Semaglutide Improves Liver Steatosis and De Novo Lipogenesis Markers in Obese and Type-2-Diabetic Mice with Metabolic-Dysfunction-Associated Steatotic Liver Disease.

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a prevalent clinical condition associated with elevated morbidity and mortality rates. Patients with MASLD treated with semaglutide, a glucagon-like peptide-1 receptor agonist, demonstrate improvement in terms of liver damage. However, the mechanisms underlaying this beneficial effect are not yet fully elucidated. We investigated the efficacy of semaglutide in halting MASLD progression using a genetic mouse model of diabesity. Leptin-receptor-deficient mice with obesity and diabetes (BKS db/db) were either untreated or administered with semaglutide for 11 weeks. Changes in food and water intake, body weight and glycemia were monitored throughout the study. Body fat composition was assessed by dual-energy X-ray absorptiometry. Upon sacrifice, serum biochemical parameters, liver morphology, lipidomic profile and liver-lipid-related pathways were evaluated. The semaglutide-treated mice exhibited lower levels of glycemia, body weight, serum markers of liver dysfunction and total and percentage of fat mass compared to untreated db/db mice without a significant reduction in food intake. Histologically, semaglutide reduced hepatic steatosis, hepatocellular ballooning and intrahepatic triglycerides. Furthermore, the treatment ameliorated the hepatic expression of de novo lipogenesis markers and modified lipid composition by increasing the amount of polyunsaturated fatty acids. The administration of semaglutide to leptin-receptor-deficient, hyperphagic and diabetic mice resulted in the amelioration of MASLD, likely independently of daily caloric intake, suggesting a direct effect of semaglutide on the liver through modulation of the lipid profile.

An Igor Pro 8.01 Procedure to Analyze Pulse Oximetry during Acute Hypoxia Test in Aircrews.

The recognition of hypoxia symptoms is a critical part of physiological training in military aviation. Acute exposure protocols have been designed in hypobaric chambers to train aircrews to recognize hypoxia and quickly take corrective actions. The goal of the acute hypoxia test is to know the time of useful consciousness and the minimal arterial oxygen saturation tolerated. Currently, there is no computer system specifically designed to analyze the physiological variables obtained during the test. This paper reports the development and analytical capabilities of a computational tool specially designed for these purposes. The procedure was designed using the Igor Pro 8.01 language, which processes oxygen saturation and heart rate signals. To accomplish this, three functional boards are displayed. The first allows the loading and processing of the data. The second generates graphs that allow for a rapid visual examination to determine the validity of individual records and calculate slopes on selected segments of the recorded signal. Finally, the third can apply filters to generate data groups for analysis. In addition, this tool makes it possible to propose new study variables that are derived from the raw signals and can be applied simultaneously to large data sets. The program can generate graphs accompanied by basic statistical parameters and heat maps that facilitate data visualization. Moreover, there is a possibility of adding other signals during the test, such as the oxygenation level in vital organs, electrocardiogram, or electroencephalogram, which illustrates the test's excellent potential for application in aerospace medicine and for helping us develop a better understanding of complex physiological phenomena.

The Synthetic Flavonoid Hidrosmin Improves Endothelial Dysfunction and Atherosclerotic Lesions in Diabetic Mice.

In diabetes, chronic hyperglycemia, dyslipidemia, inflammation and oxidative stress contribute to the progression of macro/microvascular complications. Recently, benefits of the use of flavonoids in these conditions have been established. This study investigates, in two different mouse models of diabetes, the vasculoprotective effects of the synthetic flavonoid hidrosmin on endothelial dysfunction and atherogenesis. In a type 2 diabetes model of leptin-receptor-deficient (db/db) mice, orally administered hidrosmin (600 mg/kg/day) for 16 weeks markedly improved vascular function in aorta and mesenteric arteries without affecting vascular structural properties, as assessed by wire and pressure myography. In streptozotocin-induced type 1 diabetic apolipoprotein E-deficient mice, hidrosmin treatment for 7 weeks reduced atherosclerotic plaque size and lipid content; increased markers of plaque stability; and decreased markers of inflammation, senescence and oxidative stress in aorta. Hidrosmin showed cardiovascular safety, as neither functional nor structural abnormalities were noted in diabetic hearts. Ex vivo, hidrosmin induced vascular relaxation that was blocked by nitric oxide synthase (NOS) inhibition. In vitro, hidrosmin stimulated endothelial NOS activity and NO production and downregulated hyperglycemia-induced inflammatory and oxidant genes in vascular smooth muscle cells. Our results highlight hidrosmin as a potential add-on therapy in the treatment of macrovascular complications of diabetes.

Kidney microRNA Expression Pattern in Type 2 Diabetic Nephropathy in BTBR Ob/Ob Mice.

Diabetic nephropathy (DN) is the main leading cause of chronic kidney disease worldwide. Although remarkable therapeutic advances have been made during the last few years, there still exists a high residual risk of disease progression to end-stage renal failure. To further understand the pathogenesis of tissue injury in this disease, by means of the Next-Generation Sequencing, we have studied the microRNA (miRNA) differential expression pattern in kidneys of Black and Tan Brachyury (BTBR) ob/ob (leptin deficiency mutation) mouse. This experimental model of type 2 diabetes and obesity recapitulates the key histopathological features described in advanced human DN and therefore can provide potential useful translational information. The miRNA-seq analysis, performed in the renal cortex of 22-week-old BTBR ob/ob mice, pointed out a set of 99 miRNAs significantly increased compared to non-diabetic, non-obese control mice of the same age, whereas no miRNAs were significantly decreased. Among them, miR-802, miR-34a, miR-132, miR-101a, and mir-379 were the most upregulated ones in diabetic kidneys. The in silico prediction of potential targets for the 99 miRNAs highlighted inflammatory and immune processes, as the most relevant pathways, emphasizing the importance of inflammation in the pathogenesis of kidney damage associated to diabetes. Other identified top canonical pathways were adipogenesis (related with ectopic fatty accumulation), necroptosis (an inflammatory and regulated form of cell death), and epithelial-to-mesenchymal transition, the latter supporting the importance of tubular cell phenotype changes in the pathogenesis of DN. These findings could facilitate a better understanding of this complex disease and potentially open new avenues for the design of novel therapeutic approaches to DN.

Meta-Inflammation and De Novo Lipogenesis Markers Are Involved in Metabolic Associated Fatty Liver Disease Progression in BTBR ob/ob Mice.

Metabolic associated fatty liver disease (MAFLD) is a hepatic manifestation of metabolic syndrome and usually associated with obesity and diabetes. Our aim is to characterize the pathophysiological mechanism involved in MAFLD development in Black Tan and brachyuric (BTBR) insulin-resistant mice in combination with leptin deficiency (ob/ob). We studied liver morphology and biochemistry on our diabetic and obese mice model (BTBR ob/ob) as well as a diabetic non-obese control (BTBR + streptozotocin) and non-diabetic control mice (BTBR wild type) from 4-22 weeks. Lipid composition was assessed, and lipid related pathways were studied at transcriptional and protein level. Microvesicular steatosis was evident in BTBR ob/ob from week 6, progressing to macrovesicular in the following weeks. At 12th week, inflammatory clusters, activation of STAT3 and Nrf2 signaling pathways, and hepatocellular ballooning. At 22 weeks, the histopathological features previously observed were maintained and no signs of fibrosis were detected. Lipidomic analysis showed profiles associated with de novo lipogenesis (DNL). BTBR ob/ob mice develop MAFLD profile that resemble pathological features observed in humans, with overactivation of inflammatory response, oxidative stress and DNL signaling pathways. Therefore, BTBR ob/ob mouse is an excellent model for the study of the steatosis to steatohepatitis transition.

Helicobacter pylori prevalence in healthy Mexican children: comparison between two non-invasive methods.

BACKGROUND: Helicobacter pylori detection in asymptomatic children with suspected infection or with symptoms that suggest gastric pathology is problematic, since most of the methods depend on the endoscopic study, an invasive and expensive method. Non-invasive methods can be a feasible alternative but must be validated. The purpose of this study was to evaluate the concordance between H. pylori DNA detection in saliva and dental plaque by PCR, with antigen detection in stool by immunochromatography, among asymptomatic children in the state of Guerrero, Mexico. METHODS: Dental plaque, saliva, and stool samples were obtained from 171 children between 6 and 12 years old. H. pylori detection in saliva and dental plaque was performed by PCR using specific primers for the 16S rRNA gene, while the detection in stool samples was performed by immunochromatography using the CerTest kit. RESULTS: We found an overall H. pylori prevalence of 59.6% (102/171). Of the H. pylori positive children 18% (20/111) were positive in saliva samples, 28.1% (34/121) in dental plaque samples, and 50.4% (71/141) in stool samples. A higher prevalence was found in girls (64.7%, p = 0.002). Although some of the children declared some dyspeptic symptoms, these were no related to H. pylori. In conclusion, we found a high prevalence of H. pylori in asymptomatic children and the highest proportion was detected by stool antigen test, which was the most feasible method to detect H. pylori infection.

MicroRNA-135a-5p reduces P2X7 -dependent rise in intracellular calcium and protects against excitotoxicity.

Excitotoxic cell death because of the massive release of glutamate and ATP contributes to the secondary extension of cellular and tissue loss following traumatic spinal cord injury (SCI). Evidence from blockage experiments suggests that over-expression and activation of purinergic receptors, especially P2X7 , produces excitotoxicity in neurodegenerative diseases and trauma of the central nervous system. We hypothesize that the down-regulation of specific miRNAs after the SCI contributes to the over-expression of P2X7 and that restorative strategies can be used to reduce the excitotoxic response. In the present study, we have employed bioinformatic analyses to identify microRNAs whose down-regulation following SCI can be responsible for P2X7 over-expression and excitotoxic activity. Additional luciferase assays validated microRNA-135a-5p (miR-135a) as a posttranscriptional modulator of P2X7 . Moreover, gene expression analysis in spinal cord samples from a rat SCI model confirmed that the decrease in miR-135a expression correlated with P2X7 over-expression after injury. Transfection of cultures of Neuro-2a neuronal cell line with a miR-135a inhibitory sequences (antagomiR-135a), simulating the reduction of miR-135a observed after SCI, resulted in the increase of P2X7 expression and the subsequent ATP-dependent rise in intracellular calcium concentration. Conversely, a restorative strategy employing miR-135a mimicked reduced P2X7 expression, attenuating the increase in intracellular calcium concentration that depends on this receptor and protecting cells from excitotoxic death. Therefore, we conclude that miR-135a is a potential therapeutic target for SCI and that restoration of its expression may reduce the deleterious effects of ATP-dependent excitotoxicity induced after a traumatic spinal cord injury.

Tratamiento antibiótico empírico de elección en pacientes con urosepsis secundaria a litiasis ureteral: reporte de sensibilidad local / Antimicrobial susceptibility of bacteria causing urosepsis

Background: Early inappropriate antibiotic therapy for the management of urosepsis is associated with higher mortality. Therefore, to establish an adequate empirical therapy is crucial. Aim: To determine an optimal antibiotic treatment, adjusted according local bacterial resistance in patients diagnosed with urosepsis secondary to ureteral lithiasis. Material and Methods: Urine cultures and blood cultures from a prospective cohort of patients with ureteral lithiasis admitted for urosepsis in our center between November 2013 and May 2016, were reviewed. Patients who presented two or more criteria of systemic inflammatory response syndrome (SIRS) and positive blood or urine cultures were admitted. Antimicrobial sensitivity patters derived from cultures were analyzed to describe bacterial susceptibility to commonly used antibiotics. Results: Data from 31 patients were analyzed. Seventeen blood cultures (55%) and 29 urine cultures (94%) were positive. The most commonly isolated pathogens were Escherichia coli in 65% of the cultures, followed by Klebsiella pneumoniae, Proteus mirabilis and Enterococcus faecalis. After performing an analysis of sensitivity and resistance for all bacteria in both blood and urine cultures, amikacin showed the highest sensitivity (100%), followed by 2nd and 3rd generation cephalosporins. Conclusions: Amikacin demonstrated higher antibiotic sensitivity in comparison to other antibiotics for empirical management of patients with urosepsis secondary to ureteral lithiasis.

Is a ureteral stent required after use of ureteral access sheath in presented patients who undergo flexible ureteroscopy?

INTRODUCTION: Use of a ureteral access sheath (UAS) within flexible ureteroscopy (fURS) for the management of kidney and ureteral stones has shown improvements in its effectiveness, but it is also associated with increased risk of ureteral injury. Use of ureteral stent (US) after fURS is recommended by some authors, because of its role in reducing postoperative pain and preventing complications. Our objective is to determine if postoperative stenting is necessary in pre-stented patients that underwent fURS using UAS. MATERIAL AND METHODS: A retrospective history review of patients who underwent fURS using UAS at our hospital between July 1st 2013 and May 31st 2016 was performed. Only pre-stented patients were included. All procedures were performed using the same UAS (Boston Navigator TM., 11-13 Fr.). Patients were separated according to the use or not of postoperative US. The same US (26 cm 6 Fr percuflex, Boston Scienfic) was used for all stented patients. Clinical parameters, stone demographics, operative time and postoperative events were analyzed. RESULTS: Seventy patients met the inclusion criteria. Mean stone size was 8.5 mm (SD 7.06), 68.49% were located in the renal pelvis and 31.51% were in the proximal ureter. Reasons of preoperative stenting were: 14 (19.18%) ureteral stricture, 17 (23.29%) urosepsis, 29 (39.73%) residual stones after a first intervention (stage procedure) and 13 (17.8%) unsuccessful extracorporeal shockwave lithotripsy. Mean operative time was 88 minutes (SD 37.20); 32 patients (45.71%) were stented and 38 (54.28%) were not. There were no significant differences in operative time (p = 0.85) or postoperative outcomes (p = 1). CONCLUSIONS: A postoperative ureteral stent is not necessary after fURS using UAS in pre-stented patients.

Enfrentamiento terapéutico en litiasis urinarias: adherencia de urólogos chilenos a las guías clínicas / Therapeutic confrontation in urinary lithiasis: adherence of chilian urologists to clinicals guidelines

Introducción. La urolitiasis es una patología prevalente en el mundo occidental. Hoy en día, existen distintas opciones terapéuticas para el manejo de esta patología en sus diferentes formas de presentación. En la mayoría de estas situaciones, se dispone de guías clínicas que orientan el manejo. Nuestro objetivo fue determinar la adherencia a guías clínicas de manejo de urolitiasis frente a situaciones hipotéticas, por parte de urólogos pertenecientes a la Sociedad Chilena de Urología. Materiales y Métodos. Se diseñó una encuesta en línea, a través de la plataforma Formularios de Google, consistente de preguntas generales para caracterizar a los encuestados y 11 preguntas de selección múltiple de casos clínicos hipotéticos. Los escenarios clínicos variaban en: localización, tamaño, densidad del cálculo y tiempo de evolución. La encuesta fue difundida a través de correo electrónico de urólogos pertenecientes a la Sociedad Chilena de Urología. Se excluyó del análisis a urólogos infantiles. Las variables tiempo de ejercicio profesional y número de pacientes manejados fueron dicotomizadas según media. Se realizó análisis estadístico con test exacto de Fisher. Resultados. 67 urólogos contestaron la encuesta. El 98,5 por ciento era de adultos; 73,1 por ciento realizó residencia de 3 años de duración. Un 38,8 por ciento manejó más de 80 pacientes con litiasis en el último año. La media de años de ejercicio como especialista fue 13,8 años. Un 56,1 por ciento tenían menos de 14 años de ejercicio y 43,9 por ciento 14 o más. No se observó diferencia significativa en cuanto a adherencia a guías clínicas en los distintos escenarios de litiasis ureteral, entre los grupos dicotomizados por años de ejercicio (p=0,47) ni al dicotomizarlos por número de pacientes manejados (P=0,63). Un 48 por ciento adhiere a terapia médica expulsiva y un 68 por ciento a terapia quirúrgica (p=0,000009). Conclusiones. Una mayoría de los urólogos encuestados refiere utilizar opciones terapéuticas similares a las recomendadas por las guías clínicas. No se observó diferencia en las conductas propuestas entre los grupos de mayor o menor experiencia profesional ni entre los grupos con mayor o menor número de pacientes manejados por urolitiasis. (AU)

SUMMARY Introduction. Urolithiasis is a prevalent pathology in the western world. There are different therapeutic options for the management of this pathology in its different forms of presentation. In most of these situations, clinical guidelines are available. Our objective was to determine the adherence in certain hypothetical situations to clinical guidelines of urolithiasis management, by urologists belonging to Sociedad Chilena de Urología. Materials y Methods. An online survey was developed using Google Forms platform, consisting of general questions to characterize the respondents and 11 multiple-choice questions of hypothetical clinical cases. The clinical scenarios varied in: location, size, density of the calculi and time. The survey was sent via email to urologists belonging to Sociedad Chilena de Urología. Pediatric urologists were excluded from analysis. Two variables: years of practice as a specialist and number of patients treated, were dichotomized according to mean. Statistical analysis was performed with Fisher's exact test. Results. 67 urologists answered the survey. 98.5 pertcent were non-pediatric urologists; 73.1 pertcent completed residence for 3 years. 38.8 pertcent treated more than 80 patients with lithiasis in the last year. Average number of years of practice as a specialist was 13.8 years. 56.1 pertcent had less than 14 years of exercise and 43.9 pertcent had 14 or more. There was no significant difference in adherence to clinical guidelines in the different scenarios of ureteral lithiasis between groups dichotomized by years of exercise (p = 0.47) or dichotomized by number of patients treated (p = 0.63). 48 pertcent adhered to medical expulsive therapy and 68 percent to surgical therapy (p = 0.000009). Conclusions. Most urologists surveyed use similar therapeutic options to those recommended by clinical guidelines. No difference was observed between groups of greater or lesser professional experience nor among groups with greater or lesser number of patients managed by urolithiasis. (AU)