A complex of cadherin 17 with desmocollin 1 and p120-catenin regulates colorectal cancer migration and invasion according to the cell phenotype.

BACKGROUND: Cadherin-17 (CDH17), a marker of differentiation in intestinal cells, binds and activates α2ß1 integrin to promote cell adhesion and proliferation in colorectal cancer (CRC) metastasis. Furthermore, CDH17 associates with p120- and ß-catenin in a manner yet to be fully elucidated. In this report, we explored the molecular mediators involved in this association, their contribution to CRC dissemination and potential therapeutic implications. METHODS: Proteomic and confocal analyses were employed to identify and validate CDH17 interactors. Functional characterization involved the study of proliferation, migration, and invasion in cell lines representative of various phenotypes. Immunohistochemistry was conducted on CRC tissue microarrays (TMA). In vivo animal experiments were carried out for metastatic studies. RESULTS: We found that desmocollin-1 (DSC1), a desmosomal cadherin, interacts with CDH17 via its extracellular domain. DSC1 depletion led to increased or decreased invasion in CRC cells displaying epithelial or mesenchymal phenotype, respectively, in a process mediated by the association with p120-catenin. Down-regulation of DSC1 resulted in an increased expression of p120-catenin isoform 1 in epithelial cells or a shift in cellular location in mesenchymal cells. Opposite results were observed after forced expression of CDH17. DSC1 is highly expressed in budding cells at the leading edge of the tumor and associates with poor prognosis in the stem-like, mesenchymal CRC subtypes, while correlates with a more favorable prognosis in the less-aggressive subtypes. In vivo experiments demonstrated that DSC1 silencing reduced tumor growth, liver homing, and metastasis in CRC mesenchymal cells. Furthermore, a synthetic peptide derived from CDH17, containing the NLV motif, effectively inhibited invasion and liver homing in vivo, opening up new possibilities for the development of novel therapies focused on desmosomal cadherins. CONCLUSIONS: These findings shed light on the multifaceted roles of CDH17, DSC1, and p120-catenin in CRC metastasis, offering insights into potential therapeutic interventions for targeting desmosomal cadherins in poorly-differentiated carcinomas.

The splicing factor SF3B1 is involved in brown adipocyte thermogenic activation.

The ability of alternative splicing mechanisms to control gene expression is increasingly being recognized as relevant for adipose tissue function. The expression of SF3B1, a key component of the SF3B complex directly involved in spliceosome formation, was previously reported to be significantly induced in brown adipose tissue under cold-induced thermogenic activation. Here, we identify that noradrenergic cAMP-mediated thermogenic stimulation increases SF3B1 expression in brown and beige adipocytes. We further show that pladienolide-B, a drug that binds SF3B1 to inhibit pre-mRNA splicing by targeting the SF3B complex, down-regulates key components of the thermogenic machinery (e.g., UCP1 gene expression), differentially alters the expression of alternative splicing-regulated transcripts encoding molecular actors involved in the oxidative metabolism of brown adipocytes (e.g., peroxisome proliferator-activated receptor-gamma co-activator-alpha [PGC-1α] and cytochrome oxidase subunit 7a genes), and impairs the respiratory activity of brown adipocytes. Similar alterations were found in brown adipocytes with siRNA-mediated knockdown of SF3B1 protein levels. Our findings collectively indicate that SF3B1 is a key factor in the appropriate thermogenic activation of differentiated brown adipocytes. This work exemplifies the importance of splicing processes in adaptive thermogenesis and suggests that pharmacological tools, such as pladienolide-B, may be used to modulate brown adipocyte thermogenic activity.

Third National Registry of Cardiac Rehabilitation Programs in Mexico (RENAPREC III-2022) / Tercer Registro Nacional de Programas de Rehabilitación Cardiaca en México (RENAPREC III-2022)

Abstract Introduction: In Mexico, cardiac rehabilitation (CR) as an interdisciplinary intervention with therapeutic impact in patients with heart disease is growing. There is the need to know actual conditions of CR in our country. Objectives: The objective of this National Registry is to follow-up those existing and new CR units in Mexico through the comparison between the two previous registries, RENAPREC-2009 and RENAPREC II-2015 studies. This is a descriptive study focused on diverse CR activities such as assistance training, and certification of health professionals, barriers, reference, population attended, interdisciplinarity, permanence over time, growth prospects, regulations, post-pandemic condition, integrative characteristics, and scientific research. Results: Data were collected from 45 CR centers in the 32 states, 75.5% are private practice units, 67% are new, 33% were part of RENAPREC II-2015, and 17 have continued since 2009. With a better distribution of CR units along the territory, the median reference of candidates for CR programs is 9% with a significant reduction into tiempo of enrollment to Phase II admission (19 ± 11 days). Regarding to previous registries, the coverance of Phases I, II, and III is 71%, 100%, and 93%, respectively; and a coverance increases in evaluation, risk stratification, and prescription, more comprehensive attendance and prevention strategies. Conclusions: CR in Mexico has grown in the past 7 years. Even there is still low reference and heterogeneity in specific processes, there are strengths such as interdisciplinarity, scientific professionalization of specialists, national diversification, and an official society that are consolidated over time.

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Prevalence of Chagas disease in Latin American pregnant women in Madrid, Spain: A multicentre cross-sectional study from 2011 to 2016.

OBJECTIVE: The aim of this study is to assess Trypanosoma cruzi infection prevalence among pregnant migrants living in Madrid according to the country of origin and to assess screening coverage in this at-risk population. METHODS: Retrospective multicentre cross-sectional study conducted from January 2011 to December 2016 in eight Madrid hospitals. Each hospital reviewed their microbiology data records to assess the screening coverage and serological diagnosis in all pregnant women coming from endemic areas. RESULTS: From 2011 to 2016, 149,470 deliveries were attended at the eight hospitals, and 11,048 pregnant women were screened for Chagas disease. Most cases (93.5%) were in women from Bolivia, who also showed the highest prevalence (12.4%, 95% confidence interval: 9.9-15.0). Pooled prevalence amongst the screened women was 2.9% (95% CI: 1.8-4.1). Chagas disease screening coverage varied greatly between centres, with a pooled mean coverage of 47% (95% CI: 37%-57%; 73% [95% CI: 63%-82%] for those centres with universal screening vs. 10% [95% CI: 6%-15%] for those with a selective screening approach; p < 0.001). CONCLUSION: Our study provides useful data for policy makers and epidemiologists in a non-endemic area without congenital Chagas screening programmes.

Cancer and Pregnancy: Estimates in Italy from Record-Linkage Procedures between Cancer Registries and the Hospital Discharge Database.

The aim of this study is to describe the frequency and trend of pregnancy-associated cancer (PAC) in Italy, an increasingly relevant phenomenon due to postponing age at childbirth. To this purpose, a population-based retrospective longitudinal study design based on cohorts of women aged 15-49 diagnosed with cancer and concomitant pregnancy is proposed. The study uses 19 population-based Cancer Registries, covering about 22% of Italy, and linked at an individual level with Hospital Discharge Records. A total of 2,861,437 pregnancies and 3559 PAC are identified from 74,165 women of the cohort with a rate of 1.24 PAC per 1000 pregnancies. The most frequent cancer site is breast (24.3%), followed by thyroid (23.9%) and melanoma (14.3%). The most frequent outcome is delivery (53.1%), followed by voluntary termination of pregnancy and spontaneous abortion (both 12.0%). The trend of PAC increased from 2003 to 2015, especially when the outcome is delivery, thus confirming a new attitude of clinicians to manage cancer throughout pregnancy. This represents the first attempt in Italy to describe PAC from Cancer Registries data; the methodology is applicable to other areas with the same data availability. Evidence from this study is addressed to clinicians for improving clinical management of women with PAC.

The Molecular Mechanisms of the Relationship between Insulin Resistance and Parkinson's Disease Pathogenesis.

Parkinson's disease (PD) is a degenerative condition resulting from the loss of dopaminergic neurons. This neuronal loss leads to motor and non-motor neurological symptoms. Most PD cases are idiopathic, and no cure is available. Recently, it has been proposed that insulin resistance (IR) could be a central factor in PD development. IR has been associated with PD neuropathological features like α-synuclein aggregation, dopaminergic neuronal loss, neuroinflammation, mitochondrial dysfunction, and autophagy. These features are related to impaired neurological metabolism, neuronal death, and the aggravation of PD symptoms. Moreover, pharmacological options that involve insulin signaling improvement and dopaminergic and non-dopaminergic strategies have been under development. These drugs could prevent the metabolic pathways involved in neuronal damage. All these approaches could improve PD outcomes. Also, new biomarker identification may allow for an earlier PD diagnosis in high-risk individuals. This review describes the main pathways implicated in PD development involving IR. Also, it presents several therapeutic options that are directed at insulin signaling improvement and could be used in PD treatment. The understanding of IR molecular mechanisms involved in neurodegenerative development could enhance PD therapeutic options and diagnosis.

Maresin 1 activates brown adipose tissue and promotes browning of white adipose tissue in mice.

OBJECTIVE: Maresin 1 (MaR1) is a docosahexaenoic acid-derived proresolving lipid mediator with insulin-sensitizing and anti-steatosis properties. Here, we aim to unravel MaR1 actions on brown adipose tissue (BAT) activation and white adipose tissue (WAT) browning. METHODS: MaR1 actions were tested in cultured murine brown adipocytes and in human mesenchymal stem cells (hMSC)-derived adipocytes. In vivo effects of MaR1 were tested in diet-induced obese (DIO) mice and lean WT and Il6 knockout (Il6-/-) mice. RESULTS: In cultured differentiated murine brown adipocytes, MaR1 reduces the expression of inflammatory genes, while stimulates glucose uptake, fatty acid utilization and oxygen consumption rate, along with the upregulation of mitochondrial mass and genes involved in mitochondrial biogenesis and function and the thermogenic program. In Leucine Rich Repeat Containing G Protein-Coupled Receptor 6 (LGR6)-depleted brown adipocytes using siRNA, the stimulatory effect of MaR1 on thermogenic genes was abrogated. In DIO mice, MaR1 promotes BAT remodeling, characterized by higher expression of genes encoding for master regulators of mitochondrial biogenesis and function and iBAT thermogenic activation, together with increased M2 macrophage markers. In addition, MaR1-treated DIO mice exhibit a better response to cold-induced BAT activation. Moreover, MaR1 induces a beige adipocyte signature in inguinal WAT of DIO mice and in hMSC-derived adipocytes. MaR1 potentiates Il6 expression in brown adipocytes and BAT of cold exposed lean WT mice. Interestingly, the thermogenic properties of MaR1 were abrogated in Il6-/- mice. CONCLUSIONS: These data reveal MaR1 as a novel agent that promotes BAT activation and WAT browning by regulating thermogenic program in adipocytes and M2 polarization of macrophages. Moreover, our data suggest that LGR6 receptor is mediating MaR1 actions on brown adipocytes, and that IL-6 is required for the thermogenic effects of MaR1.

[Third National Registry of Cardiac Rehabilitation Programs in Mexico (RENAPREC III-2022)]. / Tercer Registro Nacional de Programas de Rehabilitación Cardiaca en México (RENAPREC III-2022).

Introduction: In Mexico, cardiac rehabilitation (CR) as an interdisciplinary intervention with therapeutic impact in patients with heart disease is growing. There is the need to know actual conditions of CR in our country. Objectives: The objective of this National Registry is to follow-up those existing and new CR units in Mexico through the comparison between the two previous registries, RENAPREC-2009 and RENAPREC II-2015 studies. This is a descriptive study focused on diverse CR activities such as assistance training, and certification of health professionals, barriers, reference, population attended, interdisciplinarity, permanence over time, growth prospects, regulations, post-pandemic condition, integrative characteristics, and scientific research. Results: Data were collected from 45 CR centers in the 32 states, 75.5% are private practice units, 67% are new, 33% were part of RENAPREC II-2015, and 17 have continued since 2009. With a better distribution of CR units along the territory, the median reference of candidates for CR programs is 9% with a significant reduction into tiempo of enrollment to Phase II admission (19 ± 11 days). Regarding to previous registries, the coverance of Phases I, II, and III is 71%, 100%, and 93%, respectively; and a coverance increases in evaluation, risk stratification, and prescription, more comprehensive attendance and prevention strategies. Conclusions: CR in Mexico has grown in the past 7 years. Even there is still low reference and heterogeneity in specific processes, there are strengths such as interdisciplinarity, scientific professionalization of specialists, national diversification, and an official society that are consolidated over time.

Introducción: En México, la Rehabilitación Cardíaca (RC) como intervención interdisciplinaria con impacto terapéutico en paciente con cardiopatía está en crecimiento. Existe la necesidad de conocer las condiciones actuales de la RC en nuestro país. Objetivo: El objetivo de este Registro es dar seguimiento comparativo de las unidades nuevas y existentes entre los registros anteriores, RENAPREC-2009 y RENAPREC II-2015. Se trata de un estudio descriptivo centrado en diversas actividades de la RC: formación asistencial y certificación de sus profesionales, barreras, referencia, población atendida, interdisciplinariedad, permanencia en el tiempo, perspectivas de crecimiento, normativa, condición pospandemia, características integradoras e investigación. Resultados: Se recolectaron datos de 45 centros en los 32 estados, 67% son nuevos 75.5% son de práctica privada, 33% fueron parte de RENAPREC II-2015 y 17 desde 2009. Con una mejor distribución de las unidades de RC a lo largo del territorio, la mediana de referencia de pacientes candidatos a RC es ahora del 9% con reducción significativa del tiempo de admisión a Fase II (19 ± 11 días). Respecto a registros anteriores las coberturas de las Fases I, II y III son del 71%, 100% y 93%, respectivamente; con un aumento de la cobertura en evaluación, estratificación de riesgo y prescripción, atención más integral y estrategias de prevención. Conclusiones: La RC en México ha crecido en los últimos 7 años. Si bien aún existe baja referencia y heterogeneidad en procesos específicos, existen fortalezas como la interdisciplinariedad, la profesionalización científica de los especialistas, la diversificación nacional y una sociedad oficial que se consolida en el tiempo.

Adipose tissue plasticity in pheochromocytoma patients suggests a role of the splicing machinery in human adipose browning.

Adipose tissue from pheochromocytoma patients acquires brown fat features, making it a valuable model for studying the mechanisms that control thermogenic adipose plasticity in humans. Transcriptomic analyses revealed a massive downregulation of splicing machinery components and splicing regulatory factors in browned adipose tissue from patients, with upregulation of a few genes encoding RNA-binding proteins potentially involved in splicing regulation. These changes were also observed in cell culture models of human brown adipocyte differentiation, confirming a potential involvement of splicing in the cell-autonomous control of adipose browning. The coordinated changes in splicing are associated with a profound modification in the expression levels of splicing-driven transcript isoforms for genes involved in the specialized metabolism of brown adipocytes and those encoding master transcriptional regulators of adipose browning. Splicing control appears to be a relevant component of the coordinated gene expression changes that allow human adipose tissue to acquire a brown phenotype.

Consenso de la Sociedad Chilena de Infectología para el manejo de episodios de neutropenia febril en adultos y niños con cáncer

El Comité de Infecciones en Inmunocomprometidos de la Sociedad Chilena de Infectología presenta aquí una actualización en el Manejo de episodios de neutropenia febril en adultos y niños con cáncer, derivado de los grandes cambios ocurridos en los últimos años en el enfrentamiento de estos pacientes. Para estos efectos, un grupo multidisciplinario desarrolló recomendaciones en relación a: su enfrentamiento inicial, exámenes de laboratorio requeridos, el tratamiento antimicrobiano inicial empírico y frente a focos infecciosos conocidos, las infecciones fúngicas invasoras y profilaxis antimicrobiana.

The Committee of Infections in Immunocompromised Patients of the Chilean Society of Infectious Diseases presents an update in the Management of febrile neutropenia in adults and children with cancer. It comes from the significant changes that occurred in recent years in the confrontation of these patients. For which a multidisciplinary task force group developed recommendations in relation to their initial handling, laboratory exams required, the initial empirical antimicrobial treatment and in front of known infectious focus, invasive fungal infections and antimicrobial prophylaxis.

Meteorin-like levels are associated with active brown adipose tissue in early infancy.

Introduction: Meteorin-like (METRNL) is a hormonal factor released by several tissues, including thermogenically active brown and beige adipose tissues. It exerts multiple beneficial effects on metabolic and cardiovascular systems in experimental models. However, the potential role of METRNL as brown adipokine in humans has not been investigated previously, particularly in relation to the metabolic adaptations taking place in early life, when brown adipose tissue (BAT) is particularly abundant. Methods and materials: METRNL levels, as well as body composition (DXA) and circulating endocrine-metabolic variables, were assessed longitudinally in a cohort of infants at birth, and at ages 4 and 12 months. BAT activity was measured by infrared thermography at age 12 months. METRNL levels were also determined cross-sectionally in adults; METRNL gene expression (qRT-PCR) was assessed in BAT and liver samples from neonates, and in adipose tissue and liver samples form adults. Simpson-Golabi-Behmel Syndrome (SGBS) adipose cells were thermogenically activated using cAMP, and METRNL gene expression and METRNL protein released were analysed. Results: Serum METRNL levels were high at birth and declined across the first year of life albeit remaining higher than in adulthood. At age 4 and 12 months, METRNL levels correlated positively with circulating C-X-C motif chemokine ligand 14 (CXCL14), a chemokine released by thermogenically active BAT, but not with parameters of adiposity or metabolic status. METRNL levels also correlated positively with infrared thermography-estimated posterior-cervical BAT activity in girls aged 12 months. Gene expression analysis indicated high levels of METRNL mRNA in neonatal BAT. Thermogenic stimulus of brown/beige adipocytes led to a significant increase of METRNL gene expression and METRN protein release to the cell culture medium. Conclusion: Circulating METRNL levels are high in the first year of life and correlate with indices of BAT activity and with levels of an established brown adipokine such as CXCL14. These data, in addition with the high expression of METRNL in neonatal BAT and in thermogenically-stimulated brown/beige adipocytes, suggest that METRNL is actively secreted by BAT and may be a circulating biomarker of BAT activity in early life.

27-hydroxycholesterol promotes oligodendrocyte maturation: Implications for hypercholesterolemia-associated brain white matter changes.

Oxidized cholesterol metabolite 27-hydroxycholesterol (27-OH) is a potential link between hypercholesterolemia and neurodegenerative diseases since unlike peripheral cholesterol, 27-OH is transported across the blood-brain barrier. However, the effects of high 27-OH levels on oligodendrocyte function remain unexplored. We hypothesize that during hypercholesterolemia 27-OH may impact oligodendrocytes and myelin and thus contribute to the disconnection of neural networks in neurodegenerative diseases. To test this idea, we first investigated the effects of 27-OH in cultured oligodendrocytes and found that it induces cell death of immature O4+ /GalC+ oligodendrocytes along with stimulating differentiation of PDGFR+ oligodendrocyte progenitors (OPCs). Next, transgenic mice with increased systemic 27-OH levels (Cyp27Tg) underwent behavioral testing and their brains were immunohistochemically stained and lysed for immunoblotting. Chronic exposure to 27-OH in mice resulted in increased myelin basic protein (MBP) but not 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase) or myelin oligodendrocyte glycoprotein (MOG) levels in the corpus callosum and cerebral cortex. Intriguingly, we also found impairment of spatial learning suggesting that subtle changes in myelinated axons of vulnerable areas like the hippocampus caused by 27-OH may contribute to impaired cognition. Finally, we found that 27-OH levels in cerebrospinal fluid from memory clinic patients were associated with levels of the myelination regulating CNPase, independently of Alzheimer's disease markers. Thus, 27-OH promotes OPC differentiation and is toxic to immature oligodendrocytes as well as it subtly alters myelin by targeting oligodendroglia. Taken together, these data indicate that hypercholesterolemia-derived higher 27-OH levels change the oligodendrocytic capacity for appropriate myelin remodeling which is a crucial factor in neurodegeneration and aging.

Molecular Classification of Colorectal Cancer by microRNA Profiling: Correlation with the Consensus Molecular Subtypes (CMS) and Validation of miR-30b Targets.

Colorectal cancer consensus molecular subtypes (CMSs) are widely accepted and constitutes the basis for patient stratification to improve clinical practice. We aimed to find whether miRNAs could reproduce molecular subtypes, and to identify miRNA targets associated to the High-stroma/CMS4 subtype. The expression of 939 miRNAs was analyzed in tumors classified in CMS. TALASSO was used to find gene-miRNA interactions. A miR-mRNA regulatory network was constructed using Cytoscape. Candidate gene-miR interactions were validated in 293T cells. Hierarchical-Clustering identified three miRNA tumor subtypes (miR-LS; miR-MI; and miR-HS) which were significantly associated (p < 0.001) to the reported mRNA subtypes. miR-LS correlated with the low-stroma/CMS2; miR-MI with the mucinous-MSI/CMS1 and miR-HS with high-stroma/CMS4. MicroRNA tumor subtypes and association to CMSs were validated with TCGA datasets. TALASSO identified 1462 interactions (p < 0.05) out of 21,615 found between 176 miRs and 788 genes. Based on the regulatory network, 88 miR-mRNA interactions were selected as candidates. This network was functionally validated for the pair miR-30b/SLC6A6. We found that miR-30b overexpression silenced 3'-UTR-SLC6A6-driven luciferase expression in 293T-cells; mutation of the target sequence in the 3'-UTR-SLC6A6 prevented the miR-30b inhibitory effect. In conclusion CRC subtype classification using a miR-signature might facilitate a real-time analysis of the disease course and treatment response.

Hernia diafragmática derecha postraumática de presentación tardía. Un caso infrecuente / Post-traumatic right diaphragmatic hernia of late presentation. A rare case

RESUMEN La hernia diafragmática traumática se define como el paso del contenido abdominal a la cavidad torácica a través de un defecto en el diafragma producido por un trauma. Su diagnóstico es difícil, a menudo puede pasar inadvertido, debido a la gravedad de las lesiones que le acompañan. Las claves para el diagnóstico son un alto grado de sospecha y el conocimiento de los distintos signos en la tomografía computarizada. Una vez diagnosticada la ruptura diafragmática, se repara quirúrgicamente para evitar complicaciones. Se presenta el caso de un paciente masculino, de 88 años de edad con antecedentes de haber sufrido trauma toracoabdominal cerrado hacía 35 años, que acudió con un cuadro clínico de oclusión intestinal. Se publica este caso porque, además de ser una entidad poco frecuente, resulta importante el conocimiento de esta enfermedad, para valorarla dentro de las posibilidades diagnósticas en aquellos pacientes que aquejen síntomas relacionados con sus complicaciones.

ABSTRACT Traumatic diaphragmatic hernia is defined as the passage of abdominal contents into the thoracic cavity through a defect in the diaphragm caused by trauma. The diagnosis of traumatic diaphragmatic hernia is difficult, it can often go unnoticed, due to the seriousness of the accompanying injuries. The keys to diagnosis are a high degree of suspicion and knowledge of the various signs on computed tomography. Once the diaphragmatic rupture is diagnosed, it is surgically repaired in order to avoid complications. The case of an 88-year-old male patient with a history of having suffered closed thoracoabdominal trauma 35 years earlier, who presented with a clinical picture of intestinal obstruction is presented. This case is published because, in addition to being a rare entity, knowledge of this disease is important, in order to assess it within the diagnostic possibilities, in those patients who suffer from symptoms related to its complications

Bioassay-Guided Fractionation of Erythrostemon yucatanensis (Greenm.) Gagnon & GP Lewis Components with Anti-hemagglutinin Binding Activity against Influenza A/H1N1 Virus.

Erythrostemon yucatanensis (Greenm.) Gagnon & GP Lewis is a legume tree native to and widely distributed in southeast Mexico, where its branches are used in traditional medicine. An in vitro evaluation of the antiviral activity of extracts and fractions from the leaves, stem bark and roots against two strains of the AH1N1 influenza virus was performed, leading to the identification of bioactive compounds in this medicinal plant. In a cytopathic effect reduction assay, the fractions from the leaves and stem bark were the active elements at the co-treatment level. These were further fractionated based on their hemagglutination inhibition activity. The analysis of spectroscopy data identified a combination of phytosterols (ß-sitosterol, stigmasterol and campesterol) in the stem bark active fraction as the main anti-hemagglutinin binding components, while 5-hydroxy-2(2-hydroxy-3,4,5-trimethoxyphenyl)-7-metoxi-4H(chromen-4-ona), which was isolated from the leaf extracts, showed a weak inhibition of viral hemagglutinin. Time of addition experiments demonstrated that the mixture of sterols had a direct effect on viral particle infectivity at the co-treatment level (IC50 = 3.125 µg/mL). This effect was also observed in the virus plaque formation inhibition assay, where the mixture showed 90% inhibition in the first 20 min of co-treatment at the same concentration. Additionally, it was found using qRT-PCR that the NP copy number was reduced by 92.85% after 60 min of co-treatment. These results are the first report of components with anti-hemagglutinin binding activity in the genus Erythrostemon sp.

Differential effects of dolutegravir, bictegravir and raltegravir in adipokines and inflammation markers on human adipocytes.

AIMS: To assess the potential direct effects of the integrase strand-transfer inhibitors (INsTIs) dolutegravir, bictegravir, and raltegravir, drugs used as treatment for people living with human immunodeficiency virus (PLWH), on human adipose cells. MAIN METHODS: Drugs were added to the differentiation medium of human Simpson-Golabi-Behmel syndrome (SGBS) adipose cells and morphological adipogenesis was monitored for 10 days. Also, adipocytes were exposed to drugs following differentiation (day 14). The gene expression levels of selected adipogenesis markers, adipocyte metabolism markers, adipokines, and cytokines were determined by quantitative-reverse transcription polymerase-chain reaction. The release of adiponectin and leptin into the culture medium was measured using specific enzyme-linked immunosorbent assay, and release of interleukin-6 and chemokine (CC motif) ligand-2 using Multiplex assays. KEY FINDINGS: Overall morphological adipogenesis was unaltered by INsTIs. The expression of adipogenesis marker genes (peroxisome proliferator-activated receptor-Ɣ and lipoprotein lipase) was slightly reduced in dolutegravir-treated differentiating adipocytes. Bictegravir repressed gene expression and the release of pro-inflammatory cytokines in differentiating adipocytes. Dolutegravir and raltegravir increased interleukin-6 gene expression, but only dolutegravir increased interleukin-6 release. Dolutegravir repressed adiponectin expression and release in differentiating adipocytes and had a similar but milder effect on leptin. Drug treatment of mature adipocytes reduced adiponectin gene expression in response to dolutegravir. SIGNIFICANCE: The INsTIs studied do not have a significant effect on human adipose cell differentiation but exert distinct effects on gene expression and secretion of adipokines and cytokines. These findings will help understand and manage the effects of INsTI-containing treatments on body weight and metabolic dysregulation in PLWH.

Neuronal energy use and brain evolution.

Consider how advantageous it might be to have eyes on our hands, rather than on our faces: depth perception would be improved by the greater distance between the eyes, and it would be easy to look into relatively inaccessible spaces by appropriate movement of the hands. The absence of mammals that use this visual strategy draws attention to constraints on how evolution is able to 'design' the nervous system. Energy use in particular, in this case the large amount of energy that would be needed to send visual information along the ∼106 optic nerve axons over the length of the arms to the brain (instead of along the much shorter optic nerve), imposes significant design constraints on the nervous system.

Recombinant Integrin ß1 Signal Peptide Blocks Gliosis Induced by Aß Oligomers.

Glial cells participate actively in the early cognitive decline in Alzheimer's disease (AD) pathology. In fact, recent studies have found molecular and functional abnormalities in astrocytes and microglia in both animal models and brains of patients suffering from this pathology. In this regard, reactive gliosis intimately associated with amyloid plaques has become a pathological hallmark of AD. A recent study from our laboratory reports that astrocyte reactivity is caused by a direct interaction between amyloid beta (Aß) oligomers and integrin ß1. Here, we have generated four recombinant peptides including the extracellular domain of integrin ß1, and evaluated their capacity both to bind in vitro to Aß oligomers and to prevent in vivo Aß oligomer-induced gliosis and endoplasmic reticulum stress. We have identified the minimal region of integrin ß1 that binds to Aß oligomers. This region is called signal peptide and corresponds to the first 20 amino acids of the integrin ß1 N-terminal domain. This recombinant integrin ß1 signal peptide prevented Aß oligomer-induced ROS generation in primary astrocyte cultures. Furthermore, we carried out intrahippocampal injection in adult mice of recombinant integrin ß1 signal peptide combined with or without Aß oligomers and we evaluated by immunohistochemistry both astrogliosis and microgliosis as well as endoplasmic reticulum stress. The results show that recombinant integrin ß1 signal peptide precluded both astrogliosis and microgliosis and endoplasmic reticulum stress mediated by Aß oligomers in vivo. We have developed a molecular tool that blocks the activation of the molecular cascade that mediates gliosis via Aß oligomer/integrin ß1 signaling.

Hospital-wide cardiac arrest in situ simulation to identify and mitigate latent safety threats.

BACKGROUND: Cardiac arrest resuscitation requires well-executed teamwork to produce optimal outcomes. Frequency of cardiac arrest events differs by hospital location, which presents unique challenges in care due to variations in responding team composition and comfort levels and familiarity with obtaining and utilizing arrest equipment. The objective of this initiative is to utilize unannounced, in situ, cardiac arrest simulations hospital wide to educate, evaluate, and maximize cardiac arrest teams outside the traditional simulation lab by systematically assessing and capturing areas of opportunity for improvement, latent safety threats (LSTs), and key challenges by hospital location. METHODS: Unannounced in situ simulations were performed at a city hospital with multidisciplinary cardiac arrest teams responding to a presumed real cardiac arrest. Participants and facilitators identified LSTs during standardized postsimulation debriefings that were classified into equipment, medication, resource/system, or technical skill categories. A hazard matrix was used by multiplying occurrence frequency of LST in simulation and real clinical events (based on expert opinion) and severity of the LST based on agreement between two evaluators. RESULTS: Seventy-four in situ cardiac arrest simulations were conducted hospital wide. Hundreds of safety threats were identified, analyzed, and categorized yielding 106 unique latent safety threats: 21 in the equipment category, 8 in the medication category, 41 in the resource/system category, and 36 in the technical skill category. The team worked to mitigate all LSTs with priority mitigation to imminent risk level threats, then high risk threats, followed by non-imminent risk LSTs. Four LSTs were deemed imminent, requiring immediate remediation post debriefing. Fifteen LSTs had a hazard ratio greater than 8 which were deemed high risk for remediation. Depending on the category of threat, a combination of mitigating steps including the immediate fixing of an identified problem, leadership escalation, and programmatic intervention recommendations occurred resulting in mitigation of all identified threats. CONCLUSIONS: Hospital-wide in situ cardiac arrest team simulation offers an effective way to both identify and mitigate LSTs. Safety during cardiac arrest care is improved through the use of a system in which LSTs are escalated urgently, mitigated, and conveyed back to participants to provide closed loop debriefing. Lastly, this hospital-wide, multidisciplinary initiative additionally served as an educational needs assessment allowing for informed, iterative education and systems improvement initiatives targeted to areas of LSTs and areas of opportunity.