic disorders are typified by excessive connective tissue and extracellular matrix (ECM) deposition that precludes normal healing processes of different tissues. Connective tissue growth factor (CTGF) seems to be involved in the fibrotic response. Several muscular dystrophies are characterized by a progressive weakness and wasting of the musculature, and by extensive fibrosis. However, the exact role of CTGF in skeletal muscle is unknown. Here we show that myoblasts and myotubes are able to synthesize CTGF in response to transforming growth factor type-beta (TGF-beta) and lysophosphatidic acid (LPA). CTGF induced several ECM constituents such as fibronectin, collagen type I and alpha4, 5, 6, and beta1 integrin subunits in myoblasts and myotubes. CTGF had an important inhibitory effect on muscle differentiation evaluated by the decrease in the nuclear translocation of the early muscle regulatory factor myogenin and myosin. Remarkable, CTGF treatment of myoblasts induced their dedifferentiation, characterized by down regulating MyoD and desmin, two markers of committed myoblasts, together with a strong reorganization of cytoskeletal filaments. These results provide novel evidence for the underlying mechanisms and participation of skeletal muscle cells in the synthesis and role of CTGF inducing fibrosis, inhibiting myogenesis and dedifferentiating myoblasts.
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http://dx.doi.org/10.1002/jcp.21324DOI Listing
May 2008

Increase in decorin and biglycan in Duchenne Muscular Dystrophy: role of fibroblasts as cell source of these proteoglycans in the disease.

J Cell Mol Med 2006 Jul-Sep;10(3):758-69

Departamento de Neurología, Facultad de Medicina. Pontificia Universidad Católica de Chile, Santiago, Chile.

Fibrosis is a common pathological feature observed in muscles of patients with Duchenne muscular dystrophy (DMD). Biglycan and decorin are small chondroitin/dermatan sulfate proteoglycans in the muscle extracellular matrix (ECM) that belong to the family of structurally related proteoglycans called small leucine-rich repeat proteins. Decorin is considered an anti-fibrotic agent, preventing the process by blocking TGF-beta activity. There is no information about their expression in DMD patients. We found an increased amount of both proteoglycans in the ECM of skeletal muscle biopsies obtained from DMD patients. Both biglycan and decorin were augmented in the perimysium of muscle tissue, but only decorin increased in the endomysium as seen by immunohistochemical analyses. Fibroblasts were isolated from explants obtained from muscle of DMD patients and the incorporation of radioactive sulfate showed an increased synthesis of both decorin and biglycan in cultured fibroblasts compared to controls. The size of decorin and biglycan synthesized by DMD and control fibroblasts seems to be similar in size and anion charge. These findings show that decorin and biglycan are increased in DMD skeletal muscle and suggest that fibroblasts would be, at least, one source for these proteoglycans likely playing a role in the muscle response to dystrophic cell damage.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933157PMC
http://dx.doi.org/10.1111/j.1582-4934.2006.tb00435.xDOI Listing
January 2007

Cell surface and gene expression regulation molecules in dystrophinopathy: mdx vs. Duchenne.

Authors:
Ricardo Fadic

Biol Res 2005 ;38(4):375-80

Unidad Neuromuscular, Departamento de Neurología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.

Duchenne muscular dystrophy (DMD) is secondary to loss-of-function mutations in the dystrophin gene. The causes underlying the progression of DMD, differential muscle involvement, and the discrepancies in phenotypes among species with the same genetic defect are not understood. The mdx mouse, an animal model with dystrophin mutation, has a milder phenotype. This article reviews the available information on expression of signaling-related molecules in DMD and mdx. Extracellular matrix proteoglycans, growth factors, integrins, caveolin-3, and neuronal nitric oxide synthase expression do not show significant differences. Calcineurin is inconsistently activated in mdx. which is associated with lack of cardiomyopathy, compared to the permanent calcineurin activation in mdx/utrophin null mice that have a DMD-like cardiomyopathy. Levels of focal adhesion kinase (FAK) and extracellular regulated kinases (ERKs) differ among mdx and DMD. Further work is needed to identify the point of discrepancy in these signaling molecules' pathways in dystrophynopathies.
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http://dx.doi.org/10.4067/s0716-97602005000400010DOI Listing
July 2006

Distal site testing of sympathetic skin response (big toe) in diabetic polyneuropathy.

Clin Auton Res 2004 Dec;14(6):401-4

Hospital Naval, Universidad de Valparaíso Subida Alessandri s/n, 4 Norte 1093 depto, 22 Viña del Mar, Chile.

The aim of this study was to determine whether the sympathetic skin response (SSR) recorded from the big toe is more sensitive than standard SSR recorded from the sole for the detection of sudomotor fiber dysfunction in diabetic neuropathy. We recorded big toe SSR (SSRBT) and plantar SSR (SSRP) in 17 diabetic patients with non-disabling neuropathy (group A), 13 patients with disabling neuropathy (group B) and 30 age-matched normal controls. With regard to controls, SSRP amplitude was reduced only in group B. In contrast, SSRBT amplitude was reduced in both groups of patients (p<0.0001). In 8 patients in group B, SSRBT was not recordable while the SSRP still persisted. Our results suggest that SS-RBT is a more sensitive test than SSRP in detecting distal sudomotor failure in patients with diabetic neuropathy.
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http://dx.doi.org/10.1007/s10286-004-0215-xDOI Listing
December 2004

Augmented synthesis and differential localization of heparan sulfate proteoglycans in Duchenne muscular dystrophy.

J Cell Biochem 2002 ;85(4):703-13

Centro de Regulación y Patología, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, MIFAB, P. Universidad Católica de Chile, Santiago, Chile.

Muscular dystrophies are characterized by continuous cycles of degeneration and regeneration that result in extensive fibrosis and a progressive diminution of muscle mass. Cell surface heparan sulfate proteoglycans are found almost ubiquitously on the surface and in the extracellular matrix (ECM) of mammalian cells. These macromolecules interact with a great variety of ligands, including ECM constituents, adhesion molecules, and growth factors. In this study, we evaluated the expression and localization of three heparan sulfate proteoglycans in the biopsies of Duchenne muscular dystrophy (DMD) patients. Through SDS-PAGE analyses followed by specific identification of heparitinase-digested proteins with an anti-Delta-heparan sulfate specific monoclonal antibodies, we observed an increase of three forms of heparan sulfate proteoglycans, corresponding to perlecan, syndecan-3, and glypican-1. Immunohistochemistry analyses indicated a differential localization for these proteoglycans: glypican-1 and perlecan were found mainly associated to ECM structures, while syndecan-3 was associated to muscle fibers. These results suggest that the amount of specific heparan sulfate proteoglycans is augmented in skeletal muscle in DMD patients presenting a differential localization.
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http://dx.doi.org/10.1002/jcb.10184DOI Listing
October 2002