Defective glucose and lipid metabolism in rheumatoid arthritis is determined by chronic inflammation in metabolic tissues.

BACKGROUND: Rheumatoid arthritis (RA) patients are at increased risk of insulin resistance (IR); however, the specific mechanisms mediating this association are currently unknown. OBJECTIVE: To investigate whether the inflammatory activity associated with RA accounts for the observed defective glucose metabolism and lipid metabolism in these patients. METHODS: We followed two main strategies: (i) extensive metabolic profiling of a RA cohort of 100 patients and 50 healthy control subjects and (ii) mechanistic studies carried out in both a collagen-induced arthritis mouse model and 3T3-L1 adipocytes treated with conditioned serum from RA patients. RESULTS: Following the exclusion of obese and diabetic subjects, data from RA patients demonstrated a strong link between the degree of systemic inflammation and the development of IR. These results were strengthened by the observation that induction of arthritis in mice resulted in a global inflammatory state characterized by defective carbohydrate and lipid metabolism in different tissues. Adipose tissue was most susceptible to the RA-induced metabolic alterations. These metabolic effects were confirmed in adipocytes treated with serum from RA patients. CONCLUSIONS: Our results show that the metabolic disturbances associated with RA depend on the degree of inflammation and identify inflammation of adipose tissue as the initial target leading to IR and the associated molecular disorders of carbohydrate and lipid homeostasis. Thus, we anticipate that therapeutic strategies based on tighter control of inflammation and flares could provide promising approaches to normalize and/or prevent metabolic alterations associated with RA.

Dihydroceramide desaturase 1, the gatekeeper of ceramide induced lipotoxicity.

The pathogenic relevance of sphingolipid metabolism is increasingly being recognised. Here we elaborate on a new player within the sphingolipid field: the degs1 enzyme, a recently discovered enzyme that catalyses the final step in the de novo biosynthesis of ceramides controlling the step from dihydroceramides to ceramides. Here, we describe its function and dysregulation by factors such as oxidative stress, hypoxia and inflammation and provide evidence indicating that dihydroceramides constitute a biologically active molecule from the sphingolipid family with certain differential characteristics with respect to its delta-4 unsaturated counterparts, the ceramides. Finally we present pathophysiological scenarios characterised by specific increases in dihydroceramide that challenge the concept that "all ceramides species are the same". This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics.

Extracellular vesicles released by steatotic hepatocytes alter adipocyte metabolism.

The composition of extracellular vesicles (EVs) is altered in many pathological conditions, and their molecular content provides essential information on features of parent cells and mechanisms of crosstalk between cells and organs. Metabolic Syndrome (MetS) is a cluster of clinical manifestations including obesity, insulin resistance, dyslipidemia and hypertension that increases the risk of cardiovascular disease and type 2 diabetes mellitus. Here, we investigated the crosstalk between liver and adipocytes by characterizing EVs secreted by primary hepatocytes isolated from Zucker rat model, and studied the effect they have on 3T3-L1 adipocytes. We found that steatotic hepatocytes secrete EVs with significantly reduced exosomal markers in comparison with their lean counterpart. Moreover, proteomic analysis revealed that those EVs reflect the metabolic state of the parent cell in that the majority of proteins upregulated relate to fat metabolism, fatty acid synthesis, glycolysis, and pentose phosphate pathway. In addition, hepatocytes-secreted EVs influenced lipolysis and insulin sensitivity in recipient 3T3-L1 adipocytes. Untargeted metabolomic analysis detected alterations in different adipocyte metabolic pathways in cells treated with hepatic EVs. In summary, our work showed that steatosis has a significant impact in the amount and composition of EVs secreted by hepatocytes. Moreover, our data point to the involvement of hepatic-EVs in the development of pathologies associated with MetS.

Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance.

Resulting from impaired collagen turnover, fibrosis is a hallmark of adipose tissue (AT) dysfunction and obesity-associated insulin resistance (IR). Prolidase, also known as peptidase D (PEPD), plays a vital role in collagen turnover by degrading proline-containing dipeptides but its specific functional relevance in AT is unknown. Here we show that in human and mouse obesity, PEPD expression and activity decrease in AT, and PEPD is released into the systemic circulation, which promotes fibrosis and AT IR. Loss of the enzymatic function of PEPD by genetic ablation or pharmacological inhibition causes AT fibrosis in mice. In addition to its intracellular enzymatic role, secreted extracellular PEPD protein enhances macrophage and adipocyte fibro-inflammatory responses via EGFR signalling, thereby promoting AT fibrosis and IR. We further show that decreased prolidase activity is coupled with increased systemic levels of PEPD that act as a pathogenic trigger of AT fibrosis and IR. Thus, PEPD produced by macrophages might serve as a biomarker of AT fibro-inflammation and could represent a therapeutic target for AT fibrosis and obesity-associated IR and type 2 diabetes.

Application, verification and correction from an elaborate checklist with some of the recommendations («do and do not do¼) of the SEMICYUC working groups. / Aplicación, comprobación y corrección a partir de un checklist elaborado con algunas de las recomendaciones («hacer y no hacer¼) de los grupos de trabajo de la SEMICYUC.

OBJECTIVE: Based on some of the recommendations of the SEMICYUC working groups, we developed a checklist and applied it in 2 periods, analyzing their behavior as a tool for improving safety. DESIGN: A comparative pre- and post-intervention longitudinal study was carried out. SETTING: The Intensive Care Unit (ICU) of a 400-bed university hospital. PATIENTS: Random cases series in 2 periods separated by 6 months. INTERVENTIONS: We developed a checklist with 24 selected indicators that were randomly applied to 50 patients. Verification was conducted by a professional not related to care (prompter). We analyzed the results and compliance index and carried out corrective measures with training. With 6 months of preparation, we again applied the random checklist to 50 patients (post-intervention period) and compared the compliance indexes between the two timepoints. RESULTS: There were no differences in demographic characteristics or evolution between the periods. The compliance index at baseline was 0.86±0.12 versus 0.91±0.52 in the post-intervention period (P=.023). An acceptable compliance index was obtained with the 24 indicators, though at baseline the compliance index was<0.85 for 5 recommendations. These detected non-compliances were worked upon through training in the second phase of the study. The post-intervention checklist evidenced improvement in compliance with the recommendations. CONCLUSIONS: The checklist used to assess compliance with a selection of recommendations of the SEMICYUC applied and moderated by a prompter was seen to be a useful instrument allowing us to identify points for improvement in the management of Intensive Care Unit patients, increasing the quality and safety of care.

Human case of swine influenza A (H1N1), Aragon, Spain, November 2008.

A human case of swine influenza A (H1N1) in a 50-year-old woman from a village near Teruel (Aragon, in the north-east of Spain), with a population of about 200 inhabitants, has been reported in November 2008.

Frailty in patients over 65 years of age admitted to Intensive Care Units (FRAIL-ICU). / Fragilidad en pacientes mayores de 65 años ingresados en cuidados intensivos (FRAIL-ICU).

OBJECTIVE: To estimate the prevalence of frailty in patients admitted to the Intensive Care Unit (ICU) and its impact upon ICU mortality at 1 and 6 months. DESIGN: A prospective observational cohort study was carried out. SETTING: Spanish ICU. INTERVENTION: None. PATIENTS AND METHODS: Patients≥65 years of age admitted to the ICU for>24hours. Variables were registered upon admission, and functional status was assessed by telephone calls 1 and 6 months after discharge from the ICU. MAIN STUDY VARIABLES: Age, gender, frailty (FRAIL scale), functional status (Barthel, Lawton, Clinical Dementia Rating and NUTRIC score), days of mechanical ventilation (MV), functional score (APACHE II and SOFA), ICU mortality, and mortality 1 and 6 months after ICU discharge. RESULTS: A total of 132 patients were evaluated, of which 46 were frail (34.9%). Age of the frail versus non-frail patients: 78.8±7.2 and 78.6±6.4 years, respectively (P=.43); male gender: 43.8% versus 56.3% (P=.10); SOFA score: 4.7±2.9 versus 4.6±2.9 (P=.75); MV: 33.3% versus 66.7% (P=.75); days of MV: 5.6±15 versus 4.3±8.1 (P=.57); ICU mortality 13% versus 6% (P = .14), mortality at 1 month 24% versus 8% (P = .01), mortality 6 months 32% versus 15% (P = .03). Frailty is associated with mortality at one month (OR = 3.5, P <.05, 95% CI (1.22-10.03) and at 6 months after discharge from the ICU (OR = 2.62, P <.05, 95% CI (1.04-6.56). CONCLUSIONS: Frailty was present in 35% of the patients admitted to the ICU, and was associated with mortality.

[Efficient and rational laboratory diagnostics in otolaryngology]. / Rationelle und rationale Laboratoriumsdiagnostik in der Hals-Nasen-Ohren-Heilkunde.

This article describes the value of laboratory diagnostic procedures in the diagnostic arsenal of otolaryngologists. The rational and therefore the rationale of the application of laboratory medical methods are critically evaluated. In the era of diagnosis-related groups a high value is placed on a rational laboratory diagnostic, in the sense of a cost-oriented medicine, so that the laboratory diagnostic procedure is always carried out in stages, just as in other diagnostic procedures. The possibilities of clinical chemistry, separated into the theme blocks "clinical chemical basic diagnostics", "haematological parameters", "coagulation investigations" and "immunological diagnostics" are demonstrated based on examples. These are aimed at the needs of otolaryngologists, in that the emphasis in each theme block is centred on the indications and evaluation of the individual laboratory investigation.

Relationship between intra-abdominal hypertension, outcome and the revised Atlanta and determinant-based classifications in acute pancreatitis.

BACKGROUND: The aim of this study was to analyse the relationship between intra-abdominal hypertension (IAH) and severity of acute pancreatitis (AP) measured by the revised Atlanta classification (RAC) and determinant-based classification (DBC). Secondary objectives were to assess IAH as a predictor of morbidity and mortality in the ICU. METHODS: This prospective international observational study included patients admitted to the ICU with AP and at least one organ failure. Information was collected on demographics, severity scores at admission using RAC and DBC, organ failure, mechanical ventilation, continuous renal replacement therapy (CRRT), surgery and mortality. Maximum intra-abdominal pressure (IAP) during ICU stay was used for analysis. RESULTS: Some 374 patients were included. The hospital mortality rate was 28·9 per cent. IAP was measured in 301 patients (80·5 per cent), of whom 274 (91·0 per cent) had IAH and 103 (34·2 per cent) acute compartment syndrome. A higher IAH grade was more likely in patients with severe AP (42 per cent for grade I versus 84 per cent for grade IV) and acute critical pancreatitis (9 versus 25 per cent; P = 0·001). Compared with grade I IAH, patients with grade IV had more infected necrosis (16 versus 28 per cent; P = 0·005), need for surgery (27 versus 50 per cent; P = 0·006), mechanical ventilation (53 versus 84 per cent; P = 0·007) and requirement for CRRT (22 versus 66 per cent; P < 0·001). IAH predicted shock (area under receiver operating characteristic (ROC) curve (AUC) 0·79, 95 per cent c.i. 0·73 to 0·84), respiratory failure (AUC 0·82, 0·77 to 0·87), renal failure (AUC 0·93, 0·89 to 0·96) and mortality (AUC 0·89, 0·86 to 0·93). CONCLUSION: IAH was associated with severity of AP classified according to both RAC and DBC systems. IAP grade can predict outcome of AP during ICU stay.

Sphingolipids and glycerophospholipids - The "ying and yang" of lipotoxicity in metabolic diseases.

Sphingolipids in general and ceramides in particular, contribute to pathophysiological mechanisms by modifying signalling and metabolic pathways. Here, we present the available evidence for a bidirectional homeostatic crosstalk between sphingolipids and glycerophospholipids, whose dysregulation contributes to lipotoxicity induced metabolic stress. The initial evidence for this crosstalk originates from simulated models designed to investigate the biophysical properties of sphingolipids in plasma membrane representations. In this review, we reinterpret some of the original findings and conceptualise them as a sort of "ying/yang" interaction model of opposed/complementary forces, which is consistent with the current knowledge of lipid homeostasis and pathophysiology. We also propose that the dysregulation of the balance between sphingolipids and glycerophospholipids results in a lipotoxic insult relevant in the pathophysiology of common metabolic diseases, typically characterised by their increased ceramide/sphingosine pools.

Neumomediastino en pacientes con COVID-19 ingresados en UCI: serie de casos y revisión de la literatura / [Pneumomediastinum in patients with COVID-19 admitted to the ICU: case series and review of the literature]

Tras declaración de pandemia en febrero de 2020, se observa un aumento de casos de neumonías bilaterales con insuficiencia respiratoria grave, complicadas a su vez con neumomediastino. Se describe una serie de cuatro pacientes con neumomediastino asociado a distress respiratorio por neumonía por SARS-CoV-2 ingresados en cuidados intensivos del Hospital Universitario Rey Juan Carlos entre diciembre 2020 y enero 2021. En su mayoría son hombres de mediana edad, sin patología pulmonar previa, no fumadores, que han necesitado ventilación mecánica. El diagnóstico de neumomediastino se ha realizado mediante tomografía computarizada y el tratamiento ha sido conservador, con resolución total en todos los casos. Aunque esta complicación es un indicador de destrucción pulmonar y condiciona cambios en el manejo de la ventilación mecánica, no parece estar directamente relacionada con peor pronóstico o aumento de la mortalidad. (AU)

After the declaration of a pandemic in February 2020, an increase in cases of bilateral pneumonia with severe respiratory failure, in turn complicated by pneumomediastinum, has been observed. A series of four patients with pneumomediastinum associated with respiratory distress due to SARS-CoV-2 pneumonia admitted to intensive care at the Rey Juan Carlos University Hospital between December 2020 and January 2021 is described. Most of them are middle-aged men, without previous pulmonary pathology, non- smokers, who have required mechanical ventilation. The diagnosis of pneumomediastinum has been made by computed tomography and the treatment has been conservative, with complete resolution in all cases. Although this complication is an indicator of lung destruction and determines changes in the management of mechanical ventilation, it does not seem to be directly related to a worse prognosis or increased mortality. (AU)

Sex steroid receptor expression in different adipose depots is modified during midpregnancy.

Sex hormone signalling is key in the understanding of adipose tissue metabolism during pregnancy. Sex hormones play an important role in adipose tissue metabolism by activating specific receptors that alter several steps of lipolysis and lipogenesis. We analyze steroid receptor mRNA levels in different rat adipose depots and mammary fat pad, as well as the sex hormone profile during midpregnancy, coinciding with the placentation process. Thus, progesterone and estradiol plasma levels were increased as well as testosterone levels. This hormonal profile was accompanied by low glucose to insulin ratio. PR-B, ERalpha and AR receptor densities during midpregnancy were dependent on adipose depot location. In mammary fat pad, the mRNA levels of sex hormone receptors were correlated with the growth of the depot. These results demonstrate that sex steroid hormone receptor mRNA expression during midpregnancy is tissue-specific. Our results agree with the idea that the increased estrogenic and androgenic signalling could be addressed to reducing the lipogenic state in early pregnancy exerted mainly by progesterone and to prepare adipose tissue for the beginning of the catabolic phase in late pregnancy in a depot-specific manner.

Aplicación, comprobación y corrección a partir de un checklist elaborado con algunas de las recomendaciones («hacer y no hacer») de los grupos de trabajo de la SEMICYUC / Application, verification and correction from an elaborate checklist with some of the recommendations («do and do not do») of the SEMICYUC working groups

Objetivo Con algunas de las recomendaciones de los grupos de trabajo de la SEMICYUC elaboramos un checklist y lo aplicamos en 2 periodos. Analizamos su comportamiento como herramienta de mejora en la seguridad. Diseño Estudio longitudinal, comparativo pre- y postintervención. Ámbito Unidad de Cuidados Intensivos de un hospital universitario de 400 camas. Pacientes Serie de casos aleatorios en 2 periodos separados por 6 meses. Intervenciones Elaboramos un checklist con 24 indicadores seleccionados que aplicamos de forma aleatoria a 50 pacientes. La verificación fue conducida por un profesional no relacionado con el cuidado (prompter). Analizamos los resultados y el índice de cumplimiento y realizamos medidas correctoras con formación. Con 6 meses de preparación, aplicamos de nuevo el checklist aleatorio a 50 pacientes (periodo postintervención) y comparamos el índice de cumplimiento entre ambos. Resultados No observamos diferencias en características demográficas ni en la evolución entre periodos. El índice de cumplimiento en el periodo basal fue de 0,86±0,12 y en el periodo de postintervención de 0,91±0,52; p=0,023. Obtuvimos un índice de cumplimiento aceptable de los 24 indicadores, pero en el basal en 5 recomendaciones el índice de cumplimiento fue menor a 0,85. Estos incumplimientos detectados se trabajaron formativamente en la segunda fase. En el checklist postintervención observamos una mejoría en el cumplimiento de las recomendaciones. Conclusiones El checklist utilizado para comprobar el cumplimiento de una selección de recomendaciones de la SEMICYUC aplicado y moderado por un prompter fue un instrumento útil que permitió establecer puntos de mejora en la atención de los pacientes de una unidad de cuidados intensivos, aumentando la calidad y la seguridad. (AU)

Objective Based on some of the recommendations of the SEMICYUC working groups, we developed a checklist and applied it in 2 periods, analyzing their behavior as a tool for improving safety. Design A comparative pre- and post-intervention longitudinal study was carried out. Setting The Intensive Care Unit (ICU) of a 400-bed university hospital. Patients Random cases series in 2 periods separated by 6 months. Interventions We developed a checklist with 24 selected indicators that were randomly applied to 50 patients. Verification was conducted by a professional not related to care (prompter). We analyzed the results and compliance index and carried out corrective measures with training. With 6 months of preparation, we again applied the random checklist to 50 patients (post-intervention period) and compared the compliance indexes between the two timepoints. Results There were no differences in demographic characteristics or evolution between the periods. The compliance index at baseline was 0.86±0.12 versus 0.91±0.52 in the post-intervention period (P=.023). An acceptable compliance index was obtained with the 24 indicators, though at baseline the compliance index was<0.85 for 5 recommendations. These detected non-compliances were worked upon through training in the second phase of the study. The post-intervention checklist evidenced improvement in compliance with the recommendations. Conclusions The checklist used to assess compliance with a selection of recommendations of the SEMICYUC applied and moderated by a prompter was seen to be a useful instrument allowing us to identify points for improvement in the management of Intensive Care Unit patients, increasing the quality and safety of care. (AU)

Fragilidad en pacientes mayores de 65 años ingresados en cuidados intensivos (FRAIL-ICU) / Frailty in patients over 65 years of age admitted to Intensive Care Units (FRAIL-ICU)

Objetivo: Estimar la prevalencia de fragilidad en pacientes ingresados en cuidados intensivos (UCI) y su impacto sobre la mortalidad intra UCI, al mes y a los 6 meses. Diseño: Estudio de cohorte prospectiva. Ámbito: UCI polivalentes españolas. Intervención: Ninguna. Pacientes y métodos: Pacientes≥65 años ingresados en UCI>24horas. Se recogieron las variables al ingreso y la situación basal por teléfono al mes y a los 6 meses del alta de UCI. Variables de interés principal: Edad, sexo, fragilidad (escala FRAIL), situación basal (Barthel, Lawton, Clinical Dementia Rating y Nutric Score), días de ventilación mecánica (VM), escalas de gravedad (APACHE II y SOFA), mortalidad UCI, al mes y a los 6 meses del alta. Resultados: Ciento treinta y dos pacientes, 46 frágiles (34,9%). Pacientes frágiles vs. no frágiles: 78,8±7,2 vs. 78,6±6,4 años (p=0,43), varones 43,8% vs. 56,3% (p=0,10), SOFA 4,7±2,9 vs. 4,6±2,9 (p=0,75), VM 33.3% vs. 66,7% (p=0,75), días de VM 5,6±15 vs. 4,3±8,1 (p=0,57), mortalidad UCI 13% versus 6% (p = 0,14), mortalidad al mes 24% versus 8% (p = 0,01), mortalidad 6 meses 32% versus 15% (p = 0,03). La fragilidad se asocia con la mortalidad al mes (OR = 3,5; p <0,05, IC del 95% (1,22-10,03) y a los 6 meses del alta de UCI (OR = 2,62; p <0,05, IC del 95% (1,04-6,56). Conclusiones: La fragilidad está presente en el 35% de los pacientes ingresados en UCI, asociándose a la mortalidad

Objective: To estimate the prevalence of frailty in patients admitted to the Intensive Care Unit (ICU) and its impact upon ICU mortality at 1 and 6 months. Design: A prospective observational cohort study was carried out. Setting: Spanish ICU. Intervention: None. Patients and methods: Patients≥65 years of age admitted to the ICU for>24hours. Variables were registered upon admission, and functional status was assessed by telephone calls 1 and 6 months after discharge from the ICU. Main study variables: Age, gender, frailty (FRAIL scale), functional status (Barthel, Lawton, Clinical Dementia Rating and NUTRIC score), days of mechanical ventilation (MV), functional score (APACHE II and SOFA), ICU mortality, and mortality 1 and 6 months after ICU discharge. Results: A total of 132 patients were evaluated, of which 46 were frail (34.9%). Age of the frail versus non-frail patients: 78.8±7.2 and 78.6±6.4 years, respectively (P=.43); male gender: 43.8% versus 56.3% (P=.10); SOFA score: 4.7±2.9 versus 4.6±2.9 (P=.75); MV: 33.3% versus 66.7% (P=.75); days of MV: 5.6±15 versus 4.3±8.1 (P=.57); ICU mortality 13% versus 6% (P = .14), mortality at 1 month 24% versus 8% (P = .01), mortality 6 months 32% versus 15% (P = .03). Frailty is associated with mortality at one month (OR = 3.5, P <.05, 95% CI (1.22-10.03) and at 6 months after discharge from the ICU (OR = 2.62, P <.05, 95% CI (1.04-6.56). Conclusions: Frailty was present in 35% of the patients admitted to the ICU, and was associated with mortality

Leptospirosis: diagnóstico diferencial de fiebre en urgencias / Leptospirosis: differential diagnosis of fever in Emergency Departments

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