Indices of exercise induced muscle damage following low load resistance exercise with blood flow restriction in untrained males.

BACKGROUND: There is conflicting evidence regarding the presence and magnitude of exercise-induced muscle damage (EIMD) following low-load resistance training with blood flow restriction (LL+BFR), which may be related to the protocol implemented or exercise volume. Therefore, the purpose of this investigation was to examine the effects of a 75 repetition (BFR-75) (1×30, 3×15) and four sets to volitional failure (BFR-4x) protocols on indices of EIMD among untrained men. METHODS: Twelve males with no history of lower-body resistance training during the previous six months volunteered for this investigation. One leg was randomly assigned to BFR-75, and the other to BFR-4x. Participants performed isokinetic, unilateral, concentric-eccentric, leg extension muscle actions at 30% of maximal strength with BFR. Indices of EIMD (limb circumference, perceived muscle soreness, pain pressure threshold [PPT], passive range of motion, and maximal strength [MVIC]) were recorded before exercise and 0, 24, 48, 72, and 96-hours post-exercise for each protocol. RESULTS: There were no significant changes (P>0.05) in limb circumference, PPT, passive range of motion, or MVIC. For both BFR-75 and BFR-4x, perceived muscle soreness increased (P<0.001) similarly 24- (2.5±1.7 AU) and 48-hours (1.9±1.7 AU) post-exercise. CONCLUSIONS: There was an increase in muscle soreness 24-48 hours post-exercise for both conditions, which may be due to metabolic stress, but this did not affect the force-generating capacity of the muscle (MVIC), suggesting minimal EIMD. The conflicting evidence of EIMD following LL+BFR may be related to differences in restriction time or overall exercise time.

Chronic Cardiac Herniation: A Peculiar Diagnosis.

The presented case describes a 56-year-old male with adult-onset Still's disease, exhibiting polyserositis in 2019, who underwent pleurectomy and pericardiectomy. Despite treatment with tocilizumab and methylprednisolone, the patient developed deep vein thrombosis and pulmonary embolism in 2022, managed with apixaban. A contrast-enhanced chest tomography revealed no recurrent thromboembolic events. Over a year, the patient experienced progressive dyspnea, correlating with signs of constriction on transthoracic echocardiogram. Cardiac magnetic resonance imaging confirmed cardiac herniation, prompting pericardiectomy. Surgery led to complete resolution of anatomical alterations without heart failure or new abnormalities, although exertional dyspnea persists post-discharge. The pathophysiology of cardiac herniation involves complex mechanisms influenced by congenital or acquired factors, resulting in abnormal heart protrusion. Medical literature highlights varied presentations, with acute cases typically post-thoracic surgeries, while late-onset cases are less common. Imaging modalities like computed tomography (CT) and cardiac magnetic resonance (CMR) aid diagnosis, emphasizing interdisciplinary collaboration. Despite challenges posed by its rarity, timely diagnosis and treatment are crucial for favourable outcomes, demonstrating the importance of considering this entity in clinical practice.

New insight into the biological activity of Salmo salar NK-lysin antimicrobial peptides.

NK-lysin is a potent antimicrobial peptide (AMP) with antimicrobial activity against bacteria, fungi, viruses, and parasites. NK-lysin is a type of granulysin, a member of the saposin-like proteins family first isolated from a pig's small intestine. In previous work, for the first time, we identified four variants of nk-lysin from Atlantic salmon (Salmo salar) using EST sequences. In the present study, we reported and characterized two additional transcripts of NK-lysin from S. salar. Besides, we evaluated the tissue distribution of three NK-lysins from S. salar and assessed the antimicrobial, hemolytic, and immunomodulatory activities and signaling pathways of three NK-lysin-derived peptides. The synthetic peptides displayed antimicrobial activity against Piscirickettsia salmonis (LF-89) and Flavobacterium psychrophilum. These peptides induced the expression of immune genes related to innate and adaptive immune responses in vitro and in vivo. The immunomodulatory activity of the peptides involves the mitogen-activated protein kinases-mediated signaling pathway, including p38, extracellular signal-regulated kinase 1/2, and/or c-Jun N-terminal kinases. Besides, the peptides modulated the immune response induced by pathogen-associated molecular patterns (PAMPs). Our findings show that NK-lysin could be a highly effective immunostimulant or vaccine adjuvant for use in fish aquaculture.

New Formulation of a Subunit Vaccine Candidate against Lawsonia intracellularis Increases Humoral and Cellular Immune Responses.

Previously, we designed a subunit vaccine candidate based on three L. intracellularis antigens with promising results in pigs. In this study, antigens were produced individually to achieve an even antigen ratio in the formulation. The emulsion characterization included the drop size and the mechanical and thermal stability. Immune response was evaluated by indirect and sandwich ELISAs, qPCR, and flow cytometry. The vaccine candidate's safety was assessed by histopathology and monitoring the clinical behavior of animals. The average production yielded for the chimeric antigen as inclusion bodies was around 75 mg/L. The formulation showed mechanical and thermal stability, with a ratio Hu/Ho > 0.85 and a drop size under 0.15 nm. Antigens formulated at a ratio of 1:1:1 induced a significant immune response in inoculated pigs that persisted until the end of the experiment (week 14). The dose of 200 µg significantly activated cellular response measured by transcriptional and translational levels of cytokines. The cell proliferation assay revealed an increment of lymphocytes T CD4+ at the same dose. Animals gained weight constantly and showed proper clinical behavior during immunization assays. This research demonstrated the immunological robustness of the new subunit vaccine candidate against Porcine Proliferative Enteropathy evenly formulated with three chimeric antigens of L. intracellularis.

Self-expanding Metal Stents in Malignant Obstruction of the Esophagus: A 25-Year Multicentric Study

Background: Self-expanding metal prostheses improve dysphagia in patients with incurable esophageal cancer (EC). New stents have been introduced, and chemoradiotherapy has been implemented for EC, changing patients' risk profiles. It is unknown whether this has affected palliation with stents. Patients and methods: Retrospective study in three centers in Medellín-Colombia; patients undergoing placement of palliative esophageal prostheses for malignant dysphagia (1997-2022). Major and minor complications after implantation, the influence of oncological therapies, and survival were evaluated for 1997-2009 (n = 289) and 2010-2022 (n = 318). Results: 607 patients underwent esophageal prostheses; 296 (48.8%) became complicated. It was higher in the second period (52.5% vs. 48.1%), as were major complications (20.8% vs. 14.2%, p = 0.033), with no differences in minor complications (33.9% vs 31.8%, p = 0.765). Also, 190 (31.3%) patients presented with recurrent dysphagia, stable in both periods. Migration increased over time (from 13.1% to 18.2%, p = 0.09). The most common minor adverse event was pain, increasing over time (from 24.9% to 33.95%, p < 0.01), and associated factors were chemoradiotherapy, absence of fistula, and squamous cell carcinoma. Acid reflux decreased in the second group (p = 0.038). Twelve percent of patients required another intervention for feeding. Survival was not impacted by time and use of stents. Conclusions: Stents are an alternative in non-surgical malignant dysphagia, although recurrent dysphagia has not decreased over time. Minor stent-related complications are increasing in association with the implementation of chemoradiotherapy.

Antecedentes: Las prótesis metálicas autoexpandibles mejoran la disfagia en pacientes con cáncer esofágico (CE) incurable. En las últimas décadas se han introducido nuevos tipos de stents y se ha implementado la quimiorradioterapia para el CE, generando cambios en los perfiles de riesgo de los pacientes. Se desconoce si estos cambios han afectado la paliación con stents. Pacientes y métodos: Estudio retrospectivo en tres centros de Medellín-Colombia; pacientes sometidos a colocación de prótesis esofágicas paliativas para disfagia maligna (1997-2022). Se evaluaron en dos períodos: 1997-2009 (n = 289) y 2010-2022 (n = 318), complicaciones mayores y menores después del implante, la influencia de las terapias oncológicas y la sobrevida. Resultados: Se evaluaron 607 pacientes sometidos a prótesis esofágicas. 296 (48,8%) se complicaron, y fue mayor en el segundo periodo (52,5% frente a 48,1%), al igual que las complicaciones mayores (20,8% frente a 14,2%, p = 0,033), sin diferencias en complicaciones menores (33,9% frente a 31,8%, p = 0,765). 190 (31,3%) pacientes presentaron disfagia recurrente, estable en ambos períodos. La migración aumentó con el tiempo (de 13,1% a 18,2%, p = 0,09). El evento adverso menor más frecuente fue dolor, que aumentó con el tiempo (de 24,9% a 33,95%, p < 0,01), y los factores asociados fueron quimiorradioterapia, ausencia de fístula y carcinoma de células escamosas. El reflujo ácido disminuyó en el segundo grupo (p = 0,038). El 12% de pacientes requirieron otra intervención para alimentarse. No se impactó la sobrevida con el tiempo y uso de stents. Conclusiones: Los stents son una alternativa en la disfagia maligna no quirúrgica, aunque la disfagia recurrente no ha disminuido con el tiempo. Las complicaciones menores relacionadas con el stent van en aumento, asociadas a la implementación de la quimiorradioterapia.

[Post-colonoscopy colorectal cancer: Evaluation of a cohort in its clinical and colonoscopic characteristics, survival and its causes according to the World Endoscopy Organization]. / Cáncer colorrectal post-colonoscopia: Evaluación de una cohorte en sus características clínicas, colonoscópicas, sobrevida y sus causas según la Organización Mundial de Endoscopia.

Post-colonoscopy colorectal cancer (PCCRC) is a tumor that appears after a normal colonoscopy before the established time for the endoscopic follow up. Its origin reflects the quality of the colonoscopy and the different tumoral biologics between the CRC and the CRCPC. Our aim is to describe the characteristics of the PCCRC in our region, to identify risk factors, to discriminate the potential causes according to the World Endoscopý Organization (WEO) and to determine its impact in the patient's survival. We studied patients with colorectal cancer (CRC) attended at the gastro-oncology clinic of two institutions of Medellin-Colombia, between January 2012 and December 2021 that had been submitted to a colonoscopy between 6-36 months before the colonoscopy in which the CRC was diagnosed. 919 patients during 10 years for CRC, 68 cases of PCCRC (6.9%); It was more frequent in older patients (74 vs. 66 years; p=0.03), with background of adenomatous polyps (36.8% vs. 20.1%; p=0.01) and in right colon (57.4% vs. 40.6%; p=0.006), with a tendency in patients with diverticulosis (41.2% vs. 31.3%; p=0.05) and diabetes (25% vs. 14%; p=0.06); less survival at 5 and 10 years (58% and 55.2% vs. 67% and 63%; p < 0.001). According to the WEO, the PCCRC presents in 61.3% because of abnormal findings omitted in inadequate colonoscopies, 29% in a suitable colonoscopy and 9.7% incomplete resections of adenomas. In conclusion, the rate of PCCRC was 6.9% with more propension in older patients, a background of polyp resection, and proximal colon. According to the WEO, the abnormal findings omitted more frequently were related with inadequate colonoscopies. The patients with PCCRC had less survival.

Cáncer colorrectal post-colonoscopia: Evaluación de una cohorte en sus características clínicas, colonoscópicas, sobrevida y sus causas según la Organización Mundial de Endoscopia

Cáncer colorrectal post-colonoscopia (CCRP) es el tumor que aparece posterior a una colonoscopia normal antes de cumplirse el tiempo establecido para seguimiento endoscópico. Origen multifactorial, refleja la calidad de la colonoscopia y las diferentes biologías tumorales entre los cánceres colorrectales detectados (CCRD) y el CCRP. Nuestro objetivo es describir las características del CCRP en nuestro medio, identificar factores de riesgo, discriminar sus causas según la Organización Mundial de Endoscopia (OME) y determinar el efecto en la sobrevida del paciente. El estudio se realizó en pacientes con cáncer-colorrectal (CCR) atendidos en consulta de gastro-oncología de dos instituciones en Medellín-Colombia, entre enero de 2012 y diciembre de 2021 que se habían sometido a una colonoscopia en los 6 a 36 meses anteriores a la colonoscopia en la que se diagnosticó el CCR. 919 pacientes durante 10 años por CCR, 68 casos de CCRP (6,9%), se encontró que se presenta con más frecuencia en pacientes mayores (74 vs. 66 años; p=0,03), con antecedentes de pólipos adenomatosos (36,8% vs. 20,1%; p=0,01) y en colon derecho (57,4% vs. 40,6%; p=0,006), con una tendencia en pacientes con diverticulosis (41,2% vs. 31,3%; p=0,05) y diabetes (25% vs. 14%; p=0,06); menor sobrevida a 5 y 10 años (58%-55,2% vs. 67%-63%; p<0,001). Según la OME, los CCRP se presentaron en 61,3% por lesiones omitidas en colonoscopias inadecuadas, 29% colonoscopias adecuadas y 9,7% resecciones incompletas de adenomas. En conclusión, la tasa de CCRP fue de 6,9%, con mayor propensión en pacientes de mayores, antecedente de resección de pólipos, y en colon derecho. Acorde a la OME, las lesiones omitidas más frecuentemente se relacionaron con colonoscopias inadecuadas. Los pacientes con CCRP tienen menor sobrevida.

Post-colonoscopy colorectal cancer (PCCRC) is a tumor that appears after a normal colonoscopy before the established time for the endoscopic follow up. Its origin reflects the quality of the colonoscopy and the different tumoral biologics between the CRC and the CRCPC. Our aim is to describe the characteristics of the PCCRC in our region, to identify risk factors, to discriminate the potential causes according to the World Endoscopý Organization (WEO) and to determine its impact in the patient's survival. We studied patients with colorectal cancer (CRC) attended at the gastro-oncology clinic of two institutions of Medellin-Colombia, between January 2012 and December 2021 that had been submitted to a colonoscopy between 6-36 months before the colonoscopy in which the CRC was diagnosed. 919 patients during 10 years for CRC, 68 cases of PCCRC (6.9%); It was more frequent in older patients (74 vs. 66 years; p=0.03), with background of adenomatous polyps (36.8% vs. 20.1%; p=0.01) and in right colon (57.4% vs. 40.6%; p=0.006), with a tendency in patients with diverticulosis (41.2% vs. 31.3%; p=0.05) and diabetes (25% vs. 14%; p=0.06); less survival at 5 and 10 years (58% and 55.2% vs. 67% and 63%; p<0.001). According to the WEO, the PCCRC presents in 61.3% because of abnormal findings omitted in inadequate colonoscopies, 29% in a suitable colonoscopy and 9.7% incomplete resections of adenomas. In conclusion, the rate of PCCRC was 6.9% with more propension in older patients, a background of polyp resection, and proximal colon. According to the WEO, the abnormal findings omitted more frequently were related with inadequate colonoscopies. The patients with PCCRC had less survival.

Alzheimer risk gene product Pyk2 suppresses tau phosphorylation and phenotypic effects of tauopathy.

BACKGROUND: Genetic variation at the PTK2B locus encoding the protein Pyk2 influences Alzheimer's disease risk. Neurons express Pyk2 and the protein is required for Amyloid-ß (Aß) peptide driven deficits of synaptic function and memory in mouse models, but Pyk2 deletion has minimal effect on neuro-inflammation. Previous in vitro data suggested that Pyk2 activity might enhance GSK3ß-dependent Tau phosphorylation and be required for tauopathy. Here, we examine the influence of Pyk2 on Tau phosphorylation and associated pathology. METHODS: The effect of Pyk2 on Tau phosphorylation was examined in cultured Hek cells through protein over-expression and in iPSC-derived human neurons through pharmacological Pyk2 inhibition. PS19 mice overexpressing the P301S mutant of human Tau were employed as an in vivo model of tauopathy. Phenotypes of PS19 mice with a targeted deletion of Pyk2 expression were compared with PS19 mice with intact Pyk2 expression. Phenotypes examined included Tau phosphorylation, Tau accumulation, synapse loss, gliosis, proteomic profiling and behavior. RESULTS: Over-expression experiments from Hek293T cells indicated that Pyk2 contributed to Tau phosphorylation, while iPSC-derived human neuronal cultures with endogenous protein levels supported the opposite conclusion. In vivo, multiple phenotypes of PS19 were exacerbated by Pyk2 deletion. In Pyk2-null PS19 mice, Tau phosphorylation and accumulation increased, mouse survival decreased, spatial memory was impaired and hippocampal C1q deposition increased relative to PS19 littermate controls. Proteomic profiles of Pyk2-null mouse brain revealed that several protein kinases known to interact with Tau are regulated by Pyk2. Endogenous Pyk2 suppresses LKB1 and p38 MAPK activity, validating one potential pathway contributing to increased Tau pathology. CONCLUSIONS: The absence of Pyk2 results in greater mutant Tau-dependent phenotypes in PS19 mice, in part via increased LKB1 and MAPK activity. These data suggest that in AD, while Pyk2 activity mediates Aß-driven deficits, Pyk2 suppresses Tau-related phenotypes.

Emergent Endovascular Repair of a Ruptured Ascending Aorta Pseudoaneurysm With Thoracic Aortic Stent Graft.

Pseudoaneurysm of the ascending aorta is a rare complication of cardiac surgery due to tissue degeneration at the site of graft anastomosis, aortotomy, or extracorporeal circulation cannulation. We describe the case of a patient who developed an ascending aorta pseudoaneurysm after coronary artery bypass graft surgery, which initially required percutaneous closure with an atrial septal defect occlusion device. However, three years later the patient presented again with active external bleeding secondary to pseudoaneurysm enlargement and rupture, which was emergently repaired by percutaneous endovascular repair with a thoracic aortic stent graft. At one-year follow-up the patient is in good conditions and asymptomatic.

Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer's disease model.

TREM2 is a receptor for lipids expressed in microglia. The R47H variant of human TREM2 impairs ligand binding and increases Alzheimer's disease (AD) risk. In mouse models of amyloid ß (Aß) accumulation, defective TREM2 function affects microglial response to Aß plaques, exacerbating tissue damage, whereas TREM2 overexpression attenuates pathology. Thus, AD may benefit from TREM2 activation. Here, we examined the impact of an anti-human TREM2 agonistic mAb, AL002c, in a mouse AD model expressing either the common variant (CV) or the R47H variant of TREM2. Single-cell RNA-seq of microglia after acute systemic administration of AL002c showed induction of proliferation in both CV- and R47H-transgenic mice. Prolonged administration of AL002c reduced filamentous plaques and neurite dystrophy, impacted behavior, and tempered microglial inflammatory response. We further showed that a variant of AL002c is safe and well tolerated in a first-in-human phase I clinical trial and engages TREM2 based on cerebrospinal fluid biomarkers. We conclude that AL002 is a promising candidate for AD therapy.

Hospital Mortality and Effect of Adjusting PaO2/FiO2 According to Altitude Above the Sea Level in Acclimatized Patients Undergoing Invasive Mechanical Ventilation. A Multicenter Study / Mortalidad hospitalaria y efecto de ajustar el cociente PaO2/FiO2 de acuerdo con la altitud por encima del nivel del mar en pacientes aclimatados que se someten a ventilación mecánica invasiva. Un estudio multicéntrico

OBJECTIVE: (I) Analyze the effect of altitude above the sea level on the mortality rate in patients undergoing invasive mechanical ventilation. (II) Validate the traditional equation for adjusting PaO2/FiO2 according to the altitude. DESIGN: A prospective, observational, multicenter and international study conducted during August 2016. PATIENTS: Inclusion criteria: (I) age between 18 and 90 years old, (II) admitted to intensive care unit (ICU) situated at the same altitude above the sea level (AASL) in which the patients has stayed, at least, during the previous 40 days and (III) received invasive MV for at least 12 h. MATERIAL AND METHODS: All variables were registered the day of intubation (day 0). Patients were followed until death, ICU discharge or day 28. PaO2/FiO2 ratio was adjusted by the AASL according to: PaO2/FiO2 * (barometric pressure/760). Categorical variables were compared with χ2 and Cochran-Mantel-Haenszel test. Continuous variables with Mann-Whitney. Correlation between continuous variables was analyzed graphically and analytically. Logistic regression model was constructed to identify factors associated to mortality. Kapplan-Meier method was used to estimate the probability of survival according to the altitude. A 2-side p value < 0.05 was consider significant. RESULTS: 249 patients (< 1500 m n = 55; 1500 to < 2500 m n = 20; 2500 to < 3500 m n=155 and ≥ 3500 m n=19) were included. Adjusted and non-adjusted PaO2/FiO2 were correlated with several respiratory and non respiratory variables. None discordances between non adjusted and adjusted PaO2/FiO2 were identified. However, several correlations were appreciated only in patients situated < 1500 m or in > 1500 m. Seventy-nine patients died during the ICU stayed (32%). The mortality curve was not affected by the altitude above the sea level. Variables independently associated to mortality are: PEEP, age, systolic arterial blood pressure, and platelet count. AUROC: 0.72. CONCLUSION: In acclimatized patients undergoing invasive mechanical ventilation, the traditional equation for adjusting PaO2/FiO2 according the elevation above the sea level seems to be inaccurate and the altitude above the sea level does not affect the mortality risk

OBJETIVO: 1) Analizar el efecto de la altitud por encima del nivel del mar en la tasa de mortalidad de pacientes sometidos a ventilación mecánica invasiva, y 2) Validar la ecuación tradicional de ajuste de PaO2/FiO2, de acuerdo con la altitud. DISEÑO: Estudio internacional prospectivo, observacional y multicéntrico realizado durante agosto de 2016. PACIENTES: Criterios de inclusión: 1 Edad comprendida entre 18 y 90 años, 2 Haber sido ingresado en una unidad de cuidados intensivos (UCI) situada a la misma altitud por encima del nivel del mar (AASL) en la cual el paciente haya estado durante al menos los 40 días previos al estudio, y 3) Haber recibido ventilación mecánica (VM) durante al menos 12 h. MATERIALES Y MÉTODOS: Todas las variables se registraron el día de la intubación (día 0). El seguimiento se realizó hasta la muerte del paciente, el alta de la UCI o el día 28. El cociente PaO2/FiO2 se ajustó según los criterios de la AASL de acuerdo con: PaO2/FiO2 * (presión barométrica/760). Las variables categóricas se compararon mediante la prueba de χ2 y el test Cochran-Mantel-Haenszel, y las variables continuas con el test de Mann-Whitney. La correlación entre las variables continuas se analizó de forma gráfica y analítica. Para identificar los factores asociados a la mortalidad se elaboró un modelo de regresión logística. Se utilizó el método de Kaplan-Meier para estimar la probabilidad de supervivencia de acuerdo con la altitud. Un valor de p < 0,05 en la prueba bilateral se consideró como significativo. RESULTADOS: Se incluyeron 249 pacientes (< 1.500 m, n = 55; 1.500 a < 2.500 m, n = 20; 2.500 a < 3.500 m, n = 155 y ≥ 3.500 m, n = 19). El cociente PaO2/FiO2 mostró correlación con las variables graves tanto respiratorias como no respiratorias. No se registraron discordancias entre el cociente PaO2/FiO2 ajustado y sin ajustar. Únicamente se observaron diversas correlaciones entre los pacientes situados a < 1.500 m o a > 1.500 m. Setenta y nueve pacientes (32%) murieron durante la estancia en la UCI. La altitud sobre el nivel del mar no afectó a la curva de mortalidad. Las variables asociadas de forma independiente con la mortalidad fueron la presión positiva al final de la espiración (PEEP), la edad, la presión arterial sistólica y el recuento de plaquetas. El área bajo la curva ROC (AUROC) fue de 0,72. CONCLUSIÓN: En pacientes aclimatados sometidos a ventilación mecánica invasiva la ecuación tradicional para ajustar el cociente PaO2/FiO2, de acuerdo con la elevación sobre el nivel del mar parece inexacta. Por otro lado, la altitud por encima del nivel del mar no afecta al riego de mortalidad

Hospital Mortality and Effect of Adjusting PaO2/FiO2 According to Altitude Above the Sea Level in Acclimatized Patients Undergoing Invasive Mechanical Ventilation. A Multicenter Study.

OBJECTIVE: (i) Analyze the effect of altitude above the sea level on the mortality rate in patients undergoing invasive mechanical ventilation. (ii) Validate the traditional equation for adjusting PaO2/FiO2 according to the altitude. DESIGN: A prospective, observational, multicenter and international study conducted during August 2016. PATIENTS: Inclusion criteria: (i) age between 18 and 90 years old, (ii) admitted to intensive care unit (ICU) situated at the same altitude above the sea level (AASL) in which the patients has stayed, at least, during the previous 40 days and (iii) received invasive MV for at least 12h. MATERIAL AND METHODS: All variables were registered the day of intubation (day 0). Patients were followed until death, ICU discharge or day 28. PaO2/FiO2 ratio was adjusted by the AASL according to: PaO2/FiO2*(barometric pressure/760). Categorical variables were compared with χ2 and Cochran-Mantel-Haenszel test. Continuous variables with Mann-Whitney. Correlation between continuous variables was analyzed graphically and analytically. Logistic regression model was constructed to identify factors associated to mortality. Kapplan-Meier method was used to estimate the probability of survival according to the altitude. A 2-side p value <0.05 was consider significant. RESULTS: 249 patients (<1500m n=55; 1500 to <2500m n=20; 2500 to <3500m n=155 and ≥3500m n=19) were included. Adjusted and non-adjusted PaO2/FiO2 were correlated with several respiratory and non respiratory variables. None discordances between non adjusted and adjusted PaO2/FiO2 were identified. However, several correlations were appreciated only in patients situated <1500m or in >1500m. Seventy-nine patients died during the ICU stayed (32%). The mortality curve was not affected by the altitude above the sea level. Variables independently associated to mortality are: PEEP, age, systolic arterial blood pressure, and platelet count. AUROC: 0.72. CONCLUSION: In acclimatized patients undergoing invasive mechanical ventilation, the traditional equation for adjusting PaO2/FiO2 according the elevation above the sea level seems to be inaccurate and the altitude above the sea level does not affect the mortality risk.

Pyk2 Signaling through Graf1 and RhoA GTPase Is Required for Amyloid-ß Oligomer-Triggered Synapse Loss.

The intracellular tyrosine kinase Pyk2 (PTK2B) is related to focal adhesion kinase and localizes to postsynaptic sites in brain. Pyk2 genetic variation contributes to late onset Alzheimer's disease (AD) risk. We recently observed that Pyk2 is required for synapse loss and for learning deficits in a transgenic mouse model of AD. Here, we explore the cellular and biochemical basis for the action of Pyk2 tyrosine kinase in amyloid-ß oligomer (Aßo)-induced dendritic spine loss. Overexpression of Pyk2 reduces dendritic spine density of hippocampal neurons by a kinase-dependent mechanism. Biochemical isolation of Pyk2-interacting proteins from brain identifies Graf1c, a RhoA GTPase-activating protein inhibited by Pyk2. Aßo-induced reductions in dendritic spine motility and chronic spine loss require both Pyk2 kinase and RhoA activation. Thus, Pyk2 functions at postsynaptic sites to modulate F-actin control by RhoA and regulate synapse maintenance of relevance to AD risk.SIGNIFICANCE STATEMENT Genetic variation at the Pyk2 locus is a risk for Alzheimer's disease. We have observed that Pyk2 is required for AD transgenic synapse loss and memory dysfunction. However, the cellular and biochemical basis for Pyk2 function related to AD is not defined. Here, we show that brain Pyk2 interacts with the RhoGAP protein Graf1 to alter dendritic spine stability via RhoA GTPase. Amyloid-ß oligomer-induced dendritic spine loss requires the Pyk2/Graf1 pathway.

Alzheimer's Disease Risk Factor Pyk2 Mediates Amyloid-ß-Induced Synaptic Dysfunction and Loss.

Dozens of genes have been implicated in late onset Alzheimer's disease (AD) risk, but none has a defined mechanism of action in neurons. Here, we show that the risk factor Pyk2 (PTK2B) localizes specifically to neurons in adult brain. Absence of Pyk2 has no major effect on synapse formation or the basal parameters of synaptic transmission in the hippocampal Schaffer collateral pathway. However, the induction of synaptic LTD is suppressed in Pyk2-null slices. In contrast, deletion of Pyk2 expression does not alter LTP under control conditions. Of relevance for AD pathophysiology, Pyk2-/- slices are protected from amyloid-ß-oligomer (Aßo)-induced suppression of LTP in hippocampal slices. Acutely, a Pyk2 kinase inhibitor also prevents Aßo-induced suppression of LTP in WT slices. Female and male transgenic AD model mice expressing APPswe/PSEN1ΔE9 require Pyk2 for age-dependent loss of synaptic markers and for impairment of learning and memory. However, absence of Pyk2 does not alter Aß accumulation or gliosis. Therefore, the Pyk2 risk gene is directly implicated in a neuronal Aßo signaling pathway impairing synaptic anatomy and function.SIGNIFICANCE STATEMENT Genetic variation at the Pyk2 (PTK2B) locus is a risk for late onset Alzheimer's disease (AD), but the pathophysiological role of Pyk2 is not clear. Here, we studied Pyk2 neuronal function in mice lacking expression with and without transgenes generating amyloid-ß (Aß) plaque pathology. Pyk2 is not required for basal synaptic transmission or LTP, but participates in LTD. Hippocampal slices lacking Pyk2 are protected from AD-related Aß oligomer suppression of synaptic plasticity. In transgenic AD model mice, deletion of Pyk2 rescues synaptic loss and learning/memory deficits. Therefore, Pyk2 plays a central role in AD-related synaptic dysfunction mediating Aß-triggered dysfunction.

Sarcopenia and myosteatosis are accompanied by distinct biological profiles in patients with pancreatic and periampullary adenocarcinomas.

INTRODUCTION: Pancreatic and periampullary adenocarcinomas are associated with abnormal body composition visible on CT scans, including low muscle mass (sarcopenia) and low muscle radiodensity due to fat infiltration in muscle (myosteatosis). The biological and clinical correlates to these features are poorly understood. METHODS: Clinical characteristics and outcomes were studied in 123 patients who underwent pancreaticoduodenectomy for pancreatic or non-pancreatic periampullary adenocarcinoma and who had available preoperative CT scans. In a subgroup of patients with pancreatic cancer (n = 29), rectus abdominus muscle mRNA expression was determined by cDNA microarray and in another subgroup (n = 29) 1H-NMR spectroscopy and gas chromatography-mass spectrometry were used to characterize the serum metabolome. RESULTS: Muscle mass and radiodensity were not significantly correlated. Distinct groups were identified: sarcopenia (40.7%), myosteatosis (25.2%), both (11.4%). Fat distribution differed in these groups; sarcopenia associated with lower subcutaneous adipose tissue (P<0.0001) and myosteatosis associated with greater visceral adipose tissue (P<0.0001). Sarcopenia, myosteatosis and their combined presence associated with shorter survival, Log Rank P = 0.005, P = 0.06, and P = 0.002, respectively. In muscle, transcriptomic analysis suggested increased inflammation and decreased growth in sarcopenia and disrupted oxidative phosphorylation and lipid accumulation in myosteatosis. In the circulating metabolome, metabolites consistent with muscle catabolism associated with sarcopenia. Metabolites consistent with disordered carbohydrate metabolism were identified in both sarcopenia and myosteatosis. DISCUSSION: Muscle phenotypes differ clinically and biologically. Because these muscle phenotypes are linked to poor survival, it will be imperative to delineate their pathophysiologic mechanisms, including whether they are driven by variable tumor biology or host response.

Conditional Deletion of Prnp Rescues Behavioral and Synaptic Deficits after Disease Onset in Transgenic Alzheimer's Disease.

Biochemical and genetic evidence implicate soluble oligomeric amyloid-ß (Aßo) in triggering Alzheimer's disease (AD) pathophysiology. Moreover, constitutive deletion of the Aßo-binding cellular prion protein (PrPC) prevents development of memory deficits in APPswe/PS1ΔE9 mice, a model of familial AD. Here, we define the role of PrPC to rescue or halt established AD endophenotypes in a therapeutic disease-modifying time window after symptom onset. Deletion of Prnp at either 12 or 16 months of age fully reverses hippocampal synapse loss and completely rescues preexisting behavioral deficits by 17 months. In contrast, but consistent with a neuronal function for Aßo/PrPC signaling, plaque density, microgliosis, and astrocytosis are not altered. Degeneration of catecholaminergic neurons remains unchanged by PrPC reduction after disease onset. These results define the potential of targeting PrPC as a disease-modifying therapy for certain AD-related phenotypes after disease onset.SIGNIFICANCE STATEMENT The study presented here further elucidates our understanding of the soluble oligomeric amyloid-ß-Aßo-binding cellular prion protein (PrPC) signaling pathway in a familial form of Alzheimer's disease (AD) by implicating PrPC as a potential therapeutic target for AD. In particular, genetic deletion of Prnp rescued several familial AD (FAD)-associated phenotypes after disease onset in a mouse model of FAD. This study underscores the therapeutic potential of PrPC deletion given that patients already present symptoms at the time of diagnosis.

Silent Allosteric Modulation of mGluR5 Maintains Glutamate Signaling while Rescuing Alzheimer's Mouse Phenotypes.

Metabotropic glutamate receptor 5 (mGluR5) has been implicated in Alzheimer's disease (AD) pathology. We sought to understand whether mGluR5's role in AD requires glutamate signaling. We used a potent mGluR5 silent allosteric modulator (SAM, BMS-984923) to separate its well-known physiological role in glutamate signaling from a pathological role in mediating amyloid-ß oligomer (Aßo) action. Binding of the SAM to mGluR5 does not change glutamate signaling but strongly reduces mGluR5 interaction with cellular prion protein (PrPC) bound to Aßo. The SAM compound prevents Aßo-induced signal transduction in brain slices and in an AD transgenic mouse model, the APPswe/PS1ΔE9 strain. Critically, 4 weeks of SAM treatment rescues memory deficits and synaptic depletion in the APPswe/PS1ΔE9 transgenic mouse brain. Our data show that mGluR5's role in Aßo-dependent AD phenotypes is separate from its role in glutamate signaling and silent allosteric modulation of mGluR5 has promise as a disease-modifying AD intervention with a broad therapeutic window.

Cellular prion protein as a receptor for amyloid-ß oligomers in Alzheimer's disease.

Soluble oligomers of amyloid-beta (Aßo) are implicated by biochemical and genetic evidence as a trigger for Alzheimer's disease (AD) pathophysiology. A key step is Aßo interaction with the neuronal surface to initiate a cascade of altered signal transduction leading to synaptic dysfunction and damage. This review discusses neuronal cell surface molecules with high affinity selectively for oligomeric disease-associated states of Aß, with a particular focus on the role of cellular prion protein (PrPC) in this process. Additional receptors may contribute to mediation of Aßo action, but PrPC appears to play a primary role in a number of systems. The specificity of binding, the genetic necessity in mouse models of disease and downstream signaling pathways are considered. Signal transduction downstream of Aßo complexes with PrPC involves metabotropic glutamate receptor 5 (mGluR5), Fyn kinase and Pyk2 kinase, with deleterious effects on synaptic transmission and maintenance. Current data support the hypothesis that a substantial portion of Aßo toxicity in AD is mediated after initial interaction with PrPC on the neuronal surface. As such, the interaction of Aßo with PrPC is a potential therapeutic intervention site for AD.

Sobrecarga y autoeficacia percibida en cuidadores primarios informales de pacientes con insuficiencia cardíaca / Burden and perceived Self-efficacy in informal primary caregivers of patients with heart failure

Objetivo. Examinar la asociación entre autoeficacia y sobrecarga percibida del cuidador de pacientes con insuficiencia cardíaca. Diseño. Estudio exploratorio y correlacional de corte transversal. Emplazamiento. Ámbito comunitario. Instituto Nacional de Enfermedades Respiratorias 'Ismael Cosío Villegas'. Participantes. 109 cuidadores de pacientes con insuficiencia cardíaca. Mediciones Principales. Se realizó una evaluación psicológica, en la que se aplicaron los siguientes instrumentos: Escala de Carga Zarit y la Escala de Autoeficacia Percibida en Cuidadores Primarios Informales de Enfermos Crónicos. Resultados. El 49,5% (95%IC: 82,12-89,16) de la muestra reportó un nivel de autoeficacia bajo. El 27,5% (95%IC: 20,04-22,75) presentó sobrecarga leve y el 25,7% (95%IC: 37,71-47,78) sobrecarga intensa. Los resultados del análisis revelan una relación inversamente proporcional entre las variables del estudio (rs=-0,592, p<0,05), Eliminar lo siguiente: esto quiere decir que a mayor sobrecarga menor autoeficacia percibida y viceversa. Conclusiones. La sobrecarga es una de las consecuencias negativas más reportadas. Al estar relacionada con la autoeficacia percibida, este hallazgo podría ser considerado en el diseño de programas de intervención para reducir la carga del cuidador (AU)

Objective. To examine the association between perceived self-efficacy and burden in caregivers of patients with heart failure. Design. Cross-sectional exploratoy and correlational study. Location. Community level. Instituto Nacional de Enfermedades Respiratorias (National Institute of Respiratory Diseases) 'Ismael Cosío Villegas'. Participants. 109 caregivers of patients with heart failure. Main measures. A psychological evaluation was performed in which the following instruments were applied: the Zarit Burden Scale and Scale of Perceived Self-Efficacy in Informal Primary Caregivers of the Chronically Sick. Results. 49.5% (95% CI: 82.12-89.16) of the sample reported a low level of self-efficacy. 27.5% (95% CI: 20.04-22.75) had low burden and 25.7% (95% CI: 37.71-47.78) intense burden. The results of the analysis revealed an inverse relationship between the study variables (r = -0.592), so that the higher the perceived self-efficacy the lower the burden, and viceversa. Conclusions. The burden is one of the most commonly reported negative consequences. Since it is related to the perceived self-efficacy, this finding could be taken into account when designing intervention programs that reduce caregiver burden (AU)