Helminth infection modulates number and function of adipose tissue Tregs in high fat diet-induced obesity.

BACKGROUND: Epidemiological and experimental studies have shown a protective effect of helminth infections in weight gain and against the development of metabolic dysfunctions in the host. However, the mechanisms Treg cells exert in the helminth-obesity interface has been poorly investigated. The present study aimed to verify the influence of Heligmosomoides polygyrus infection in early stages of high fat diet-induced obesity. PRINCIPAL FINDINGS: The presence of infection was able to prevent exacerbated weight gain in mice fed with high fat diet when compared to non-infected controls. In addition, infected animals displayed improved insulin sensitivity and decreased fat accumulation in the liver. Obesity-associated inflammation was reduced in the presence of infection, demonstrated by lower levels of leptin and resistin, lower infiltration of Th1 and Th17 cells in adipose tissue, higher expression of IL10 and adiponectin, increased infiltration of Th2 and eosinophils in adipose tissue of infected animals. Of note, the parasite infection was associated with increased Treg frequency in adipose tissue which showed higher expression of cell surface markers of function and activation, like LAP and CD134. The infection could also increase adipose Treg suppressor function in animals on high fat diet. CONCLUSION: These data suggest that H. polygyrus modulates adipose tissue Treg cells with implication for weight gain and metabolic syndrome.

Group VR experiences can produce ego attenuation and connectedness comparable to psychedelics.

With a growing body of research highlighting the therapeutic potential of experiential phenomenology which diminishes egoic identity and increases one's sense of connectedness, there is significant interest in how to elicit such 'self-transcendent experiences' (STEs) in laboratory contexts. Psychedelic drugs (YDs) have proven particularly effective in this respect, producing subjective phenomenology which reliably elicits intense STEs. With virtual reality (VR) emerging as a powerful tool for constructing new perceptual environments, we describe a VR framework called 'Isness-distributed' (Isness-D) which harnesses the unique affordances of distributed multi-person VR to blur conventional self-other boundaries. Within Isness-D, groups of participants co-habit a shared virtual space, collectively experiencing their bodies as luminous energetic essences with diffuse spatial boundaries. It enables moments of 'energetic coalescence', a new class of embodied intersubjective experience where bodies can fluidly merge, enabling participants to include multiple others within their self-representation. To evaluate Isness-D, we adopted a citizen science approach, coordinating an international network of Isness-D 'nodes'. We analyzed the results (N = 58) using 4 different self-report scales previously applied to analyze subjective YD phenomenology (the inclusion of community in self scale, ego-dissolution inventory, communitas scale, and the MEQ30 mystical experience questionnaire). Despite the complexities associated with a distributed experiment like this, the Isness-D scores on all 4 scales were statistically indistinguishable from recently published YD studies, demonstrating that distributed VR can be used to design intersubjective STEs where people dissolve their sense of self in the connection to others.

Inconsistent effects of gluten on obesity: is there a role for the haptoglobin isoforms?

BACKGROUND AND AIMS: There is no clear evidence about the effects of gluten intake on obesity. It is known that gluten's effects on gut permeability are mediated by zonulin, a protein identified as pre-haptoglobin 2, a physiological regulator of the intestinal barrier. We investigated the obesogenic and inflammatory effects of gluten and its association with the haptoglobin genotype. METHODS: This was a single blinded, crossover study, including 40 overweight or obesity women free of celiac disease. Participants adopted a gluten-free diet (GFD) for 8 weeks and consumed a gluten-free muffin (GF-M) or a gluten-containing muffin (GLU-M, 24 g gluten) for 4 weeks, switching muffin type during the subsequent 4 weeks. During a follow-up period of 4 weeks we evaluated the usual diet (UD). Food diaries were collected to estimate the macronutrient intake and dietary inflammatory index (DII®). Bodyweight and composition, resting energy expenditure (REE), and cytokines were assessed. Haptoglobin alleles (Hp1 and Hp2) were genotyped to characterize zonulin expression. RESULTS: Energy and macronutrient intakes were similar during both periods, except for protein intake, which was higher during GLU-M. DII scores indicated a more inflammatory profile during the GF-M and GLU-M periods compared to UD. No differences were observed in body composition or REE between interventions when the Hp genotype was not considered. Nonetheless, those carrying the Hp2-2 genotype (overexpressing zonulin) presented lower REE and higher levels of IL6 and IL1beta only during gluten intake (GLU-M and UD) compared to age- and body mass index-matched Hp1-1 carrier. These results suggest an obesogenic and inflammatory action of gluten only in those overexpressing zonulin (Hp2-2). CONCLUSION: These results highlight the importance of zonulin as the mediator of gluten obesogenic and inflammatory effects. Our data suggest that in the presence of gluten, zonulin release is associated with a reduction of REE and an increase of inflammatory markers that are not seen in zonulin low producers.

Appetite control: hormones or diet strategies?

PURPOSE OF REVIEW: Appetite control results from metabolic, behavioral, and environmental factors that influence hunger and the desire to eat. We summarize the latest advances in the hormonal and nutritional strategies to control appetite and reduce hunger. RECENT FINDINGS: The fed-hunger-state is regulated by central and peripheric hormones, which modulate energy balance. Leptin, insulin, ghrelin, peptide YY (PYY), and other gut-derived peptides represent the main appetite controllers. The role of orexins, obestatin, and liver-expressed antimicrobial peptide 2 has been uncovered recently. New insights have demonstrated the role of hippocampal activity as a possible mechanism of action. Glucagon-like peptide 1 (GLP1) receptor agonists are well known agents controlling appetite. Association of GLP1 receptor agonist, PYY, or glucose-dependent insulinotropic polypeptide agonists have been tested as new approaches. Appetite-control hormones have also risen as factors involved in the efficacy of bariatric procedures. High-protein, ketogenic diet, and intermittent fasting have been described as nutritional strategies to reduce appetite, although the physiological mechanism and long-term safety remains unclear. SUMMARY: Appetite control has been an important target for the treatment of obesity and associated disorders. New studies have demonstrated promising adoption of dietary approaches, hormone-based drugs, and bariatric surgery to control energy intake. Further research will establish a significant association, benefits, and safety of these new therapies.

Interleukin-10 and Zonulin Are Associated With Postoperative Delayed Gastric Emptying in Critically Ill Surgical Pediatric Patients: A Prospective Pilot Study.

BACKGROUND: Impaired gastric emptying (GE) is associated with morbidity in surgical critically ill children. The relationship between inflammation, gut barrier integrity (lipopolysaccharide binding protein [LBP]; zonulin), and GE has not been described in this cohort. METHODS: Children ≥2 years of age and requiring critical care after surgery were enrolled. Preoperative and postoperative levels of serum cytokines, LBP, and zonulin, and GE by the acetaminophen absorption test, were measured, allowing patients to serve as their own controls. Postoperative delayed GE was defined as a decrease in GE by ≥20% compared with preoperative GE. The following were examined : comparison between postoperative andpreoperative values, correlations between fold change (postoperative/preoperative) in study variables, and fold change in study variables between patients with and without postoperative delayed GE. RESULTS: Twenty patients, median age 14 years (12.25, 18), 12 female, were included. Eight of 20 patients had postoperative delayed GE. Postoperative interleukin-6 (IL-6), IL-8, IL-10, and LBP were increased, and zonulin was decreased (P-values < .05). Fold change in IL-10 and zonulin were inversely correlated (ρ -0.618, P = .004). Patients with postoperative delayed GE had greater fold increase in IL-10 (P = .0159) and fold decrease in zonulin (P = .0160). Five of 7 (71%) patients with both fold increase in IL-10 and decrease in zonulin had delayed GE. CONCLUSION: Postoperative changes in IL-10 and zonulin were associated with delayed GE in surgical critically ill children, which might suggest a mechanism to for delayed GE in postoperative inflammation and gut barrier dysregulation after surgery.

Scientific evidence of diets for weight loss: Different macronutrient composition, intermittent fasting, and popular diets.

New dietary strategies have been created to treat overweight and obesity and have become popular and widely adopted. Nonetheless, they are mainly based on personal impressions and reports published in books and magazines, rather than on scientific evidence. Animal models and human clinical trials have been employed to study changes in body composition and metabolic outcomes to determine the most effective diet. However, the studies present many limitations and should be carefully analyzed. The aim of this review was to discuss the scientific evidence of three categories of diets for weight loss. There is no one most effective diet to promote weight loss. In the short term, high-protein, low-carbohydrate diets and intermittent fasting are suggested to promote greater weight loss and could be adopted as a jumpstart. However, owing to adverse effects, caution is required. In the long term, current evidence indicates that different diets promoted similar weight loss and adherence to diets will predict their success. Finally, it is fundamental to adopt a diet that creates a negative energy balance and focuses on good food quality to promote health.

Intestinal Epithelium Modulates Macrophage Response to Gliadin in Celiac Disease.

Celiac disease is an immune-mediated enteropathy triggered by ingestion of gluten. Although its pathogenesis has been extensively studied and the contribution from both innate and adaptive immune responses has been reported, little is still known about the contribution of macrophages to the onset or maintenance of the disease. Macrophages are extremely plastic immune cells that can be directed toward a pro- or anti-inflammatory phenotype by the surrounding microenvironment. Of note, gliadin, the most prominent causative agent of the disease, has been reported to trigger the production of pro-inflammatory cytokines in this cell population. In the present study, we aimed at investigating how the intestinal milieu and more specifically the epithelium can shape the macrophage response to gliadin. Using patient-derived organoids we showed that the intestinal epithelium derived from celiac disease donors releases anti-inflammatory factors that curb the macrophage response to gliadin. Furthermore, we uncovered that the celiac macrophages were better responders than macrophages derived from non-celiac controls. Finally, we demonstrated that IFNγ released by the epithelium is in part responsible of the observed anti-inflammatory effect. Our data shed light on the cross-talk between the immune system and the epithelium and its critical role in the intestinal homeostasis. Furthermore, we provide more evidence how alterations in the innate immune machinery in celiac patients may contribute to the onset of the disease.

Human gut derived-organoids provide model to study gluten response and effects of microbiota-derived molecules in celiac disease.

Celiac disease (CD) is an immune-mediated disorder triggered by gluten exposure. The contribution of the adaptive immune response to CD pathogenesis has been extensively studied, but the absence of valid experimental models has hampered our understanding of the early steps leading to loss of gluten tolerance. Using intestinal organoids developed from duodenal biopsies from both non-celiac (NC) and celiac (CD) patients, we explored the contribution of gut epithelium to CD pathogenesis and the role of microbiota-derived molecules in modulating the epithelium's response to gluten. When compared to NC, RNA sequencing of CD organoids revealed significantly altered expression of genes associated with gut barrier, innate immune response, and stem cell functions. Monolayers derived from CD organoids exposed to gliadin showed increased intestinal permeability and enhanced secretion of pro-inflammatory cytokines compared to NC controls. Microbiota-derived bioproducts butyrate, lactate, and polysaccharide A improved barrier function and reduced gliadin-induced cytokine secretion. We concluded that: (1) patient-derived organoids faithfully express established and newly identified molecular signatures characteristic of CD. (2) microbiota-derived bioproducts can be used to modulate the epithelial response to gluten. Finally, we validated the use of patient-derived organoids monolayers as a novel tool for the study of CD.

Human Fetal-Derived Enterospheres Provide Insights on Intestinal Development and a Novel Model to Study Necrotizing Enterocolitis (NEC).

BACKGROUND & AIMS: Untreated necrotizing enterocolitis (NEC) can lead to massive inflammation resulting in intestinal necrosis with a high mortality rate in preterm infants. Limited access to human samples and relevant experimental models have hampered progress in NEC pathogenesis. Earlier evidence has suggested that bacterial colonization of an immature and developing intestine can lead to an abnormally high inflammatory response to bacterial bioproducts. The aim of our study was to use human fetal organoids to gain insights into NEC pathogenesis. METHODS: RNA sequencing analysis was performed to compare patterns of gene expression in human fetal-derived enterospheres (FEnS) and adult-derived enterospheres (AEnS). Differentially expressed genes were analyzed using computational techniques for dimensional reduction, clustering, and gene set enrichment. Unsupervised cluster analysis, Gene Ontology, and gene pathway analysis were used to predict differences between gene expression of samples. Cell monolayers derived from FEnS and AEnS were evaluated for epithelium function and responsiveness to lipopolysaccharide and commensal bacteria. RESULTS: Based on gene expression patterns, FEnS clustered according to their developmental age in 2 distinct groups: early and late FEnS, with the latter more closely resembling AEnS. Genes involved in maturation, gut barrier function, and innate immunity were responsible for these differences. FEnS-derived monolayers exposed to either lipopolysaccharide or commensal Escherichia coli showed that late FEnS activated gene expression of key inflammatory cytokines, whereas early FEnS monolayers did not, owing to decreased expression of nuclear factor-κB-associated machinery. CONCLUSIONS: Our results provide insights into processes underlying human intestinal development and support the use of FEnS as a relevant human preclinical model for NEC. Accession number of repository for expression data: GSE101531.

Widely Used Commercial ELISA Does Not Detect Precursor of Haptoglobin2, but Recognizes Properdin as a Potential Second Member of the Zonulin Family.

BACKGROUND: There is increasing evidence for the role of impaired intestinal permeability in obesity and associated metabolic diseases. Zonulin is an established serum marker for intestinal permeability and identical to pre-haptoglobin2. Here, we aimed to investigate the relationship between circulating zonulin and metabolic traits related to obesity. METHODS: Serum zonulin was measured by using a widely used commercial ELISA kit in 376 subjects from the metabolically well-characterized cohort of Sorbs from Germany. In addition, haptoglobin genotype was determined in DNA samples from all study subjects. RESULTS: As zonulin concentrations did not correlate to the haptoglobin genotypes, we investigated the specificity of the zonulin ELISA assay using antibody capture experiments, mass spectrometry, and Western blot analysis. Using serum samples that gave the highest or lowest ELISA signals, we detected several proteins that are likely to be captured by the antibody in the present kit. However, none of these proteins corresponds to pre-haptoglobin2. We used increasing concentrations of recombinant pre-haptoglobin2 and complement C3 as one of the representative captured proteins and the ELISA kit did not detect either. Western blot analysis using both the polyclonal antibodies used in this kit and monoclonal antibodies rose against zonulin showed a similar protein recognition pattern but with different intensity of detection. The protein(s) measured using the ELISA kit was (were) significantly increased in patients with diabetes and obesity and correlated strongly with markers of the lipid and glucose metabolism. Combining mass spectrometry and Western blot analysis using the polyclonal antibodies used in the ELISA kit, we identified properdin as another member of the zonulin family. CONCLUSION: Our study suggests that the zonulin ELISA does not recognize pre-haptoglobin2, rather structural (and possibly functional) analog proteins belonging to the mannose-associated serine protease family, with properdin being the most likely possible candidate.

Perceção dos enfermeiros acerca da cultura de segurança do doente hospitalizado / Nurses' perceptions of the safety culture safety of the hospitalized patient

A segurança do doente é uma preocupação dos governos, tendo a Organização Mundial de Saúde recomendado a avaliação da cultura de segurança do doente a cada 2 anos, a fim de se conhecer as áreas problemáticas neste âmbito e também permitir a monitorização e a implementação de medidas que contribuem para a qualidade e segurança dos cuidados. Assim, a fim de conhecer a perceção dos enfermeiros relativamente à cultura de segurança do doente hospitalizado formulou-se a seguinte questão de investigação: Qual a perceção dos enfermeiros do Centro Hospitalar do Baixo Vouga (CHBV) - unidade de Aveiro acerca da cultura de segurança do doente hospitalizado? Formulou-se como objetivos deste estudo: conhecer a perceção dos enfermeiros do CHBV - Unidade de Aveiro acerca da cultura de segurança do doente hospitalizado; saber se a idade, a experiência profissional, formação dos enfermeiros na área da segurança do doente/gestão de risco e as habilitações académicas interferem na perceção destes sobre cultura de segurança e identificar os pontos fortes e os pontos que necessitam de melhoria no que diz respeito à cultura de segurança. Desenvolveu-se um estudo descritivo, exploratório e correlacional de abordagem quantitativa, numa amostra de 217 enfermeiros do CHBV ? unidade de Aveiro, a quem aplicamos o questionário ?Hospital Survey on Patient Safety Culture? traduzido para a população Portuguesa, para colheita de dados. Das dimensões estudadas não se identificaram dimensões como pontos fortes da cultura de segurança do doente hospitalizado. No entanto, as dimensões mais positivas foram: ?o trabalho em equipa?, as ?transições? e a ?abertura na comunicação?. As dimensões identificadas como oportunidades de melhoria que se destacaram por apresentarem valores percentuais de respostas positivas abaixo dos 20% foram as dimensões: ?resposta ao erro não punitiva?, ?frequência da notificação de eventos? e ?apoio à segurança do doente pela gestão?. Em suma, deve-se continuar a investir numa cultura de incentivo à aprendizagem, à notificação do erro e à implementação de politicas de saúde centrada no doente. Isto é possível através de formação dos profissionais na área da segurança/gestão de risco, mas também através da desmistificação da culpabilização, do trabalho em equipa, da comunicação e partilha de informações de modo a que todos os profissionais de saúde possam, em conjunto, contribuir para a segurança dos cuidados de saúde.

Intestinal toxicity evaluation of long-circulating and pH-sensitive liposomes loaded with cisplatin.

Cisplatin (CDDP) is a chemotherapeutic agent widely used in several anticancer protocols for instance head and neck, testicle, ovarian, lung and peritoneal carcinomatosis. According to the literature, the use of CDDP is associated with several side effects; among them, we highlighted the mucositis. CDDP, when administered by IP, promoted significant intestinal epithelium alterations in an experimental model. Our research group has proposed that the incorporation of CDDP into long-circulating and pH-sensitive liposomes (SpHL-CDDP) could help to overcome some side effects induced by this drug. Thus, we evaluated signs of intestinal toxicity 24h and 72h after the administration of a single i.p dose of free CDDP or SpHL-CDDP to healthy Swiss mice. Twenty-four hours after administration of free CDDP, the mice showed signs of intestinal toxicity, principally weight loss, increased intestinal permeability associated with a decrease in expression of tight junctions, and histological damage with the presence of inflammatory infiltrates and activation of ERK1/2 and NF-κB. These changes persisted after 72h. While signs of intestinal toxicity were also observed 24h after administration of SpHL-CDDP, after 72h body weight and intestinal permeability of mice in this group were similar to those of mice in the control group. In comparison with the free CDDP treatment group, 72h after treatment mice in the SpHL-CDDP group showed better histological parameters, lower levels of inflammatory infiltrate with increased IL-10 and IgA levels, and less activation of caspase-3, ERK1/2 and NF-κB. These differences could account for the recovery of the intestinal epithelium observed in mice treated with SpHL-CDDP but not in mice treated with free CDDP. In conclusion, here we show that encapsulation of CDDP in SpHL lessens intestinal damage and that, as such, SpHL-CDDP is a promising candidate for clinical use.

Synthesis and evaluation of platinum complexes with potential antitumor activity

Abstract A novel series of platinum (II) complexes was synthesized and the complexes were evaluated for their in vitro cytotoxicity against four human cancer cells lines. Five platinum complexes showed activity against at least one tumor cell line. Complexes 3 and 6 were promising, being active, at micromolar concentrations, against all the assayed tumor cell lines. Compound 3 was selected for further studies in mice with Ehrlich solid tumors and it was able to reduce the rate of tumor growth significantly during the first seven days. However, at the end of the experiments, there was no significant difference between the group of animals treated with 3 and the control group. The low solubility of the compound in the assay conditions can explain, at least in part, these results.

Food quality, physical activity, and nutritional follow-up as determinant of weight regain after Roux-en-Y gastric bypass.

OBJECTIVE: Assess the lifestyle habits, including food patterns, of patients who underwent Roux-en-Y gastric bypass (RYGB) and to identify predictive factors in weight loss and regain. METHODS: Obese patients (100) who underwent RYGB from 1998 to 2008 were included. Dietary habits were assessed by using 24 h dietary recall and the Food Frequency Questionnaire. Rates of weight regain and the percentage of excess weight loss (EWL) were calculated. Patients were also asked whether they attended nutritional follow-up visits after the operation and about the type and regularity of physical activities. RESULTS: The mean age was 45.1 ± 9.9 y, and the majority of the patients were women (84%). Mean EWL was 59.1 ± 20.3%. Weight regain was seen in 56% of the patients with 29% of the patients having regained over 10.1% of the minimum weight reached after RYGB. Weight regain increased significantly with time after surgery (up to 2 y: 14.7%; from 2 to 5 y: 69.7%; over 5 y: 84.8%). Poor diet quality characterized by excessive intake of calories, snacks, sweets, and fatty foods was statistically higher among those who regained weight. Sedentary lifestyle and lack of nutritional counseling follow-up were also significantly associated with regaining weight. CONCLUSION: Despite satisfactory results of EWL, the patients did not properly maintain the lost weight, mainly after 5 y postsurgery. Major factors that influenced this weight gain were poor diet quality, sedentary lifestyle, and lack of nutritional counseling follow-up.