Plasma Metabolome Signatures to Predict Responsiveness to Neoadjuvant Chemotherapy in Breast Cancer.

BACKGROUND: Neoadjuvant chemotherapy (NACT) has arisen as a treatment option for breast cancer (BC). However, the response to NACT is still unpredictable and dependent on cancer subtype. Metabolomics is a tool for predicting biomarkers and chemotherapy response. We used plasma to verify metabolomic alterations in BC before NACT, relating to clinical data. METHODS: Liquid chromatography coupled to mass spectrometry (LC-MS) was performed on pre-NACT plasma from patients with BC (n = 75). After data filtering, an SVM model for classification was built and validated with 75%/25% of the data, respectively. RESULTS: The model composed of 19 identified metabolites effectively predicted NACT response for training/validation sets with high sensitivity (95.4%/93.3%), specificity (91.6%/100.0%), and accuracy (94.6%/94.7%). In both sets, the panel correctly classified 95% of resistant and 94% of sensitive females. Most compounds identified by the model were lipids and amino acids and revealed pathway alterations related to chemoresistance. CONCLUSION: We developed a model for predicting patient response to NACT. These metabolite panels allow clinical gain by building precision medicine strategies based on tumor stratification.

Factors that Influence Growth Rates of Abdominal Aortic Aneurysms. Analysis of a Mexican Cohort.

OBJECTIVE: Abdominal Aortic Aneurysms (AAA) growth remains a process not fully understood. The objective of this study was to analyze risk factors associated with changes in AAA diameter in a Mexican cohort. METHODS: An observational study in which we analyzed the entirely of patients in which an AAA was reported in a Computed Tomography (CT) study from 2014 to 2021 who had a follow-up CT. We divided them by groups depending on the diagnosis of type 2 diabetic mellitus and pharmacological history (diabetic vs non-diabetic, metformin vs non-metformin intake and statin vs non-statin intake). We compared pre and post follow-up AAA diameters using paired t-tests. A multivariate analysis was performed in order to identify independent variables associated with an increased growth rate. Statistical analysis was performed on Stata 17. RESULTS: During the studied period 72 (39.77%) patients had a follow-up CT. Mean age was 75 years (±9.05) and 52 (72.22%) were men. When comparing infra-renal largest diameter through time based on metformin intake, a significant difference was found only in the metformin non-intake group (42.05 ± 12.54 vs45.34 ± 12.06 [P = 0.02]), in contrast the metformin intake group measures were non-significantly different (36.13 ± 7.04 vs 37.00 ± 4.51; P = 0.57) through follow-up. In the multivariate analysis AAA largest diameter at diagnosis correlated with significantly increased growth rate (coeff = 0.06, P < 0.05). CONCLUSIONS: AAA diameters appear to change through time in a non-linear pattern influenced by different epidemiological and clinical factors. Metformin intake appears to promote a stability in AAA diameter growth in our studied population.

Diversity, Prevalence and Virulence of Colletotrichum Species Causing Anthracnose on Cassava Leaves in the Northern Region of Brazil.

Cassava (Manihot esculenta Crantz) is a staple crop widely cultivated by small farmers in tropical countries. However, despite the low level of technology required for its management, it can be affected by several diseases, with anthracnose as the main threat. There is little information about the main species of Colletotrichum that infect cassava in Brazil. Thus, the objective of this work was to study the diversity, prevalence and virulence of Colletotrichum species that cause anthracnose in cassava leaves in northern Brazil. Twenty municipalities of the Pará and Tocantins states were selected, and leaves with symptoms were collected in those locations. Pure cultures were isolated in the laboratory. Species were identified using phylogenetic analyses of multiple loci, and their pathogenicity, aggressivity and virulence levels were assessed. Our results showed the greatest diversity of Colletotrichum associated with anthracnose in cassava plants of the "Formosa" cultivar in the Tocantins and Pará states. We determined the presence of Colletotrichum chrysophilum, C. truncatum, C. siamense, C. fructicola, C. plurivorum, C. musicola and C. karsti, with C. chrysophilum as the most aggressive and virulent. Our findings provide accurate identifications of species of Colletotrichum causing anthracnose in cassava crops, which are of great relevance for cassava breeding programs (e.g., the search for genotypes with polygenic resistance since the pathogen is so diverse) and for developing anthracnose management strategies that can work efficiently against species complexes of Colletotrichum.

Alpha-Synuclein Gene Alterations Modulate Tyrosine Hydroxylase in Human iPSC-Derived Neurons in a Parkinson's Disease Animal Model.

Parkinson's disease (PD) caused by SNCA gene triplication (3XSNCA) leads to early onset, rapid progression, and often dementia. Understanding the impact of 3XSNCA and its absence is crucial. This study investigates the differentiation of human induced pluripotent stem cell (hiPSC)-derived floor-plate progenitors into dopaminergic neurons. Three different genotypes were evaluated in this study: patient-derived hiPSCs with 3XSNCA, a gene-edited isogenic line with a frame-shift mutation on all SNCA alleles (SNCA 4KO), and a normal wild-type control. Our aim was to assess how the substantia nigra pars compacta (SNpc) microenvironment, damaged by 6-hydroxydopamine (6-OHDA), influences tyrosine hydroxylase-positive (Th+) neuron differentiation in these genetic variations. This study confirms successful in vitro differentiation into neuronal lineage in all cell lines. However, the SNCA 4KO line showed unusual LIM homeobox transcription factor 1 alpha (Lmx1a) extranuclear distribution. Crucially, both 3XSNCA and SNCA 4KO lines had reduced Th+ neuron expression, despite initial successful neuronal differentiation after two months post-transplantation. This indicates that while the SNpc environment supports early neuronal survival, SNCA gene alterations-either amplification or knock-out-negatively impact Th+ dopaminergic neuron maturation. These findings highlight SNCA's critical role in PD and underscore the value of hiPSC models in studying neurodegenerative diseases.

Neurodegenerative Diseases: Unraveling the Heterogeneity of Astrocytes.

The astrocyte population, around 50% of human brain cells, plays a crucial role in maintaining the overall health and functionality of the central nervous system (CNS). Astrocytes are vital in orchestrating neuronal development by releasing synaptogenic molecules and eliminating excessive synapses. They also modulate neuronal excitability and contribute to CNS homeostasis, promoting neuronal survival by clearance of neurotransmitters, transporting metabolites, and secreting trophic factors. Astrocytes are highly heterogeneous and respond to CNS injuries and diseases through a process known as reactive astrogliosis, which can contribute to both inflammation and its resolution. Recent evidence has revealed remarkable alterations in astrocyte transcriptomes in response to several diseases, identifying at least two distinct phenotypes called A1 or neurotoxic and A2 or neuroprotective astrocytes. However, due to the vast heterogeneity of these cells, it is limited to classify them into only two phenotypes. This review explores the various physiological and pathophysiological roles, potential markers, and pathways that might be activated in different astrocytic phenotypes. Furthermore, we discuss the astrocyte heterogeneity in the main neurodegenerative diseases and identify potential therapeutic strategies. Understanding the underlying mechanisms in the differentiation and imbalance of the astrocytic population will allow the identification of specific biomarkers and timely therapeutic approaches in various neurodegenerative diseases.

Mortality and hospitalization trends for aortic aneurysms and dissections in Mexico.

BACKGROUND: In Mexico, there is a paucity of evidence on mortality and hospitalization patterns associated with aortic aneurysms and dissections. OBJECTIVE: To analyze national databases and describe the epidemiological characteristics of different aortic pathologies. MATERIAL AND METHODS: Retrospective, cross-sectional, observational study, in which mortality and hospitalization attributed to aortic aneurysms and dissections were analyzed. Statistical analysis was performed on Stata 16. RESULTS: A total of 6,049 deaths were documented in the general population, which included 2,367 hospitalizations and 476 (20.1%) in-hospital deaths. In addition, a statistically significant age difference was found between mean age at death in the general population (69.5 years) and the in-hospital death group (64.1 years, p < 0.001). As for hospitalizations secondary to ruptured abdominal aortic aneurysms, 149 cases were identified, with a mean age of 65.6 years, out of whom 53 (35.5%) were under 65 years of age, with a mean age of 47.8 years. CONCLUSIONS: Epidemiological reports of aortic pathology in Mexico are scarce; therefore, implementation of screening and detection programs for aortic pathologies is necessary in order to address the disparities identified in this analysis.

ANTECEDENTES: Existe evidencia escasa en México respecto a la mortalidad y patrones del ingreso hospitalario asociados a aneurismas y disecciones aórticos. OBJETIVO: Analizar las bases de datos nacionales y describir las características epidemiológicas de diferentes patologías aórticas agudas. MATERIAL Y MÉTODOS: Estudio transversal y observacional de una base de datos retrospectiva, en el que se analizó la mortalidad y hospitalización atribuidas a aneurismas y disecciones aórticos. El análisis estadístico se realizó en Stata 16. RESULTADOS: Se documentaron 6049 muertes en la población general, 2367 hospitalizaciones y 476 muertes intrahospitalarias. Adicionalmente, se encontró una diferencia estadísticamente significativa entre las medias de edad de fallecimiento de la población general (65.5 años) y de los pacientes que murieron en el hospital (64.1 años), p < 0.001. En cuanto a las hospitalizaciones secundarias a aneurisma de aorta abdominal roto, 149 casos fueron evidenciados con una media de edad de 65.6 años; 53 (35.5 %) de estos tenía menos de 65 años, con una media de edad de 47.8 años. CONCLUSIONES: Los reportes epidemiológicos de patología aórtica en México son escasos, por ello la implementación de programas de tamizaje y la detección de patologías aórticas son necesarias para mejorar las disparidades encontradas en este análisis.

Updated distribution and morphological variation of the genus Pseudanos in the Río de la Plata basin (Characiformes: Anostomidae).

Pseudanos is a fish genus with cis-Andean distribution in South America. Pseudanos trimaculatus is originally known from the Amazon and Orinoco basins. Three decades ago, a few specimens collected in the Río de la Plata basin were identified as P. trimaculatus, what remained to be confirmed and understood. The aim of this contribution is to analyze these specimens. Consequently, the morphological variation of P. trimaculatus is discussed and updated. Morphometric and meristic data were taken from the specimens and compared with those of the type and non-type specimens of the species. Multivariate analyses of the size-corrected measurements were used to explore the morphological variation. Size-corrected PCA revealed that the specimens collected in the Río de la Plata basin nested with the remaining specimens, being slightly closer to those from the Guaporé, Napo and Uatumã rivers. Measurements such as caudal peduncle depth, body depth, and body width affected more heavily the first components. Cluster analysis did not show well-defined groups based on the hydrogeographic basins. The studied specimens from the Río de la Plata basin are herein confirmed as conspecific with P. trimaculatus. The species is added to the list of fish species shared between the Amazon and Río de la Plata basins.

ATTRv-V30M Type A amyloid fibrils from heart and nerves exhibit structural homogeneity.

ATTR amyloidosis is a systemic disease characterized by the deposition of amyloid fibrils made of transthyretin, a protein integral to transporting retinol and thyroid hormones. Transthyretin is primarily produced by the liver and circulates in blood as a tetramer. The retinal epithelium also secretes transthyretin, which is secreted to the vitreous humor of the eye. Because of mutations or aging, transthyretin can dissociate into amyloidogenic monomers triggering amyloid fibril formation. The deposition of transthyretin amyloid fibrils in the myocardium and peripheral nerves causes cardiomyopathies and neuropathies, respectively. Using cryo-electron microscopy, here we determined the structures of amyloid fibrils extracted from cardiac and nerve tissues of an ATTRv-V30M patient. We found that fibrils from both tissues share a consistent structural conformation, similar to the previously described structure of cardiac fibrils from an individual with the same genotype, but different from the fibril structure obtained from the vitreous humor. Our study hints to a uniform fibrillar architecture across different tissues within the same individual, only when the source of transthyretin is the liver. Moreover, this study provides the first description of ATTR fibrils from the nerves of a patient and enhances our understanding of the role of deposition site and protein production site in shaping the fibril structure in ATTRv-V30M amyloidosis.

Retrocarotid dissection technique compared to the caudocranial approach for the surgical treatment of carotid body tumors: A 15-year experience.

INTRODUCTION: Carotid body tumors are rare neoplasms with malignant potential. We aim to follow up on our initial experience published in 2015 and compare the occurrence of complications and postoperative outcomes with the use of retrocarotid dissection (RCD) against the standard caudocranial (SCCD) technique. METHODS: This was an observational, case-control study in which we analyzed all of the carotid body tumor resections performed from 1986 to 2022. Parametric and nonparametric tests were used accordingly. Statistical analysis was performed on Stata 17. RESULTS: A total of 181 surgical procedures were included, mean age was 56 years (± 13.63), and 168 (93%) were performed in women. The mean medio-lateral diameter was larger in the RCD group (2.85 ± 1.57 cm vs 1.93 ±1.85 cm; p = 0.002) and presurgical embolization was more frequently performed in the SCCD group (27.5% vs 0.7%; p < 0.001). A total of 40 (22.09%) resections were performed using the SCCD technique. In contrast, in 141 (77.91%) procedures the RCD technique was used. The mean surgical time in the RCD group was lower (197.37 ± 70.56 min vs 232 ± 98.34 min; p = 0.01). No statistically significant difference was found between SCCD and RCD in terms of vascular lesions (n = 20 [11.04%], 15% vs 9%, respectively; p = 0.36), transient or permanent nerve injuries (25% vs 33%, respectively; p = 0.31), or mean intraoperative bleeding (SCCD: 689.95 ± 680.05 mL vs RCD: 619.64 ± 837.94 mL; p > 0.05). CONCLUSIONS: RCD appears to be a safe and equivalent alternative to the standard caudocranial approach in terms of intraoperative bleeding or vascular lesions, with a sustained, significant decrease in surgical time.

Fifteen Years of Experience with Surgical Management of Bilateral Non-familial Carotid Body Tumors.

BACKGROUND: Bilateral carotid body tumors (CBTs) clinical manifestation is infrequent. We conducted this work to describe our experience in the surgical treatment of bilateral CBT and to analyze our results. METHODS: A retrospective, observational study. We analyzed the totality of bilateral CBT resections that had been performed in our institution from January 2008 to September 2023. Data was obtained from medical records and anonymized, ethics approval was obtained from our institution committee. As the number of observations was less than those required by the central limit theorem our sample was considered nonparametric. Statistical analysis was performed on Stata 17. RESULTS: We evaluated 16 patients with a total of 32 CBT; surgical resection was performed in 28 cases (87.50%). Median age of the patients was 60 years (interquartile range [IQR] 46-64). Regarding the Shamblin classification, 9 CBTs (32.14%) were classified as Shamblin I, 11 (39.29%) as Shamblin II, and 8 (28.57%) as Shamblin III. The median Distance to the Base of the Skull (DTBOS) was 3.5 cm (IQR 2.7-5.1), and the median tumor volume was 11.25 cc (IQR 3.4-18.7). The median bleeding volume was 300 ml (IQR 200-500), and the median surgical time was 190 min (IQR 145-240). All surgeries were performed using the Retrocarotid Dissection technique. We documented 9 (32.14%) cases of nerve injuries, all of which were transitory. In the median regression a statistically significant association was found between DTBOS, Shamblin classification and tumor volume with intraoperative bleeding and length of stay. CONCLUSIONS: Surgical treatment remains safe and should be considered the gold standard for accurate histologic diagnosis. DTBOS and tumor volume, in addition to Shamblin classification, must be considered in preoperative planning to predict bleeding and hospital stay.

ER-associated degradation adapter Sel1L is required for CD8+ T cell function and memory formation following acute viral infection.

The maintenance of antigen-specific CD8+ T cells underlies the efficacy of vaccines and immunotherapies. Pathways contributing to CD8+ T cell loss are not completely understood. Uncovering the pathways underlying the limited persistence of CD8+ T cells would be of significant benefit for developing novel strategies of promoting T cell persistence. Here, we demonstrate that murine CD8+ T cells experience endoplasmic reticulum (ER) stress following activation and that the ER-associated degradation (ERAD) adapter Sel1L is induced in activated CD8+ T cells. Sel1L loss limits CD8+ T cell function and memory formation following acute viral infection. Mechanistically, Sel1L is required for optimal bioenergetics and c-Myc expression. Finally, we demonstrate that human CD8+ T cells experience ER stress upon activation and that ER stress is negatively associated with improved T cell functionality in T cell-redirecting therapies. Together, these results demonstrate that ER stress and ERAD are important regulators of T cell function and persistence.

Synergistic effect of human uterine cervical mesenchymal stem cell secretome and paclitaxel on triple negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer and, despite its adverse effects, chemotherapy is the standard systemic treatment option for TNBC. Since, it is of utmost importance to consider the combination of different agents to achieve greater efficacy and curability potential, MSC secretome is a possible innovative alternative. METHODS: In the present study, we proposed to investigate the anti-tumor effect of the combination of a chemical agent (paclitaxel) with a complex biological product, secretome derived from human Uterine Cervical Stem cells (CM-hUCESC) in TNBC. RESULTS: The combination of paclitaxel and CM-hUCESC decreased cell proliferation and invasiveness of tumor cells and induced apoptosis in vitro (MDA-MB-231 and/or primary tumor cells). The anti-tumor effect was confirmed in a mouse tumor xenograft model showing that the combination of both products has a significant effect in reducing tumor growth. Also, pre-conditioning hUCESC with a sub-lethal dose of paclitaxel enhances the effect of its secretome and in combination with paclitaxel reduced significantly tumor growth and even allows to diminish the dose of paclitaxel in vivo. This effect is in part due to the action of extracellular vesicles (EVs) derived from CM-hUCESC and soluble factors, such as TIMP-1 and - 2. CONCLUSIONS: In conclusion, our data demonstrate the synergistic effect of the combination of CM-hUCESC with paclitaxel on TNBC and opens an opportunity to reduce the dose of the chemotherapeutic agents, which may decrease chemotherapy-related toxicity.

Perfil molecular de cáncer de endometrio en mujeres de Bogotá D.C., Colombia

Introducción: El cáncer de endometrio ocupa el sexto lugar en incidencia del cáncer en mujeres. La caracterización molecular de este cáncer permite optimizar la estratificación de riesgo para mejorar el tratamiento de las pacientes. Objetivo: Determinar el perfil molecular TCGA de pacientes con cáncer de endometrio en Bogotá, D.C., Colombia. Método: Estudio descriptivo en una cohorte de pacientes con cáncer de endometrio. Las mutaciones en los exones 9 a 14 del gen POLE fueron identificadas mediante amplificación por reacción en cadena de la polimerasa, seguida de secuenciación Sanger y análisis bioinformático. La expresión de las proteínas MMR y p53 se identificó mediante inmunohistoquímica. Resultados: Se incluyeron 40 pacientes con una mediana de edad de 66 años. El 15% presentaron mutaciones en el dominio exonucleasa de POLE. El 32% de las pacientes que no presentaron mutaciones manifestaron deficiencia en el sistema MMR. El 43,47% de las pacientes sin mutaciones en POLE ni alteración del sistema MMR presentaron alteración de la proteína p53. Conclusiones: La población de cáncer de endometrio analizada presenta un perfil molecular TCGA similar a lo reportado para otras poblaciones.

Introduction: Endometrial cancer ranks sixth in cancer incidence among women. Its molecular characterization allows for a more precise risk stratification with the aim of improving patient treatment. Objective: To determine the TCGA molecular profile of patients with endometrial cancer in Bogota, Colombia. Method: A descriptive study of a cohort of patients with endometrial cancer. The expression of MMR proteins and p53 was identified through immunohistochemistry. Mutations in exons 9 to 14 of the POLE gene were identified through polymerase chain reaction amplification, followed by Sanger sequencing and bioinformatic analysis. Results: Forty patients were included in the study, with a median age of 66 years, 15% of them exhibited mutations in the exonuclease domain of POLE, while 32% of patients without mutations showed deficiency in the MMR system. Forty three percent of patients without mutations in POLE or MMR alterations showed aberrant p53 protein expression. Conclusions: The analyzed population of endometrial cancer presents a TCGA molecular profile similar to that reported for other populations.

Life-history traits of an exploited skate: The short-tail yellownose skate Zearaja brevicaudata (Chondrichthyes: Rajiformes).

The short-tail yellownose skate, Zearaja brevicaudata, occurs off southern Brazil and along the Argentine continental shelf, including waters surrounding the Islas Malvinas and the upper slope, and is very frequently caught by trawl fisheries throughout its range. The age, growth, and maturity of Z. brevicaudata were investigated using 204 individuals collected by commercial fishing vessels from northern Argentina, between March 2016 and September 2019. Age was determined on a sample comprising vertebrae from 151 individuals, 60 males, ranging in size from 391 to 956 mm total length (TL), and 91 females, ranging in size from 324 to 1060 mm TL. Maximum ages determined for males and females were 22 and 29 years, respectively. A Bayesian framework was employed with a set of three candidate models to estimate growth parameters (von Bertalanffy, Gompertz, and Logistic). The von Bertalanffy model had the best fit, and the sexes showed undistinguishable growth parameters. For sexes combined, derived growth mean parameters (± S.D.) were L∞ = 1081 mm ± 64.34 mm, k = 0.09 ± 0.01 years-1, and L0 = 248 mm ± 23.52 mm. The age at maturity was estimated at 13.15 and 14.66 years for males and females, respectively.

A mutation in F-actin polymerization factor suppresses the distal arthrogryposis type 5 PIEZO2 pathogenic variant in Caenorhabditis elegans.

The mechanosensitive PIEZO channel family has been linked to over 26 disorders and diseases. Although progress has been made in understanding these channels at the structural and functional levels, the underlying mechanisms of PIEZO-associated diseases remain elusive. In this study, we engineered four PIEZO-based disease models using CRISPR/Cas9 gene editing. We performed an unbiased chemical mutagen-based genetic suppressor screen to identify putative suppressors of a conserved gain-of-function variant pezo-1[R2405P] that in human PIEZO2 causes distal arthrogryposis type 5 (DA5; p. R2718P). Electrophysiological analyses indicate that pezo-1(R2405P) is a gain-of-function allele. Using genomic mapping and whole-genome sequencing approaches, we identified a candidate suppressor allele in the C. elegans gene gex-3. This gene is an ortholog of human NCKAP1 (NCK-associated protein 1), a subunit of the Wiskott-Aldrich syndrome protein (WASP)-verprolin homologous protein (WAVE/SCAR) complex, which regulates F-actin polymerization. Depletion of gex-3 by RNAi, or with the suppressor allele gex-3(av259[L353F]), significantly increased brood size and ovulation rate, as well as alleviating the crushed oocyte phenotype of the pezo-1(R2405P) mutant. Expression of GEX-3 in the soma is required to rescue the brood size defects in pezo-1(R2405P) animals. Actin organization and orientation were disrupted and distorted in the pezo-1 mutants. Mutation of gex-3(L353F) partially alleviated these defects. The identification of gex-3 as a suppressor of the pathogenic variant pezo-1(R2405P) suggests that the PIEZO coordinates with the cytoskeleton regulator to maintain the F-actin network and provides insight into the molecular mechanisms of DA5 and other PIEZO-associated diseases.

Knockdown of Antisense Noncoding Mitochondrial RNA Reduces Tumorigenicity of Patient-Derived Clear Cell Renal Carcinoma Cells in an Orthotopic Xenograft Mouse Model.

Clear cell renal cell carcinoma (ccRCC) is the most prevalent form of renal cancer and its treatment is hindered by a resistance to targeted therapies, immunotherapies and combinations of both. We have reported that the knockdown of the antisense noncoding mitochondrial RNAs (ASncmtRNAs) with chemically modified antisense oligonucleotides induces proliferative arrest and apoptotic death in tumor cells from many human and mouse cancer types. These studies have been mostly performed in vitro and in vivo on commercially available cancer cell lines and have shown that in mouse models tumor growth is stunted by the treatment. The present work was performed on cells derived from primary and metastatic ccRCC tumors. We established primary cultures from primary and metastatic ccRCC tumors, which were subjected to knockdown of ASncmtRNAs in vitro and in vivo in an orthotopic xenograft model in NOD/SCID mice. We found that these primary ccRCC cells are affected in the same way as tumor cell lines and in the orthotopic model tumor growth was significantly reduced by the treatment. This study on patient-derived ccRCC tumor cells represents a model closer to actual patient ccRCC tumors and shows that knockdown of ASncmtRNAs poses a potential treatment option for these patients.

Tendencias de mortalidad y hospitalización por aneurismas y disecciones de aorta en México / Mortality and hospitalization trends for aortic aneurysms and dissections in Mexico

Resumen Antecedentes: Existe evidencia escasa en México respecto a la mortalidad y patrones del ingreso hospitalario asociados a aneurismas y disecciones aórticos. Objetivo: Analizar las bases de datos nacionales y describir las características epidemiológicas de diferentes patologías aórticas agudas. Material y métodos: Estudio transversal y observacional de una base de datos retrospectiva, en el que se analizó la mortalidad y hospitalización atribuidas a aneurismas y disecciones aórticos. El análisis estadístico se realizó en Stata 16. Resultados: Se documentaron 6049 muertes en la población general, 2367 hospitalizaciones y 476 muertes intrahospitalarias. Adicionalmente, se encontró una diferencia estadísticamente significativa entre las medias de edad de fallecimiento de la población general (65.5 años) y de los pacientes que murieron en el hospital (64.1 años), p < 0.001. En cuanto a las hospitalizaciones secundarias a aneurisma de aorta abdominal roto, 149 casos fueron evidenciados con una media de edad de 65.6 años; 53 (35.5 %) de estos tenía menos de 65 años, con una media de edad de 47.8 años. Conclusiones: Los reportes epidemiológicos de patología aórtica en México son escasos, por ello la implementación de programas de tamizaje y la detección de patologías aórticas son necesarias para mejorar las disparidades encontradas en este análisis.

Abstract Background: In Mexico, there is a paucity of evidence on mortality and hospitalization patterns associated with aortic aneurysms and dissections. Objective: To analyze national databases and describe the epidemiological characteristics of different acute aortic pathologies. Material and methods: Retrospective, cross-sectional, observational study, in which mortality and hospitalization attributed to aortic aneurysms and dissections were analyzed. Statistical analysis was performed on Stata 16. Results: A total of 6,049 deaths were documented in the general population, which included 2,367 hospitalizations and 476 in-hospital deaths. In addition, a statistically significant difference was found between mean age at death in the general population (69.5 years) and the in-hospital death group (64.1 years), p < 0.001. As for hospitalizations secondary to ruptured abdominal aortic aneurysm, 149 cases were identified, with a mean age of 65.6 years, out of whom 53 (35.5 %) were under 65 years of age, with a mean age of 47.8 years. Conclusions: Epidemiological reports of aortic pathology in Mexico are scarce; therefore, implementation of screening and detection programs for aortic pathologies is necessary in order to address the disparities identified in this analysis.

The influence of virginiamycin on digestion and ruminal parameters under feedlot conditions.

This experiment aimed to assess the impact of virginiamycin on in vitro gas production dynamics, rumen kinetics, and nutrient digestibility in beef steers fed a grain-based diet. Nine ruminally cannulated British-crossbred steers (596 ±â€…49 kg) were assigned to this experiment. Animals were housed in three pens (n = 3/pen) equipped with a Calan gate feed system and water troughs. Pens were enrolled in a 3 × 3 Latin square design containing three periods of 16 d, and a 5-d washout interval between periods. Dietary treatments consisted of virginiamycin (VM) administration at 0 (VM0), 180 (VM180), or 240 mg/d (VM240). During days 15 and 16 of each period, about 600 mL of rumen fluid and urine samples were collected before (0 h), and at 4, 8, 12, and 16 h after the morning feed (0730 hours), rumen inoculum was used to take pH and redox potential measurements immediately after collection using a portable pH and redox meter, and subsamples were taken for volatile fatty acids (VFA) and NH3-N analyses, and urine samples were composited daily and analyzed for creatinine and purine derivatives (PD) content to estimate microbial crude protein flow. During the 4-h post-morning feed rumen collection, rumen inoculum was utilized to perform in vitro gas production measurements. Fecal samples were collected on day 16 of each period to estimate nutrient digestibility using acid detergent insoluble ash as an internal marker. Animals were considered the experimental unit for the statistical analyses, and periods and squares were included as random variables. The total and rate of gas production were similar among treatments (P ≥ 0.17). The second-pool (i.e., fiber) gas production increased linearly as VM inclusion increased (P = 0.01), with VM240 being greater compared to VM180 and VM0 (7.84, 6.94, and 6.89 mL, respectively). Ruminal pH linearly increased as VM increased, with VM240 being greater than VM0 and VM180 intermediate (5.90, 5.82, and 5.86, respectively; P = 0.03). The VFA concentrations did not differ (P ≥ 0.13), but the acetate-to-propionate ratio was the highest in VM240 (P = 0.005). Branched-chain VFA increased (P ≤ 0.03) while lactate concentrations decreased (P = 0.005) linearly with VM. The ruminal NH3-N concentration was the lowest in the VM0 (P = 0.006). The estimated absorbed PD, purine derivative to creatinine index, and microbial N flow increased linearly with VM (P ≤ 0.07). The provision of VM influenced rumen dynamics in a dose-dependent manner.

Caldendrin Is a Repressor of PIEZO2 Channels and Touch Sensation in Mice.

The sense of touch is crucial for cognitive, emotional, and social development and relies on mechanically activated (MA) ion channels that transduce force into an electrical signal. Despite advances in the molecular characterization of these channels, the physiological factors that control their activity are poorly understood. Here, we used behavioral assays, electrophysiological recordings, and various mouse strains (males and females analyzed separately) to investigate the role of the calmodulin-like Ca2+ sensor, caldendrin, as a key regulator of MA channels and their roles in touch sensation. In mice lacking caldendrin (Cabp1 KO), heightened responses to tactile stimuli correlate with enlarged MA currents with lower mechanical thresholds in dorsal root ganglion neurons (DRGNs). The expression pattern of caldendrin in the DRG parallels that of the major MA channel required for touch sensation, PIEZO2. In transfected cells, caldendrin interacts with and inhibits the activity of PIEZO2 in a manner that requires an alternatively spliced sequence in the N-terminal domain of caldendrin. Moreover, targeted genetic deletion of caldendrin in Piezo2-expressing DRGNs phenocopies the tactile hypersensitivity of complete Cabp1 KO mice. We conclude that caldendrin is an endogenous repressor of PIEZO2 channels and their contributions to touch sensation in DRGNs.

Unilateral rNurr1-V5 transgene expression in nigral dopaminergic neurons mitigates bilateral neuropathology and behavioral deficits in parkinsonian rats with α-synucleinopathy.

JOURNAL/nrgr/04.03/01300535-202409000-00039/figure1/v/2024-01-16T170235Z/r/image-tiff Parkinsonism by unilateral, intranigral ß-sitosterol ß-D-glucoside administration in rats is distinguished in that the α-synuclein insult begins unilaterally but spreads bilaterally and increases in severity over time, thus replicating several clinical features of Parkinson's disease, a typical α-synucleinopathy. As Nurr1 represses α-synuclein, we evaluated whether unilateral transfected of rNurr1-V5 transgene via neurotensin-polyplex to the substantia nigra on day 30 after unilateral ß-sitosterol ß-D-glucoside lesion could affect bilateral neuropathology and sensorimotor deficits on day 30 post-transfection. This study found that rNurr1-V5 expression but not that of the green fluorescent protein (the negative control) reduced ß-sitosterol ß-D-glucoside-induced neuropathology. Accordingly, a bilateral increase in tyrosine hydroxylase-positive cells and arborization occurred in the substantia nigra and increased tyrosine hydroxylase-positive ramifications in the striatum. In addition, tyrosine hydroxylase-positive cells displayed less senescence marker ß-galactosidase and more neuron-cytoskeleton marker ßIII-tubulin and brain-derived neurotrophic factor. A significant decrease in activated microglia (positive to ionized calcium-binding adaptor molecule 1) and neurotoxic astrocytes (positive to glial fibrillary acidic protein and complement component 3) and increased neurotrophic astrocytes (positive to glial fibrillary acidic protein and S100 calcium-binding protein A10) also occurred in the substantia nigra. These effects followed the bilateral reduction in α-synuclein aggregates in the nigrostriatal system, improving sensorimotor behavior. Our results show that unilateral rNurr1-V5 transgene expression in nigral dopaminergic neurons mitigates bilateral neurodegeneration (senescence and loss of neuron-cytoskeleton and tyrosine hydroxylase-positive cells), neuroinflammation (activated microglia, neurotoxic astrocytes), α-synuclein aggregation, and sensorimotor deficits. Increased neurotrophic astrocytes and brain-derived neurotrophic factor can mediate the rNurr1-V5 effect, supporting its potential clinical use in the treatment of Parkinson's disease.