Role of Sodium-Glucose Co-Transporter 2 Inhibitors in the Regulation of Inflammatory Processes in Animal Models.

Sodium-glucose co-transporter 2 inhibitors, also known as gliflozins, were developed as a novel class of anti-diabetic agents that promote glycosuria through the prevention of glucose reabsorption in the proximal tubule by sodium-glucose co-transporter 2. Beyond the regulation of glucose homeostasis, they resulted as being effective in different clinical trials in patients with heart failure, showing a strong cardio-renal protective effect in diabetic, but also in non-diabetic patients, which highlights the possible existence of other mechanisms through which gliflozins could be exerting their action. So far, different gliflozins have been approved for their therapeutic use in T2DM, heart failure, and diabetic kidney disease in different countries, all of them being diseases that have in common a deregulation of the inflammatory process associated with the pathology, which perpetuates and worsens the disease. This inflammatory deregulation has been observed in many other diseases, which led the scientific community to have a growing interest in the understanding of the biological processes that lead to or control inflammation deregulation in order to be able to identify potential therapeutic targets that could revert this situation and contribute to the amelioration of the disease. In this line, recent studies showed that gliflozins also act as an anti-inflammatory drug, and have been proposed as a useful strategy to treat other diseases linked to inflammation in addition to cardio-renal diseases, such as diabetes, obesity, atherosclerosis, or non-alcoholic fatty liver disease. In this work, we will review recent studies regarding the role of the main sodium-glucose co-transporter 2 inhibitors in the control of inflammation.

Bartonella henselae infection in the pediatric solid organ transplant recipient.

Bartonella henselae infection can cause a wide spectrum of diseases in both the immunocompetent and immunocompromised host with BA a severe form relegated to immunocompromised hosts, including solid organ transplant population. There are established criteria for diagnosis of Bartonella infection based on clinical presentation, serologic testing, imaging studies and, when indicated, tissue sampling for histopathological evaluation, particularly for BA. However, treatment recommendations for BA are inconclusive. Furthermore, there are no studies in the pediatric solid organ transplant population for antimicrobial therapy during BA secondary to Bartonella henselae infection. A case of BA following heart transplant is presented along with a literature review of clinical presentation; diagnosis and therapy for BA in the pediatric solid organ transplant population.

SARS-COV-2 infection during pregnancy, a risk factor for eclampsia or neurological manifestations of COVID-19? Case report.

BACKGROUND: There are no published cases of tonic-clonic seizures and posterior bilateral blindness during pregnancy and Severe Acute Respiratory Syndrome (SARS) Coronavirus (COV) 2 (SARS-COV-2) infection. We do not just face new and unknown manifestations, but also how different patient groups are affected by SARS-COV-2 infection, such as pregnant women. Coronavirus Disease 2019 (COVID-19), preeclampsia, eclampsia and posterior reversible leukoencephalopathy share endothelium damage and similar pathophysiology. CASE PRESENTATION: A 35-year-old pregnant woman was admitted for tonic-clonic seizures and SARS-COV-2 infection. She had a normal pregnancy control and no other symptoms before tonic-clonic seizures development. After a Caesarean section (C-section) she developed high blood pressure, and we initiated antihypertensive treatment with labetalol, amlodipine and captopril. Few hours later she developed symptoms of cortical blindness that resolved in 72 h with normal brain computed tomography (CT) angiography. CONCLUSION: The authors conclude that SARS COV-2 infection could promote brain endothelial damage and facilitate neurological complications during pregnancy.

Fecal Calprotectin as Predictor of Relapse in Patients With Inflammatory Bowel Disease Under Maintenance Infliximab Therapy.

BACKGROUND AND GOALS: Predicting relapse in Inflammatory Bowel Disease (IBD) could allow for early changes of treatment. Close monitoring of fecal calprotectin (FC) could be useful to predict relapse in IBD. Aim of the study was to evaluate the predictive value of a rapid FC test to predict flares in patients with IBD under maintenance therapy with Infliximab. STUDY: A prospective observational cohort study was designed. IBD patients in clinical remission under maintenance Infliximab therapy were included. FC was measured using a rapid test on a stool sample obtained within 24 hours before Infliximab infusion. Clinical examination was performed 2 months after that infusion. RESULTS: Fifty-three patients were included (52.8% female). Thirty-three patients (62.3%) had Crohn's disease and 20 (37.7%) had ulcerative colitis. All patients were in remission at inclusion. After 2 months, 41 patients (77.4%) remained in clinical remission and 12 (22.6%) presented a relapse. FC (mean±SD) in relapsing and not-relapsing disease was 332±168 and 110±163 µg/g, respectively (P<0.005). A FC concentration>160 µg/g had a sensitivity of 91.7%, and specificity of 82.9% to predict relapse. CONCLUSIONS: In IBD patients under Infliximab maintenance therapy, high FC levels allow predicting relapse within the following 2 months. Long-term remission is associated with low calprotectin levels. Further studies are required to confirm these results.

The lipidomic and inflammatory profiles of visceral and subcutaneous adipose tissues are distinctly regulated by the SGLT2 inhibitor empagliflozin in Zucker diabetic fatty rats.

The pharmacological inhibition of sodium-glucose cotransporter 2 (SGLT2) has emerged as a treatment for patients with type 2 diabetes mellitus (T2DM), cardiovascular disease and/or other metabolic disturbances, although some of the mechanisms implicated in their beneficial effects are unknown. The SGLT2 inhibitor (SGLT2i) empagliflozin has been suggested as a regulator of adiposity, energy metabolism, and systemic inflammation in adipose tissue. The aim of our study was to evaluate the impact of a 6-week-empagliflozin treatment on the lipidome of visceral (VAT) and subcutaneous adipose tissue (SAT) from diabetic obese Zucker Diabetic Fatty (ZDF) rats using an untargeted metabolomics approach. We found that empagliflozin increases the content of diglycerides and oxidized fatty acids (FA) in VAT, while in SAT, it decreases the levels of several lysophospholipids and increases 2 phosphatidylcholines. Empagliflozin also reduces the expression of the cytokines interleukin-1 beta (IL-1ß), IL-6, tumor necrosis factor-alpha (TNFα), monocyte-chemotactic protein-1 (MCP-1) and IL-10, and of Cd86 and Cd163 M1 and M2 macrophage markers in VAT, with no changes in SAT, except for a decrease in IL-1ß. Empagliflozin treatment also shows an effect on lipolysis increasing the expression of hormone-sensitive lipase (HSL) in SAT and VAT and of adipose triglyceride lipase (ATGL) in VAT, together with a decrease in the adipose content of the FA transporter cluster of differentiation 36 (CD36). In conclusion, our data highlighted differences in the VAT and SAT lipidomes, inflammatory profiles and lipolytic function, which suggest a distinct metabolism of these two white adipose tissue depots after the empagliflozin treatment.

[Metabolic abnormalities and relationship with cardiovascular risk factors in children]. / Riesgo cardiovascular y alteraciones metabólicas en niños.

OBJECTIVE: to describe cardiovascular risk factors in pediatric patients of the General Hospital Zone 58 and its relationship with metabolic abnormalities. METHODS: we studied a population of 30 healthy; children randomized. We measured weight, height, body mass index, blood pressure, waist circumference, determination of blood glucose, total cholesterol, HDL, LDL, triglycerides and uric acid. We applied a structured questionnaire about: how many hours a day the child watch television, hours of sleeping, birth weight, consumption of junk food, plus additional questions to investigate family history of cardiovascular disease. RESULTS: the group consisted of 17 girls (56 %) and 13 children (44 %), average age: 9.7 years. Patients who had at least one abnormal laboratory result were 27 (90 %). Cardiovascular risk factors showed an arithmetic mean birth weight 3175 g, 3.6 h hours of watching TV, sleep diary 8.9, lots of junk food every day 2.9. 15 patients had normal BMI, 5 more than the 95 centile and 7 below the 10 centile. CONCLUSIONS: the main factor that determined metabolic disorders was family history of cardiovascular disease or lipid disorders.

[Euthanasia and assisted suicide in people with mental disorders]. / Eutanasia y suicidio asistido en personas con enfermedad mental.

Until 2020, only Belgium, Luxembourg, Switzerland, and the Netherlands admitted, under differentiated legal coverage, requests for euthanasia and / or assisted suicide in patients with non-terminal illnesses, and for reasons of intractable and unbearable suffering. Since March 2021 this is also possible in Spain. The objective of this work is to review the existing studies and characteristics of the practice of euthanasia and assisted suicide (ESA) in people with mental disorders (TM) and / or dementia (D) and see if the legal requirements essential in ESA applications in these patients are to be met. The hypothesis is that compliance with these requirements is especially difficult in patients with TM-D, either because of the characteristics of the disease itself, or because of the recognized legal security failures. Likewise, there may be sources of fraud not actually prosecuted by the State, either due to the complicity of society and / or due to the necessary cooperation of Medicine. As a result of this review, we raise criticaethical-deontological considerations about the approval of ESA for patients with TM-D, and its errors and consequences, to the reflection of the readers. We propose as an alternative to ESA the so-called ″palliative psychiatry″, which aims at improving the quality of life of patients and their families by facing the problems associated with severe persistent mental illness -potentially fatal- through the prevention and relief of suffering.

The Treatment With the SGLT2 Inhibitor Empagliflozin Modifies the Hepatic Metabolome of Male Zucker Diabetic Fatty Rats Towards a Protective Profile.

The EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcome Event Trial in patients with Type 2 Diabetes Mellitus (T2DM)) trial evidenced the potential of sodium-glucose cotransporter 2 (SGLT2) inhibitors for the treatment of patients with diabetes and cardiovascular disease. Recent evidences have shown the benefits of the SGLT2 inhibitor empagliflozin on improving liver steatosis and fibrosis in patients with T2DM. Metabolomic studies have been shown to be very useful to improve the understanding of liver pathophysiology during the development and progression of metabolic hepatic diseases, and because the effects of empagliflozin and of other SGLT2 inhibitors on the complete metabolic profile of the liver has never been analysed before, we decided to study the impact on the liver of male Zucker diabetic fatty (ZDF) rats of a treatment for 6 weeks with empagliflozin using an untargeted metabolomics approach, with the purpose to help to clarify the benefits of the use of empagliflozin at hepatic level. We found that empagliflozin is able to change the hepatic lipidome towards a protective profile, through an increase of monounsaturated and polyunsaturated glycerides, phosphatidylcholines, phosphatidylethanolamines, lysophosphatidylinositols and lysophosphatidylcholines. Empagliflozin also induces a decrease in the levels of the markers of inflammation IL-6, chemerin and chemerin receptor in the liver. Our results provide new evidences regarding the molecular pathways through which empagliflozin could exert hepatoprotector beneficial effects in T2DM.

Collaboration between civilian and military healthcare professionals: a better way for planning, preparing, and responding to all hazard domestic events.

Collaboration is used by the US National Security Council as a means to integrate inter-federal government agencies during planning and execution of common goals towards unified, national security. The concept of collaboration has benefits in the healthcare system by building trust, sharing resources, and reducing costs. The current terrorist threats have made collaborative medical training between military and civilian agencies crucial. This review summarizes the long and rich history of collaboration between civilians and the military in various countries and provides support for the continuation and improvement of collaborative efforts. Through collaboration, advances in the treatment of injuries have been realized, deaths have been reduced, and significant strides in the betterment of the Emergency Medical System have been achieved. This review promotes collaborative medical training between military and civilian medical professionals and provides recommendations for the future based on medical collaboration.

Crystal, Fivefold and Glass Formation in Clusters of Polymers Interacting with the Square Well Potential.

We present results, from Monte Carlo (MC) simulations, on polymer systems of freely jointed chains with spherical monomers interacting through the square well potential. Starting from athermal packings of chains of tangent hard spheres, we activate the square well potential under constant volume and temperature corresponding effectively to instantaneous quenching. We investigate how the intensity and range of pair-wise interactions affected the final morphologies by fixing polymer characteristics such as average chain length and tolerance in bond gaps. Due to attraction chains are brought closer together and they form clusters with distinct morphologies. A wide variety of structures is obtained as the model parameters are systematically varied: weak interactions lead to purely amorphous clusters followed by well-ordered ones. The latter include the whole spectrum of crystal morphologies: from virtually perfect hexagonal close packed (HCP) and face centered cubic (FCC) crystals, to random hexagonal close packed layers of single stacking direction of alternating HCP and FCC layers, to structures of mixed HCP/FCC character with multiple stacking directions and defects in the form of twins. Once critical values of interaction are met, fivefold-rich glassy clusters are formed. We discuss the similarities and differences between energy-driven crystal nucleation in thermal polymer systems as opposed to entropy-driven phase transition in athermal polymer packings. We further calculate the local density of each site, its dependence on the distance from the center of the cluster and its correlation with the crystallographic characteristics of the local environment. The short- and long-range conformations of chains are analyzed as a function of the established cluster morphologies.

Antimicrobial stewardship program at a tertiary care academic medical hospital: Clinical, microbiological and economic impact. A 5-year temporary descriptive study.

INTRODUCTION: Few prospective studies analyze, with sufficient duration, the impact of an antimicrobial stewardship program (AMSP) carried out entirely in a hospital. METHODS: Descriptive study evaluating the consumption of antimicrobials expressed in defined daily doses (DDD) per 100 hospital occupied bed-days (OBDs) stratified in medical, surgical and intensive care unit (ICU) and the incidence of densities (ID) per 1,000 hospital OBDs of the prevalent multidrug-resistant organisms (MDRO) in a tertiary hospital, over a period of 5 years before and after the implementation of an AMSP. Analysis of direct costs and those associated with hospital stay and mortality. RESULTS: A total of 32,802 patients with antibiotic treatment were included in the intervention period (2013-2017). Non-imposed advice was exercised in 14.9%. The degree of adherence to recommendation was 87.9%, direct treatment and de-escalation being the most frequently admitted interventions (P<0.001). Overall hospital consumption of antibacterials in DDD/100s decreased by 5.7% (77.04 vs. 71.33) between 2008 and 2017. In ICU, the average DDD/100s showed a reduction from 155 to 113 (mean difference -18, P=0.005). There was a decrease in the DI/1000 OBDs of MDROs in the post-intervention period (RR 0.78; CI 95% [0.73, 0.84], P<0.001). The average annual cost of antibacterials declined from €1,435,048 to €955,805 (mean difference -€469,243; P=0.001). CONCLUSION: Long-term maintenance of a hospital AMSP was associated with a reduction in antibiotic consumption, especially in ICU, as well as a beneficial ecological impact and economic savings.

Empagliflozin reduces the levels of CD36 and cardiotoxic lipids while improving autophagy in the hearts of Zucker diabetic fatty rats.

The EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcome Event Trial in patients with Type 2 Diabetes Mellitus (T2DM)) trial made evident the potentiality of pharmacological sodium-glucose cotransporter 2 (SGLT2) inhibition for treating patients with diabetes and cardiovascular disease. Since the effect of empagliflozin or other SGLT2 inhibitors on the whole cardiac metabolic profile was never analysed before, and with the purpose to contribute to elucidate the benefits at cardiac level of the use of empagliflozin, we explored the effect of the treatment with empagliflozin for six weeks on the cardiac metabolomic profile of Zucker diabetic fatty rats, a model of early stage T2DM, using untargeted metabolomics approach. Empagliflozin reduced significantly the cardiac content of sphingolipids (ceramides and sphingomyelins) and glycerophospholipids (major bioactive contributing factors linking insulin resistance to cardiac damage) and decreased the cardiac content of the fatty acid transporter cluster of differentiation 36 (CD36); induced significant decreases of the cardiac levels of essential glycolysis intermediaries 2,3-bisphosphoglycerate and phosphoenolpyruvate, and regulated the abundance of several amino acids of relevance as tricarboxylic acid suppliers and/or in the metabolic control of the cardiac function as glutamic acid, gamma-aminobutyric acid and sarcosine. Empagliflozin treatment activated the cardioprotective master regulator of cellular energyhomeostasis AMP-activatedproteinkinase (AMPK) and enhanced autophagy at cardiac level, while it decreased significantly the cardiac mRNA levels of the pro-inflammatory cytokines interleukin-6 (IL-6), chemerin, TNF-α and MCP-1, reinforcing the hypothesis of a direct role for empagliflozin in attenuating cardiac inflammation. Our results provide an advancement on the knowledge of the mechanisms linking the therapy with empagliflozin with protective effects on the development of cardiometabolic diseases whose course is associated with remarkable cardiac bioenergetics dysregulation and disarrangement in cardiac metabolome and lipidome.

[The Identity of Medicine in the Thought of Edmund D. Pellegrino]. / Identidad de la Medicina en el Pensamiento de Edmund D. Pellegrino.

This essay addresses Pellegrino's thought on Philosophy of Medicine; it also provides an approach to his concerns on the changing relationship between patients and physicians which took place in the late twentieth century in the United States and, finally, to his contribution to the identity of Medicine debate. From an Aristotelian-Thomist way of thinking, and from a phenomenological approach to the medical act, he identifies the ending of Medicine and also its limits concerning to ″healing″, in his two moments, curing and helping, which includes caring. Medicine, the essence of Medicine, tends to healing, for this relationship between patient and physician tends to a ″good″ which ultimately ends up being its finality. Medical ethics germinates within this relationship, the clinical encounter, as a universal experience of illness, pain and humane limitation. Therefore, healing is the essence of Medicine and truly its genuine identity. Besides healing any other act is not strictly medical. From the doctrine of Pellegrino emerges that original and classic idea of ″the good of the patient″ as the main and ruling principle of medical ethics. Medical act is no longer just a technique, a technical act, but also a moral enterprise, which our teacher relates to the so called ″medical virtues″. But this ″good″ may not be understood nowadays in the old Hippocratic terms and should also be related to the dignity of the patients and to his or her moral autonomy. And accordingly an updating of the concept of good is demanded by the teacher who, to this intent, stresses four main aspects which are summoned in the article.

Effect of carbon source on pyrimidine biosynthesis in Pseudomonas alcaligenes ATCC 14909.

The effect of carbon source on the regulation of the de novo pyrimidine biosynthetic enzymes in Pseudomonas alcaligenes ATCC 14909 was investigated. The de novo pyrimidine biosynthetic enzymes were measured in extracts of P. alcaligenes ATCC 14909 cells and of cells from an auxotroph deficient for orotate phosphoribosyltransferase activity. Pyrimidine biosynthetic enzyme activities in ATCC 14909 were influenced by pyrimidine supplementation to the culture medium but not by the carbon source present. Pyrimidine limitation of the auxotroph elevated the de novo enzyme activities indicating that this pathway may be controlled at the transcriptional level by a pyrimidine-related compound. Its regulation seemed to be subject to less transcriptional control by a pyrimidine-related compound than what was observed in the closely related species Pseudomonas pseudoalcaligenes.

[An approach to the thinking of Edmund D. Pellegrino (I)]. / Una Aproximación al Pensamiento de Edmund D. Pellegrino (I).

This essay contains an approach to the moral thinking of Pellegrino. This first part addresses the elementary sources of Medicine identity, as seen by the author, which was the starting point for his research on the role of both physicians and Medicine, and led him to his proposal to reform medical ethics. His thinking is developed in four different scopes: 1) the ideal of medical education; 2) Medicine as a moral enterprise; 3) the medical humanities in the formation and professional life of physicians; 4) the philosophy of Medicine as source and origin of medical ethics.

[Portrait of a teacher]. / Semblanza de un Maestro.

Some biographical data are given about the life of Edmund D. Pellegrino, his modest origins, his effort to get to study Medicine and an overview to his professional life as internist physician, Medicine professor and writer, besides his multiple nominations and high-responsibility appointments in healthcare institutions, medical schools and universities throughout the United States. There are several mentions of his impressive resume and of the numerous tributes he received, as well as appointments and distinctions, and finally, it is also stressed his extraordinary contribution to clinical bioethics. His last decades at Georgetown University and his creative contribution to reform medical ethics led him to achieve a legendary prestige.

[Self-effacement]. / Self-effacement o desprendimiento altruista.

The authors reflect around a medical virtue much needed in estimating the doctor-patient relationship in our time, they call "self-effacement". That is, the attitude and disposition of medical professional to be faithful to the trust placed in him patient, always willing to help and search for their best interests. Whenever decisions respected and physician conscience is maintained.