From surgery to functional capacity: muscle strength modifications in women post sleeve gastrectomy.

BACKGROUND: Severe obesity is characterized by excessive accumulation of fat generating a general health decline. Multidisciplinary treatment of obesity leads to significant weight loss in a few patients; therefore, many incur bariatric surgery. The main purpose of the study is to evaluate changes in functional capacity of people with obesity undergoing bariatric surgery and, in parallel, to correlate pre-surgery functional capacity with weight loss to improve exercise prescription during pre-operatory stage. METHODS: sixty women with diagnosed obesity were included. Maximal oxygen consumption, upper and lower limb strength and level of physical activity were recorded 1 month before and 6 months after sleeve gastrectomy. RESULTS: significant reduction on body weight (-30.1 kg) and Body Mass Index (-11.4 kg/m2) were highlighted after surgery. Absolute grip strength decreased significantly (-1.1 kg), while body weight normalized grip and lower limb strength increased significantly. The level of physical activity increased especially in leisure time (+ 593 METs/week) and active transport (+ 189.3 METs/week). Pre-surgery BMI and age predicted the amount of weight loss after surgery. CONCLUSIONS: Sleeve gastrectomy induces a reduction of muscle strength despite the increase of time spent in physical activity. Further research is necessary to integrate these results with data on body composition, and objective evaluation of physical activity level to define useful information for exercise prescription in terms of surgery pre-habilitation. TRIAL REGISTRATION: Padova University Hospital Board (protocol n. 2027 dated January 12, 2017).

Mitochondrial Ca2+ signaling is a hallmark of specific adipose tissue-cancer crosstalk.

Obesity is associated with increased risk and worse prognosis of many tumours including those of the breast and of the esophagus. Adipokines released from the peritumoural adipose tissue promote the metastatic potential of cancer cells, suggesting the existence of a crosstalk between the adipose tissue and the surrounding tumour. Mitochondrial Ca2+ signaling contributes to the progression of carcinoma of different origins. However, whether adipocyte-derived factors modulate mitochondrial Ca2+ signaling in tumours is unknown. Here, we show that conditioned media derived from adipose tissue cultures (ADCM) enriched in precursor cells impinge on mitochondrial Ca2+ homeostasis of target cells. Moreover, in modulating mitochondrial Ca2+ responses, a univocal crosstalk exists between visceral adipose tissue-derived preadipocytes and esophageal cancer cells, and between subcutaneous adipose tissue-derived preadipocytes and triple-negative breast cancer cells. An unbiased metabolomic analysis of ADCM identified creatine and creatinine for their ability to modulate mitochondrial Ca2+ uptake, migration and proliferation of esophageal and breast tumour cells, respectively.

Soluble P2X7 Receptor Plasma Levels in Obese Subjects before and after Weight Loss via Bariatric Surgery.

Obesity is a systemic disease frequently associated with important complications such as type 2 diabetes and cardiovascular diseases. It has also been proven that obesity is a disease associated with chronic low-grade systemic inflammation and that weight loss improves this low-grade chronic inflammatory condition. The P2X7 purinergic receptor (P2X7R), belonging to the family of the receptors for extracellular ATP, is a main player in inflammation, activating inflammasome and pro-inflammatory cytokine production. In this study, we evaluated the plasma levels of soluble P2X7R (sP2X7R) measured in a group of obese patients before and one year after bariatric surgery. Furthermore, we evaluated the relation of sP2X7R to inflammatory marker plasma levels. We enrolled 15 obese patients who underwent laparoscopic sleeve gastrectomy, evaluating anthropometric parameters (weight, height, BMI and waist circumference) before and after surgery. Moreover, we measured the plasma levels of inflammatory markers (CRP, TNFα and IL-6) before and after weight loss via bariatric surgery. The results of our study show that one year after bariatric surgery, obese patients significantly decrease body weight with a significant decrease in CRP, TNF-alfa and IL-6 plasma levels. Similarly, after weight loss, obese subjects showed a significant reduction in sP2X7R plasma levels. Moreover, before surgery, plasma levels of sP2X7R were inversely related with those of CRP, TNF-alfa and IL-6. Given the role of P2X7R in inflammation, we hypothesized that, in obese subjects, sP2X7R could represent a possible marker of chronic low-grade inflammation, hypothesizing a possible role as a mediator of obesity complications.

Non-aromatizable androgens modulate the lipopolysaccharide induced expression of the P2X7 receptor in human adipocytes.

Introduction: The activation of the P2X7 receptor subtype (P2X7R) has a main role in orchestrating the cellular inflammatory response in many different tissues. Obesity is characterized by dysfunctional fat deposition leading to a tissue-specific and systemic low-grade inflammation. Androgens and estrogens contribute to the whole adipose tissue inflammatory state, but the involvement of sex steroids in the purinergic signaling modulation in adipocytes is still unknown. Methods: We performed an in vitro study to evaluate the possible role of sex hormones on the P2X7R gene expression in human adipocytes, at baseline and after stimulation with bacterial lipopolysaccharide (LPS). We evaluated P2X7R gene expression during in vitro differentiation of human adipocytes, in the absence and presence of testosterone (T) and 17ß-estradiol (E2) in the presence and absence of LPS. Furthermore, we analyzed the effects of incubation with dihydrotestosterone (DHT), a non-aromatizable androgen, using the co-incubation of isolated human adipocytes with T alone or in combination with anastrozole, an inhibitor of aromatase, the enzyme responsible of T conversion to E2. Results: At baseline, incubation of adipocytes with T or E2 did not significantly affect P2X7R gene expression. On the contrary, the incubation with DHT was associated with a significant reduction of P2X7R gene expression. LPS incubation significantly increased gene expression of P2X7R with respect to baseline. Interestingly, after LPS stimulation, DHT exposure showed an additional effect, markedly increasing the P2X7R gene expression. This amplificatory effect was confirmed by the incubation of adipocytes to both anastrozole and testosterone. In these experimental conditions, while no effect was observed at baseline, an amplification of the expression of the P2X7R mRNA was observed after stimulation with LPS. Discussion: The purinergic system is involved in the inflammatory response of adipocytes, and androgens may modulate its activity. In particular DHT, a non-aromatizable androgen, amplifies the LPS-induced P2X7R gene expression in human adipocytes thus showing a gender regulated response of the expression of this purinergic receptor strongly involved in the inflammatory response in adipose tissue.

Ferric Carboxymaltose in Patients with Acute Decompensated Heart Failure and Iron Deficiency: A Real-Life Study.

Background: The correction of iron deficiency (ID) with ferric carboxymaltose (FCM) is a recommended intervention in heart failure (HF) with reduced ejection fraction. Our aim is to evaluate, in a real-life setting, the clinical significance of ID screening and FCM treatment in acute decompensated HF (ADHF). Methods: In a cohort of ADHF patients, the prevalence of ID and FCM administration were investigated. Among the 104 patients admitted for ADHF, in n = 90 (median age 84, 53.5% with preserved left ventricular ejection fraction-LVEF), a complete iron status evaluation was obtained. ID was detected in n = 73 (81.1%), 55 of whom were treated with in-hospital FCM. The target dose was reached in n = 13. Results: No significant differences were detected in terms of age, sex, comorbidities, or LVEF between the FCM-supplemented and -unsupplemented patients. During a median follow-up of 427 days (IQR 405-466) among the FCM-supplemented patients, only 14.5% received FCM after discharge; the mortality and rehospitalizations among FCM-supplemented and -unsupplemented patients were similar (p = ns). In a follow-up evaluation, ID was still present in 75.0% of the FCM-supplemented patients and in 69.2% of the unsupplemented patients (p = ns). Conclusions: In this real-life ADHF cohort, FCM was administered at lower-than-prescribed doses, thus having no impact on ID correction. The significance of our findings is that only achieving the target dose of FCM and pursuing outpatient treatment can correct ID and produce long-term clinical benefits.

Down-staging of obesity one year after bariatric surgery: a new proposal of Edmonton obesity staging system.

Background: Different approaches are used to classify obesity severity. The Edmonton Obesity Staging System (EOSS) considers medical, physical and psychological parameters. A new modified EOSS with a different functional evaluation method, measuring Cardiorespiratory Fitness (CRF), has been recently proposed, EOSS-CRF. Bariatric surgery (BS) is one of the most efficient treatments of obesity and all aspect of related disorders. No studies have yet applied EOSS-CRF after BS. Therefore, the aim of this study was to evaluate modifications in EOSS and EOSS-CRF before and after BS. Methods: This observational study finally enrolled 72 patients affected by obesity. A multi-disciplinary assessment in order to evaluate eligibility to surgical treatment has been performed, including anamnesis, physical evaluation, anthropometric data measurement, biochemical blood exams and cardiopulmonary exercise testing. One year after BS the same protocol was applied. Patients have been classified according to EOSS and EOSS-CRF before and one year after BS. Results: After BS, patients categorized in classes associated to severe obesity (EOSS ≥ 2 or EOSS-CRF ≥ 2) reduced significantly. Using EOSS, patients without functional impairment were 61% before surgery and 69% after BS (p=0.383). Using EOSS-CRF, patients considered without functional impairment were only 9.7% before BS; this percentage significantly raised to 50% after BS (p<0.001). The impact of functional domains before and after BS is different in grading patients in EOSS and EOSS-CRF, respectively. Conclusions: Improvements obtained after BS are adequately summarized by EOSS and EOSS-CRF. The EOSS-CRF grading method for functional impairment seems to better reflect the known amelioration obtained after BS. Objective measurements of CRF may provide additional value to classify severity of obesity, also in the follow-up after BS.

Body Weight Reduction by Bariatric Surgery Reduces the Plasma Levels of the Novel Orexigenic Gut Hormone Insulin-like Peptide 5 in Patients with Severe Obesity.

Insulin-like factor 5 (INSL5), a novel hormone secreted by the enteroendocrine cells of the distal colon, has been implicated in appetite and body weight regulation in animals given its orexigenic properties. We investigated basal INSL5 plasma levels in a group of morbidly obese subjects before and after laparoscopic sleeve gastrectomy. Furthermore, we analyzed the expression of INSL5 in human adipose tissue. Before bariatric surgery, obese subjects showed basal INSL5 plasma levels that were positively correlated with BMI, fat mass, and leptin plasma levels. After weight loss by laparoscopic sleeve gastrectomy, INSL5 plasma levels in obese subjects were significantly lower than those observed before surgery. Finally, we did not detect any expression of the INSL5 gene in human adipose tissue, both at the mRNA and protein levels. The present data show that subjects with obesity have INSL5 plasma levels positively correlating with adiposity markers. After bariatric surgery, INSL5 plasma levels decreased significantly, and this decrease was not directly due to the loss of adipose tissue since this tissue does not express INSL5. Considering the orexigenic properties of INSL5, the reduction of its plasma levels after bariatric surgery in obese subjects could participate in the still unclear mechanisms leading to appetite reduction that characterize bariatric surgery procedures.

Semi-Quantification of Myocardial Uptake of Bone-Seeking Agents in Suspected Cardiac Amyloidosis.

INTRODUCTION: Bone scintigraphy has emerged as a key tool for non-invasive etiologic diagnosis of transthyretin (ATTR) cardiac amyloidosis (CA). We focused on a new semi-quantification method (on planar imaging) that could complement the qualitative/visual Perugini scoring system, especially when SPET/CT is not available. MATERIAL AND METHODS: We retrospectively/qualitatively evaluated 8674 consecutive, planar 99mTc-biphosphonate scintigraphies (performed for non-cardiac reasons), identifying 68 (0.78%) individuals (mean age 79 ± 7 years, range 62-100 years; female/male ratio 16/52) presenting myocardial uptake. Due to the retrospective nature of the study, no SPET/CT, pathologic or genetic confirmation was obtained. The Perugini scoring system was determined (in patients presenting cardiac uptake) and compared with three newly proposed semi-quantitative indices. We took 349 consecutive bone scintigraphies, qualitatively absent of any cardiac/pulmonary uptake, as "healthy controls" (HC). RESULTS: The heart-to-thigh ratio (RHT) and lung-to-thigh ratio (RLT) indices were significantly higher in patients than in HCs (p ≤ 0.0001). There were statistically significant differences for RHT in HCs vs. patients with qualitative Perugini scores of 1 or >1 (with p ranging from ≤0.001 to ≤0.0001). ROC curves showed that RHT outperformed the other indices and was more accurate in both male and female groups. Furthermore, in the male population, RHT accurately distinguished HCs and patients with scores of 1 (less likely affected by ATTR) from patients with qualitative scores >1 (more likely affected by ATTR) with an AUC of 99% (sensitivity: 95%; specificity: 97%). CONCLUSION: The proposed semi-quantitative RHT index can accurately/semi-quantitatively distinguish between HCs and subjects probably affected by CA (Perugini scores from 1 to 3), and could be particularly useful when no SPET/CT data are available (such as in retrospective studies and data mining). Furthermore, RHT can semi-quantitatively predict, with very high accuracy, subjects in the male population more likely to be affected by ATTR. The present study, although using a very large sample, is however retrospective, monocentric, and therefore the generalizability of the results should be proved by an accurate external validation. ADVANCES IN KNOWLEDGE: The proposed heart-to-thigh ratio (RHT) can distinguish healthy controls and subjects that are probably affected by cardiac amyloidosis in a simple and more reproducible way, as compared to standard qualitative/visual evaluation.

Obesity, the Adipose Organ and Cancer in Humans: Association or Causation?

Epidemiological observations, experimental studies and clinical data show that obesity is associated with a higher risk of developing different types of cancer; however, proof of a cause-effect relationship that meets the causality criteria is still lacking. Several data suggest that the adipose organ could be the protagonist in this crosstalk. In particular, the adipose tissue (AT) alterations occurring in obesity parallel some tumour behaviours, such as their theoretically unlimited expandability, infiltration capacity, angiogenesis regulation, local and systemic inflammation and changes to the immunometabolism and secretome. Moreover, AT and cancer share similar morpho-functional units which regulate tissue expansion: the adiponiche and tumour-niche, respectively. Through direct and indirect interactions involving different cellular types and molecular mechanisms, the obesity-altered adiponiche contributes to cancer development, progression, metastasis and chemoresistance. Moreover, modifications to the gut microbiome and circadian rhythm disruption also play important roles. Clinical studies clearly demonstrate that weight loss is associated with a decreased risk of developing obesity-related cancers, matching the reverse-causality criteria and providing a causality correlation between the two variables. Here, we provide an overview of the methodological, epidemiological and pathophysiological aspects, with a special focus on clinical implications for cancer risk and prognosis and potential therapeutic interventions.

The incidence of cardiac arrhythmias during exercise stress testing: a focus on patients with severe obesity undergoing sleeve gastrectomy.

INTRODUCTION: Obesity is associated with a higher risk of cardiac arrhythmias. Sleeve gastrectomy (SG) is a common bariatric surgery with beneficial effects on weight loss and comorbidities. The study aimed to investigate the prevalence of arrhythmias during maximal exercise testing in patients with moderate-severe obesity and to evaluate the impact of SG on these arrhythmic events. METHODS: All patients with moderate or severe obesity who were considered suitable candidates for SG between June 2015 and September 2020 were recruited. Each patient underwent three incremental, maximal, ECG-monitored cardiopulmonary exercise test 1 month before and 6 and 12 months after SG; the frequency and complexity of ventricular premature beats (VPBs) and atrial premature beats (APBs) have been evaluated during rest, exercise and recovery phases. RESULTS: Fifty patients with severe obesity (BMI 46.39 ± 7.89 kg/m2) were included in the study. After SG, patients presented a decreased BMI (34.15 ± 6.25 kg/m2 at 6 months post-SG and 31.87 ± 5.99 kg/m2 at 12 months post-SG). At 6 months post-SG, an increase in VPBs, mainly during the recovery phase, was observed. At 12 months post-SG, a reduction in VPBs compared with the 6 months evaluation was showed. CONCLUSION: Although in the early post-surgical phase the risk of exercise-induced arrhythmias may be higher, SG does not seem to increase the occurrence of arrhythmias in the long-term. No life-threating arrhythmias were found during post-SG evaluations.

Hematopoietic Stem Cells and Metabolic Deterioration in Alström Syndrome, a Rare Genetic Model of the Metabolic Syndrome.

Alström syndrome (AS) is a rare genetic disease caused by ALMS1 mutations, characterized by short stature, and vision and hearing loss. Patients with AS develop the metabolic syndrome, long-term organ complications, and die prematurely. We explored the association between AS and a shortage of hematopoietic stem/progenitor cells (HSPCs), which is linked to metabolic diseases and predicts diabetic complications. We included patients with AS at a national referral center. We measured HSPCs with flow cytometry at baseline and follow-up. We followed patients up to January 2022 for metabolic worsening and end-organ damage. We evaluated HSPC levels and mobilization as well as bone marrow histology in a murine model of AS. In 23 patients with AS, we found significantly lower circulating HSPCs than in healthy blood donors (-40%; P = .002) and age/sex-matched patients (-25%; P = .022). Longitudinally, HSPCs significantly declined by a further 20% in patients with AS over a median of 36 months (interquartile range 30-44). Patients with AS who displayed metabolic deterioration over 5.3 years had lower levels of HSPCs, both at baseline and at last observation, than those who did not deteriorate. Alms1-mutated mice were obese and insulin resistant and displayed significantly reduced circulating HSPCs, despite no overt hematological abnormality. Contrary to what was observed in diabetic mice, HSPC mobilization and bone marrow structure were unaffected. We found depletion of HSPCs in patients with AS, which was recapitulated in Alms1-mutated mice. Larger and longer studies will be needed to establish HSPCs shortage as a driver of metabolic deterioration leading to end-organ damage in AS.

Histopathological Landscape of Precursor Lesions of Gastro-Entero-Pancreatic Neuroendocrine Neoplasms.

BACKGROUND: Despite the important advances in research on neuroendocrine neoplasms of the gastro-entero-pancreatic tract, their precursor lesions are much less well known. SUMMARY: This review analyzes the preneoplastic neuroendocrine lesions of the gastro-entero-pancreatic tract, by adopting a coherent anatomical benchmark. In particular, the settings in which neuroendocrine precursor lesions represent well-recognized pathophysiological and morphological entities (with eventual molecular correlates) have been distinguished from the ones in which the nature of preneoplastic changes is still obscure. KEY MESSAGES: The aim of the paper was to summarize what is known about precursor lesions of gastro-entero-pancreatic neuroendocrine tumors, with the goal of providing a useful tool for future research aimed at obtaining a fuller understanding of the underlying biology and early development of these diseases.

The Influence of Weight Loss in Postural Control in Women Undergoing Sleeve Gastrectomy.

BACKGROUND: Bariatric surgery is the most effective procedure for obesity management, with a greater body weight loss and the remission of several diseases. The aim of this study was to analyze the relationships between the anthropometric profile and postural control outcomes in a group of obese adult women, and the effect of bariatric surgery on postural control. METHODS: eighty-eight women candidates for bariatric surgery were recruited. Static balance was measured with the ARGO stabilometric platform under two conditions: open eyes (OE) and closed eyes (CE). RESULTS: Multiple linear regression indicated BMI as the first predictor for postural control in all parameters, except for APO in open eyes, predicted mainly by height. Changes in body weight and BMI showed no statistically significant correlations with modification of postural control parameters (OE), while they appeared to exert an influence under closed eyes conditions. CONCLUSIONS: Before surgery, obese patients with a higher BMI showed a better postural control. After surgery, the sway path and antero-posterior oscillation improved under open eyes conditions, while the magnitude of weight loss was negatively correlated with differences in postural control.

The antigen CD300e drives T cell inflammation in adipose tissue and elicits an antibody response predictive of the insulin sensitivity recovery in obese patients.

Obesity and insulin resistance (IR), the key features of metabolic syndrome, are closely associated with a state of chronic, low-grade inflammation. Bariatric surgery leads to a considerable reduction in the adipose tissue mass and systemic inflammation along with a reduction of IR, with a whole-body metabolic improvement. However, a sizable portion of people experience an IR relapse within few years of remission.Numerous studies have attempted to explore the best clinical predictors of the improvement of insulin sensitivity and the maintenance of glucose homeostasis after bariatric surgery, but no simple fasting blood test has been found to be effective in predicting the short and long-term beneficial effects on glycaemia.With the present study, we investigated T-cell and antibody responses against CD300e, an antigen highly expressed in the adipose tissue of patients with obesity before the bariatric surgery-induced weight loss. We found both in fat tissue and in peripheral blood anti-CD300e-specific T helper 1 responses. Moreover, we evidenced in the sera of individuals with obesity an antibody response towards CD300e and revealed the existence of a significant correlation between the level of antibodies before surgery and the maintenance of glucose control after the intervention.

Metabolic Slowing Vanished 5 Years After Sleeve Gastrectomy in Patients With Obesity and Prediabetes/Diabetes.

BACKGROUND: Resting energy expenditure (REE) decreases after weight loss more than expected according to body composition changes. Metabolic adaptation (MA) or metabolic slowing represents the difference between measured (m) and predicted (p) REE, and it is not clear whether it persists in the long-term. The aim of this study is to evaluate MA occurring 1 year (V1) and 5 years (V5) after laparoscopic sleeve gastrectomy (LSG) in patients with obesity and normal glucose tolerance, prediabetes (preDM) and type 2 diabetes (T2DM). METHODS: We reassessed 37 patients (14 males/23 females) of 44.8 ±â€…10 years old, since they registered all the biochemical, body composition, and REE assessments at baseline (V0), V1, and V5. Physical activity (PA) was assessed by interview and questionnaire. RESULTS: Patients displayed a percentage of weight loss of 31.5 ±â€…7.4% at V1 and a weight regain of 8.9 ±â€…7.5% at V5. Comparing V1 and V5, fat mass showed a slight increase (P = 0.011), while free fat mass remained unchanged (P = 0.304). PA improved at V1 (P < 0.001), remaining stable at V5 (P = 0.9). Measured REE (mREE) displayed a 31.2% reduction with a corresponding decrease of predicted REE (pREE) of 21.4% at V1, compared with V0 (P = 0.005), confirming a significant MA at V1. Conversely, no difference between mREE and pREE was observed at V5 (P = 0.112). CONCLUSION: Our results suggested that only patients with preDM and T2DM displayed MA at V1, which vanished 5 years after LSG. Patients who practiced more PA prevent MA after surgery-induced wight loss.

Bone metastases from neuroendocrine tumors: clinical and biological considerations.

We considered 351 patients affected by neuroendocrine tumors (NETs), followed at the University Hospital of Padua and at the Veneto Oncological Institute. Of these, 72 (20.5%) suffered from bone metastases. The sample was divided according to the timing of presentation of bone metastases into synchronous (within 6 months of diagnosis of primary tumor) and metachronous (after 6 months). We collected data on the type and grading of the primary tumor and on the features of bone metastases. Our analysis shows that the group of synchronous metastases generally presents primary tumors with a higher degree of malignancy rather than the ones of the metachronous group. This is supported by the finding of a Ki-67 level in GEP-NETs, at the diagnosis of bone metastases, significantly higher in the synchronous group. Moreover, in low-grade NETs, chromogranin A values are higher in the patients with synchronous metastases, indicating a more burden of disease. The parameters of phospho-calcium metabolism are within the normal range, and we do not find significant differences between the groups. Serious bone complications are not frequent and are not correlated with the site of origin of the primary tumor. From the analysis of the survival curves of the total sample, a cumulative survival rate of 33% at 10 years emerges. The average survival is 80 months, higher than what is reported in the literature, while the median is 84 months. In our observation period, synchronous patients tend to have a worse prognosis than metachronous ones with 52-months survival rates of 58 and 86%.

Time-series analysis of multidimensional clinical-laboratory data by dynamic Bayesian networks reveals trajectories of COVID-19 outcomes.

BACKGROUND AND OBJECTIVE: COVID-19 severity spans an entire clinical spectrum from asymptomatic to fatal. Most patients who require in-hospital care are admitted to non-intensive wards, but their clinical conditions can deteriorate suddenly and some eventually die. Clinical data from patients' case series have identified pre-hospital and in-hospital risk factors for adverse COVID-19 outcomes. However, most prior studies used static variables or dynamic changes of a few selected variables of interest. In this study, we aimed at integrating the analysis of time-varying multidimensional clinical-laboratory data to describe the pathways leading to COVID-19 outcomes among patients initially hospitalised in a non-intensive care setting. METHODS: We collected the longitudinal retrospective data of 394 patients admitted to non-intensive care units at the University Hospital of Padova (Padova, Italy) due to COVID-19. We trained a dynamic Bayesian network (DBN) to encode the conditional probability relationships over time between death and all available demographics, pre-existing conditions, and clinical laboratory variables. We applied resampling, dynamic time warping, and prototyping to describe the typical trajectories of patients who died vs. those who survived. RESULTS: The DBN revealed that the trajectory linking demographics and pre-existing clinical conditions to death passed directly through kidney dysfunction or, more indirectly, through cardiac damage. As expected, admittance to the intensive care unit was linked to markers of respiratory function. Notably, death was linked to elevation in procalcitonin and D-dimer levels. Death was associated with persistently high levels of procalcitonin from admission and throughout the hospital stay, likely reflecting bacterial superinfection. A sudden raise in D-dimer levels 3-6 days after admission was also associated with subsequent death, possibly reflecting a worsening thrombotic microangiopathy. CONCLUSIONS: This innovative application of DBNs and prototyping to integrated data analysis enables visualising the patient's trajectories to COVID-19 outcomes and may instruct timely and appropriate clinical decisions.

Effects of acute administration of trimethylamine N-oxide on endothelial function: a translational study.

Elevated circulating levels of nutrient-derived trimethylamine N-oxide (TMAO) have been associated with the onset and progression of cardiovascular disease by promoting athero-thrombosis. However, in conditions like bariatric surgery (Roux-en-Y gastric bypass, RYGB), stable increases of plasma TMAO are associated with improved endothelial function and reduced cardiovascular morbidity and mortality, thus questioning whether a mechanistic relationship between TMAO and endothelial dysfunction exists. Herein, we translationally assessed the effects of acute TMAO exposure on endothelial dysfunction, thrombosis and stroke. After RYGB, fasting circulating levels of TMAO increased in patients and obese rats, in parallel with an improved gluco-lipid profile and higher circulating bile acids. The latter enhanced FXR-dependent signalling in rat livers, which may lead to higher TMAO synthesis post RYGB. In lean rats, acute TMAO injection (7 mg kg-1) 1.5-h before sacrifice and ex-vivo 30-min incubation of thoracic aortas with 10-6 M TMAO did not impair vasodilation in response to acetylcholine (Ach), glucagon-like peptide 1, or insulin. Similarly, in lean WT mice (n = 5-6), TMAO injection prior to subjecting mice to ischemic stroke or arterial thrombosis did not increase its severity compared to vehicle treated mice. Endothelial nitric oxide synthase (eNOS) activity and intracellular stress-activated pathways remained unaltered in aorta of TMAO-injected rats, as assessed by Western Blot. Pre-incubation of human aortic endothelial cells with TMAO (10-6 M) did not alter NO release in response to Ach. Our results indicate that increased plasmatic TMAO in the near-physiological range seems to be a neutral bystander to vascular function as translationally seen in patients after bariatric surgery or in healthy lean rodent models and in endothelial cells exposed acutely to TMAO.

Molecular and Pharmacological Evidence for the Expression of Multiple Functional P2 Purinergic Receptors in Human Adipocytes.

Extracellular ATP exerts important functions as an extracellular signaling molecule via the activation of specific P2 purinergic receptors (P2X and P2Y). We investigated the expression of the different P2 receptors and their possible functional activation in human adipocytes in primary culture. We performed molecular expression analysis of the P2 receptors in human mature adipocytes; examined their functional activation by different nucleotides evaluating [Ca2+]i modifications and IL-6 secretion, and determined the ability of adipocytes to release ATP in the extracellular medium. Human adipocytes express different P2X and P2Y receptors. Extracellular ATP elicited a rise in [Ca2+]i via the activation of P2X and P2Y receptor subtypes. Human adipocytes spontaneously released ATP in the extracellular medium and secreted IL-6 both at rest and after stimulation with ATP. This stimulatory effect of ATP on IL-6 secretion was inhibited by pre-incubation with apyrase, an ATP metabolizing enzyme. These results demonstrate that human adipocytes express different P2X and P2Y receptors that are functionally activated by extracellular nucleotides. Furthermore, human adipocytes spontaneously release ATP, which can act in an autocrine/paracrine fashion on adipocytes, possibly participating in the regulation of inflammatory cytokine release. Thus, P2 purinergic receptors could be a potential therapeutic target to contrast the inflammatory and metabolic complications characterizing obesity.