Biomarkers of Oxidative Stress in Huntington's Disease and Other Neurological Disorders: a Comparative Study

Foundation: biomarkers of oxidative stress in Huntington's disease could predict the course of the disease and evaluate new treatments, but their nonspecific nature seems to prevent the identification of any useful marker. Clarifying similarities and differences of this phenomenon and its behavior with clinical characteristics may be essential. Objective: compare biomarkers of oxidative stress between patients with Huntington's disease and other neurological disorders. Methods: an analytical, retrospective and case-control study was carried out (Huntington's disease, amyotrophic lateral sclerosis, spinocerebellar ataxia type 2 and ischemic stroke: acute and chronic stage). Demographic and clinical variables and markers of oxidative damage (malonildialdehyde, advanced protein oxidation products) and antioxidants (superoxide dismutase: catalase: glutathione peroxidase, plasma antioxidant capacity) were collected. Results: there were significant differences in malonyldialdehyde in Huntington's disease compared to the control (p=0.02), but not with the rest of the groups. The enzyme superoxide dismutase in Huntington's disease was statistically lower compared to amyotrophic lateral sclerosis, although for catalase it was higher in relation to the rest of the patients. FRAP in Huntington's disease was significantly lower versus amyotrophic lateral sclerosis and acute ischemic stroke. Advanced products of protein oxidation were directly correlated with the biological and onset ages of Huntington's disease. Motor activity in amyotrophic lateral sclerosis and neurological deficit in acute ischemic stroke were correlated with malonyldialdehyde and glutathione peroxidase, respectively. Conclusions: huntington's disease seems to show specific characteristics in its antioxidant system. Protein oxidation could be related to the accumulation of mutated huntingtin over time

Case report: Efficacy of immunotherapy as conversion therapy in dMMR/MSI-H colorectal cancer: a case series and review of the literature

Immunotherapy has demonstrated a role in the therapeutic landscape of a small subset of patients with colorectal carcinoma (CRC) that harbor a microsatellite instability (MSI-H) status due to a deficient DNA mismatch repair (dMMR) system. The remarkable responses to immune checkpoint inhibitors (ICIs) are now being tested in the neoadjuvant setting in localized CRC, where the dMMR/MSI-H status can be found in up to 15% of patients, with remarkable results obtained in NICHE2 and 3 trials, among others. This case series aims to report our experience at a tertiary center and provide a comprehensive analysis of the possible questions and challenges to overcome if ICIs were established as standard of care in a neoadjuvant setting, as well as the potential role they may have as conversion therapy not only in locoregional advanced CRC but also in oligometastatic disease

Diverse Large HIV-1 Non-subtype B Clusters Are Spreading Among Men Who Have Sex With Men in Spain

In Western Europe, the HIV-1 epidemic among men who have sex with men (MSM) is dominated by subtype B. However, recently, other genetic forms have been reported to circulate in this population, as evidenced by their grouping in clusters predominantly comprising European individuals. Here we describe four large HIV-1 non-subtype B clusters spreading among MSM in Spain. Samples were collected in 9 regions. A pol fragment was amplified from plasma RNA or blood-extracted DNA. Phylogenetic analyses were performed via maximum likelihood, including database sequences of the same genetic forms as the identified clusters. Times and locations of the most recent common ancestors (MRCA) of clusters were estimated with a Bayesian method. Five large non-subtype B clusters associated with MSM were identified. The largest one, of F1 subtype, was reported previously. The other four were of CRF02_AG (CRF02_1; n = 115) and subtypes A1 (A1_1; n = 66), F1 (F1_3; n = 36), and C (C_7; n = 17). Most individuals belonging to them had been diagnosed of HIV-1 infection in the last 10 years. Each cluster comprised viruses from 3 to 8 Spanish regions and also comprised or was related to viruses from other countries: CRF02_1 comprised a Japanese subcluster and viruses from 8 other countries from Western Europe, Asia, and South America; A1_1 comprised viruses from Portugal, United Kingom, and United States, and was related to the A1 strain circulating in Greece, Albania and Cyprus; F1_3 was related to viruses from Romania; and C_7 comprised viruses from Portugal and was related to a virus from Mozambique. A subcluster within CRF02_1 was associated with heterosexual transmission. Near full-length genomes of each cluster were of uniform genetic form. Times of MRCAs of CRF02_1, A1_1, F1_3, and C_7 were estimated around 1986, 1989, 2013, and 1983, respectively. MRCA locations for CRF02_1 and A1_1 were uncertain (however initial expansions in Spain in Madrid and Vigo, respectively, were estimated) and were most probable in Bilbao, Spain, for F1_3 and Portugal for C_7. These results show that the HIV-1 epidemic among MSM in Spain is becoming increasingly diverse through the expansion of diverse non-subtype B clusters, comprising or related to viruses circulating in other countries

Errores innatos del metabolismo: Enfermedades lisosomales

Dentro de los errores innatos del metabolismo se encuentran las enfermedades de almacenamiento lisosomal o enzimopatías lisosomales, las cuáles se caracterizan por un déficit enzimático específico, la excreción de metabolitos por la orina y la acumulación de los compuestos no degradados en diferentes órganos y tejidos que ocasionan la disfución de éstos. Tienen un patrón de herencia autosómico recesivo, excepto para la enfermedad de Fabry y la enfermedad de Hunter en las que el patrón de herencia está ligado al cromosoma X. Estas enfermedades tienen una baja incidencia en general, aunque hay poblaciones donde algunas de ellas tienen una alta incidencia. Su importancia radica en la magnitud que representan como problema de salud, por la pobre calidad de vida de esos pacientes, así como su fallecimiento prematuro, motivo por el cual hay que evitar los nacimientos de nuevos niños afectados.<br>Among the metabolism inborn errors, there are the lysosomal storage diseases or lysosomal enzymopathies that are characterized by an specific enzymatic deficiency, excretion of metabollites in urine and accumulation of non-degraded compounds in various organs and tissues causing their dysfunction. These diseases have a recessive autosomal heredity, except for Fabry´s disease and Hunter’s disease in which the pattern of heredity is chromosome X-linked. These diseases have a low incidence in general although there are populations where they show a high incidence. Their importance lies in what they represent as a health problem because of the poor quality of life of these patients and their early death, therefore, it is necessary to prevent the birth of new infants affected with these diseases

Diagnosis of GM-1 gangliodosis in Cuba

<strong>Background:</strong> GM-1 gangliosidosis is included in the group of lysosomal diseases and is characterized by a deficiency of the enzyme b-galactosidase, which as a consequence produces accumulation of GM1 ganglioside in nervous cells and galactosil oligosaccharides and products of keratan sulfate degradation in other tissues. Clinically this disease presents with an early psychomotor impairment, macular cherry red spots, facial dysmorphia, bone deformities and hepatosplenomegaly. It has a hereditary autosomic-recessive pattern. <strong>Objective:</strong> To determine of β-galactosidase acid activity in patients with suspicion of GM-1 gangliosidosis. <strong>Methods:</strong> From 1986 to 2006, 1851 patients have been received in our laboratory from all the country, of which 851 had the diagnostic impression of GM-1 gangliosidosis. In samples from patients, parents and controls, the activity of leukocyte b-galactosidase was determined by a fluorimetric technique (metilumbelliferil derivatives) and leukocyte protein level was determined according to Lowry’s method. <strong>Results and conclusions:</strong> The diagnosis of GM-1 gangliosidosis was attained in 11 patients, and the enzymatic activity was three times lower in patients with respect to their parents and five times lower with respect to controls. The enzymatic activity was not related with gender or age. <strong><br /></strong

Cuantificación de la inmunoglobulina G y la albúmina en el líquido cefalorraquídeo mediante las modificaciones de las técnicas para otros fluidos biológicos

To evaluate the results of estimating the functional status of blood–cerebrospinal fluid barrier (B–CSFB) and intrathecal immunoglobulin synthesis (ITS) of IgG for central nervous system by modified commercial techniques designed for other biological fluids. Methods: Disc polyacrylamide gel electrophoresis and quantification of CSF total protein in CSF and serum of 61 patients were conducted at the Institute of Neurology and Neurosurgery (INN) between April and September 2014. The concentration of albumin and IgG was determined by commercial standardized techniques and by modifications of commercial techniques. Albumin ratio and IgG index were calculated and employed to evaluate B–CSFB permeability and ITS, respectively. Results: Total protein and protein electrophoresis patterns were correlated with the quantifications performed by modified commercial techniques. There was no significant difference between validated commercial techniques and modified techniques for quantifications of CSF albumin (Z=0,41; p=0,6791), serum albumin (Z=0,08; p=0,9382), Qalb (Z=0,21; p=0,8361), CSF IgG (Z=1,65; p=0,0995) and IgG index (Z=1,10; p=0,2721). Conclusions: The immunological studies in CSF obtained from modifying commercial techniques designed for other biological fluids are useful to estimate the functionality of B–CSFB and intrathecal immunoglobulin synthesis. The modifications carried out for the turbidimetric technique and for the UMELISA kit should be standardized for the validation of BCSF–B permeability and IgG ITS by the nervous system.OBJETIVO: Evaluar los resultados de la estimación del estado funcional de la barrera sangre–líquido cefalorraquídeo (LCR) y la síntesis intratecal de inmunoglobulina G (IgG) por el sistema nervioso central mediante las modificaciones de las técnicas comerciales diseñadas para otros fluidos biológicos.MÉTODOS: A muestras de LCR y suero de 61 pacientes se les realizaron electroforesis de disco en geles de poliacrilamida y cuantificación de proteínas totales (PT) en el Instituto de Neurología y Neurocirugía, Habana, Cuba (INN), entre los meses de abril y diciembre de 2014. Se determino las concentraciones de albúmina e IgG empleando paralelamente técnicas comerciales modificadas en el laboratorio y métodos validados para estos estudios. Se calculó el cociente albúmina (Qalb) y el índice IgG, como indicadores del estado funcional de la barrera sangre–LCR y de la síntesis intratecal (SIT), respectivamente.RESULTADOS: Las PT y los patrones de electroforesis se correlacionaron con el Qalb y albúmina, realizado por las técnicas modificadas. No se encontraron diferencias significativas entre las cuantificaciones de las técnicas validadas y modificadas para los valores de albúmina en LCR (Z=0,41; p=0,6791), albúmina en suero (Z=0,08; p=0,9382), el Qalb (Z=0,21; p=0,8361), IgG en LCR (Z=1,65; p=0,0995) e índice IgG (Z=1,10; p=0,2721).CONCLUSIONES: Se demuestra que estas modificaciones en técnicas comerciales diseñadas para otros fluidos bilógicos resultan útiles para estimar la funcionalidad de la BS–LCR y calcular la SIT de inmunoglobulinas. Las modificaciones introducidas a la técnica turbidimétrica y al UMELISA pueden ser estandarizadas para su validación en el diagnóstico de daño de la BS–LCR y de síntesis intratecal de IgG por el sistema nervioso

Las alteraciones lipídicas en el infarto cerebral

Se realizó un estudio prospectivo tipo caso-control en pacientes y controles, para definir los principales desórdenes lipídicos en pacientes con infarto cerebral y comparar la relación de estos con factores de riesgo vascular. Se observaron valores significativamente más elevados de triglicéridos, lipoproteínas de baja densidad e índice aterogénico, en los pacientes respecto de los controles. No hubo diferencias para el colesterol total ni las lipoproteínas de muy baja densidad entre los 2 grupos. La hipertensión arterial como factor de riesgo se asoció con valores más bajos de lipoproteínas de alta densidad, y más elevados de lipoproteínas de baja densidad, triglicéridos, lipoproteínas de muy baja densidad e índice aterogénico. No se encontró relación entre la hipertensión arterial y el colesterol total. Se concluyó que era necesario controlar los lípidos en el infarto cerebral.A case-control prospective study was conducted in patients and controls to define the main lipid disorders in patients with cerebral infarction and to compare their relation with vascular risk factors. Significantly more elevated values of triglycerides, low density lipoproteins and atherogenic index were observed in patients compared with controls. There were no differences between the two groups as regards total cholesterol and low density lipoproteins. Arterial hypertension as a risk factor was associated with lower values of high density lipoproteins and with more elevated values of low density lipoproteins, triglycerides, very low density lipoproteins and atherogenic index. No relation was found between arterial hypertension and total cholesterol. It was concluded that it was necessary to control lipids in cerebral infarction