GM1 Ganglioside role in the interaction of Alpha-synuclein with lipid membranes: Morphology and structure.

Alpha-Synuclein (AS) is the protein playing the major role in Parkinson's disease (PD), a neurological disorder characterized by the degeneration of dopaminergic neurons and the accumulation of AS into amyloid plaques. The aggregation of AS into intermediate aggregates, called oligomers, and their pathological relation with biological membranes are considered key steps in the development and progression of the disease. Here we propose a multi-technique approach to study the effects of AS in its monomeric and oligomeric forms on artificial lipid membranes containing GM1 ganglioside. GM1 is a component of functional membrane micro-domains, called lipid rafts, and has been demonstrated to bind AS in neurons. With the aim to understand the relation between gangliosides and AS, here we exploit the complementarity of microscopy (Atomic Force Microscopy) and neutron scattering (Small Angle Neutron Scattering and Neutron Reflectometry) techniques to analyze the structural changes of two different membranes (Phosphatidylcholine and Phosphatidylcholine/GM1) upon binding with AS. We observe the monomer- and oligomer-interactions are both limited to the external membrane leaflet and that the presence of ganglioside leads to a stronger interaction of the membranes and AS in its monomeric and oligomeric forms with a stronger aggressiveness in the latter. These results support the hypothesis of the critical role of lipid rafts not only in the biofunctioning of the protein, but even in the development and the progression of the Parkinson's disease.

Metástasis de carcinoma diferenciado de tiroides en localizaciones infrecuentes: serie de 30 pacientes / Unusual metastases from differentiated thyroid carcinoma: series of 30 patients and review of literature

RESUMEN Introducción Las metástasis son la principal causa de mortalidad específica en carcinoma diferenciado de tiroides (CDT). Las localizaciones más frecuentes son el pulmón y el hueso. El compromiso de otros sitios es inusual. Se desconoce el impacto que tienen en la evolución y sobrevida de los pacientes. Objetivos Evaluar la prevalencia de metástasis infrecuentes (MI) en pacientes con CDT, sus características clínico-patológicas y el impacto en la mortalidad. Material y métodos: Estudio multicéntrico retrospectivo. Se incluyeron pacientes con CDT y MI (diferentes de pulmón y hueso). Se analizaron las características basales, las localizaciones de las MI, el subtipo histológico, el tiempo de aparición desde el diagnóstico inicial (sincrónicas o metacrónicas), sintomatología asociada. Resultados La localización más frecuente fue el sistema nervioso central (31%). El 76,6% fueron metacrónicas, y presentaron criterios de refractariedad al yodo en 76,6% de los casos. La mitad de los pacientes presentó síntomas específicos. En 73,28% de los casos implicaron cambios en la conducta terapéutica. 19 pacientes (63,3%) fallecieron a causa de la enfermedad, con una mediana de sobrevida desde el diagnóstico de la MI de 11 meses. La sobrevida fue menor en pacientes con MI yodorefractarias y sintomáticas. Conclusiones: Las MI tuvieron una prevalencia baja, y se presentaron en forma metacrónica. Determinaron cambios en la estrategia terapéutica y se relacionaron con la mortalidad específica en más de la mitad de los casos, lo que resalta la importancia de una estadificación precisa en pacientes con enfermedad avanzada.

ABSTRACT Introduction Complications related to metastatic disease are the main cause of specific mortality in differentiated thyroid cancer (DTC.) The most common sites of metastses are lung and bone. Other localizations are infrequent and they have been reported as isolated cases or small series. The impact of unusual metastases (UM) in patient management and prognosis remains largely unknown. Objectives To retrospectively evaluate the prevalence of UM in DTC patients, define their clinical-pathological characteristics and analyze its relevance in management and mortality. Patients and methods: We retrospectively reviewed file records from 7 databases. DTC patients who had metastatic disease in sites different from lung or bone were included. UM were diagnosed by: i) biopsy and/or ii) radioiodine (RAI) bone uptake + elevated thyroglobulin (Tg) levels and/or c) bone uptake of 18-FDG in the PET-CT scan + elevated Tg levels. We analyzed histopathologic characteristics, clinical presentation, localization, time of diagnosis (synchronic vs. metachronic presentation), diagnostic and therapeutic modalities and final outcome of patients. Results UM were diagnosed in 30 out of 2986 DTC patients (1%). The most common site of UM was the central nervous system (CNS 31%). Twenty percent of the patients had more than one UM. In 93% of the cases, UM coexisted with either lung and/or bone metastases and/or locoregional disease. Papillary histology was found in 75% of cases; 76.6% were metachronic with DTC diagnosis, and 76.6% fulfilled radioiodine refractoriness criteria. Half of the patients reported symptoms related to the UM. In 73.2% of the cases, therapeutic decisions were influenced by the diagnosis of the UM. Nineteen patients (63.3%) died of DTC related causes, with a mean survival of 11 months. The most frequent cause of death was CNS progression. Survival was shorter in patients with radioiodine refractory and symptomatic lesions. Conclusions Prevalence of UM was low; they were predominantly metachronic and iodine refractory. UM were found in patients with widespread disease, however, treatment strategies were modified by their diagnosis. UM were associated with poor survival and disease specific mortality.

Gota y tofos en pulpejos / Gout and finger pads tophi

No existen datos exactos relativos a la prevalencia de tofos en pulpejos como manifestación inicial de la gota. El objetivo de este estudio es describir la población de pacientes con gota y evaluar la presencia de tofos en pulpejos de dedos de manos, pies y articulaciones interfalángicas distales, comparando los datos clínicos entre los pacientes con y sin tofos. Se reclutaron 161 pacientes con gota. Si bien los pacientes con tofos en pulpejos (12 pacientes) tenían mayor edad que aquellos sin tofos en esta localización, tenían mayor tiempo de evolución de la gota, mayor número de ellos tenían compromiso renal y menor porcentaje de enfermedades asociadas, ninguno de estos datos alcanzó significancia estadística.

There are no accurate data on the prevalence of tophi in finger padsas the initial manifestation of gout. The aim of this study is to describethe patients population with gout and evaluate the presence of tophiin pads of fingers, feet and distal interphalangeal joints comparingthe clinical data between patients with and without tophi.161 gout patients were recruited. While patients with tophi in pads(12 patients) were older than those without tophi at this location,had a longer history of gout, as many of them had renal involvementand lower percentage of associated diseases, none of these datareached statistical significance.

Manifestaciones inusuales de histoplasmosis en enfermedades del tejido conectivo / Unusual manifestation of histoplasmosis in connective tissue diseases

Este artículo describe la coexistencia de siete pacientes con enfermedades reumáticas: lupus eritematoso sistémico, artritis reumatoide y dermatomiositis e infección concomitante por Histoplasma capsulatum. Las enfermedades del tejido conectivo y la histoplasmosis comparten varios hallazgos clínicos. Por lo tanto, la histoplasmosis puede ser mal diagnosticada como enfermedades del tejido conectivo o como un brote de estas enfermedades. Estos casos resaltan la importancia de la concientización sobre la histoplasmosis en pacientes inmunocomprometidos, especialmente en aquellos procedentes de zonas endémicas.(AU)

Manifestaciones inusuales de histoplasmosis en enfermedades del tejido conectivo / Unusual manifestation of histoplasmosis in connective tissue diseases

Este artículo describe la coexistencia de siete pacientes con enfermedades reumáticas: lupus eritematoso sistémico, artritis reumatoide y dermatomiositis e infección concomitante por Histoplasma capsulatum. Las enfermedades del tejido conectivo y la histoplasmosis comparten varios hallazgos clínicos. Por lo tanto, la histoplasmosis puede ser mal diagnosticada como enfermedades del tejido conectivo o como un brote de estas enfermedades. Estos casos resaltan la importancia de la concientización sobre la histoplasmosis en pacientes inmunocomprometidos, especialmente en aquellos procedentes de zonas endémicas.

Registro Iberoamericano de Espondiloartritis (RESPONDIA): Argentina / RESPONDIA. Iberoamerican spondyloarthritis Registry: Argentina

Objetivo: Describir las principales características de las espondiloartritis (SpA) en la población argentina. Material y métodos: Se realizó un análisis descriptivo y transversal de la información recogida entre marzo y diciembre de 2007 y almacenada en línea, en la página electrónica del grupo Registro de Espondiloartritis de la Sociedad Española de Reumatología (REGISPONSER). Participaron 11 centros de Argentina, siguiendo todos similares pautas de evaluación del paciente y de registro de datos. Resultados: Se incluyó a 405 pacientes con SpA, 238 varones (59%), con una edad media desviación estándar de 48,1 15,7 años y un tiempo de evolución medio de la enfermedad de 10,9 9,5 años. La artritis psoriásica (APs) fue el diagnóstico prevalente (46,7%), y siguiendo en orden de frecuencia estaban la espondilitis anquilosante (EA) (30,3%) y la SpA indiferenciada (12,4%). La edad al inicio fue de 38,4 16,6 años y el tiempo de evolución hasta el diagnóstico fue de 7,5 8,6 años. Los síntomas de inicio más frecuentes fueron artritis periférica (66%), lumbalgia (54%) y sacroileítis (39%). El 43% presentó dactilitis y el 10%, uveítis durante la evolución de la enfermedad. El tratamiento incluyó inhibidores del factor de necrosis tumoral en un 10,4% de los pacientes. El BASDAI promedio fue de 4 2,5 puntos y el BASFI, de 3,3 2,9 puntos. Los pacientes con EA presentaron una edad menor, más discapacidad laboral, más dolor, una afectación axial mayor y más daño radiológico que los pacientes con APs. Regis Conclusión: Los pacientes de Argentina con SpA presentan las clásicas características de afectación axial y periférica, y con frecuencia presentan manifestaciones extraarticulares (AU)

Objective: To describe the principal characteristics of spondyloarthritis in the Argentina population. Material and methods: A descriptive transversal study was carried out with information obtained between March and December 2007 and stored online at the Spondyloarthropathy Records website of the Spanish Society for Rheumatology (REGISPONSER). Eleven Argentine Centers participated and they all adopted similar criteria to assess patients and data were collected in the same database. Results: A total of 405 patients with spondyloarthritis (SpA) were included: 238 were males (59%) with an average age standard deviation 48.1 15.7 years and an average disease progress of 10.9 9.5 years. The majority was diagnosed with psoriatic arthritis (PsA) (46.7%), followed by ankylosing spondylitis (AS) (30.3%) and undifferentiated spondyloarthritis (U-SpA) (12.4%). Average age at onset was 38.4 16.6 years and time until diagnosis was 7.5 8.6 years. The most common initial symptoms were peripheral arthritis (66%), lumbago (54%) and sacroiliitis (39%). 43% of these patients presented dactylitis and 10% uveitis during the disease Obj progress. TNF inhibitor treatment was administered in 10.4% of the patients. Average BASDAI score was 4 2.5 and BASFI 3.3 2.9. Patients with ankylosing spondylitis were younger, showed a higher incapacity for work, felt more pain and presented more axial disorders and more evidence of radiologic damage than psoriatic arthritis patients. Conclusion. Argentina spondyloarthritis patients presented classical characteristics of axial and peripheral disorders and extraarticular symptoms were common (AU)

Unusual manifestation of histoplasmosis in connective tissue diseases.

This report describes the coexistence of three patients with rheumatic diseases (systemic lupus erythematosus, rheumatoid arthritis, and dermatomyositis) and infections because of Histoplasma capsulatum. Connective tissue diseases and histoplasmosis share several clinical findings. Therefore, histoplasmosis could be misdiagnosed as connective tissue disease or a flare of these diseases. Such cases highlight the importance of awareness of histoplasmosis in immunocompromised patients, particularly in those originating from endemic areas.

Influencia de factores sociodemográficos en actividad de enfermedad, estadofuncional y calidad de vida de pacientes con artritis psoriásica / Influence of sociodemographic features on clinical manifestations, disease activity, functional status and quality of life of patients with psoriatic artritis

Objetivo: Determinar la influencia de factores sociodemográficos en las manifestaciones clínicas, actividad de la enfermedad, estado funcional y calidad de vida de pacientes con artritis psoriásica (APs). Métodos: Se incluyeron 148 pacientes con APs reclutados de varios centros de reumatología de Argentina. Se determinaron factores sociodemográficos: edad, sexo, raza, nivel de educación, fuentes de ingreso personal, escala de Graffar y clases sociales. Al inicio de la enfermedad se evaluaron las siguientes variables: edad al inicio, duración de la enfermedad, manifestaciones clínicas y forma clínica de presentación. La actividad de la enfermedad fue evaluada mediante número de articulaciones activas, escala visual análoga (EVA) global del paciente y BASDAI. El estado funcional y la calidad de vida de los pacientes se determinó por medio de BASFI, ASQoL y SF-12 (Versión 1.0). Para el análisis estadístico de los datos obtenidos se utilizó test de Chi-cuadrado, test exacto de Fisher y test de Kruskal-Wallis. Resultados: De los 148 pacientes, 58,8% fueron mujeres con una edad media al inicio de la enfermedad de 53,2 ± 13,6 años y una duración media de enfermedad de 9,3 ± 8,9 años. La edad al inicio, el sexo, la raza y la escala de Graffar no estuvieron asociados con manifestaciones clínicas, actividad de la enfermedad, estado funcional y calidad de vida

Hydrogen peroxide: effects on DNA, chromosomes, cell cycle and apoptosis induction in Fanconi's anemia cell lines.

Fanconi's anemia (FA) is an inherited autosomal recessive syndrome; cells from FA patients are very sensitive to crosslinking agents and to oxygen. Epstein-Barr virus (EBV)-transformed lymphoblasts belonging to different FA complementation groups and normal EBV-transformed lymphoblasts were studied for their response to treatment with the oxidizing agent hydrogen peroxide (H2O2). The analysis of 8-hydroxy-2'-deoxyguanosine (8-OHdG) content in the DNA of untreated cells showed an increased basal level of damage in cells from the complementation groups FA-C and FA-E. H2O2-induced 8-OHdG was higher in FA than in normal cell lines. The removal of 8-OHdG after H2O2 treatment was significantly reduced in the cells from complementation group E. However, all FA cell lines showed a normal ability in the resealing of DNA breaks, at least soon after treatment. All cell lines were also equally efficient in the removal of damaged pyrimidines. Compared with normal cells, FA cell lines showed an increase in the baseline level of micronuclei, but not in the number of micronuclei induced by H2O2. Micronuclei in FA cells originated prevalently from chromosomal fragmentation and, at a minor extent, from chromosome loss. After H2O2 treatment, FA cell lines accumulated in G(2) phase to a greater extent than normal lymphoblasts. However, reversion of mutation in FA-A and FA-C cells did not result in the correction of this phenotype. In cells evaluated for apoptosis no ladder formation was found in FA-C, FA-E and corrected FA-C cells. In conclusion, among the FA cell lines examined, only FA-E showed a defect in the repair of H2O2-induced damage. On the other hand, differences found in the cell cycle and apoptosis might be due to irreversible changes occurring in FA cell lines as a consequence of the primary defect.

Effects of simulated microgravity on metabolic activities related to DNA damage and repair in lymphoblastoid cells.

We adopted a simple experimental framework to follow the dependence of structural aberrations and the modifications in selected metabolic processes correlated with the exposure of cells to microgravity. Alterations to the cellular metabolism induced by exposure to microgravity are evidentiated in the modification of PARP activity (strongly dependent to the presence of DNA damages and to the altered gene expression), in the modification of the repair ability and in the cell's energy homeostasis (NAD and ATP). Cells are exposed continuously to microgravity in a Random Positioning Machine (RPM) in complete medium for 48 hours. At the end of this period a part of these cells are immediately analysed for the parameters reported above and the remaining were furtherly incubated in standard laboratory conditions to document eventual defects during the phases of the recovery process. A part of cells, just after exposure to microgravity, were also subjected to treatment with a strong damaging agent, KBrO3, and these cells were subsequently analyzed. This final treatment was meant to amplify the eventual deficiencies experienced by microgravity-exposed cells in the DNA repair process also in dependence with the alterated metabolic conditions resulting after the exposure to microgravity.

Chromosomal aberrations evaluated by CGH, FISH and GTG-banding in a case of AIDS-related Burkitt's lymphoma.

BACKGROUND AND OBJECTIVE: We have previously reported on a complex chromosome rearrangement [der(17)] in a B-cell line, BRG A, established from an AIDS patient with Burkitt's lymphoma (BL). The aim of the present study was the definition of der(17) composition and the identification of complete or partial chromosome gains and losses in two cell clones (BRG A and BRG M) derived from this patient. DESIGN AND METHODS: We applied comparative genome hybridization (CGH) to detect the DNA misrepresentations in the genome of the two cell clones. Findings from CGH and banding analysis could then direct the choice of probes for chromosome painting experiments to elucidate der(17) composition. RESULTS: CGH analysis identified gains of chromosomes 1q, 7q, 12q, 13q, 15q, 17p, 20p,q and losses of chromosomes 3p and 5q in BRG A and gain of chromosome 1q and loss in chromosome 6q in BRG M. Some of the detected alterations had already been described in lymphomas, while others appeared to be new. The combination of these techniques allowed a precise definition of der(17), composed by translocated regions from chromosomes 12 and 15. INTERPRETATION AND CONCLUSIONS: We demonstrated CGH to be a powerful tool in the identification of recurrent chromosome aberrations in an AIDS-related BL and in ascertaining the origin of marker chromosomes. We were also able to identify a different pattern of aberrations and assess an independent sequence of events leading to the 1p gain in the two subclones.

Extensive cutaneous necrosis associated with anticardiolipin antibodies.

Extensive cutaneous necrosis (ECN) associated with antiphospholipid antibodies is a rare presentation. We describe 2 patients with ECN and high titers of anticardiolipin antibodies. The mechanism by which these antibodies act has not been established and there is still controversy regarding treatment of these patients without established guidelines. In the few documented cases the use of pulse steroid therapy, anticoagulants, fibrinolytic agents, plasmapheresis, or a combination of them has shown some benefit. Early recognition and treatment of the antiphospholipid syndrome may limit the extent of thrombotic complications that can result in tissue necrosis.

Enteropathic arthritis in association with collagenous colitis.

A 46-year-old man simultaneously developed chronic seronegative non destructive oligoarthritis and chronic watery diarrhoea. Biopsies from the colorectal mucosa showed a thickened subepithelial collagen layer consistent with collagenous colitis. Collagenous colitis should be added to the list of causes of enteropathic arthritis.

UV-sensitive rodent mutant cell lines of complementation groups 6 and 8 differ phenotypically from their human counterparts.

Rodent UV-sensitive mutant cell lines of complementation groups 6 and 8 are the genetic counterparts of human Cockayne syndrome CS-B and CS-A, respectively. The original mutant in this group, UV61, was described as defective in cyclobutane pyrimidine dimer removal after high doses of UV. We have examined the responses of several cell lines from group 6 to low doses of UV irradiation, and find that these mutants have wild-type capacity for DNA repair as indicated by incision, cyclobutane pyrimidine dimer, and (6-4) photoproduct removal. ERCC6, the product of the gene defective in CS-B and group 6 mutants, is implicated in the regulation of repair of actively transcribed genes in Cockayne syndrome; however, this protein clearly is not required for the processing of low levels of damage in CHO cells, which occurs remarkably efficiently, 40-50% of dimers being removed in both wild-type and group 6 mutants in 5 hours following 0.1 Jm(-2) of UV. The group 8 mutant cell line US31, on the other hand, is very deficient in repair of UV damage, showing a more extreme phenotype than is seen in the corresponding human syndrome CS-A. In both complementation groups, expression of mutations in a gene involved in regulation of DNA repair takes very different forms in human and rodent cells.

Study on aneuploidy and p53 mutations in astrocytomas.

To determine whether a correlation exists between aneuploidy and p53 status in astrocytic tumors we analyzed 48 astrocytomas with different grades of malignancy for the presence of p53 mutations and aneuploidy of chromosomes 10 and 17 (Ch10, Ch17), known to be particularly involved with this type of tumor. We used polymerase chain reaction (PCR)-based denaturing gradient gel electrophoresis (DGGE) analysis on exons 5-8 of the p53 gene, and fluorescence in situ hybridization (FISH) analysis on interphase nuclei using chromosome specific pericentromeric probes, respectively. Our results showed that Ch10/Ch17 aneuploidy is a common early event in astrocytomas (90% of low grade tumors are aneuploid). p53 mutations and Ch17 aneuploidy are early events, but their incidence is not dependent on tumor grade. Loss of Ch10 is the only alteration that significantly correlates with tumor progression. No significant correlation between the presence of Ch10/Ch17 aneuploidy and p53 mutations was found. However, the coexistence of p53 mutations and aneuploidy, was observed in a subset of cases. The presence of p53 mutations appeared to be a significant predictor of a poor prognosis. In conclusion, genomic instability may or may not be associated with p53 mutations in astrocytomas, thus suggesting that other cellular determinants can also be responsible for the aneuploidy observed.

Chromosomal assignment of human O6-methylguanine-DNA-methyltransferase gene by hamster-human somatic cell hybrids.

Using an in vitro assay to measure O6-methylguanine-DNA-methyltransferase (MT) activity in cell extracts from a panel of human-hamster cell hybrids, we were able to locate the human MT gene on chromosome 10. Chinese hamster cells have little or no MT activity and the presence of human chromosome 10 was a necessary condition for MT activity in cell hybrids. In some cell hybrids carrying chromosome 10, however, MT activity was not higher than that of hamster cells. As an explanation for this result, genetic determinants repressing MT expression and/or activity might be present in other human chromosomes carried by MT-negative cell hybrids. Partial hyperploidy of the hamster karyotype, variable activity of the parental human cell lines and changes during subculturing of the cell hybrids might also account for the lack of enzymatic activity in chromosome 10 containing hybrids.