Exploring Functional Products and Early-Life Dynamics of Gut Microbiota.

Research on the microbiome has progressed from identifying specific microbial communities to exploring how these organisms produce and modify metabolites that impact a wide range of health conditions, including gastrointestinal, metabolic, autoimmune, and neurodegenerative diseases. This review provides an overview of the bacteria commonly found in the intestinal tract, focusing on their main functional outputs. We explore biomarkers that not only indicate a well-balanced microbiota but also potential dysbiosis, which could foreshadow susceptibility to future health conditions. Additionally, it discusses the establishment of the microbiota during the early years of life, examining factors such as gestational age at birth, type of delivery, antibiotic intake, and genetic and environmental influences. Through a comprehensive analysis of current research, this article aims to enhance our understanding of the microbiota's foundational development and its long-term implications for health and disease management.

Prostaglandin Transporter and Dipeptidyl Peptidase-4 as New Pharmacological Targets in the Prevention of Acute Kidney Injury in Diabetes: An In Vitro Study.

The probability of acute kidney injury (AKI) is higher in septic diabetic patients, which is associated with, among other factors, proximal tubular cell (PTC) injury induced by the hypoxic/hyperglycemic/inflammatory microenvironment that surrounds PTCs in these patients. Here, we exposed human PTCs (HK-2 cells) to 1% O2/25 mM glucose/inflammatory cytokines with the aim of studying the role of prostaglandin uptake transporter (PGT) and dipeptidyl peptidase-4 (DPP-4, a target of anti-hyperglycemic agents) as pharmacological targets to prevent AKI in septic diabetic patients. Our model reproduced two pathologically relevant mechanisms: (i) pro-inflammatory PTC activation, as demonstrated by the increased secretion of chemokines IL-8 and MCP-1 and the enhanced expression of DPP-4, intercellular leukocyte adhesion molecule-1 and cyclo-oxygenase-2 (COX-2), the latter resulting in a PGT-dependent increase in intracellular prostaglandin E2 (iPGE2); and (ii) epithelial monolayer injury and the consequent disturbance of paracellular permeability, which was related to cell detachment from collagen IV and the alteration of the cell cytoskeleton. Most of these changes were prevented by the antagonism of PGE2 receptors or the inhibition of COX-2, PGT or DPP-4, and further studies suggested that a COX-2/iPGE2/DPP-4 pathway mediates the pathogenic effects of the hypoxic/hyperglycemic/inflammatory conditions on PTCs. Therefore, inhibitors of PGT or DPP-4 ought to undergo testing as a novel therapeutic avenue to prevent proximal tubular damage in diabetic patients at risk of AKI.

Exploring the Metabolic Differences between Cisplatin- and UV Light-Induced Apoptotic Bodies in HK-2 Cells by an Untargeted Metabolomics Approach.

Among the extracellular vesicles, apoptotic bodies (ABs) are only formed during the apoptosis and perform a relevant role in the pathogenesis of different diseases. Recently, it has been demonstrated that ABs from human renal proximal tubular HK-2 cells, either induced by cisplatin or by UV light, can lead to further apoptotic death in naïve HK-2 cells. Thus, the aim of this work was to carry out a non-targeted metabolomic approach to study if the apoptotic stimulus (cisplatin or UV light) affects in a different way the metabolites involved in the propagation of apoptosis. Both ABs and their extracellular fluid were analyzed using a reverse-phase liquid chromatography-mass spectrometry setup. Principal components analysis showed a tight clustering of each experimental group and partial least square discriminant analysis was used to assess the metabolic differences existing between these groups. Considering the variable importance in the projection values, molecular features were selected and some of them could be identified either unequivocally or tentatively. The resulting pathways indicated that there are significant, stimulus-specific differences in metabolites abundancies that may propagate apoptosis to healthy proximal tubular cells; thus, we hypothesize that the share in apoptosis of these metabolites might vary depending on the apoptotic stimulus.

Colorectal cancer: immune response in laparoscopic versus open colorectal surgery.

INTRODUCTION: Colorectal cancer is the second most frequent cause of deaths from cancer worldwide. Enhanced recovery protocols (ERPs) were developed in 90s to improve the recovery of these patients. Within ERPs, this work aims to compare immune response between open and laparoscopic procedures to support the best surgical approach. MATERIALS AND METHODS: The immune status of 148 patients undergoing colorectal surgery (74 by laparoscopic and 74 by open surgery [OS]) was studied in three moments: before surgery (POD0) and on the 1st and 3th post-operative days (POD1 and POD3). RESULTS: Comparing to the laparoscopic group, in the OS group, C-reactive protein levels were significantly higher on POD1 and POD3 (p < 0.001), whereas lymphocyte levels were significantly lower (p = 0.006) and neutrophil levels were higher (p = 0.012) on POD1. On the other hand, higher levels of B cells (p = 0.023) were observed on POD1 in the laparoscopic group. Natural killer cell levels were significantly reduced (p = 0.034) in this group on POD3. CONCLUSIONS: Within the ERP, immune response pattern in both surgery approaches appears to be similar. Nevertheless, a greater inflammatory response of the OS is observed, whereas earlier recovery of the immune levels baseline seems to be a trend in the laparoscopic surgery.

INTRODUCCIÓN: El cáncer colorrectal es la segunda causa más frecuente de muerte por cáncer en todo el mundo. Los protocolos de recuperación mejorados (ERP) se desarrollaron en los años 90 para mejorar la recuperación de estos pacientes. Dentro de los ERP, este trabajo tiene como objetivo comparar la respuesta inmune entre procedimientos abiertos y laparoscópicos para respaldar el mejor abordaje quirúrgico. MATERIAL Y MÉTODOS: Se estudió el estado inmunológico de 148 pacientes sometidos a cirugía colorrectal (74 por vía laparoscópica y 74 por cirugía abierta) en tres momentos: antes de la cirugía (POD0) y en el 1 y 3 días postoperatorios (POD1 y POD3). RESULTADOS: En comparación con el grupo laparoscópico, en el grupo de cirugía abierta los niveles de proteína C reactiva fueron significativamente más altos en POD1 y POD3 (p < 0.001), mientras que los niveles de linfocitos fueron significativamente más bajos (p = 0.006) y los niveles de neutrófilos fueron más altos (p = 0.012) en POD1. Por otro lado, se observaron niveles más altos de células B (p = 0.023) en POD1 en el grupo laparoscópico. Los niveles de células asesinas naturales se redujeron significativamente (p = 0.034) en este grupo en POD3. CONCLUSIONES: Dentro del ERP, el patrón de respuesta inmune en ambos enfoques quirúrgicos parece ser similar. Sin embargo, se observa una mayor respuesta inflamatoria de la cirugía abierta, mientras que la recuperación más temprana de los niveles inmunitarios basales parece ser una tendencia en la cirugía laparoscópica.

Factors associated with short-term mortality after emergency department care of residents living in aged care homes: findings from the multicenter Caregency study. / Factores asociados con mortalidad a corto plazo en personas que viven en residencias atendidas en servicios de urgencias: resultados del estudio multicéntrico Caregency.

OBJECTIVES: To evaluate short-term mortality in people transferred from aged care homes for treatment in a hospital emergency department (ED) and to analyze factors associated with mortality. MATERIAL AND METHODS: Multicenter study of a random sample of retrospective data of patients treated in 5 EDs in Catalonia in 2017. The patients were over the age of 65 years and lived in residential care facilities. In addition to short-term mortality (in the ED or within 30 days of discharge), we analyzed sociodemographic characteristics, prior functional and cognitive status, multimorbidity, triage level on arrival, length of stay in the ED, and hospital admission. Odds ratios (ORs) for factors associated with short-term mortality were calculated by multivariate regression analysis. RESULTS: A total of 2444 ED admissions were analyzed. The patients' mean (SD) age was 85.9 (7.1) years, and 67.7% .were women. Short-term mortality (in 15.5%) was associated with age >90 years (OR, 1.50; 95% CI, 1.5-1.95 years), a Charlson index >2 (OR, 1.47; 95% CI, 1.14-1.90), and dependency assessed as moderate (OR, 1.50; 95% CI, 1.03- 2.20) or severe (OR, 2.56; 95% CI, 1.84-3.55). Other associated factors were a higher level of urgency on triage, duration of ED stay, and hospital admission. CONCLUSION: Aged residents with the characteristics associated with short-term mortality could benefit from interventions for potentially avoiding unnecessary transfers to an ED, and from the implementation of comprehensive geriatric care within the ED. This could be useful to support good quality of care at the end of life.

OBJETIVO: Evaluar la frecuencia y los factores asociados con la mortalidad a corto plazo de personas que viven en residencias tras ingreso en urgencias. METODO: Análisis retrospectivo multicéntrico de una muestra aleatoria de admisiones de personas $ 65 años que viven en residencias en cinco servicios de urgencias de Cataluña, a lo largo de 2017. Se analizaron características sociodemográficas, el estado funcional y cognitivo previo, multimorbilidad, nivel de triaje de las urgencias, duración de la estancia en urgencias, hospitalización y mortalidad a corto plazo (en urgencias o en los 30 días posteriores al alta). Se utilizó un análisis de regresión multivariante para investigar los factores asociados con la mortalidad a corto plazo. RESULTADOS: Se analizaron 2.444 admisiones en urgencias, con una edad media de 85,9 (DE 7,1) años, 67,7% mujeres. La mortalidad a corto plazo (15,5%) se asoció con una edad > 90 años (OR 1,50; IC 95%: 1,5-1,95), un índice de Charlson > 2 (OR 1,47; IC 95%: 1,14-1,90), y un grado de dependencia moderado (OR 1,50; IC 95%: 1,03-2,20) y grave (OR 2,56; IC 95%: 1,84-3,55). También se asoció con un mayor nivel de triaje de la urgencia, duración de la estancia en urgencias e ingreso en planta de hospitalización. CONCLUSIONES: Los ancianos residentes con las características descritas podrían beneficiarse especialmente de intervenciones dirigidas a la prevención de traslados potencialmente innecesarios a urgencias y a la implementación de una atención integral geriátrica dentro de los servicios de urgencias, a fin de garantizar una buena calidad de los cuidados en fases finales de la vida.

Mitochondria selective trackers for long-term imaging based on readily accessible neutral BODIPYs.

We report the design of a new model based on a small neutral 8-aryl-3-formylBODIPY and its suitability to develop privileged highly bright and photostable fluorescent probes for selective and, more importantly, covalent staining of mitochondria.

Intracellular prostaglandin E2 contributes to hypoxia-induced proximal tubular cell death.

Proximal tubular cells (PTC) are particularly vulnerable to hypoxia-induced apoptosis, a relevant factor for kidney disease. We hypothesized here that PTC death under hypoxia is mediated by cyclo-oxygenase (COX-2)-dependent production of prostaglandin E2 (PGE2), which was confirmed in human proximal tubular HK-2 cells because hypoxia (1% O2)-induced apoptosis (i) was prevented by a COX-2 inhibitor and by antagonists of prostaglandin (EP) receptors and (ii) was associated to an increase in intracellular PGE2 (iPGE2) due to hypoxia-inducible factor-1α-dependent transcriptional up-regulation of COX-2. Apoptosis was also prevented by inhibitors of the prostaglandin uptake transporter PGT, which indicated that iPGE2 contributes to hypoxia-induced apoptosis (on the contrary, hypoxia/reoxygenation-induced PTC death was exclusively due to extracellular PGE2). Thus, iPGE2 is a new actor in the pathogenesis of hypoxia-induced tubular injury and PGT might be a new therapeutic target for the prevention of hypoxia-dependent lesions in renal diseases.

Author Correction: Mechanism and Consequences of The Impaired Hif-1α Response to Hypoxia in Human Proximal Tubular HK-2 Cells Exposed to High Glucose.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Retinoic acid receptor-beta prevents cisplatin-induced proximal tubular cell death.

Cisplatin's toxicity in renal tubular epithelial cells limits the therapeutic efficacy of this antineoplastic drug. In cultured human proximal tubular HK-2 cells (PTC) a prostaglandin uptake transporter (PGT)-dependent increase in intracellular prostaglandin E2 (iPGE2) mediates cisplatin's toxicity (i.e. increased cell death and loss of cell proliferation) so that it is prevented by PGT inhibitors. Here we found in cisplatin-treated PTC that 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), a PGT inhibitor, prevented cisplatin's toxicity but not the increase in iPGE2. Because expression of retinoic acid receptor-ß (RAR-ß) is dependent on iPGE2 and because RAR-ß is a regulator of cell survival and proliferation, we hypothesized that RAR-ß might mediate the protective effect of DIDS against cisplatin's toxicity in PTC. Our results confirmed this hypothesis because: i) protection of PTC by DIDS was abolished by RAR-ß antagonist LE-135; ii) DIDS increased the expression of RAR-ß in PTC and prevented its decrease in cisplatin-treated PTC but not in cisplatin-treated human cervical adenocarcinoma HeLa cells in which DIDS failed to prevent cisplatin's toxicity; iii) while RAR-ß expression decreased in cisplatin-treated PTC, RAR-ß over-expression prevented cisplatin's toxicity. RAR-ß agonist CH55 or RAR pan-agonist all-trans retinoic acid did not prevent cisplatin's toxicity, which suggests that RAR-ß does not protect PTC through activation of gene transcription. In conclusion, RAR-ß might be a new player in cisplatin-induced proximal tubular injury and the preservation of its expression in proximal tubules through treatment with DIDS might represent a novel strategy in the prevention of cisplatin's nephrotoxicity without compromising cisplatin's chemotherapeutic effect on cancer cells.

Beyond the CNS: The many peripheral roles of APOE.

Apolipoprotein E (APOE) is a multifunctional protein synthesized and secreted by multiple mammalian tissues. Although hepatocytes contribute about 75% of the peripheral pool, APOE can also be expressed in adipose tissue, the kidney, and the adrenal glands, among other tissues. High levels of APOE production also occur in the brain, where it is primarily synthesized by glia, and peripheral and brain APOE pools are thought to be distinct. In humans, APOE is polymorphic, with three major alleles (ε2, ε3, and ε4). These allelic forms dramatically alter APOE structure and function. Historically, the vast majority of research on APOE has centered on the important role it plays in modulating risk for cardiovascular disease and Alzheimer's disease. However, the established effects of this pleiotropic protein extend well beyond these two critical health challenges, with demonstrated roles across a wide spectrum of biological conditions, including adipose tissue function and obesity, metabolic syndrome and diabetes, fertility and longevity, and immune function. While the spectrum of biological systems in which APOE plays a role seems implausibly wide at first glance, there are some potential unifying mechanisms that could tie these seemingly disparate disorders together. In the current review, we aim to concisely summarize a wide breadth of APOE-associated pathologies and to analyze the influence of APOE in the development of several distinct disorders in order to provide insight into potential shared mechanisms implied in these various pathophysiological processes.

Association Between Use of Enhanced Recovery After Surgery Protocol and Postoperative Complications in Total Hip and Knee Arthroplasty in the Postoperative Outcomes Within Enhanced Recovery After Surgery Protocol in Elective Total Hip and Knee Arthroplasty Study (POWER2).

Importance: The Enhanced Recovery After Surgery (ERAS) care protocol has been shown to improve outcomes compared with traditional care in certain types of surgery. Objective: To assess the association of use of the ERAS protocols with complications in patients undergoing elective total hip arthroplasty (THA) and total knee arthroplasty (TKA). Design, Setting, and Participants: This multicenter, prospective cohort study included patients recruited from 131 centers in Spain from October 22 through December 22, 2018. All consecutive adults scheduled for elective THA or TKA were eligible for inclusion. Patients were stratified between those treated in a self-designated ERAS center (ERAS group) and those treated in a non-ERAS center (non-ERAS group). Data were analyzed from June 15 through September 15, 2019. Exposures: Total hip or knee arthroplasty and perioperative management. Sixteen individual ERAS items were assessed in all included patients, whether they were treated at a center that was part of an established ERAS protocol or not. Main Outcomes and Measures: The primary outcome was postoperative complications within 30 days after surgery. Secondary outcomes included length of stay and mortality. Results: During the 2-month recruitment period, 6146 patients were included (3580 women [58.2%]; median age, 71 [interquartile range (IQR), 63-76] years). Of these, 680 patients (11.1%) presented with postoperative complications. No differences were found in the number of patients with overall postoperative complications between ERAS and non-ERAS groups (163 [10.2%] vs 517 [11.4%]; odds ratio [OR], 0.89; 95% CI, 0.74-1.07; P = .22). Fewer patients in the ERAS group had moderate to severe complications (73 [4.6%] vs 279 [6.1%]; OR, 0.74; 95% CI, 0.56-0.96; P = .02). The median overall adherence rate with the ERAS protocol was 50.0% (IQR, 43.8%-62.5%), with the rate for ERAS facilities being 68.8% (IQR, 56.2%-81.2%) vs 50.0% (IQR, 37.5%-56.2%) at non-ERAS centers (P < .001). Among the patients with the highest and lowest quartiles of adherence to ERAS components, the patients with the highest adherence had fewer overall postoperative complications (144 [10.6%] vs 270 [13.0%]; OR, 0.80; 95% CI, 0.64-0.99; P < .001) and moderate to severe postoperative complications (59 [4.4%] vs 143 [6.9%]; OR, 0.62; 95% CI, 0.45-0.84; P < .001) and shorter median length of hospital stay (4 [IQR, 3-5] vs 5 [IQR, 4-6] days; OR, 0.97; 95% CI, 0.96-0.99; P < .001). Conclusions and Relevance: An increase in adherence to the ERAS program was associated with a decrease in postoperative complications, although only a few ERAS items were individually associated with improved outcomes.

Mechanism and Consequences of The Impaired Hif-1α Response to Hypoxia in Human Proximal Tubular HK-2 Cells Exposed to High Glucose.

Renal hypoxia and loss of proximal tubular cells (PTC) are relevant in diabetic nephropathy. Hypoxia inhibits hypoxia-inducible factor-1α (HIF-1α) degradation, which leads to cellular adaptive responses through HIF-1-dependent activation of gene hypoxia-responsive elements (HRE). However, the diabetic microenvironment represses the HIF-1/HRE response in PTC. Here we studied the mechanism and consequences of impaired HIF-1α regulation in human proximal tubular HK-2 cells incubated in hyperglycemia. Inhibition at different levels of the canonical pathway of HIF-1α degradation did not activate the HIF-1/HRE response under hyperglycemia, except when proteasome was inhibited. Further studies suggested that hyperglycemia disrupts the interaction of HIF-1α with Hsp90, a known cause of proteasomal degradation of HIF-1α. Impaired HIF-1α regulation in cells exposed to hyperglycemic, hypoxic diabetic-like milieu led to diminished production of vascular endothelial growth factor-A and inhibition of cell migration (responses respectively involved in tubular protection and repair). These effects, as well as impaired HIF-1α regulation, were reproduced in normoglycemia in HK-2 cells incubated with microparticles released by HK-2 cells exposed to diabetic-like milieu. In summary, these results highlight the role of proteasome-dependent mechanisms of HIF-1α degradation on diabetes-induced HK-2 cells dysfunction and suggest that cell-derived microparticles may mediate negative effects of the diabetic milieu on PTC.

Men's Bodily Attractiveness: Muscles as Fitness Indicators.

Bodily attractiveness is an important component of mate value. Musculature-a crucial component of men's bodily attractiveness-provides women with probabilistic information regarding a potential mate's quality. Overall musculature is comprised of several muscle groups, each of which varies in information value; different muscles should be weighted differently by attractiveness-assessment adaptations as a result. In the current study, women and men ( N = 1,742) reported size preferences for 14 major muscle groups. Women's reported preferences provided only partial support for our hypotheses that women will prefer muscles that most reliably differentiate between potential mates to be larger; men tended to prefer larger upper-body muscles. We discuss possible interpretations of these mixed findings. Ultimately, our findings suggest that attractiveness-assessment adaptations are sensitive to the information contained within specific muscle groups and they highlight the potential for additional research on the nuances of bodily attractiveness assessment.

Postoperative Outcomes Within Enhanced Recovery After Surgery Protocol in Elective Total Hip and Knee Arthroplasty. POWER.2 Study: Study Protocol for a Prospective, Multicentre, Observational Cohort Study.

OBJECTIVE: The number of indications for total hip replacement (THR) and total knee replacement (TKR) surgery is increasing. Enhanced recovery after surgery (ERAS) represents the next step in the evolution of standardised care. The primary aim of this study is to measure the in-hospital 30-day medical and surgical postoperative complications rate. The study's secondary aims are to determine the length of stay, 30-day mortality rate, 30-day reoperation and readmission rates, the ERAS overall compliance and predefined ERAS individual items compliance. METHODS: This multicentre, prospective, observational study will include adult patients (aged >18 years) undergoing elective THR and TKR surgery. Consecutive patients undergoing surgery within the 2-month data collection period will be included. Centres that offer the THR and/or TKR surgery will be eligible to participate. The data collection will be done through an online data collection form via a secure, password-protected platform at each centre with predefined data fields. RESULTS: Ethical approval for this study has been obtained from the Comité de Ética de la Investigación de la Comunidad Autónoma de Aragón (C.P.-C.I. PI18/135; on 23 May 2018). It was prospectively registered on 27 June 2018, at www.clinicaltrials.gov with identification no. NCT03570944. CONCLUSION: The study will be disseminated through the SPARN-RedGERM, SEDAR, GERM and through social media. Peer-reviewed publications will be published under corporate authorship, including POWER.2 Study Group and SPARN-RedGERM.

Apoptosis and cell proliferation in proximal tubular cells exposed to apoptotic bodies. Novel pathophysiological implications in cisplatin-induced renal injury.

The therapeutic efficacy of the antineoplastic drug cisplatin is limited by its nephrotoxicity, which affects particularly to proximal tubular cells (PTC). Cisplatin-induced cytotoxicity appears to be multifactorial and involves inflammation, oxidative stress as well as apoptosis. We have recently shown that the cyclo-oxygenase-2 (COX-2)/intracellular prostaglandin E2 (iPGE2)/EP receptor pathway mediates the apoptotic effect of cisplatin on human proximal tubular HK-2 cells. Here, we studied the effects on HK-2 cells of apoptotic bodies (ABs) generated after treatment of HK-2 cells with cisplatin. We found that ABs inhibited cell growth, induced apoptosis and increased COX-2 expression and iPGE2 in ABs-recipient HK-2 cells. Inhibition of the COX-2/iPGE2/EP receptor pathway in these cells prevented the effects of ABs without interfering with their internalization. Interestingly, 2nd generation ABs (i.e. ABs released by cells undergoing apoptosis upon treatment with ABs) did not trigger apoptosis in naïve HK-2 cells, and stimulated cell proliferation through the COX-2/iPGE2/EP receptor pathway. These results suggest that ABs, through iPGE2-dependent mechanisms, might have a relevant role in the natural history of cisplatin-induced acute kidney failure because they contribute first to the propagation of the noxious effects of cisplatin to non-injured PTC and then to the promotion of the proliferative tubular response required for proximal tubule repair. Since iPGE2 also mediates both cisplatin-induced HK-2 cell apoptosis, intervention in the COX-2/iPGE2/EP receptor pathway might provide us with new therapeutic avenues in patients with cisplatin-induced acute kidney injury.

Changes in amino acid profiles and liver alterations in pregnant rats with a high carbohydrate/low protein diet.

INTRODUCTION AND AIM: Intake of a high-carbohydrate, low-protein diet (HCD/LPD) during pregnancy promotes metabolic disturbances. It has been suggested that liver function during pregnancy contributes to the synthesis of proteins necessary for fetal development during this stage. The liver is a site of response to the synthesis of macronutrients such as proteins. However, it is unknown how HCD/LPD is associated with modifications to the amino acid profiles and hepatic alterations in the maternal environment during pregnancy. MATERIALS AND METHODS: A transverse longitudinal study was done in primiparous mothers during gestation (G) (G1 day 1, G5 day 5, G15 day 15, and G20 day 20). Histological analysis was used to assess hepatic alterations, and amino acid profiles in the liver were analyzed with high performance liquid chromatography (HPLC). Food and water intake was quantified, and peripheral biochemical indicators in serum were measured. RESULTS: Mothers with HCD/LPD had increased micro and macro vesicles of fat, necrosis, and inflammation in the liver on G5. The total concentration of hepatic amino acids increased by 40% on G1, 17% on G5, and 25% on G15; and, there was a 12% decrease on G20. The following increases were observed in the liver on G1: arginine 68%, histidine 75%, alanine 18%, methionine 71%, and phenylalanine 51% (p>0.05); on G5: arginine 12%, methionine 34%, and phenylalanine 83% (p>0.05); on G15: arginine and phenylalanine 66%, tryptophan 81% and histidine 60.4% (p>0.05); and on G20: arginine 32% (p>0.05). No weight loss, changes in food consumption, or hepatomegaly occurred. CONCLUSIONS: HCD/LPD during pregnancy in primiparous mothers may promote development of fat vesicles. Possibly, this condition causes metabolic adaptations and nitrogen management reflected in decreased levels of serum urea and altered amino acid profiles in the liver.

PROSTAGLANDIN E2 stimulates cancer-related phenotypes in prostate cancer PC3 cells through cyclooxygenase-2.

Cyclooxygenase (COX)-derived prostaglandin E2 (PGE2 ) affects many mechanisms that have been shown to play roles in carcinogenesis. Recently, we found that, in androgen-independent prostate cancer PC3 cells, PGE2 acts through an intracrine mechanism by which its uptake by the prostaglandin transporter (PGT) results in increased intracellular PGE2 (iPGE2 ), leading to enhanced cell proliferation, migration, invasion, angiogenesis, and loss of cell adhesion to collagen I. These iPGE2 -mediated effects were dependent on hypoxia-inducible factor 1-α (HIF-1α), whose expression increased upon epidermal growth factor receptor (EGFR) transactivation by a subset of intracellular PGE2 receptors. Here, we aimed to study the role of COX in PGE2 protumoral effects in PC3 cells and found that the effects were prevented by inhibition of COX-2, which highlights its crucial role amplifying the levels of iPGE2 . Treatment with exogenous PGE2 determined a transcriptional increase in COX-2 expression, which was abolished by genetic or pharmacologic inhibition of PGT. PGE2 -induced increase in COX-2 expression and, thereby, in transcriptional increase in HIF-1α expression was due to EGFR activation, leading to the activation of Phosphoinositide 3-kinase/Akt, Extracellular signal -regulated kinases 1/2, p38 and Mitogen- and stress-activated protein kinase-1 (PI3K/Akt, Erk1/2, p38 and MSK-1). Collectively, the data suggest that EGFR-dependent COX-2 upregulation by a novel positive feedback loop triggered by iPGE2 underlies the intracrine pro-tumoral effects of PGE2 in PC3 cells. Therefore, this feedback loop may be relevant in prostate cancer for the maintenance of PGE2 -dependent cancer cell growth through amplifying the activity of the COX-2 pathway.

Association of positive screening for dysphagia with nutritional status and long-term mortality in hospitalized elderly patients. / Asociación de un cribado positivo para disfagia con el estado nutricional y la mortalidad a largo plazo en pacientes ancianos hospitalizados.

OBJECTIVES: To assess the prevalence of oropharyngeal dysphagia (OD) using the Eating Assessment Tool (EAT-10) and its association with malnutrition and long-term mortality. MATERIAL AND METHODS: A retrospective cohort study of patients admitted to the general internal medicine ward. In the first 48hours after hospital admission, OD was assessed using the EAT-10, and presence of malnutrition with the Mini Nutritional Assessment-Short Form (MNA-SF). Association of OD to malnutrition and long-term mortality was analyzed. RESULTS: Ninety patients with a mean age of 83 (SD: 11.8) years were enrolled. Of these, 56.7% were at risk of OD according to EAT-10. This group of patients had greater prevalence rates of malnutrition (88.2% vs. 48.7%; P=.001) and mortality (70% vs 35.9%; P=.001). During follow-up for 872.71 (SD: 642.89) days, risk of DO according to EAT-10 was an independent predictor of mortality factor in a multivariate analysis (HR: 2.8; 95%CI: 1.49-5.28; P=.001). CONCLUSIONS: The EAT-10 is a useful tool for screening OD. Adequate screening for OD is important because of its associated risks of malnutrition and long-term mortality.

Intracrine prostaglandin E2 pro-tumoral actions in prostate epithelial cells originate from non-canonical pathways.

Prostaglandin E2 (PGE2 ) increases cell proliferation and stimulates migratory and angiogenic abilities in prostate cancer cells. However, the effects of PGE2 on non-transformed prostate epithelial cells are unknown, despite the fact that PGE2 overproduction has been found in benign hyperplastic prostates. In the present work we studied the effects of PGE2 in immortalized, non-malignant prostate epithelial RWPE-1 cells and found that PGE2 increased cell proliferation, cell migration, and production of vascular endothelial growth factor-A, and activated in vitro angiogenesis. These actions involved a non-canonic intracrine mechanism in which the actual effector was intracellular PGE2 (iPGE2 ) instead of extracellular PGE2 : inhibition of the prostaglandin uptake transporter (PGT) or antagonism of EP receptors prevented the effects of PGE2 , which indicated that PGE2 activity depended on its carrier-mediated translocation from the outside to the inside of cells and that EP receptors located intracellularly (iEP) mediated the effects of PGE2 . iPGE2 acted through transactivation of epidermal growth factor-receptor (EGFR) by iEP, leading to increased expression and activity of hypoxia-inducible factor-1α (HIF-1α). Interestingly, iPGE2 also mediates the effects of PGE2 on prostate cancer PC3 cells through the axis iPGE2 -iEP receptors-EGFR-HIF-1α. Thus, this axis might be responsible for the growth-stimulating effects of PGE2 on prostate epithelial cells, thereby contributing to prostate proliferative diseases associated with chronic inflammation. Since this PGT-dependent non-canonic intracrine mechanism of PGE2 action operates in both benign and malignant prostate epithelial cells, PGT inhibitors should be tested as a novel therapeutic modality to treat prostate proliferative disease.