[Laparoscopic cholecystectomy with common bile duct exploration in situs inversus totalis patient]. / Colecistectomía con exploración de vías biliares laparoscópica en paciente con situs inversus totalis.

We present the case of a 77-year-old male patient with a diagnosis of chronic calculous cholecystitis and choledocholithiasis, with a history of situs inversus totalis. Therefore, a laparoscopic cholecystectomy with common bile duct exploration were performed, using the "french mirror technique", with stone extraction. Patient evolved favorably. The aim of this study is to present this clinical case that is rarely reported in the world literature (only 9 cases). Its importance lies in the fact that it would be the first published clinical case report of a laparoscopic cholecystectomy and bile duct exploration with removal of the common bile duct stones in a patient with situs inversus totalis, performed in Peru.

Effect of 6-min Walk Test on pro-BNP Levels in Patients with Pulmonary Arterial Hypertension.

BACKGROUND: Plasma pro-BNP (brain natriuretic peptide) levels are often elevated in response to right ventricular (RV) volume and pressure overload, parameters potentially affected by exercise. Plasma pro-BNP levels change in association with long-term changes in pulmonary hemodynamics, thereby serving as a potential biomarker in pulmonary arterial hypertension (PAH). The 6-min Walk Test (6MWT) and pro-BNP level are often checked in a single office visit. There is no universal standard for measuring Pro-BNP levels relative to the timing of the 6MWT. Based on the studies in normal subjects indicating that pro-BNP levels changes after exercise, we hypothesized that the pro-BNP might rise after the 6MWT in PAH patients, potentially impacting clinical decisions. METHODS: Patients at our center with WHO Group 1 PAH on active therapy at a stable dose for 30 days or more were enrolled. After resting the patient for 30 min, blood was drawn for baseline pro-BNP and a 6MWT was performed. Pro-BNP levels were drawn immediately after the 6MWT and 1 and 2 h later. Pro-BNP was measured using a commercially available ELISA kit. The levels before exercise and after exercise were compared using student's paired t tests. RESULTS: There were 17 females and 3 male subjects. The mean age was 53 ± 11 years. Seven patients had systemic lupus erythematosus-related PAH, six had idiopathic PAH, three had scleroderma, three had portopulmonary hypertension, and one had HIV-related PAH. The mean PA pressure was 50 ± 15 mmHg with a mean pulmonary vascular resistance of 10 ± 4 Wood units. The majority of the patients were on multimodality PAH therapy, including parenteral prostacyclins. Mean 6MWT distance was 377 ± 140 m. In 14/20 patients, the pro-BNP level increased immediately after the 6MWT; in 12/20 patients, the pro-BNP level was elevated at 1 h post exercise. In the majority of the patients, the pro-BNP fell to baseline 2 h post 6MWT. CONCLUSION: There appears to be a trend of pro-BNP level increasing immediately after exercise and continuing to be elevated at 1 h. Pro-BNP levels then return to baseline at 2 h post 6MWT.

Dose-dependent effects of siRNA-mediated inhibition of SCAP on PCSK9, LDLR, and plasma lipids in mouse and rhesus monkey.

SREBP cleavage-activating protein (SCAP) is a key protein in the regulation of lipid metabolism and a potential target for treatment of dyslipidemia. SCAP is required for activation of the transcription factors SREBP-1 and -2. SREBPs regulate the expression of genes involved in fatty acid and cholesterol biosynthesis, and LDL-C clearance through the regulation of LDL receptor (LDLR) and PCSK9 expression. To further test the potential of SCAP as a novel target for treatment of dyslipidemia, we used siRNAs to inhibit hepatic SCAP expression and assess the effect on PCSK9, LDLR, and lipids in mice and rhesus monkeys. In mice, robust liver Scap mRNA knockdown (KD) was achieved, accompanied by dose-dependent reduction in SREBP-regulated gene expression, de novo lipogenesis, and plasma PCSK9 and lipids. In rhesus monkeys, over 90% SCAP mRNA KD was achieved resulting in approximately 75, 50, and 50% reduction of plasma PCSK9, TG, and LDL-C, respectively. Inhibition of SCAP function was demonstrated by reduced expression of SREBP-regulated genes and de novo lipogenesis. In conclusion, siRNA-mediated inhibition of SCAP resulted in a significant reduction in circulating PCSK9 and LDL-C in rodent and primate models supporting SCAP as a novel target for the treatment of dyslipidemia.

Riociguat in patients with sickle cell disease and hypertension or proteinuria (STERIO-SCD): a randomised, double-blind, placebo controlled, phase 1-2 trial.

BACKGROUND: Although nitric oxide based therapeutics have been shown in preclinical models to reduce vaso-occlusive events and improve cardiovascular function, a clinical trial of a phosphodiesterase 5 inhibitor increased rates of admission to hospital for pain. We aimed to examine if riociguat, a direct stimulator of the nitric oxide receptor soluble guanylate cyclase, causes similar increases in vaso-occlusive events. METHODS: This was a phase 1-2, randomised, double blind, placebo-controlled trial. Eligible patients were 18 years or older, had confirmed sickle cell disease documented by haemoglobin electrophoresis or HPLC fractionation (haemoglobin SS, SC, Sß-thalassemia, SD, or SO-Arab), and stage 1 hypertension or proteinuria. Participants were randomly assigned 1:1 to receive either riociguat or matching placebo via a web-based system to maintain allocation concealment. Both treatments were administered orally starting at 1·0 mg three times a day up to 2·5 mg three times a day (highest tolerated dose) for 12 weeks. Dose escalation by 0·5 mg was considered every 2 weeks if systolic blood pressure was greater than 95 mm Hg and the participant had no signs of hypotension; otherwise, the last dose was maintained. The primary outcome was the proportion of participants who had at least one adjudicated treatment-emergent serious adverse event. The analysis was performed by the intention-to-treat. This trial is registered with ClinicalTrials.gov (NCT02633397) and was completed. FINDINGS: Between April 11, 2017, and Dec 31, 2021, 165 participants were screened and consented to be enrolled into the study. Of these, 130 participants were randomly assigned to either riociguat (n=66) or placebo (n=64). The proportion of participants with at least one treatment-emergent serious adverse event was 22·7% (n=15) in the riociguat group and 31·3% (n=20) in the placebo group (difference -8·5% [90% CI -21·4 to 4·5]; p=0·19). A similar pattern emerged in other key safety outcomes, sickle cell related vaso-occlusive events (16·7 [n=11] vs 21·9% [n=14]; difference -5·2% [-17·2 to 6·5]; p=0·42), mean pain severity (3·18 vs 3·32; adjusted mean difference -0·14 [-0·70 to 0·42]; p=0·69), and pain interference (3·15 vs 3·12; 0·04 [-0·62 to 0·69]; p=0·93) at 12 weeks were similar between groups. Regarding the key clinical efficacy endpoints, participants taking riociguat had a blood pressure of -8·20 mm Hg (-10·48 to -5·91) compared with -1·24 (-3·58 to 1·10) in those taking placebo (-6·96 mm Hg (90% CI -10·22 to -3·69; p<0·001). INTERPRETATION: Riociguat was safe and had a significant haemodynamic effect on systemic blood pressure. The results of this study provide measures of effect and variability that will inform power calculations for future trials. FUNDING: Bayer Pharmaceuticals.

Quantifying apoprotein synthesis in rodents: coupling LC-MS/MS analyses with the administration of labeled water.

Stable isotope tracer studies of apoprotein flux in rodent models present difficulties as they require working with small volumes of plasma. We demonstrate the ability to measure apoprotein flux by administering either (2)H- or (18)O-labeled water to mice and then subjecting samples to LC-MS/MS analyses; we were able to simultaneously determine the labeling of several proteolytic peptides representing multiple apoproteins. Consistent with relative differences reported in the literature regarding apoprotein flux in humans, we found that the fractional synthetic rate of apoB is greater than apoA1 in mice. In addition, the method is suitable for quantifying acute changes in protein flux: we observed a stimulation of apoB production in mice following an intravenous injection of Intralipid and a decrease in apoB production in mice treated with an inhibitor of microsomal triglyceride transfer protein. In summary, we demonstrate a high-throughput method for studying apoprotein kinetics in rodent models. Although notable differences exist between lipoprotein profiles that are observed in rodents and humans, we expect that the method reported here has merit in studies of dyslipidemia as i) rodent models can be used to probe target engagement in cases where one aims to modulate apoprotein production and ii) the approach should be adaptable to studies in humans.

Discovery of pyrimidine carboxamides as potent and selective CCK1 receptor agonists.

A series of six-membered heterocycle carboxamides were synthesized and evaluated as cholecystokinin 1 receptor (CCK1R) agonists. A pyrimidine core proved to be the best heterocycle, and SAR studies resulted in the discovery of analog 5, a potent and structurally diverse CCK1R agonist.

Asociación entre sistemas venosos insuficientes y manifestaciones clínicas en enfermedad venosa crónica de miembros inferiores / Association between insufficient venous systems and clinical manifestations in chronic venous disease of the lower limbs

RESUMEN Introducción: La clasificación clínica, etiológica, anatómica y fisiopatológica (CEAP) estandariza las manifestaciones de la enfermedad venosa de miembros inferiores. Objetivo: Investigar la asociación entre los sistemas venosos insuficientes y la clasificación clínica del CEAP. Método: Se realizó una investigación tipo cuantitativa, transversal, con diseño analítico, correlacional. El muestreo es no probabilístico por conveniencia. El tamaño de muestra fue136 miembros inferiores de 71 pacientes. Se utilizó las pruebas estadísticas de Chi-cuadrado, Monte Carlo y Odd ratio (OR) con intervalos de confianza del 95 %, mediante regresión logística bivariada (p<0,05). Resultados: El 71,8 % fue femenino con edad media de 66,1. El sistema venoso insuficiente más frecuente fue el superficial: 61,7 %. El 100% de las venas safenas mayores (VSM) dilatadas tenían insuficiencia. La clase clínica CEAP más frecuente fue la C2: 44,9 %; el 35,1 % de C1 (telangiectasia) tenían un sistema venoso insuficiente; el 50 % de C2, insuficiencia de la VSM (p=0,227). Hubo una asociación entre la insuficiencia de los sistemas venosos superficial y profundo y la clasificación clínica del CEAP (p=<0,001). El sistema venoso profundo estuvo asociado a la enfermedad venosa crónica de miembros inferiores grave OR (6,04) con IC95 % (1,02-35,73) y p=0,047. Conclusiones: Se evidenció una asociación entre la insuficiencia de los sistemas venosos superficial y profundo con la clasificación clínica del CEAP. Un tercio de los miembros inferiores con C1 (telangiectasias) tenían un sistema venoso insuficiente.

ABSTRACT Introduction: The clinical, etiological, anatomical and pathophysiological classification (CEAP) standardizes the manifestations of lower limb venous disease. Objetive: To investigate the association between insufficient venous systems and the clinical classification of CEAP. Method: A quantitative, cross-sectional, analytical, correlational design was carried out. Non-probability sampling for convenience. Sample size was 136 lower limbs from 71 patients. Chi-square, Monte Carlo and Odd ratio (OR) statistical tests were used with 95% confidence intervals through bivariate logistic regression (p<0.05). Results: 71.8% were female, average age of 66.1. The most frequent insufficient venous system was the superficial one (61.7%). 100% of the dilated great saphenous veins (GSV) had insufficiency. The most frequent CEAP clinical class was C2: 44.9%); 35.1% of C1 (telangiectasia) had an insufficient venous system and 50% of C2 had GSV insufficiency (p=0.227). There was an association between insufficiency of the superficial and deep venous systems and the CEAP clinical classification (p=<0.001). The deep venous system was associated with severe chronic venous disease of the lower limbs OR (6.04) with 95% CI (1.02-35.73) and p=0.047. Conclusions: An association was evident between the insufficiency of the superficial and deep venous systems with the clinical classification of CEAP. One third of lower limbs with C1 (telangiectasias) had an insufficient venous system.

Impact of drug distribution into adipose on tissue function: The cholesteryl ester transfer protein (CETP) inhibitor anacetrapib as a test case.

Anacetrapib is an inhibitor of cholesteryl ester transfer protein (CETP) previously under development as a lipid-modifying agent that reduces LDL-cholesterol and increases HDL-cholesterol in hypercholesterolemic patients. Anacetrapib demonstrates a long terminal half-life and accumulates in adipose tissue, which contributes to a long residence time of anacetrapib. Given our previous report that anacetrapib distributes into the lipid droplet of adipose tissue, we sought to understand whether anacetrapib affected adipose function, using a diet-induced obese (DIO) mouse model. Following 20 weeks of treatment with anacetrapib (100 mg/kg/day), levels of the drug increased to approximately 0.6 mmol/L in white adipose tissue. This level of anacetrapib was not associated with any impairment in adipose functionality as evidenced by a lack of any reduction in biomarkers of adipose functionality (plasma adiponectin, leptin, insulin; adipose adiponectin, leptin mRNA). In DIO wild-type (WT) mice treated with anacetrapib for 2 weeks and then subjected to 30% food restriction during washout to induce weight loss (18%) and fat mass loss (7%), levels of anacetrapib in adipose and plasma were not different between food restricted and ad lib-fed mice. These data indicate that despite deposition and long-term residence of ~0.6 mmol/L levels of anacetrapib in adipose tissue, adipose tissue function appears to be unaffected in mice. In addition, these data also indicate that even with severe caloric restriction and acute loss of fat mass, anacetrapib does not appear to be mobilized from the fat depot, thereby solidifying the role of adipose as a long-term storage site of anacetrapib.

2-Substituted piperazine-derived imidazole carboxamides as potent and selective CCK1R agonists for the treatment of obesity.

The discovery and structure-activity relationship of 1,2-diarylimidazole piperazine carboxamides bearing polar side chains as potent and selective cholecystokinin 1 receptor (CCK1R) agonists are described. Optimization of this series resulted in the discovery of isopropyl carboxamide 40, a CCK1R agonist with sub-nanomolar functional and binding activity as well as excellent potency in a mouse overnight food intake reduction assay.

Discovery of imidazole carboxamides as potent and selective CCK1R agonists.

High-throughput screening revealed diaryl pyrazole 3 as a selective albeit modest cholecystokinin 1 receptor (CCK1R) agonist. SAR studies led to the discovery and optimization of a novel class of 1,2-diaryl imidazole carboxamides. Compound 44, which was profiled extensively, showed good in vivo mouse gallbladder emptying (mGBE) and lean mouse overnight food intake (ONFI) reduction activities.

Apendicolito libre postapendicectomía

El apendicolito libre postapendicectomía es una complicación rara que puede ocurrir como consecuencia de la salida del apendicolito del apéndice debido a una perforación previa o al no identificar el apendicolito. El fecalito generalmente se vuelve sintomático con el tiempo, debido a la formación de un absceso, obstrucción intestinal, trayecto fistuloso o inflamación del muñón apendicular. Se describen dos casos de apendicolito libre postapendicectomía. Caso 1: mujer de 23 años, que fue sometida a una apendicectomía un día antes, ingresó por emergencia por presentar dolor en el hipogastrio. En la tomografía computarizada (TC) se evidenció un apendicolito libre en la fosa iliaca derecha, y en la laparoscopía diagnóstica se observaron abscesos intraabdominales y un apendicolito libre en el muñón apendicular. Caso 2: varón de 77 años de edad, que fue operado de apendicitis aguda causada por apendicolitos, presentó distensión abdominal al sexto día del posoperatorio. La TC reveló obstrucción intestinal y la presencia de apendicolito libre a nivel de las interasas intestinales; en la reintervención quirúrgica se evidenció erosión del mesenterio por causa del apendicolito. En ambos casos, los pacientes evolucionaron favorablemente después de las reoperaciones. Se desconoce actualmente la incidencia del apendicolito libre después de una apendicectomía, pues se dispone de pocos datos en la literatura a nivel mundial. Por tal motivo es importante la presentación de estos casos, para poder ampliar la casuística y contribuir al conocimiento de los apendicolitos libres postapendicectomía. Asimismo, permite evidenciar sus complicaciones si no son removidos precozmente y cómo prevenirlos. Conclusión: los apendicolitos libres postapendicectomía deben extraerse precozmente para evitar complicaciones.

Dropped appendicolith following an appendectomy is a rare complication which may occur as a consequence of appendicolith expulsion from the appendix due to a previous perforation or failure to identify the appendicolith. A fecalith generally becomes symptomatic over time, as a result of abscess formation, intestinal obstruction, fistula tract or inflammation of the appendiceal stump. Two cases of dropped appendicolith following an appendectomy are described hereinbelow. Case 1: A 23-year-old female patient, who underwent an appendectomy the previous day, was admitted to the emergency room due to hypogastric pain. A computed tomography (CT) scan revealed a dropped appendicolith in the right iliac fossa, and a diagnostic laparoscopy showed intra-abdominal abscesses and a dropped appendicolith in the appendicular stump. Case 2: A 77-year-old male patient, who underwent surgery for acute appendicitis caused by appendicoliths, showed abdominal distension on the sixth postoperative day. The CT scan revealed intestinal obstruction and a dropped appendicolith at bowel loops. In the surgical reintervention, erosion of the mesentery caused by the appendicolith was evidenced. Both patients progressed after the reoperations. The incidence of dropped appendicolith following an appendectomy is currently unknown since few data are available in the literature worldwide. Therefore, it is important to present these cases to expand the casuistry, learn more about dropped appendicoliths following an appendectomy, demonstrate their complications if they are not removed early and show how to prevent them. In conclusion, dropped appendicoliths following an appendectomy must be removed early to avoid complications.

The Value of Bedside Echocardiogram in the Setting of Acute and Chronic Pulmonary Embolism.

Echocardiography is valuable in the evaluation and risk stratification of patients with acute and chronic pulmonary embolism (PE). Patients with acute PE who have echocardiographic evidence of right ventricular dilatation and/or right ventricular dysfunction have a worse prognosis. A minority of patients with acute PE can develop chronic thromboembolic pulmonary hypertension. Patients with chronic thromboembolic pulmonary hypertension often have echocardiographic evidence of elevated pulmonary arterial pressures, right ventricular hypertrophy, right ventricular dysfunction, and/or left ventricular impaired relaxation.

Colecistectomía con exploración de vías biliares laparoscópica en paciente con situs inversus totalis

Se presenta el caso de un paciente varón de 77 años con diagnóstico de colecistitis crónica calculosa y coledocolitiasis, con antecedente de situs inversus totalis. Se le realizó una colecistectomía con exploración de vías biliares laparoscópica, utilizando la "técnica francesa en espejo", con extracción de los cálculos. El paciente evolucionó favorablemente. El objetivo del presente trabajo es dar a conocer el caso clínico que es poco frecuente su reporte en la literatura mundial (solo 9 casos). Su importancia radica en que sería el primer reporte de caso clínico publicado de una colecistectomía y exploración de vías biliares laparoscópica con retiro del cálculo en colédoco en un paciente con situs inversus totalis, realizado en el Perú.

We present the case of a 77-year-old male patient with a diagnosis of chronic calculous cholecystitis and choledocholithiasis, with a history of situs inversus totalis. Therefore, a laparoscopic cholecystectomy with common bile duct exploration were performed, using the "french mirror technique", with stone extraction. Patient evolved favorably. The aim of this study is to present this clinical case that is rarely reported in the world literature (only 9 cases). Its importance lies in the fact that it would be the first published clinical case report of a laparoscopic cholecystectomy and bile duct exploration with removal of the common bile duct stones in a patient with situs inversus totalis, performed in Peru.

Relación entre el quiste hepático simple múltiple y la litiasis vesicular / Relationship between multiple simple hepatic cysts and vesicular lithiasis

Objetivo: Conocer si hay relación entre el quiste hepático simple múltiple y la litiasis vesicular. Materiales y métodos: Se realizó un estudio observacional, retrospectivo y transversal. Con un muestreo no probabilístico por conveniencia de tipo accidental. El tamaño de la muestra fue de 50 pacientes, con diagnóstico por imágenes de quiste hepático simple. Resultados: El grupo etario más frecuente fue entre 61-70 años (32 %). El género femenino fue el más frecuente con 92 %. Los quistes hepáticos simples tuvieron una media de 87,58 cc de volumen, con un mínimo de 0,16 cc y un máximo de 1255 cc. Un 48 % de los quistes fueron múltiples. El Coeficiente de correlación lineal de Pearson para las variables edad y volumen del quiste fue de 0,035. Se localizaron en un 55,4 % en el lóbulo derecho, siendo el segmento II el más frecuente (17,3 %). El 56 % de los quistes hepáticos simples se encontraron en hígados normales, seguido por un 36 % en hígados con esteatosis. El 83,78 % no presentaron litiasis vesicular. No se encontró dilatación de vías biliares en el 100 % de los casos. No hubo relación entre el quiste hepático simple múltiple y la presencia de litiasis 0,828 (p < 0,05). Conclusiones: No se evidenció una relación entre la presencia del quiste hepático simple múltiple y la litiasis vesicular

Objective: To know if there is a relationship between multiple simple hepatic cysts and vesicular lithiasis. Materials and methods: An observational, retrospective and cross-sectional study was performed with a non-probability convenience (accidental) sampling. The sample size consisted of 50 patients diagnosed with simple hepatic cysts by ultrasound. Results: The most frequent age group was between 61 and 70 years (32 %), and the female gender was the most common one (92 %). The simple hepatic cysts had a mean volume of 87.58 cc, with a minimum volume of 0.16 cc and a maximum of 1255 cc. Multiple cysts accounted for 48 % of all cysts. Pearson's linear correlation coefficient for variables age and cyst volume was 0.035. Fifty-five point four percent (55.4 %) of the cysts were located in the right lobe, mostly on segment II (17.3 %). Fifty-six percent (56 %) of simple hepatic cysts were found in normal livers, followed by 36 % in livers with steatosis. Eighty- three point seven eight percent (83.78 %) did not show vesicular lithiasis. No dilation of bile ducts was found in 100 % of the cases. There was no relationship between multiple simple hepatic cysts and lithiasis (0.828) (p < 0.05). Conclusions: There was no evidence of a relationship between multiple simple hepatic cysts and vesicular lithiasis

Safety and feasibility of obtaining wedged pulmonary artery samples and differential distribution of biomarkers in pulmonary hypertension.

This study aims to evaluate the safety and feasibility of obtaining wedged pulmonary artery (PA) samples and investigate the differential vascular beds' distribution of select inflammatory and cellular adhesion molecules that are implicated in pulmonary arterial hypertension (PAH) pathogenesis. This is a cross-sectional study of adult patients. Serum samples were simultaneously drawn from three different vascular sites during right heart catheterization as part of PAH evaluation: The superior vena cava, distal pulmonary artery prior to wedging, and distal pulmonary artery after (and distal to) wedging. The study group was comprised of patients with either PAH or chronic thromboembolic pulmonary hypertension (i.e., WHO/Dana Point Group 1 or 4). The internal control group included patients whose hemodynamics were not consistent with pulmonary hypertension. The external control group consisted of healthy volunteers who had a peripheral venous sample drawn. The mean age of the 25 study patients was 55 ± 14 years and mean BMI was 31 ± 10, and those of the 25 internal control patients were 49 ± 14 years and 26 ± 5, respectively. There were no complications resulting from obtaining wedged PA samples. Obtaining adequate wedged samples was successful in 80% of patients. More severe pulmonary hypertension was associated with lower success rates. There were no significant differences in the concentrations of the different biomarkers studied amongst the different vascular sites (n = 25 study patients). There was a nonsignificant trend of decreasing biomarkers concentrations from peripheral to wedged to un-wedged PA samples. Compared to the healthy external controls, sVCAM-1 levels were higher in the study group. Obtaining wedged PA blood samples is safe and feasible in adult patients with pulmonary hypertension. There were no differences in the distribution of markers between the vascular beds within patients.

The glucagon receptor is involved in mediating the body weight-lowering effects of oxyntomodulin.

Oxyntomodulin (OXM) is a peptide secreted postprandially from the L-cells of the gut that has a weak affinity for both the glucagon-like peptide-1 receptor (GLP1R) and the glucagon receptor (GCGR). Peripheral administration of OXM in humans and rodents causes weight loss reducing food intake and increasing energy expenditure. It has been suggested that OXM modulates energy intake solely through GLP1R agonism. Because glucagon decreases food intake in rodents and humans, we examined whether activation of the GCGR is involved in the body weight-lowering effects of OXM. We identified an equipotent GLP1R-selective peptide agonist that differs from OXM by only one residue (Q3→E, OXMQ3E), but has no significant GCGR agonist activity in vitro and ~100-fold reduced ability to stimulate liver glycogenolysis. Chronic treatment of obese mice with OXM and OXMQ3E demonstrated that OXM exhibits superior weight loss and lipid-lowering efficacy, and antihyperglycemic activity that is comparable to the corresponding GLP1R-selective agonist. Studies in Glp1r(-/-) mice and coadministration of OXM and a GCGR antagonist revealed that the antiobesity effect of OXM requires activation of both GLP1R and GCGR. Our data provide new insight into the mechanism of action of OXM and suggest that activation of GCGR is involved in the body weight-lowering action of OXM.

Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms.

Short-chain fatty acids (SCFAs), primarily acetate, propionate, and butyrate, are metabolites formed by gut microbiota from complex dietary carbohydrates. Butyrate and acetate were reported to protect against diet-induced obesity without causing hypophagia, while propionate was shown to reduce food intake. However, the underlying mechanisms for these effects are unclear. It was suggested that SCFAs may regulate gut hormones via their endogenous receptors Free fatty acid receptors 2 (FFAR2) and 3 (FFAR3), but direct evidence is lacking. We examined the effects of SCFA administration in mice, and show that butyrate, propionate, and acetate all protected against diet-induced obesity and insulin resistance. Butyrate and propionate, but not acetate, induce gut hormones and reduce food intake. As FFAR3 is the common receptor activated by butyrate and propionate, we examined these effects in FFAR3-deficient mice. The effects of butyrate and propionate on body weight and food intake are independent of FFAR3. In addition, FFAR3 plays a minor role in butyrate stimulation of Glucagon-like peptide-1, and is not required for butyrate- and propionate-dependent induction of Glucose-dependent insulinotropic peptide. Finally, FFAR3-deficient mice show normal body weight and glucose homeostasis. Stimulation of gut hormones and food intake inhibition by butyrate and propionate may represent a novel mechanism by which gut microbiota regulates host metabolism. These effects are largely intact in FFAR3-deficient mice, indicating additional mediators are required for these beneficial effects.

Thermodilution and Fick cardiac outputs differ: impact on pulmonary hypertension evaluation.

BACKGROUND: The relationship between thermodilution and indirect Fick cardiac output determination methods has not been well described. OBJECTIVE: To describe the relationship between these two cardiac output determination methods in patients evaluated for pulmonary hypertension and to highlight potential clinical implications. METHODS: A retrospective review of charts of all adult patients who underwent a right heart catheterization (RHC) between January 1, 2007 and November 10, 2010, and participated in the pulmonary hypertension program of the pulmonary division at an academic institution was conducted. For validation, the charts of all patients who underwent RHC during the same period within the cardiology division were reviewed. RESULTS: A total of 198 patients underwent 213 RHCs, 79 (40%) of whom had pulmonary arterial hypertension, were included. Forty-three per cent of patients had >20% difference between thermodilution and Fick. The average difference (thermodilution - Fick ±SD) was -0.39±2.03 L/min (n=213; P=0.006). There was no significant difference in bias or variability between thermodilution and Fick among patients with tricuspid regurgitant jet velocity (TRJ) of <3 m/s versus those with TRJ >3 m/s (-0.41±2.10 L/min versus -0.36±1.93 L/min, respectively; P=0.87). In a multivariable analysis, the thermodilution-Fick difference increased with age (P=0.001). DISCUSSION: The presence of such discrepancy in 36% of patients evaluated for heart failure and/or heart transplant validated the results. In total, 37% of the 1315 procedures (213 performed by pulmonologists and 1102 performed by cardiologists) had a difference of >20% between thermodilution and Fick. CONCLUSION: Significant discrepancy exists between thermodilution and indirect Fick methods. This discrepancy potentially impacts pulmonary arterial hypertension prognostication and diagnosis, and is independent of TRJ.

Variación estacional de la apendicitis aguda / Seasonal variation of acute appendicitis

Objetivo: conocer si aumentaron los casos de apendicitis agudas atendidos en las estaciones de verano y primaveradurante 2005-2014 en el Hospital de Emergencias Grau de Lima.Material y Métodos: Estudio observacional, transversal y retrospectivo. Muestreo no probabilístico, tamaño de la muestra de 6,917 operados por apendicitis aguda entre los años 2005 – 2014 en el Hospital de Emergencias Grau de Lima. Se utilizóuna ficha de recolección de datos de historias clínicas elaborándose una base de datos. Se aplicó test de análisis devarianzas de apendicetomías y correlación entre temperaturas y número de apendicitis.Resultados: La edad mínima y máxima fue de 14 y 93 años. El 52.6% (3,639) de los casos fueron de sexo femenino. En enerose realizó el mayor número mensual de apendicectomías, con 648, 634 en marzo y 616 en febrero. El Análisis de Varianzaobtuvo un valor p de 0.24, no hubo diferencias significativas entre las estaciones del año. Hubo correlación parcial entretemperatura mensual y número de apendicectomías. Conclusiones: Existe un patrón estacional con aumento de la frecuencia de la apendicitis aguda en verano y primavera, yun descenso en otoño e invierno. El aumento de casos de apendicitis aguda es del 3.32% y 3.75% en verano con respecto aotoño e invierno, sin diferencia estadística significativa entre las cuatro estaciones del año.

Objective: to know if there was an increase in acute appendicitis cases treated in summer and spring among 2005-2014 in Grau Emergency Hospital in Lima. Material and Methods: Observational, cross-sectional and retrospective study. Non-probabilistic sampling, sample size of 6,917 operated on for acute appendicitis during 2005-2014 in the Grau Emergency Hospital in Lima. We used a form for data collection from medical records to develop a database. Analysis of variance test was applied to appendectomies numbers and correlation between temperature and number of appendicitis. Results: The minimum and maximum age was 14 and 93 years old. 52.6% (3,639) of the cases were female. January was the highest monthly number of appendectomies, with 648; 634 in March and 616 in February. The analysis of variance obtained a p value = 0.24, there was no significant difference among the seasons of the year. There was a partial correlation between monthly temperature and number of appendectomies. Conclusions: There is a seasonal pattern with increase in the frequency of acute appendicitis during summer and spring, and a decline in autumn and winter. The increase in cases of acute appendicitis is 3.32% and 3.75% in summer compared to autumn and winter, with no significant statistical difference among the four seasons of the year.

Effects of peripherally administered neuromedin U on energy and glucose homeostasis.

Neuromedin U (NMU) is a highly conserved peptide reported to modulate energy homeostasis. Pharmacological studies have shown that centrally administered NMU inhibits food intake, reduces body weight, and increases energy expenditure. NMU-deficient mice develop obesity, whereas transgenic mice overexpressing NMU become lean and hypophagic. Two high-affinity NMU receptors, NMUR1 and NMUR2, have been identified. NMUR1 is found primarily in the periphery and NMUR2 primarily in the brain, where it mediates the anorectic effects of centrally administered NMU. Given the broad expression pattern of NMU, we evaluated whether peripheral administration of NMU has effects on energy homeostasis. We observed that acute and chronic peripheral administration of NMU in rodents dose-dependently reduced food intake and body weight and that these effects required NMUR1. The anorectic effects of NMU appeared to be partly mediated by vagal afferents. NMU treatment also increased core body temperature and metabolic rate in mice, suggesting that peripheral NMU modulates energy expenditure. Additionally, peripheral administration of NMU significantly improved glucose excursion. Collectively, these data suggest that NMU functions as a peripheral regulator of energy and glucose homeostasis and the development of NMUR1 agonists may be an effective treatment for diabetes and obesity.