Neurological disease in xeroderma pigmentosum: prospective cohort study of its features and progression.

Xeroderma pigmentosum (XP) results from biallelic mutations in any of eight genes involved in DNA repair systems, thus defining eight different genotypes (XPA, XPB, XPC, XPD, XPE, XPF, XPG and XP variant or XPV). In addition to cutaneous and ophthalmological features, some patients present with XP neurological disease. It is unknown whether the different neurological signs and their progression differ among groups. Therefore, we aim to characterize the XP neurological disease and its evolution in the heterogeneous UK XP cohort. Patients with XP were followed in the UK National XP Service, from 2009 to 2021. Age of onset for different events was recorded. Cerebellar ataxia and additional neurological signs and symptoms were rated with the Scale for the Assessment and Rating of Ataxia (SARA), the Inventory of Non-Ataxia Signs (INAS) and the Activities of Daily Living questionnaire (ADL). Patients' mutations received scores based on their predicted effects. Data from available ancillary tests were collected. Ninety-three XP patients were recruited. Thirty-six (38.7%) reported neurological symptoms, especially in the XPA, XPD and XPG groups, with early-onset and late-onset forms, and typically appearing after cutaneous and ophthalmological symptoms. XPA, XPD and XPG patients showed higher SARA scores compared to XPC, XPE and XPV. SARA total scores significantly increased over time in XPD (0.91 points/year, 95% confidence interval: 0.61, 1.21) and XPA (0.63 points/year, 95% confidence interval: 0.38, 0.89). Hyporeflexia, hypopallesthaesia, upper motor neuron signs, chorea, dystonia, oculomotor signs and cognitive impairment were frequent findings in XPA, XPD and XPG. Cerebellar and global brain atrophy, axonal sensory and sensorimotor neuropathies, and sensorineural hearing loss were common findings in patients. Some XPC, XPE and XPV cases presented with abnormalities on examination and/or ancillary tests, suggesting underlying neurological involvement. More severe mutations were associated with a faster progression in SARA total score in XPA (0.40 points/year per 1-unit increase in severity score) and XPD (0.60 points/year per 1-unit increase), and in ADL total score in XPA (0.35 points/year per 1-unit increase). Symptomatic and asymptomatic forms of neurological disease are frequent in XP patients, and neurological symptoms can be an important cause of disability. Typically, the neurological disease will be preceded by cutaneous and ophthalmological features, and these should be actively searched in patients with idiopathic late-onset neurological syndromes. Scales assessing cerebellar function, especially walking and speech, and disability can show progression in some of the groups. Mutation severity can be used as a prognostic biomarker for stratification purposes in clinical trials.

Biostimulated-sesame sprout extracts as potential agents against Leishmania mexicana.

Leishmania mexicana is one of the causal agents of cutaneous leishmaniasis. Current antileishmanial chemotherapeutics have demonstrated adverse side effects; thus, alternative treatments are needed. In this study, we performed in silico and in vitro analyses of the leishmanicidal potential of the most abundant phenolic compounds identified in black sesame sprouts biostimulated with Bacillus clausii. The molecular docking analysis showed strong interactions (binding free energies between -6.5 and -9.5 kcal/mol) of sesaminol 2-O-triglucoside, pinoresinol dihexoside, isoverbascoside, and apigenin with the arginase, leishmanolysin, cysteine peptidase B, and pyruvate kinase leishmanial enzymes. Furthermore, almost all phenolic compounds interacted with the active site residues of L. mexicana enzymes. In vitro, the B. clausii-biostimulated sprout phenolic extracts and apigenin inhibited the growth of promastigotes with IC50 values of 0.08 mg gallic acid equivalent/mL and 6.42 µM (0.0017 mg/mL), respectively. Additionally, in the macrophage infection model, cells treated with B. clausii-biostimulated sprout phenolic extracts and infected with L. mexicana exhibited significantly (P < 0.05) reduced nitric oxide production and decreased parasite burden. Altogether, our study provides important data related to high efficacy and less toxic natural antileishmanial candidates against promastigotes of L. mexicana.

Stem-Loop Structures in Iron-Regulated mRNAs of Giardia duodenalis.

Giardia duodenalis is a significant cause of waterborne and foodborne infections, day-care center outbreaks, and traveler's diarrhea worldwide. In protozoa such as Trichomonas vaginalis and Entamoeba histolytica, iron affects the growth, pathogenicity mechanisms, and expression of virulence genes. One of the proposed iron regulatory mechanisms is at the post-transcriptional level through an IRE/IRP-like (iron responsive element/iron regulatory protein) system. Recently, the expression of many putative giardial virulence factors in the free-iron levels has been reported in subsequent RNAseq experiments; however, the iron regulatory mechanism remains unknown. Thus, this work aimed to determine the effects of iron on the growth, gene expression, and presence of IRE-like structures in G. duodenalis. First, the parasite's growth kinetics at different iron concentrations were studied, and the cell viability was determined. It was observed that the parasite can adapt to an iron range from 7.7 to 500 µM; however, in conditions without iron, it is unable to survive in the culture medium. Additionally, the iron modulation of three genes was determined by RT-PCR assays. The results suggested that Actin, glucosamine-6-phosphate deaminase, and cytochrome b5 mRNA were down-regulated by iron. To investigate the presence of IRE-like structures, in silico analyses were performed for different mRNAs from the Giardia genome database. The Zuker mfold v2.4 web server and theoretical analysis were used to predict the secondary structures of the 91 mRNAs analyzed. Interestingly, the iron-induced downregulation of the genes analyzed corresponds to the location of the stem-loop structures found in their UTR regions. In conclusion, iron modulates the growth and expression of specific genes, likely due to the presence of IRE-like structures in G. duodenalis mRNAs.

The frequency of non-motor symptoms in SCA3 and their association with disease severity and lifestyle factors.

BACKGROUND: Non-motor symptoms (NMS) are a substantial burden for patients with SCA3. There are limited data on their frequency, and their relation with disease severity and activities of daily living is not clear. In addition, lifestyle may either influence or be affected by the occurrence of NMS. OBJECTIVE: To characterize NMS in SCA3 and investigate possible associations with disease severity and lifestyle factors. METHODS: In a prospective cohort study, we performed a cross-sectional analysis of NMS in 227 SCA3 patients, 42 pre-ataxic mutation carriers, and 112 controls and tested for associations with SARA score, activities of daily living, and the lifestyle factors alcohol consumption, smoking and physical activity. RESULTS: Sleep disturbance, restless legs syndrome, mild cognitive impairment, depression, bladder dysfunction and pallhypesthesia were frequent among SCA3 patients, while mainly absent in pre-ataxic mutation carriers. Except for restless legs syndrome, NMS correlated significantly with disease severity and activities of daily living. Alcohol abstinence was associated with bladder dysfunction. Patients with higher physical activity showed less cognitive impairment and fewer depressive symptoms, but these differences were not significant. CONCLUSION: This study revealed a clear association between disease severity and NMS, likely driven by the progression of the widespread neurodegenerative process. Associations between lifestyle and NMS can probably be attributed to the influence of NMS on lifestyle.

First evidence of systemic infection and specific cytotoxic T lymphocyte immune response evoked by oral infection with recombinant Salmonella entérica serovar Albany-Ovalbumin in C57BL/6 mice / Primera evidencia de infección sistémica y respuesta inmune celular citotóxicaespecífica evocada por la infección oral en ratones C57BL/6 con Salmonella entericaserovar Albany-Ovoalbúmina recombinante

Abstract Our group isolated Salmonella enterica serovar Albany from food and feces of wildcaptive carnivores in a zoo from northwestern Mexico. This serovar was also associated with thedeath of an ocelot (Leopardus pardalis) in the same zoo. Another group associated S. Albanywith the death of a human patient. It is due to this zoonotic potential that the in vivo study of thehost-S. Albany relationship is critical. The recombinant S. Albany-Ovalbumin (rSAO) strain wasused to analyze a murine oral infection and its specific cytotoxic T lymphocyte (CTL) response.Our results have shown for the first time that rSAO establishes a systemic infection and evokesepitope-specific lysis with a Th1-like cytokine profile in vivo.

Resumen Salmonella entérica serovar Albany fue aislada por nuestro grupo de investigación de alimentos contaminados y de heces de animales carnívoros en cautiverio en un zoológico del noroeste de México; posteriormente, se logró asociar a este serovar con la muerte de un ocelote (Leopardus pardalis), dentro de este mismo zoológico. Otro grupo de investigación asoció a este serovar con la muerte de un paciente. Es debido a este potencial zoonótico que el estudio in vivo de la relación hospedero-S. Albany es crítico. La cepa recombinante S. Albany-Ovoalbúmina (rSAO) fue utilizada para analizar la infección múrida, al igual que la respuesta inmune celular citotóxica específica. Nuestros resultados demuestran, por primera vez, que rSAO establece una infección sistémica y evoca lisis epítopo-específica con un perfil de citocinas tipo Th1 in vivo.

Clinical outcomes associated with Mu variant infection during the third epidemic peak of COVID-19 in Colombia.

BACKGROUND: The higher number of cases and deaths caused by COVID-19 in Colombia occurred during the third epidemic peak, where the Mu variant was associated with 50% of the cases. OBJECTIVE: To evaluate the association between the clinical outcome of COVID-19 with health conditions and SARS-CoV-2 lineages. METHODS: In this study, clinical metadata and SARS-CoV-2 lineages from 535 patients with different degrees of COVID-19 severity were obtained after the SARS-CoV-2 genomic surveillance in Colombia. Then, the associations between these variables were determined using a multidimensional unfolding analysis. RESULTS: Asymptomatic, symptomatic, severe, and deceased outcomes represented 15.2%, 29.7%, 7.3%, and 47.8% of the cases, respectively. Males tend to develop more serious COVID-19, and severe or fatal outcomes were typically observed in patients aged >60 years with comorbidities, including chronic obstructive pulmonary disease, heart disease, kidney disease, obesity, asthma, and smoking history. The SARS-CoV-2 Mu and Gamma variants dominated the third epidemic peak and accounted for most fatal cases with odd ratio values of 128.2 (CI 53.0-310.1) and 18.6 (CI 8.294-41.917). CONCLUSION: This study shows the high impact of SARS-CoV-2 lineages with higher prevalence on public health and the importance of monitoring COVID-19 risk factors to control the associated mortality.

Monkeypox virus genome sequence from an imported human case in Colombia / Secuencia genómica del virus de la viruela símica de un caso importado en Colombia

Introduction: Monkeypox virus (MPXV) is an enveloped double-stranded DNA virus with a genome of approximately 197.209 bp. The current classification divides MPXV into three clades: Clade I (Central African or Congo Basin clade) and clades IIa and IIb (West African clades). Objective: To report the complete genome and phylogenetic analysis of a human monkeypox case detected in Colombia. Materials and methods: Exudate from vesicular lesions was obtained from a male patient with recent travel history to Spain. A direct genomic approach was implemented in which total DNA from the sample was purified through a column-based method, followed by sequencing on the Nanopore GridION. Reads were aligned against the MPXV reference genome using minimap2 v.2.24 and phylogenetic inference was performed using maximum likelihood estimation. Results: A total of 11.951 reads mapped directly to a reference genome with 96.8% of coverage (190.898 bp). Conclusion: Phylogenetic analysis of the MPXV circulating in Colombia demonstrated its close relationship to clade IIb responsible for the multi-country outbreak in 2022.

Introducción. El virus de la viruela del mono (MPXV) está compuesto por un genoma de ADN bicatenario, aproximadamente, de 197.209 pb. La clasificación actual agrupa el MPXV en tres clados: clado I (de la cuenca del Congo en África central), y clados IIa y IIb (de África occidental). Objetivo. Reportar el genoma completo y el análisis filogenético de un caso humano de viruela símica detectado en Colombia. Materiales y métodos. Se obtuvo exudado de lesiones vesiculares de un paciente varón con el antecedente de un viaje reciente a España. Se implementó un enfoque directo, en el cual se purificó el ADN total de la muestra mediante un método basado en columnas, seguido de la secuenciación directa en la plataforma Nanopore GridION. Las lecturas se alinearon con el genoma de referencia del MPXV, utilizando minimap2, v.2.24, y la inferencia filogenética fue realizada mediante la estimación por máxima verosimilitud. Resultados. Un total de 11.951 lecturas se alinearon directamente con el genoma de referencia con una cobertura del 96,8 % (190.898 pb). Conclusión. El análisis filogenético del MPXV circulante en Colombia demostró su estrecha relación con el clado de África occidental (clado IIb) responsable del brote en múltiples países en el 2022.

Characterization of Lifestyle in Spinocerebellar Ataxia Type 3 and Association with Disease Severity.

BACKGROUND: Lifestyle could influence the course of hereditary ataxias, but representative data are missing. OBJECTIVE: The objective of this study was to characterize lifestyle in spinocerebellar ataxia type 3 (SCA3) and investigate possible associations with disease parameters. METHODS: In a prospective cohort study, data on smoking, alcohol consumption, physical activity, physiotherapy, and body mass index (BMI) were collected from 243 patients with SCA3 and 119 controls and tested for associations with age of onset, disease severity, and progression. RESULTS: Compared with controls, patients with SCA3 were less active and consumed less alcohol. Less physical activity and alcohol abstinence were associated with more severe disease, but not with progression rates or age of onset. Smoking, BMI, or physiotherapy did not correlate with disease parameters. CONCLUSION: Differences in lifestyle factors of patients with SCA3 and controls as well as associations of lifestyle factors with disease severity are likely driven by the influence of symptoms on behavior. No association between lifestyle and disease progression was detected. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Polyglutamine-Expanded Ataxin-3: A Target Engagement Marker for Spinocerebellar Ataxia Type 3 in Peripheral Blood.

BACKGROUND: Spinocerebellar ataxia type 3 is a rare neurodegenerative disease caused by a CAG repeat expansion in the ataxin-3 gene. Although no curative therapy is yet available, preclinical gene-silencing approaches to reduce polyglutamine (polyQ) toxicity demonstrate promising results. In view of upcoming clinical trials, quantitative and easily accessible molecular markers are of critical importance as pharmacodynamic and particularly as target engagement markers. OBJECTIVE: We aimed at developing an ultrasensitive immunoassay to measure specifically polyQ-expanded ataxin-3 in plasma and cerebrospinal fluid (CSF). METHODS: Using the novel single molecule counting ataxin-3 immunoassay, we analyzed cross-sectional and longitudinal patient biomaterials. RESULTS: Statistical analyses revealed a correlation with clinical parameters and a stability of polyQ-expanded ataxin-3 during conversion from the pre-ataxic to the ataxic phases. CONCLUSIONS: The novel immunoassay is able to quantify polyQ-expanded ataxin-3 in plasma and CSF, whereas ataxin-3 levels in plasma correlate with disease severity. Longitudinal analyses demonstrated a high stability of polyQ-expanded ataxin-3 over a short period. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Enfermedad indiferenciada del tejido conectivo con progresión a esclerosis sistémica / Undifferentiated disease of the connective tissue with progression to systemic sclerosis

La enfermedad indiferenciada del tejido conectivo es una condición de etiología desconocida que comparte características clínicas, patológicas y de laboratorio de varias colagenosis, sin cumplir los criterios del Colegio Americano de Reumatología para el diagnóstico de una enfermedad reumática específica y muchos pacientes evolucionan a condiciones definidas a lo largo del tiempo tales como Lupus, Esclerosis sistémica progresiva, Enfermedad de Sjögren entre otros. Antecedentes: Linfoma Hodgkin diagnosticado desde 2012 para lo cual recibió múltiples esquemas de quimioterapia. Las muestras de ganglio y médula ósea se habían enviado al laboratorio de Inmunopatologia de la Universidad de Stanford y allí no se apreciaron hallazgos compatibles con enfermedad linfoproliferativa. Enfermedad actual: Mujer de 27 años de edad con cuadro clínico de 1 mes de evolución, caracterizado por edema blando en miembros inferiores acompañado de edema palpebral matutino; concomitantemente presenta aumento de temperatura intermitente sin patrón especifico y dolor osteomuscular generalizado con limitación para la deambulación. Se ingresa. Al examen físico, regulares condiciones clínicas. En la piel se aprecia engrosamiento cutáneo importante. Se realizó biopsia cutánea y los hallazgos fueron compatibles con Esclerosis Sistémica(AU)

Undifferentiated connective tissue disease is a condition of unknown etiology that shares clinical, pathological and laboratory characteristics of several collagenopathies that do not meet the criteria of the American College of Rheumatology for the diagnosis of a specific disease; a large number of patients evolve to conditions defined over time such as Lupus, Systemic Sclerosis, Sjogren's Disease, among others. Past history: Hodgkin lymphoma was diagnosed since 2012 for which she received multiple chemotherapy schemes. A gland biopsy was sent to the Stanford University, as well as a bone marrow sample, and lymphoma was discarded. Present history: this 27-year-old female consulted for edema in lower limbs present during one month, accompanied by eyelid edema in the mornings; also fever without a specific pattern, myalgias and arthralgias. On physical examination, the skin was thickened and limb edema was present. A skin biopsy was performed, and the findings were consistent with Systemic Sclerosis. The patient is receiving cyclophosphamide and Azathioprine and leading her normal life(AU)

A novel circulating tamiami mammarenavirus shows potential for zoonotic spillover.

A detailed understanding of the mechanisms underlying the capacity of a virus to break the species barrier is crucial for pathogen surveillance and control. New World (NW) mammarenaviruses constitute a diverse group of rodent-borne pathogens that includes several causative agents of severe viral hemorrhagic fever in humans. The ability of the NW mammarenaviral attachment glycoprotein (GP) to utilize human transferrin receptor 1 (hTfR1) as a primary entry receptor plays a key role in dictating zoonotic potential. The recent isolation of Tacaribe and lymphocytic choriominingitis mammarenaviruses from host-seeking ticks provided evidence for the presence of mammarenaviruses in arthropods, which are established vectors for numerous other viral pathogens. Here, using next generation sequencing to search for other mammarenaviruses in ticks, we identified a novel replication-competent strain of the NW mammarenavirus Tamiami (TAMV-FL), which we found capable of utilizing hTfR1 to enter mammalian cells. During isolation through serial passaging in mammalian immunocompetent cells, the quasispecies of TAMV-FL acquired and enriched mutations leading to the amino acid changes N151K and D156N, within GP. Cell entry studies revealed that both substitutions, N151K and D156N, increased dependence of the virus on hTfR1 and binding to heparan sulfate proteoglycans. Moreover, we show that the substituted residues likely map to the sterically constrained trimeric axis of GP, and facilitate viral fusion at a lower pH, resulting in viral egress from later endosomal compartments. In summary, we identify and characterize a naturally occurring TAMV strain (TAMV-FL) within ticks that is able to utilize hTfR1. The TAMV-FL significantly diverged from previous TAMV isolates, demonstrating that TAMV quasispecies exhibit striking genetic plasticity that may facilitate zoonotic spillover and rapid adaptation to new hosts.

The Role of Receptor Tyrosine Kinases in Lassa Virus Cell Entry.

The zoonotic Old World mammarenavirus Lassa (LASV) causes severe hemorrhagic fever with high mortality and morbidity in humans in endemic regions. The development of effective strategies to combat LASV infections is of high priority, given the lack of a licensed vaccine and restriction on available treatment to off-label use of ribavirin. A better understanding of the fundamental aspects of the virus's life cycle would help to improve the development of novel therapeutic approaches. Host cell entry and restriction factors represent major barriers for emerging viruses and are promising targets for therapeutic intervention. In addition to the LASV main receptor, the extracellular matrix molecule dystroglycan (DG), the phosphatidylserine-binding receptors of the Tyro3/Axl/Mer (TAM), and T cell immunoglobulin and mucin receptor (TIM) families are potential alternative receptors of LASV infection. Therefore, the relative contributions of candidate receptors to LASV entry into a particular human cell type are a complex function of receptor expression and functional DG availability. Here, we describe the role of two receptor tyrosine kinases (RTKs), Axl and hepatocyte growth factor receptor (HGFR), in the presence and absence of glycosylated DG for LASV entry. We found that both RTKs participated in the macropinocytosis-related LASV entry and, regardless of the presence or absence of functional DG, their inhibition resulted in a significant antiviral effect.

Las células dendríticas plasmacitoides evocan la respuesta efectora de los linfocitos T citotóxicos específicos para Salmonella / The plasmacytoid dendritic cells evoke Salmonella-specific CTL effector response

Resumen Introducción. La función inmunológica de las células dendríticas plasmacitoides durante las infecciones bacterianas, como la de Salmonella spp., es poco conocida. En ese contexto, se analizó su función efectora para presentar antígenos de Salmonella Typhimurium ante linfocitos T citotóxicos. Objetivo. Analizar la respuesta de los linfocitos T citotóxicos específicos para Salmonella evocada por las células dendríticas plasmacitoides. Materiales y métodos. Se usaron células dendríticas plasmacitoides marcadas con éster de succinimidil-carboxifluoresceína, pulsadas con el epítopo de Salmonella OmpC73 Kb- restringido o infectadas con S. Typhimurium como blanco en ensayos de citotoxicidad. Resultados. La lisis específica tuvo significación estadística usando células dendríticas plasmacitoides positivas pulsadas con OmpC73 en todas las relaciones de células efectoras y blanco (E:B) (p≤0,05); en cuanto a las células dendríticas plasmacitoides positivas para S. Typhimurium, solo se observó significación estadística en la relación de 1:100 (p≤0,05) usando las células efectoras OmpC73. Conclusión. Las células dendríticas plasmacitoides pueden evocar la respuesta de los linfocitos T citotóxicos durante la infección con S. Typhimurium.

Abstract Introduction: The immunological role of plasmacytoid dendritic cells (pDC) in bacterial infections such as Salmonella has been poorly documented. Therefore, we analyzed the effector function of these cells by presenting cytotoxic T lymphocytes (CTL) with Salmonella Typhimurium antigens. Objective: To analyze the Salmonella-specific CTL response evoked by pDCs. Materials and methods: We used plasmacytoid dendritic cells stained with carboxyfluorescein succinimidyl ester (CFSE) and pulsed with OmpC73, Salmonella Kb- restricted epitopes or S. Typhimurium as targets for cytotoxicity assays. Results: Specific lysis was shown to be statistically significant in pDC + OmpC73 for all effector:target ratios (p≤0.05). For pDC + S. Typhimurium, statistical significance was only observed at a 1:100 ratio (p≤0.05) using OmpC73. Conclusion: Plasmacytoid dendritic cells evoke CTL response during S. Typhimurium infection.

Frecuencia de infecciones en los pacientes con patología reumatológica del IAHULA Mérida 2016-2017

Introducción: Las infecciones se ha señalado que son causa de la descompensación de algunas enfermedades del tejido conectivo. Objetivos: Describir la frecuencia de infecciones asociadas a las diversas patologías reumatológicas en los pacientes que acuden al Hospital Universitario de Los Andes. Métodos: Estudio retrospectivo en el que se revisaron 3 328 historias clínicas pertenecientes a los pacientes del servicio de Reumatología. Resultados: La mayor parte de los pacientes eran del género femenino. La principal patología reumatológica fue artritis reumatoide, seguido del lupus eritematoso sistémico, artrosis en 3 lugar y finalmente otras entidades. Las principales infecciones fueron las del tracto urinario, en segunda instancia piel y partes blandas, en tercer lugar neumonías y en último lugar las no incluidas anteriormente. En cuanto al uso de la terapéutica y el tipo de patología reumatológica se encontró significancia estadística P 0,001. En cuanto al tipo de infección y la patología reumatológica en la cual se presentó dicho evento el valor de P fue 0,724. La principal causa de hospitalización en los 4 grupos de pacientes fue debido a causas infecciosas con un valor de P de 0,001. Discusión: Las infecciones fueron la principal causa de hospitalización en estos pacientes. La infección es causa de morbimortalidad importante en los pacientes reumatológicos. Conclusiones: Se recomienda en base a las observaciones obtenidas en el presente estudio, se evalúen a través de sistemas de estratificación los riesgos para el desarrollo de infecciones en los pacientes reumatológicos y así generar estrategias que disminuyan su frecuencia.

Introduction: Infections have been reported to be the cause of the decompensation of some connective tissue diseases. Objectives: To describe the frequency of infections associated with the rheumatological pathologies in patients of the University Hospital of the Andes. Methods: Retrospective study in which 3 328 clinical histories belonging to the patients of the Rheumatology service were reviewed. Results: Most of the patients were female. The main rheumatological pathology was Rheumatoid Arthritis, followed by Systemic Lupus Erythematosus, Arthrosis in third place and finally other entities. The main infections were those of the urinary tract, secondly skin and soft tissues, thirdly Pneumonia and lastly not previously included. Regarding the use of therapeutics and the type of rheumatological pathology, statistical significance was found P 0.001. Regarding the type of infection and the rheumatological pathology in which the event was presented, the P value was 0.724. The main cause of hospitalization in the 4 groups of patients was due to infectious causes with a p-value of 0.001. Discussion: Infections were the main cause of hospitalization in these patients. Infection is an important cause of morbidity and mortality in rheumatological patients. Conclusions: It is recommended based on the observations obtained in the present study, the risks for the development of infections in rheumatological patients be evaluated through stratification systems and generate strategies that decrease their frequency.

Dynamic Dystroglycan Complexes Mediate Cell Entry of Lassa Virus.

Recognition of functional receptors by viruses is a key determinant for their host range, tissue tropism, and disease potential. The highly pathogenic Lassa virus (LASV) currently represents one of the most important emerging pathogens. The major cellular receptor for LASV in human cells is the ubiquitously expressed and evolutionary highly conserved extracellular matrix receptor dystroglycan (DG). In the host, DG interacts with many cellular proteins in a tissue-specific manner. The resulting distinct supramolecular complexes likely represent the functional units for viral entry, and preexisting protein-protein interactions may critically influence DG's function in productive viral entry. Using an unbiased shotgun proteomic approach, we define the largely unknown molecular composition of DG complexes present in highly susceptible epithelial cells that represent important targets for LASV during viral transmission. We further show that the specific composition of cellular DG complexes can affect DG's function in receptor-mediated endocytosis of the virus. Under steady-state conditions, epithelial DG complexes underwent rapid turnover via an endocytic pathway that shared some characteristics with DG-mediated LASV entry. However, compared to steady-state uptake of DG, LASV entry via DG occurred faster and critically depended on additional signaling by receptor tyrosine kinases and the downstream effector p21-activating kinase. In sum, we show that the specific molecular composition of DG complexes in susceptible cells is a determinant for productive virus entry and that the pathogen can manipulate the existing DG-linked endocytic pathway. This highlights another level of complexity of virus-receptor interaction and provides possible cellular targets for therapeutic antiviral intervention.IMPORTANCE Recognition of cellular receptors allows emerging viruses to break species barriers and is an important determinant for their disease potential. Many virus receptors have complex tissue-specific interactomes, and preexisting protein-protein interactions may influence their function. Combining shotgun proteomics with a biochemical approach, we characterize the molecular composition of the functional receptor complexes used by the highly pathogenic Lassa virus (LASV) to invade susceptible human cells. We show that the specific composition of the receptor complexes affects productive entry of the virus, providing proof-of-concept. In uninfected cells, these functional receptor complexes undergo dynamic turnover involving an endocytic pathway that shares some characteristics with viral entry. However, steady-state receptor uptake and virus endocytosis critically differ in kinetics and underlying signaling, indicating that the pathogen can manipulate the receptor complex according to its needs. Our study highlights a remarkable complexity of LASV-receptor interaction and identifies possible targets for therapeutic antiviral intervention.

Identification of Clotrimazole Derivatives as Specific Inhibitors of Arenavirus Fusion.

Arenaviruses are a large family of emerging enveloped negative-strand RNA viruses that include several causative agents of viral hemorrhagic fevers. For cell entry, human-pathogenic arenaviruses use different cellular receptors and endocytic pathways that converge at the level of acidified late endosomes, where the viral envelope glycoprotein mediates membrane fusion. Inhibitors of arenavirus entry hold promise for therapeutic antiviral intervention and the identification of "druggable" targets is of high priority. Using a recombinant vesicular stomatitis virus pseudotype platform, we identified the clotrimazole-derivative TRAM-34, a highly selective antagonist of the calcium-activated potassium channel KCa3.1, as a specific entry inhibitor for arenaviruses. TRAM-34 specifically blocked entry of most arenaviruses, including hemorrhagic fever viruses, but not Lassa virus and other enveloped viruses. Anti-arenaviral activity was likewise observed with the parental compound clotrimazole and the derivative senicapoc, whereas structurally unrelated KCa3.1 inhibitors showed no antiviral effect. Deletion of KCa3.1 by CRISPR/Cas9 technology did not affect the antiarenaviral effect of TRAM-34, indicating that the observed antiviral effect of clotrimazoles was independent of the known pharmacological target. The drug affected neither virus-cell attachment, nor endocytosis, suggesting an effect on later entry steps. Employing a quantitative cell-cell fusion assay that bypasses endocytosis, we demonstrate that TRAM-34 specifically inhibits arenavirus-mediated membrane fusion. In sum, we uncover a novel antiarenaviral action of clotrimazoles that currently undergo in vivo evaluation in the context of other human diseases. Their favorable in vivo toxicity profiles and stability opens the possibility to repurpose clotrimazole derivatives for therapeutic intervention against human-pathogenic arenaviruses.IMPORTANCE Emerging human-pathogenic arenaviruses are causative agents of severe hemorrhagic fevers with high mortality and represent serious public health problems. The current lack of a licensed vaccine and the limited treatment options makes the development of novel antiarenaviral therapeutics an urgent need. Using a recombinant pseudotype platform, we uncovered that clotrimazole drugs, in particular TRAM-34, specifically inhibit cell entry of a range of arenaviruses, including important emerging human pathogens, with the exception of Lassa virus. The antiviral effect was independent of the known pharmacological drug target and involved inhibition of the unusual membrane fusion mechanism of arenaviruses. TRAM-34 and its derivatives currently undergo evaluation against a number of human diseases and show favorable toxicity profiles and high stability in vivo Our study provides the basis for further evaluation of clotrimazole derivatives as antiviral drug candidates. Their advanced stage of drug development will facilitate repurposing for therapeutic intervention against human-pathogenic arenaviruses.

High frequency of HPV16 European variant E350G among Mexican women from Sinaloa.

BACKGROUND & OBJECTIVES: Human papillomavirus (HPV) infections play a crucial role in the aetiology of cervical cancer (CC), and HPV16 is the primary viral genotype associated with CC. A number of variants of the HPV16 E6 gene are involved in the progression of CC, differing in their prevalence and biological and biochemical properties. This study was designed to determine the frequency of HPV types 16/18 and to identify the presence of HPV16 E6-variants in asymptomatic Mexican women. METHODS: A total of 189 cervical Pap smears were collected from women attending public health services in three different cities in Sinaloa, Mexico. Viral DNA was identified by amplification of E6 viral gene fragments using polymerase chain reaction (PCR). Identification of variants was done by sequencing a DNA fragment (321bp) of the HPV16 E6 gene. RESULTS: More than half of the women tested were HPV-positive (52.38%), with HPV16 being the most frequent genotype (21.16%), followed by HPV18 (8.99%). Sequence analysis of the E6-HPV16 PCR products showed that in all cases, the viruses corresponded to European variants. It was further observed that the E350G intra-variant was the most common (>76%). INTERPRETATION & CONCLUSIONS: This study showed a predominance of European lineage variants of HPV16 among asymptomatic women from Sinaloa, Mexico, predominantly with of the E350G variant. This variant has been shown to be associated with an increased risk of early development of CC. The use of molecular identification of carcinogenic HPV and Pap test screening may be a good strategy for monitoring women to prevent CC.

Xeroderma pigmentosum is a definite cause of Huntington's disease-like syndrome.

Xeroderma pigmentosum is characterized by cutaneous, ophthalmological, and neurological features. Although it is typical of childhood, late presentations can mimic different neurodegenerative conditions. We report two families presenting as Huntington's disease-like syndromes. The first case (group G) presented with neuropsychiatric features, cognitive decline and chorea. Typical lentigines were only noticed after the neurological disease started. The second case (group B) presented adult-onset chorea and neuropsychiatric symptoms after an aggressive ocular melanoma. Xeroderma pigmentosum can manifest as a Huntington's Disease-like syndrome. Classic dermatological and oncological features have to be investigated in choreic patients with negative genetic tests for Huntington's disease-like phenotypes.

Axl Can Serve as Entry Factor for Lassa Virus Depending on the Functional Glycosylation of Dystroglycan.

Fatal infection with the highly pathogenic Lassa virus (LASV) is characterized by extensive viral dissemination, indicating broad tissue tropism. The major cellular receptor for LASV is the highly conserved extracellular matrix receptor dystroglycan (DG). Binding of LASV depends on DG's tissue-specific posttranslational modification with the unusual O-linked polysaccharide matriglycan. Interestingly, functional glycosylation of DG does not always correlate with viral tropism observed in vivo The broadly expressed phosphatidylserine (PS) receptors Axl and Tyro3 were recently identified as alternative LASV receptor candidates. However, their role in LASV entry is not entirely understood. Here, we examine LASV receptor candidates in primary human cells and found coexpression of Axl with differentially glycosylated DG. To study LASV receptor use in the context of productive arenavirus infection, we employed recombinant lymphocytic choriomeningitis virus expressing LASV glycoprotein (rLCMV-LASV GP) as a validated biosafety level 2 (BSL2) model. We confirm and extend previous work showing that Axl can contribute to LASV entry in the absence of functional DG using "apoptotic mimicry" in a way similar to that of other enveloped viruses. We further show that Axl-dependent LASV entry requires receptor activation and involves a pathway resembling macropinocytosis. Axl-mediated LASV entry is facilitated by heparan sulfate and critically depends on the late endosomal protein LAMP-1 as an intracellular entry factor. In endothelial cells expressing low levels of functional DG, both receptors are engaged by the virus and can contribute to productive entry. In sum, we characterize the role of Axl in LASV entry and provide a rationale for targeting Axl in antiviral therapy.IMPORTANCE The highly pathogenic arenavirus Lassa virus (LASV) represents a serious public health problem in Africa. Although the principal LASV receptor, dystroglycan (DG), is ubiquitously expressed, virus binding critically depends on DG's posttranslational modification, which does not always correlate with tissue tropism. The broadly expressed phosphatidylserine receptor Axl was recently identified as an alternative LASV receptor candidate, but its role in LASV entry is unclear. Here, we investigate the exact role of Axl in LASV entry as a function of DG's posttranslational modification. We found that in the absence of functional DG, Axl can mediate LASV entry via apoptotic mimicry. Productive entry requires virus-induced receptor activation, involves macropinocytosis, and critically depends on LAMP-1. In endothelial cells that express low levels of glycosylated DG, both receptors can promote LASV entry. In sum, our study defines the roles of Axl in LASV entry and provides a rationale for targeting Axl in antiviral therapy.

Encefalomielitis aguda diseminada viral / Acute disseminated viral encephalomyelitis

La encefalomielitis aguda diseminada (EMAD) es un trastorno neurológico caracterizado por inflamación del cerebro y médula espinal causada por un daño a la mielina, afectando al sistema nervioso central de manera difusa. Esta afección puede manifestarse de manera espontánea o secundaria a infecciones o a vacunación. La mayoría de las veces evoluciona de manera monofásica con manifestaciones clínicas inespecíficas, por lo que la sospecha diagnóstica es fundamental. La EMAD es la causa más frecuente de afectación de sustancia blanca. La incidencia es mayor en la edad prepuberal con una incidencia de aproximadamente 0,2-0,4 casos/100000 habitantes año. Tiene predominio estacional, siendo más frecuente en los meses de invierno y primavera. Afecta más a varones. A continuación presentaremos nuestra experiencia con un caso sin diagnóstico previo de esta excepcional y poco frecuente patología el cual se convirtió en un reto diagnóstico(AU)

Acute disseminated encephalomyelitis ADEM is a neurological disorder characterized by inflammation of the brain and spinal cord caused by damage to the myelin, affecting diffusely the central nervous system. This condition can appear spontaneously or secondary to infections or vaccination. Most of the time it evolves in a monophasic manner with nonspecific clinical manifestations, so that he diagnostic suspicion is fundamental. ADEM is the most frequent cause of white matter involvement. The incidence is higher in the prepubertal age with an incidence of approximately 0.2-0.4 cases / 100,000 inhabitants per year. It has a seasonal predominance, being more frequent in the winter and spring months. It affects more males. Below we present our experience with a case without previous diagnosis of this rare pathology which became a diagnostic challenge(AU)