A trispecific antibody targeting HER2 and T cells inhibits breast cancer growth via CD4 cells.

Effective antitumour immunity depends on the orchestration of potent T cell responses against malignancies1. Regression of human cancers has been induced by immune checkpoint inhibitors, T cell engagers or chimeric antigen receptor T cell therapies2-4. Although CD8 T cells function as key effectors of these responses, the role of CD4 T cells beyond their helper function has not been defined. Here we demonstrate that a trispecific antibody to HER2, CD3 and CD28 stimulates regression of breast cancers in a humanized mouse model through a mechanism involving CD4-dependent inhibition of tumour cell cycle progression. Although CD8 T cells directly mediated tumour lysis in vitro, CD4 T cells exerted antiproliferative effects by blocking cancer cell cycle progression at G1/S. Furthermore, when T cell subsets were adoptively transferred into a humanized breast cancer tumour mouse model, CD4 T cells alone inhibited HER2+ breast cancer growth in vivo. RNA microarray analysis revealed that CD4 T cells markedly decreased tumour cell cycle progression and proliferation, and also increased pro-inflammatory signalling pathways. Collectively, the trispecific antibody to HER2 induced T cell-dependent tumour regression through direct antitumour and indirect pro-inflammatory/immune effects driven by CD4 T cells.

Parkinson's Disease Gene Screening in Familial Cases from Central and South America.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease following Alzheimer's disease. Nearly 30 causative genes have been identified for PD and related disorders. However, most of these genes were identified in European-derived families, and little is known about their role in Latin American populations. OBJECTIVES: Our goal was to assess the spectrum and frequency of pathogenic variants in known PD genes in familial PD patients from Latin America. METHODS: We selected 335 PD patients with a family history of PD from the Latin American Research Consortium on the Genetics of PD. We capture-sequenced the coding regions of 26 genes related to neurodegenerative parkinsonism. Of the 335 PD patients, 324 had sufficient sequencing coverage to be analyzed. RESULTS: We identified pathogenic variants in 41 individuals (12.7%) in FBXO7, GCH1, LRRK2, PARK7, PINK1, PLA2G6, PRKN, SNCA, and TARDBP, GBA1 risk variants in 25 individuals (7.7%), and variants of uncertain significance in another 24 individuals (7.4%) in ATP13A2, ATP1A3, DNAJC13, DNAJC6, GBA1, LRKK2, PINK1, VPS13C, and VPS35. Of the 70 unique variants identified, 19 were more frequent in Latin Americans than in any other population. CONCLUSIONS: This is the first screening of known PD genes in a large cohort of patients with familial PD from Latin America. There were substantial differences in the spectrum of variants observed in comparison to previous findings from PD families of European origin. Our data provide further evidence that differences exist between the genetic architecture of PD in Latinos and European-derived populations. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Inhibition of tumorigenesis driven by different Wnt proteins requires blockade of distinct ligand-binding regions by LRP6 antibodies.

Disregulated Wnt/beta-catenin signaling has been linked to various human diseases, including cancers. Inhibitors of oncogenic Wnt signaling are likely to have a therapeutic effect in cancers. LRP5 and LRP6 are closely related membrane coreceptors for Wnt proteins. Using a phage-display library, we identified anti-LRP6 antibodies that either inhibit or enhance Wnt signaling. Two classes of LRP6 antagonistic antibodies were discovered: one class specifically inhibits Wnt proteins represented by Wnt1, whereas the second class specifically inhibits Wnt proteins represented by Wnt3a. Epitope-mapping experiments indicated that Wnt1 class-specific antibodies bind to the first propeller and Wnt3a class-specific antibodies bind to the third propeller of LRP6, suggesting that Wnt1- and Wnt3a-class proteins interact with distinct LRP6 propeller domains. This conclusion is further supported by the structural functional analysis of LRP5/6 and the finding that the Wnt antagonist Sclerostin interacts with the first propeller of LRP5/6 and preferentially inhibits the Wnt1-class proteins. We also show that Wnt1 or Wnt3a class-specific anti-LRP6 antibodies specifically block growth of MMTV-Wnt1 or MMTV-Wnt3 xenografts in vivo. Therapeutic application of these antibodies could be limited without knowing the type of Wnt proteins expressed in cancers. This is further complicated by our finding that bivalent LRP6 antibodies sensitize cells to the nonblocked class of Wnt proteins. The generation of a biparatopic LRP6 antibody blocks both Wnt1- and Wnt3a-mediated signaling without showing agonistic activity. Our studies provide insights into Wnt-induced LRP5/6 activation and show the potential utility of LRP6 antibodies in Wnt-driven cancer.

Psychometric properties and construct validity of the Parkinson's Disease-Cognitive Rating Scale (PD-CRS) in Colombia.

Background: Cognitive impairment is frequent among people living with Parkinson's disease: up to 40% of patients exhibit symptoms of mild cognitive impairment and 25% meet the criteria for dementia. Parkinson's Disease Cognitive Rating Scale (PD-CRS) is one of the recommended scales by the Movement Disorders Society Task Force for level 1 screening of dementia. However, its psychometric properties have not been studied in the Colombian population. Methods: A cross-sectional study was conducted on 100 patients with Parkinson's disease diagnosed by a movement disorders neurologist. Patients were evaluated with PD-CRS and MoCA. Principal component analysis was conducted, and then confirmatory factor analysis was implemented through the maximum-likelihood method. Internal consistency was evaluated using Cronbach α. Convergent and divergent validity were also calculated and concurrent validity with the MoCA was assessed. Results: 62% were males. Their median age was 68 years (IQR 57-74) and the median disease duration was 4 years (IQR 2-9). 77% were classified in early stages (Hoehn and Yahr stage ≤ 2), while the MDS-UPDRS part III score was 25 (IQR 15.5-38). In the principal component factor analysis, the pattern matrix unveiled a mnesic and a non-mnesic domain. Confirmatory factor analysis showed similar explanatory capacity (λ ≥ 0.50) for items other than naming (λ = 0.34). Cronbach's α for the full 9-items instrument was 0.74. MoCA and PD-CRS total scores were correlated (ρ = 0.71, p = 0.000). Assuming a cut-off score of 62 points, there is an agreement of 89% with the definition of dementia by MoCA for Colombia (κ = 0.59; p = 0.000). Conclusion: PD-CRS has acceptable psychometric properties for the Colombian population and has significant correlation and agreement with a validated scale (MoCA).

Machine Learning Classifiers to Evaluate Data From Gait Analysis With Depth Cameras in Patients With Parkinson's Disease.

Introduction: The assessments of the motor symptoms in Parkinson's disease (PD) are usually limited to clinical rating scales (MDS UPDRS III), and it depends on the clinician's experience. This study aims to propose a machine learning technique algorithm using the variables from upper and lower limbs, to classify people with PD from healthy people, using data from a portable low-cost device (RGB-D camera). And can be used to support the diagnosis and follow-up of patients in developing countries and remote areas. Methods: We used Kinect®eMotion system to capture the spatiotemporal gait data from 30 patients with PD and 30 healthy age-matched controls in three walking trials. First, a correlation matrix was made using the variables of upper and lower limbs. After this, we applied a backward feature selection model using R and Python to determine the most relevant variables. Three further analyses were done using variables selected from backward feature selection model (Dataset A), movement disorders specialist (Dataset B), and all the variables from the dataset (Dataset C). We ran seven machine learning models for each model. Dataset was divided 80% for algorithm training and 20% for evaluation. Finally, a causal inference model (CIM) using the DoWhy library was performed on Dataset B due to its accuracy and simplicity. Results: The Random Forest model is the most accurate for all three variable Datasets (Dataset A: 81.8%; Dataset B: 83.6%; Dataset C: 84.5%) followed by the support vector machine. The CIM shows a relation between leg variables and the arms swing asymmetry (ASA) and a proportional relationship between ASA and the diagnosis of PD with a robust estimator (1,537). Conclusions: Machine learning techniques based on objective measures using portable low-cost devices (Kinect®eMotion) are useful and accurate to classify patients with Parkinson's disease. This method can be used to evaluate patients remotely and help clinicians make decisions regarding follow-up and treatment.

CXCR4 inhibitor AMD3100 disrupts the interaction of multiple myeloma cells with the bone marrow microenvironment and enhances their sensitivity to therapy.

The interaction of multiple myeloma (MM) cells with their microenvironment in the bone marrow (BM) provides a protective environment and resistance to therapeutic agents. We hypothesized that disruption of the interaction of MM cells with their BM milieu would lead to their sensitization to therapeutic agents such as bortezomib, melphalan, doxorubicin, and dexamethasone. We report that the CXCR4 inhibitor AMD3100 induces disruption of the interaction of MM cells with the BM reflected by mobilization of MM cells into the circulation in vivo, with kinetics that differed from that of hematopoietic stem cells. AMD3100 enhanced sensitivity of MM cell to multiple therapeutic agents in vitro by disrupting adhesion of MM cells to bone marrow stromal cells (BMSCs). Moreover, AMD3100 increased mobilization of MM cells to the circulation in vivo, increased the ratio of apoptotic circulating MM cells, and enhanced the tumor reduction induced by bortezomib. Mechanistically, AMD3100 significantly inhibited Akt phosphorylation and enhanced poly(ADP-ribose) polymerase (PARP) cleavage as a result of bortezomib, in the presence of BMSCs in coculture. These experiments provide a proof of concept for the use of agents that disrupt interaction with the microenvironment for enhancement of efficacy of cytotoxic agents in cancer therapy.

Discovery of Selective, Covalent FGFR4 Inhibitors with Antitumor Activity in Models of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) accounts for a majority of primary liver cancer and is one of the most common forms of cancer worldwide. Aberrant signaling of the FGF19-FGFR4 pathway leads to HCC in mice and is hypothesized to be a driver in FGF19 amplified HCC in humans. Multiple small molecule inhibitors have been pursued as targeted therapies for HCC in recent years, including several selective FGFR4 inhibitors that are currently being evaluated in clinical trials. Herein, we report a novel series of highly selective, covalent 2-amino-6,8-dimethyl-pyrido[2,3-d]pyrimidin-7(8H)-ones that potently and selectively inhibit FGFR4 signaling through covalent modification of Cys552, which was confirmed by X-ray crystallography. Correlative target occupancy and pFGFR4 inhibition were observed in vivo, as well as tumor regression in preclinical models of orthotopic and sorafenib-resistant HCC.

Trispecific antibodies enhance the therapeutic efficacy of tumor-directed T cells through T cell receptor co-stimulation.

Despite the significant therapeutic advances provided by immune-checkpoint blockade and chimeric antigen receptor T cell treatments, many malignancies remain unresponsive to immunotherapy. Bispecific antibodies targeting tumor antigens and activating T cell receptor signaling have shown some clinical efficacy; however, providing co-stimulatory signals may improve T cell responses against tumors. Here, we developed a trispecific antibody that interacts with CD38, CD3 and CD28 to enhance both T cell activation and tumor targeting. The engagement of both CD3 and CD28 affords efficient T cell stimulation, whereas the anti-CD38 domain directs T cells to myeloma cells, as well as to certain lymphomas and leukemias. In vivo administration of this antibody suppressed myeloma growth in a humanized mouse model and also stimulated memory/effector T cell proliferation and reduced regulatory T cells in non-human primates at well-tolerated doses. Collectively, trispecific antibodies represent a promising platform for cancer immunotherapy.

Emotional state and self-perception of quality of life of patients with Parkinson's disease in the first wave of COVID-19 in Cali, Colombia / Estado emocional y autopercepción de la calidad de vida de pacientes con enfermedad de Parkinson en la primera ola de COVID-19, en Cali, Colombia

Abstract Introducción: Desde marzo del año 2020, la Organización Mundial de la Salud (OMS) declaró como pandemia al COVID-19 y esta situación representó grandes retos para los pacientes con enfermedad de Parkinson (EP). Los efectos en los cambios de las rutinas diarias, la práctica de actividades lúdicas, el relacionamiento y la salud mental, conllevaron a un deterioro secundario. Nuestro objetivo fue caracterizar el estado emocional y la calidad de vida de una cohorte de pacientes con enfermedad de Parkinson, así como explorar cuál fue la percepción de la calidad de vida en la pandemia causada por COVID-19. Métodos: Esta fue una investigación mixta que incluyó un análisis descriptivo para los datos sociodemográficos y las variables clínicas, y un análisis del discurso con base a las categorías relacionadas con la percepción de la calidad de vida de los pacientes con EP. Las categories analizadas fueron: pandemia COVID-19, cuidadores, estrategias de adaptación, manejo de la enfermedad y actividades lúdicas. Resultados: En este estudio hubo 12 pacientes, de los cuales el 75 % tenían una media de edad de 75 años (DE 2,9), donde el 50 % presentó niveles leves de ansiedad y el 41 % presentó niveles leves y graves de depresión. La calidad de vida (CV) estuvo afectada por: la movilidad 37,5 (RIC 10,6-45), seguida por el malestar corporal 25 (RIC 10,4-45,8) y la cognición 21,9 (RIC 14-34,3). El 89 % de los hombres vivía con su esposa y el 67 % de las mujeres vivían con uno de sus hijos. Discusión: La entrevista sobre la percepción de la CV durante la pandemia COVID-19 permitió comprender que la experiencia personal es fundamental para mejorar el manejo y el empoderamiento de los pacientes, cuidadores y familiares. Conclusiones: La calidad de vida es un factor mediado por dimensiones dinámicas y es afectada por la percepción subjetiva y los cambios en el entorno como la pandemia COVID-19.

Resumen Introduction: Since March 2020, the World Health Organization (WHO) declared COVID-19 as a pandemic. This crisis had big challenges for the patients with Parkinson's disease (PD), due to the effects related to changes in daily routines, the practice of leisure activities, relationships and mental health leading to secondary deterioration. Our aim was to characterize the emotional state and quality of life in a cohort of patients with Parkinson's disease as well as to explore the perception of the quality of life during the COVID-19 pandemic. Materials and methods: This investigation was conducted as an exploratory mixed study. Descriptive analysis for sociodemographic and clinical variables and, a discourse analysis was carried out based on categories related to the perception of quality of life of patients with PD. Categories analyzed were: Covid-19 pandemic, caregivers, adaptation strategies, management of the disease, and leisure activities. Results: There were twelve patients total in this study. 75% were men with a median age of 75 (SD 2.9). 50% presented mild levels of anxiety and 41% presented mild and severe depression. The QoL was affected for: mobility 37.5 (IRC 10.6-45), body discomfort 25 (IQR 10.4-45.8) and, cognition 21.9 (IQR 14-34.3). 89% lived with their wife and 67% of women lived with one of their children. Discussion: The interview about perception of QoL during Covid-19 pandemic allowed to understand that individual experiences are crucial to improve the management and empowerment the patients, caregivers and families. Conclusion: Quality of life is a factor made up of dynamic dimensions and it is influenced for subjective perspective and changes in environment as a Covid-19 pandemic.

Age Matters: Objective Gait Assessment in Early Parkinson's Disease Using an RGB-D Camera.

BACKGROUND: Gait alterations are hallmarks for the diagnosis and follow-up of patients with Parkinson's disease (PD). In normal conditions, age could affect gait dynamics. Although it is known that objective assessment of gait is a valuable tool for diagnosis and follow-up of patients with PD, only few studies evaluate the effect of aging on the gait pattern of patients with PD. OBJECTIVE: The purpose of this study was to assess differences in gait dynamics between PD patients and healthy subjects and to investigate the effects of aging on these differences using a low-cost RGB-D depth-sensing camera. METHODS: 30 PD patients and 30 age-matched controls were recruited. Descriptive analysis was used for clinical variables, and Spearman's rank correlation was used to correlate age and gait variables. The sample was distributed in age groups; then, Mann-Whitney U test was used for comparison of gait variables between groups. RESULTS: PD patients exhibited prolonged swing (p=0.002) and stance times (p < 0.001) and lower speed values (p < 0.001) compared to controls. This was consistent in all age groups, except for the one between 76 and 88 years old, in which the controls were slower and had longer swing and stance times. These results were statically significant for the group from 60 to 66 years. CONCLUSION: Gait speed, swing, and stance times are useful for differentiating PD patients from controls. Quantitative gait parameters measured by an RGB-D camera can complement clinical assessment of PD patients. The analysis of these spatiotemporal variables should consider the age of the subject.

Objective Arm Swing Analysis in Early-Stage Parkinson's Disease Using an RGB-D Camera (Kinect®).

BACKGROUND: Arm swing changes are common even in the early stages of Parkinson's disease (PD). We hypothesized that arm swing changes decrease with age and can be detected using a low-cost, RGB-D depth-sensing camera. OBJECTIVE: This study aimed to assess the differences in arm swing between PD patients and healthy participants and to investigate the possible effects of aging on these differences. METHODS: Twenty-five PD patients (aged 45-87 years) and 25 age-matched, healthy subjects (aged 46-88 years) were included. Clinical variables were evaluated using a descriptive analysis. No spatiotemporal variables were normally distributed; therefore, we used a Mann-Whitney U test to compare the continuous variables between groups and to perform age-stratified analysis. A receiver operating characteristic analysis was generated to evaluate the discrimination activity of arm swing asymmetry (ASA). RESULTS: The PD group showed significant reductions in arm swing magnitude (left, p = 0.002; right, p = 0.006) and arm swing speed (left, p = 0.002; right, p = 0.004) and significantly greater ASA (p < 0.001). The age-stratified analysis showed significant differences in ASA in the 40-59-year group (p = 0.001) and bilateral arm swing magnitude in the 60-66-year group. No differences were found in those aged >67 years. CONCLUSIONS: The camera detected differences in ASA, arm swing speed, and arm swing magnitude between PD patients and healthy individuals. Analysis of arm swing variables should be stratified by age, and the validity of the analysis may be questionable in patients aged >67 years.

Comportamiento de la sífilis gestacional y congénita en Colombia (2014-2021). Análisis ecológico, georreferenciado por departamentos / Behavior of gestational and congenital syphilis in Colombia between 2014-2021. Ecological analysis, geo-referenced at the departmental level

Resumen OBJETIVO: Describir el comportamiento de la sífilis gestacional y congénita en Colombia, con un análisis ecológico georreferenciado de la infección por departamentos, durante el periodo 2014-2021. MATERIALES Y MÉTODOS: Estudio retrospectivo, transversal, descriptivo y ecológico basado en fuentes secundarias de información. Para el análisis se calculó la tasa de sífilis gestacional y sífilis congénita como medidas globales para cada uno de los departamentos. La información se extrajo de los boletines epidemiológicos semanales y de los reportes anuales publicados por el Instituto Nacional de Salud 2014-2021. RESULTADOS: La incidencia de sífilis congénita en Colombia ( 2014-2021) se cuadruplicó: pasó de 0.9 x 1000 nacidos vivos en el año 2014 a 3.3 x 1000 en el año 2021, con una tasa de incidencia promedio de sífilis congénita de 1.7 por mil nacimientos. Este mismo comportamiento tuvo la sífilis gestacional, con tasas de entre 5.1 (2014) y 17.1 x 1000 nacidos vivos (2021). La proporción de casos de sífilis congénita-gestacional pasó de 17.1% en 2014 a 20.8% en 2015, lo que representa un aumento de 12.3% en este indicador. CONCLUSIONES: Ante el aumento en la incidencia de sífilis gestacional y congénita en Colombia, se hace evidente la necesidad de plantear estrategias diferentes a las que actualmente están en marcha en los programas de eliminación de esas infecciones.

Abstract OBJECTIVE: To describe the behavior of gestational and congenital syphilis in Colombia, with a georeferenced ecological analysis of infection by department, during the period 2014 to 2021. MATERIALS AND METHODS: Retrospective, cross-sectional, descriptive and ecological study based on secondary sources of information. For the analysis, the rate of gestational syphilis and congenital syphilis were calculated as global measures for each of the departments. The information was extracted from the weekly epidemiological bulletins and annual reports published by the National Institute of Health 2014-2021. RESULTS: The incidence of congenital syphilis in Colombia ( 2014-2021) quadrupled: it went from 0.9 x 1000 live births in 2014 to 3.3 x 1000 in 2021, with an average incidence rate of congenital syphilis of 1.7 per thousand births. This same behavior had gestational syphilis, with rates between 5.1 (2014) and 17.1 x 1000 live births (2021). The proportion of congenital-gestational syphilis cases increased from 17.1% in 2014 to 20.8% in 2015, representing a 12.3% increase in this indicator. CONCLUSIONS: Given the increase in the incidence of gestational and congenital syphilis in Colombia, the need to propose strategies different from those currently in place in the programs for the elimination of these infections is evident.

Prevalencia de Blastocystis sp en niños en edad escolar de Reynosa, México / Blastocystis prevalence in school age children from Reynosa, Mexico

Resumen Objetivo: Determinar la prevalencia de Blastocystis sp. en niños residentes de la ciudad de Reynosa, Tamaulipas, México. Material y Método: Estudio transversal que incluyó 238 muestras de heces de niños con edad de 5 a 12 años de escuelas primarias de la ciudad de Reynosa, Tamaulipas, México. Resultados: Del total de muestras, el 13,8% tuvo presencia de Blastocystis sp.; siendo este el más prevalente dentro de los parásitos encontrados; también se re porta la presencia de Entamoeba histolytica/dispar, Giardia intestinalis y Enterobius vermicularis. Conclusiones: La prevalencia de Blastocystis en zonas de México es poco conocida; sin embargo, los estudios en diversas partes del mundo sugieren un aumento, por lo que es importante determinar la presencia y su relación como patógeno u oportunista humano.

Abstract Objective: To determine the prevalence of Blastocystis spp. in children living in the city of Reynosa, Tamaulipas, Mexico. Material y Method: Cross-sectional study that included 238 stool samples from children aged 5 to 12 years from elementary schools in the city of Reynosa, Tamaulipas, Mexico. Results: Of the total number of samples, 13.8% showed the presence of Blastocystis spp., being the most prevalent among the parasites found; the presence of Entamoeba histolytica/dispar, Giardia intestinalis and Enterobius vermicularis was also reported. Conclusions: The prevalence of Blastocystis in areas of Mexico is poorly known; however, studies in various parts of the world suggest an increase, so it is important to determine the presence and its relationship as a human pathogen or opportunist.

Glutaminase is essential for the growth of triple-negative breast cancer cells with a deregulated glutamine metabolism pathway and its suppression synergizes with mTOR inhibition.

Tumor cells display fundamental changes in metabolism and nutrient uptake in order to utilize additional nutrient sources to meet their enhanced bioenergetic requirements. Glutamine (Gln) is one such nutrient that is rapidly taken up by tumor cells to fulfill this increased metabolic demand. A vital step in the catabolism of glutamine is its conversion to glutamate by the mitochondrial enzyme glutaminase (GLS). This study has identified GLS a potential therapeutic target in breast cancer, specifically in the basal subtype that exhibits a deregulated glutaminolysis pathway. Using inducible shRNA mediated gene knockdown, we discovered that loss of GLS function in triple-negative breast cancer (TNBC) cell lines with a deregulated glutaminolysis pathway led to profound tumor growth inhibition in vitro and in vivo. GLS knockdown had no effect on growth and metabolite levels in non-TNBC cell lines. We rescued the anti-tumor effect of GLS knockdown using shRNA resistant cDNAs encoding both GLS isoforms and by addition of an α-ketoglutarate (αKG) analog thus confirming the critical role of GLS in TNBC. Pharmacological inhibition of GLS with the small molecule inhibitor CB-839 reduced cell growth and led to a decrease in mammalian target of rapamycin (mTOR) activity and an increase in the stress response pathway driven by activating transcription factor 4 (ATF4). Finally, we found that GLS inhibition synergizes with mTOR inhibition, which introduces the possibility of a novel therapeutic strategy for TNBC. Our study revealed that GLS is essential for the survival of TNBC with a deregulated glutaminolysis pathway. The synergistic activity of GLS and mTOR inhibitors in TNBC cell lines suggests therapeutic potential of this combination for the treatment of vulnerable subpopulations of TNBC.

Assessment transcallosal Diaschisis in a model of focal cerebral ischemia in rats.

OBJECTIVE: To evaluate transcallosal changes after a local ischemic injury in rats by using the monoclonal marker anti-NeuN (Mouse anti-neuronal nuclei). METHODS: Twenty-eight adult, male, Wistar rats were subjected to focal injury in the right hemisphere. The technique used was the experimental model of focal ischemic injury through intraluminal suture of the middle cerebral artery. Analyses were made for the five groups: after the lesion (control), at 24 h, 96 h, 10 days and 20 days. Exofocal neuronal damage was inferred from neuronal immunoreactivity changes to NeuN. RESULTS: In the cortex contralateral to the lesion, immunoreactivity was diminished. This finding was most notable in the supra-granular sheets 24 h post ischemia. After 96 h, there was a generalized diminishment of the inmmunoreactivity in the supra and infra-granular sheets. At 10 and 20 days, the tissue recovered some immunoreactivity to NeuN, but there were some changes in the VI layer. CONCLUSION: The immunoreactive changes to NeuN support the process of inter-hemispheric diaschisis. Changes in immunoreactivity could indicate metabolic stress secondary to the disruption in connectivity to the site of lesion.

OBJETIVO: Evaluar los cambios exofocales transcallosos después de lesión isquémica focal en ratas, mediante marcación inmunohistoquímica con el anticuerpo monoclonal anti-NeuN (Mouse Anti-Neuronal Nuclei). MÉTODOS: Se intervinieron 28 ratas machos Wistar adultas. Mediante el modelo experimental de isquemia cerebral focal del territorio de la arteria cerebral media por filamento intraluminal, se les ocasionó una lesión focal en el hemisferio derecho. Posteriormente se evaluó el hemisferio contralateral, marcando la población neuronal con el anticuerpo monoclonal anti-NeuN. Se definieron cinco grupos de evaluación: uno de control, 24 horas, 96 horas, 10 días y 20 días. Se evaluaron los cambios neuronales exofocales después de la lesión con base en la observación de los cambios en la inmunoreactividad de las neuronas al NeuN. RESULTADOS: Se redujo la inmunoreactividad en la corteza contralateral a la lesión. Este fenómeno fue más notable en las capas supragranulares después de 24 h post isquemia. Después de 96 h hubo una disminución generalizada de la inmmunoreactivity en las capas supra e infragranulares. A los 10 y 20 días, el tejido recobró alguna inmunoreactividad NeuN, estos cambios se dieron en la capa VI. CONCLUSIONES: Los cambios inmunorreactivos a NeuN apoyan el proceso de diasquisis interhemisférica. Los cambios en la inmunorreactividad podrían indicar estrés metabólico secundario a la interrupción en la conectividad con el sitio de la lesión.

Fungemia por Malassezia sympodialis en una Unidad de Cuidados Intensivos Neonatal de Colombia / Fungemia by malassezia sympodialis in a neonatal intensive care unit in Colombia

Resumen El género Malassezia comprende levaduras lipofílicas, comensales de la piel de humanos y animales, responsables de infecciones dermatológicas y sistémicas, particularmente en recién nacidos pretérmino hospitalizados en Unidades de Cuidados Intensivos Neonatal (UCIN) con catéteres venosos centrales, antibióticos de amplio espectro y nutrición parenteral rica en lípidos. La información acerca de las fungemias por este microorganismo es limitada, sin embargo, la mayoría de infecciones invasivas reportadas en la literatura han sido asociadas con M. furfur y M. pachydermatis. Se reporta un caso de fungemia por M. sympodialis en un recién nacido pretérmino hospitalizado en la UCIN de un hospital colombiano con sospecha clínica de sepsis neonatal, antibioticoterapia de amplio espectro y hemocultivos de rutina negativos. El aislamiento fue susceptible a fluconazol y voriconazol, y resistente a anfotericina B. Existen pocos reportes de fungemia producida por M. sympodialis, pero todos concuerdan en que es una levadura subestimada en individuos con factores predisponentes.

Abstract The genus Malassezia comprises lipophilic yeasts, commensals of the skin of humans and animals, responsible for dermatological and systemic infections, particu larly in preterm infants hospitalized in Neonatal Intensive Care Units (NICU) with central venous catheters, broad-spectrum antibiotics and parenteral nutrition rich in lipids. Information about fungemia by this microorganism is limited, however, the majority of invasive infections reported in the literature have been associated with M. furfur and M. pachydermatis. A case of M. sympodialis fungemia is reported in a preterm newborn hospitalized in the NICU of a Colombian hospital with clinical suspicion of neonatal sepsis, broad-spectrum antibiotic therapy and negative routine blood cultures. The isolation was susceptible to fluconazole and voriconazole, and resistant to amphotericin B. There are few reports of fungemia produced by M. sympodialis, but all agree that it is an underestimated yeast in individuals with predisposing factors.

Espectro clínico y tratamiento del trastorno cognoscitivo y demencia asociada a la enfermedad de Parkinson / Clinical spectrum, evaluation and treatment of cognitive disorder and dementia associated with Parkinson's disease

RESUMEN La prevalencia del deterioro cognitivo mínimo en pacientes con EP está en un rango de 20-50 %. La prevalen-cia puntual de la demencia asociada a la enfermedad se estima en alrededor del 25-30 °% con un incremento proporcional en relación con la edad y el tiempo de evolución de la enfermedad. El perfil clínico puede ser heterogéneo y hace referencia a la alteración en los diferentes dominios que supone un substrato neurobiológico diferente. La disfunción ejecutiva suele ser más frecuente en etapas tempranas de la enfermedad, aunque también hay perfiles clínicos corticales. Hay síntomas neuropsiquiátricos como la depresión, la ansiedad y el discontrol de impulsos que pueden afectar la cognición. La valoración rutinaria de las actividades de la vida diaria y el desempeño funcional se ha relacionado con el grado de compromiso así como con el rendimiento cognitivo global. Pacientes en estadios avanzados y candidatos a la cirugía de estimulación cerebral profunda requieren la evaluación neuropsicológica para seguimiento e identificación de potenciales riesgos o contraindicaciones cognitivas, comportamentales y/o emocionales. Las conclusiones del consenso de cognición son: 1) el deterioro cognitivo mínimo es común en los pacientes, incluso en estadios tempranos; 2) el perfil clínico es heterogéneo, aunque la disfunción ejecutiva es más frecuente; 3) la valoración inicial permite detectar perfiles de riesgo a demencia; 4) deben usarse instrumentos validados para esta población; 5) los síntomas neuropsiquiátricos pueden afectar el desempeño del paciente, y 6) la valoración de la independencia funcional permite explorar el impacto de la cognición en la cotidianidad.

SUMMARY The prevalence of minimal cognitive impairment in patients with PD is between 20-50 °%. The prevalence of dementia associated with the disease is estimated at around 25-30 °% with a proportional increase in relation to age and time of disease progression. The clinical profile can be heterogeneous and refers to the alteration in the different domains that a different neurobiological substrate supposes. Executive dysfunction is usually more frequent in the early stages of the disease, although there are also clinical cortical profiles. There are neuropsychiatric symptoms such as depression, anxiety and impulse control disorders that can affect cognition. The routine assessment of activities of daily living and functional performance has been related to the degree of commitment as well as to the overall cognitive performance. Patients in advanced stages and candidates for deep brain stimulation surgery require neuropsychological evaluation to monitor and identify potential risks or cognitive, behavioral and/or emotional contraindications. The conclusions of the consensus of cognition are 1. Minimal cognitive deterioration is common in patients even in early stages, 2. The clinical profile is heterogeneous, although executive dysfunction is more frequent, 3. An initial assessment allows detecting risk profiles to dementia, 4. Validated instruments should be used for this population, 5. Neuropsychiatric symptoms can affect the patient's performance and 6. The assessment of functional independence allows for exploring the impact of cognition in everyday life.