Integrative omics identifies conserved and pathogen-specific responses of sepsis-causing bacteria.

Even in the setting of optimal resuscitation in high-income countries severe sepsis and septic shock have a mortality of 20-40%, with antibiotic resistance dramatically increasing this mortality risk. To develop a reference dataset enabling the identification of common bacterial targets for therapeutic intervention, we applied a standardized genomic, transcriptomic, proteomic and metabolomic technological framework to multiple clinical isolates of four sepsis-causing pathogens: Escherichia coli, Klebsiella pneumoniae species complex, Staphylococcus aureus and Streptococcus pyogenes. Exposure to human serum generated a sepsis molecular signature containing global increases in fatty acid and lipid biosynthesis and metabolism, consistent with cell envelope remodelling and nutrient adaptation for osmoprotection. In addition, acquisition of cholesterol was identified across the bacterial species. This detailed reference dataset has been established as an open resource to support discovery and translational research.

Multi-omics of the esophageal microenvironment identifies signatures associated with progression of Barrett's esophagus.

BACKGROUND: The enrichment of Gram-negative bacteria of oral origin in the esophageal microbiome has been associated with the development of metaplasia. However, to date, no study has comprehensively assessed the relationships between the esophageal microbiome and the host. METHODS: Here, we examine the esophageal microenvironment in gastro-esophageal reflux disease and metaplasia using multi-omics strategies targeting the microbiome and host transcriptome, followed by targeted culture, comparative genomics, and host-microbial interaction studies of bacterial signatures of interest. RESULTS: Profiling of the host transcriptome from esophageal mucosal biopsies revealed profound changes during metaplasia. Importantly, five biomarkers showed consistent longitudinal changes with disease progression from reflux disease to metaplasia. We showed for the first time that the esophageal microbiome is distinct from the salivary microbiome and the enrichment of Campylobacter species as a consistent signature in disease across two independent cohorts. Shape fitting and matrix correlation identified associations between the microbiome and host transcriptome profiles, with a novel co-exclusion relationship found between Campylobacter and napsin B aspartic peptidase. Targeted culture of Campylobacter species from the same cohort revealed a subset of isolates to have a higher capacity to survive within primary human macrophages. Comparative genomic analyses showed these isolates could be differentiated by specific genomic features, one of which was validated to be associated with intracellular fitness. Screening for these Campylobacter strain-specific signatures in shotgun metagenomics data from another cohort showed an increase in prevalence with disease progression. Comparative transcriptomic analyses of primary esophageal epithelial cells exposed to the Campylobacter isolates revealed expression changes within those infected with strains with high intracellular fitness that could explain the increased likelihood of disease progression. CONCLUSIONS: We provide a comprehensive assessment of the esophageal microenvironment, identifying bacterial strain-specific signatures with high relevance to progression of metaplasia.

Global Cardiovascular Risk Profile and Cerebrovascular Abnormalities in Presymptomatic Individuals with CADASIL or Autosomal Dominant Alzheimer's Disease.

BACKGROUND: Cardiovascular risk factors increase the risk of developing dementia, including Alzheimer's disease and vascular dementia. OBJECTIVE: Studying individuals with autosomal dominant mutations leading to the early onset of dementia, this study examines the effect of the global cardiovascular risk profile on early cognitive and neuroimaging features of Alzheimer's disease and vascular dementia. METHODS: We studied 85 non-demented and stroke-free individuals, including 20 subjects with Presenilin1 (PSEN1) E280A mutation leading to the early onset of autosomal dominant Alzheimer's disease (ADAD), 20 subjects with NOTCH3 mutations leading to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and to the early onset of vascular dementia, and 45 non-affected family members (non-carriers). All subjects underwent clinical and neuropsychological evaluations and an MRI. The global cardiovascular risk profile was estimated using the office-based Framingham Cardiovascular Risk Profile (FCRP) score. RESULTS: In individuals with CADASIL, a higher FCRP score was associated with a reduced hippocampal volume (B = -0.06, p < 0.05) and an increased severity of cerebral microbleeds (B = 0.13, p < 0.001), lacunes (B = 0.30, p < 0.001), and perivascular space enlargement in the basal ganglia (B = 0.50, p < 0.05). There was no significant association between the FCRP score and neuroimaging measures in ADAD or non-carrier subjects. While the FCRP score was related to performance in executive function in non-carrier subjects (B = 0.06, p < 0.05), it was not significantly associated with cognitive performance in individuals with CADASIL or ADAD. CONCLUSION: Our results suggest that individuals with CADASIL and other forms of vascular cognitive impairment might particularly benefit from early interventions aimed at controlling cardiovascular risks.

Genetic and nongenetic factors associated with CADASIL: A retrospective cohort study.

OBJECTIVE: To explore the role of cardiovascular risk factors and the different NOTCH-3 mutations to explain the variability observed in the clinical presentation of CADASIL. METHODS: This was a retrospective cohort study of 331 individuals, 90 were carriers of four mutations in the NOTCH3 gene. These four mutations are the ones identified in our region from the genetic evaluation of probands. Cox proportional hazards models were fitted to estimate the effect of genetic and cardiovascular factors on the onset of migraine, first stroke, and dementia. Competing risk regression models considered death as risk. RESULTS: Noncarriers (healthy controls from the same families without NOTCH3 mutations) and NOTCH3 mutation carriers had similar frequencies for all cardiovascular risk factors. Diabetes (SHR 2.74, 95% CI 1.52-4.94) was associated with a younger age at onset of strokes among carriers. Additionally, a genotype-phenotype relationship was observed among C455R mutation carriers, with higher frequency of migraines (100%), younger age at onset of migraine (median age 7 years, IQR 8) and strokes (median age 30.5 years, IQR 26). Moreover, fewer carriers of the R141C mutation exhibited migraines (20%), and it was even lower than the frequency observed in the noncarrier group (44.8%). CONCLUSIONS: This study characterizes extended family groups, allowing us a comparison in the genotype-phenotype. The results suggest a complex interplay of genetic and cardiovascular risk factors that may help explain the variability in the clinical presentation and severity of CADASIL.

Enfoque del paciente con cefalea en tiempos de covid-19 / Approach to the patient with headache in times of COVID-19

RESUMEN Ante el número cada vez mayor de pacientes con covid-19 y los rápidos cambios que ha traído consigo la pandemia en los estilos de vida, se redactó el presente documento, con el objetivo de proveer una recomendación a los neurológos y médicos en general para el abordaje del paciente con cefalea. Inicialmente, se realiza el abordaje de la cefalea como uno de los síntomas del covid-19, revisando las series de casos y proponiendo posibles clasificaciones diagnósticas para explicar su presencia en estos pacientes. Posteriormente, se evaluará la cefalea secundaria a otros trastornos neurológicos también reportados en pacientes con covid-19 y los signos de alarma para realizar estudios complementarios. Por último se revisará como ha cambiado el seguimiento de los pacientes con cefalea primaria en medio de la pandemia, recomendaciones sobre ajustes que se deben hacer durante este tiempo en su manejo y formulación, y finalmente recomendaciones sobre interacciones en sus medicamentos en caso de enfermar por covid-19.

SUMMARY Given the increasing number of patients with COVID-19 and the rapid changes that the pandemic has brought about in lifestyles, this document was developed with the aim of providing a recommendation to neurologists and doctors in general for the approach of the patient with headache. Initially, the headache was treated as one of the symptoms of COVID-19, reviewing the case series and proposing possible diagnostic classifications to explain its presence in these patients. Subsequently, headache secondary to other neurological disorders also reported in patients with COVID-19 and the warning signs will be evaluated to carry out complementary studies. Finally, it will be reviewed how the follow-up of patients with primary headache in the midst of the pandemic has changed, recommendations on adjustments to be made during this time in its management and formulation, and finally recommendations on drug interactions in case of illness due to COVID-19.

The INECO Frontal Screening for the Evaluation of Executive Dysfunction in Cerebral Small Vessel Disease: Evidence from Quantitative MRI in a CADASIL Cohort from Colombia.

OBJECTIVES: Executive dysfunction is a predominant cognitive symptom in cerebral small vessel disease (SVD). The Institute of Cognitive Neurology Frontal Screening (IFS) is a well-validated screening tool allowing the rapid assessment of multiple components of executive function in Spanish-speaking individuals. In this study, we examined performance on the IFS in subjects with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), an inherited condition leading to the early onset of SVD. We further explored associations between performance on the IFS and magnetic resonance imaging (MRI) markers of SVD. METHODS: We recruited 24 asymptomatic CADASIL subjects and 23 noncarriers from Colombia. All subjects underwent a research MRI and a neuropsychological evaluation, including the IFS. Structural MRI markers of SVD were quantified in each subject, together with an SVD Sum Score representing the overall burden of cerebrovascular alterations. General linear model, correlation, and receiver operating characteristic curve analyses were used to explore group differences on the IFS and relationships with MRI markers of SVD. RESULTS: CADASIL subjects had a significantly reduced performance on the IFS Total Score. Performance on the IFS correlated with all quantified markers of SVD, except for brain atrophy and perivascular spaces enlargement. Finally, while the IFS Total Score was not able to accurately discriminate between carriers and noncarriers, it showed adequate sensitivity and specificity in detecting the presence of multiple MRI markers of SVD. CONCLUSIONS: These results suggest that the IFS may be a useful screening tool to assess executive function and disease severity in the context of SVD.

Cognitive performance in asymptomatic carriers of mutations R1031C and R141C in CADASIL.

CADASIL is the most common hereditary cause of repeated ischemic strokes, and has also been identified as a model of pure vascular dementia. The objective of this study was to establish the cognitive performance of asymptomatic carriers with the mutations R1031C and R141C. This observational crosssectional analytical study divided subjects into three groups: asymptomatic carriers of the R1031C mutation (𝑛 = 39), asymptomatic carries of the R141C mutation (𝑛 = 8) and noncarriers (𝑛 = 50). Statistically significant differences were found (𝑝 < 0.05) between the group of the R1031C mutation and the noncarriers in constructional praxis, executive function and abstract reasoning. For the R141C mutation, scores below expected values in executive function and mental calculation were observed. It is concluded that asymptomatic carriers of the two mutations showed low performance in working memory, mental abstraction and processing speed, which could be associated with preclinical cognitive biomarkers preceding the presentation of the first vascular event.

La Arteriopatía Cerebral Autosómica Dominante con Infartos Subcorticales y Leucoencefalopatía (CADASIL), es producida por mutaciones en el gen NOTCH3, es la causa hereditaria más común de accidentes cerebrovasculares isquémicos repetidos. Objetivo: establecer el desempeño cognitivo en portadores asintomáticos con las mutaciones R1031C Y R141C. Método: estudio observacional, analítico transversal. Se dividieron en tres grupos: portadores asintomáticos con mutación R1031C (𝑛 = 39), asintomáticos con mutación R141C (𝑛 = 8) y no portadores (𝑛 = 50). Resultados: se encontraron diferencias estadísticamente significativas (𝑝 < 0.05) entre el grupo de portadores asintomáticos de la mutación R1031C y los no portadores en praxias construccionales, función ejecutiva y razonamiento abstracto. En la mutación R141C, se observaron puntuaciones bajas en función ejecutiva y cálculo mental. Conclusiones: los portadores asintomáticos de las dos mutaciones evidenciaron bajo rendimiento en memoria de trabajo, abstracción mental y velocidad de procesamiento, pudiendo estar asociados como biomarcadores cognitivos preclínicos, antes del primer evento vascular o los primeros síntomas.

Blood biomarkers in a mouse model of CADASIL.

Mutations in NOTCH 3 are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a neurological disorder characterized by stroke, and vascular cognitive impairment and dementia. Loss of vascular smooth muscle cells (VSMC) and accumulation of granular osmiophilic material (GOM) deposits are hallmarks of CADASIL. There are no therapies for CADASIL and experimental endpoints to examine the preclinical efficacy of potential drugs are lacking. This study aims to use a mouse carrying the C455R mutation in Notch 3 to identify biomarkers associated with CADASIL. Mass spectrometry and antibody arrays were used to explore the aorta and blood proteomes of CADASIL mice, ELISA assays were utilized for biomarker validation, a ligand-dependent assay was applied to examine the relationship between Notch signaling and biomarker expression, and retinal histology was performed for quantification of VSMC loss in arteries. Two-hundred day-old mice with the C455R CADASIL mutation in Notch 3 mice display robust VSMC loss in retinal arteries and had increased plasma levels of collagen18α1/endostatin (col18α1) and high-temperature requirement A serine peptidase 1 (HTRA1) and reduced levels of Notch 3 extracellular domain (N3ECD), compared to control wild type mice. Measurements of plasma endostatin, HTRA1 and N3ECD, along with VSMC quantification in retinal arteries, may serve as surrogate endpoints for assessing efficacy in preclinical therapeutic studies of CADASIL using mice.

Características clínico-epidemiológicas de pacientes con esquizofrenia atendidos en el Hospital Psiquiátrico Universitario del Valle, Colombia / Clinical and epidemiological features of patients with schizophrenia and treated at the Psychiatric University Hospital del Valle, Colombia / aracterísticas clínicas e epidemiológicas de pacientes com esquizofrenia atendidos no Hospital Universitário de Psiquiatria del Valle, Colômbia

Introducción. En Colombia, la esquizofrenia presenta una prevalencia similar a la de otras partes del mundo, de 1 %, lo que permite estimar una población de 471.052 colombianos con esta enfermedad. En regiones como Cali y Bogotá, alcanza el 1,5 %, por encima del promedio mundial. Objetivo. Describir el perfil sociodemográfico y clínico de un grupo de pacientes con esquizofrenia, atendidos en el Hospital Psiquiátrico Universitario del Valle, en el período de enero a diciembre de 2012. Materiales y métodos. Se trata de un estudio descriptivo y retrospectivo, en el que se revisaron 8.472 historias clínicas de la base de datos de pacientes con diagnóstico de esquizofrenia; se identificaron aquellas que cumplían con los criterios de inclusión y, finalmente, se incluyeron 1.410 historias clínicas. Resultados. El 65 % de los pacientes eran hombres y la edad osciló entre los 13 y los 89 años, con un promedio de 40 (DE=31,6). El 89 % eran solteros (IC95% 87,2-90,6 %), el 98 % provenían de la zona urbana (IC95% 97,3-99,4 %) y el 76,6 % residía en la ciudad de Cali. La esquizofrenia indiferenciada fue el diagnóstico más frecuente (81 %), seguida de la paranoide (9 %) y de la de tipo desorganizada (3 %). Los fármacos más prescritos fueron clozapina (18 %), biperideno (15 %) y levomepromazina (14 %). Conclusiones. La descripción de la esquizofrenia en el hospital muestra que la mayoría de los pacientes cumplen con el tratamiento farmacológico indicado; la principal razón para no observarlo, lo cual sucede en un bajo porcentaje de los pacientes, es la falta de conciencia de la enfermedad.

Introduction: In Colombia, schizophrenia prevalence is similar to that of other parts of the world, 1%, which allows estimating a population of 471,052 Colombians with this disease. In regions such as Cali and Bogotá, it reaches 1.5%, above the world average Objective: To describe the sociodemographic and clinical profile of a group of patients with schi-zophrenia treated at the Hospital Psiquiátrico Universitario del Valle, from January to December of 2012. Materials and methods: A retrospective descriptive study was conducted; 8,472 medical records from the database of patients diagnosed with schizophrenia were reviewed; those meeting the inclu-sion criteria were selected for a total of 1,410 medical records. Results: 65% of patients were male aged between 13 and 89 with an average of 40 years (SD=31.6). 89% were single (CI 95% 87.2%-90.6%) and 98% came from urban areas (CI 95% 97.3%- 9.4%), 76.6% lived in the city of Cali. Undifferentiated schizophrenia was the most frequent diagnosis (81%), followed by paranoid (9%), and disorganized type (3%). The most prescribed medicines were clozapine (18%), biperideno (15%) and levomepromazina (14%). Conclusions: The description of schizophrenia in the Hospital Psiquiátrico Universitario del Valle evi-dences compliance and adherence to the established pharmacological treatment. Among the low percentage of patients with no adherence, the main cause was found to be the lack of awareness of the disease

Introdução. Na Colômbia, a esquizofrenia apresenta uma prevalência semelhante à de outras partes do mundo, de 1%, o que permite estimar uma população de 471,052 colombianos com esta doença. Em regiões tais como Cali e Bogotá, atinge 1,5%, acima da média mundial. Objetivo. Descrever o perfil sociodemográfico e clínico de um grupo de pacientes com esquizofrenia atendidos no Hospital Psiquiátrico Universitário del Valle, no período de Janeiro a Dezembro de 2012. Materiais e métodos. Se realizo um estudo descritivo e retrospectivo, foram revisados 8,472 registros médicos do banco de dados dos pacientes diagnosticados com esquizofrenia; aqueles que atenderam com os critérios de inclusão foram selecionados obtendo 1,410 registros médicos Resultados. 65% dos pacientes eram do sexo masculino e a idade variou entre 13 a 89 anos, com uma média de 40 (DP = 31,6). O 89% eram solteiros (95% CI 87,2-90,6%), 98% eram procedentes de áreas urbanas (95% IC 97,3-99,4%) e 76,6% moravam na cidade de Cali. A esquizofrenia indiferenciada foi o diagnóstico mais comum (81%), seguido por paranoico (9%) e o tipo desorganizado (3%). Os medicamentos mais prescritos foram clozapina (18%), biperideno (15%) e levomepromazina (14%). Conclusões. A descrição da esquizofrenia no hospital mostra que a maioria dos pacientes cumprem com o tratamento farmacológico indicado; a principal razão para não observar o tratamento ade-quado, que ocorre em uma pequena porcentagem de pacientes, é a falta de conscientização sobre a doença.

Distribución de conocimiento y usos por generación y género de plantas comestibles en tres comunidades afrodescendientes en bolívar, Colombia / Distribution of knowledge and of uses of edible plants by generation and gender in three african descendant communities in bolívar, Cloombia

Durante las últimas dos décadas se han desarrollado muchas iniciativas para el rescate y la valoración de la diversidad de plantas útiles subutilizadas en distintas regiones del mundo. En Colombia se han realizado varias investigaciones etnobotánicas, sin embargo, se requiere ampliar las investigaciones sobre el uso de plantas comestibles por comunidades afrodescendientes. El objetivo global de la investigación era contribuir a la identificación de los saberes de las comunidades afrodescendientes de la Costa Caribe colombiana con respecto a la utilización, sistemas de manejo y producción de las plantas comestibles tradicionales. Este artículo se enfoca en la pregunta de cómo se distribuyen los saberes y cambian las prácticas de uso por generación y género de las plantas en tres comunidades del departamento de Bolívar. A través de una actividad con familias sobre el reconocimiento de 91 plantas se evidenció una pérdida intergeneracional de saberes y tradiciones de uso. Los porcentajes altos de no consumo y/o de consumo no reciente en combinación con las explicaciones dadas en grupos focales sugieren un declive en el uso alimenticio de alrededor de 20 plantas, en su mayoría silvestres y semisilvestres. Las razones dadas variaban según las plantas e incluían percepciones de cambio en las costumbres de producción, preparación de alimentos y consumo, y desaparición de ciertas plantas a causa de cambios en las prácticas de gestión del territorio y de los recursos naturales. Los adultos mayores pueden reconocer más plantas de las que usan. Los hombres reportaron niveles de reconocimiento más altos en comparación a las mujeres para el caso de 28 especies, principalmente de estatus silvestre. Los resultados muestran que el diseño de estrategias exitosas de fomento de procesos de desarrollo rural sostenible que pongan en valor la gran diversidad de plantas comestibles de la región necesita un enfoque diferencial según usuarios y recursos.

In the last two decades a significant number of initiatives have been undertaken to promote and revalue the diversity of useful under-utilized plants in various regions around the world. In Colombia there have been various ethnobotanical studies, however, there is still a need for further research, particularly on the use of food plants in Afro-descendant communities. The overall objective of this research project was to contribute to the documentation of the use of traditional food plants and knowledge of the management and production systems by Afro-descendant communities in the Colombian Caribbean coastal region. This article focuses specifically on the question of how knowledge is distributed and how use practices of the plants change by generation and gender in three communities in the department of Bolívar. Through a recognition exercise, undertaken with families on 91 plants, evidence was found of intergenerational loss of knowledge and traditions of use. High percentages of reported non-consumption and/or not recent consumption combined with explanations given in focus groups, suggest a decline in the food use of about 20 species, the majority of them having wild and semi-wild status. The reasons given varied depending on the plant species and included perceptions of change in production and food preparation and consumption practices and the disappearance of certain plants because of changes in land use and natural resource management. Older respondents recognized more plants than they actually used. Recognition rates by men were higher in comparison to women in the case of 28 plants, mainly wild resources. These results highlight that the design of successful strategies to promote sustainable rural development processes which revalue the significant diversity of food plants in the region requires a differential focus depending on the user and the type of resource.

Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small-vessel disease.

The most common monogenic cause of small-vessel disease leading to ischemic stroke and vascular dementia is the neurodegenerative syndrome cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is associated with mutations in the Notch 3 receptor. CADASIL pathology is characterized by vascular smooth muscle cell degeneration and accumulation of diagnostic granular osmiophilic material (GOM) in vessels. The functional nature of the Notch 3 mutations causing CADASIL and their mechanistic connection to small-vessel disease and GOM accumulation remain enigmatic. To gain insight into how Notch 3 function is linked to CADASIL pathophysiology, we studied two phenotypically distinct mutations, C455R and R1031C, respectively associated with early and late onset of stroke, by using hemodynamic analyses in transgenic mouse models, receptor activity assays in cell culture, and proteomic examination of postmortem human tissue. We demonstrate that the C455R and R1031C mutations define different hypomorphic activity states of Notch 3, a property linked to ischemic stroke susceptibility in mouse models we generated. Importantly, these mice develop osmiophilic deposits and other age-dependent phenotypes that parallel remarkably the human condition. Proteomic analysis of human brain vessels, carrying the same CADASIL mutations, identified clusterin and collagen 18 α1/endostatin as GOM components. Our findings link loss of Notch signaling with ischemic cerebral small-vessel disease, a prevalent human condition. We determine that CADASIL pathophysiology is associated with hypomorphic Notch 3 function in vascular smooth muscle cells and implicate the accumulation of clusterin and collagen 18 α1/endostatin in brain vessel pathology.