Inborn errors of metabolism: Lessons from iPSC models.

The possibility of reprogramming human somatic cells to pluripotency has opened unprecedented opportunities for creating genuinely human experimental models of disease. Inborn errors of metabolism (IEMs) constitute a greatly heterogeneous class of diseases that appear, in principle, especially suited to be modeled by iPSC-based technology. Indeed, dozens of IEMs have already been modeled to some extent using patient-specific iPSCs. Here, we review the advantages and disadvantages of iPSC-based disease modeling in the context of IEMs, as well as particular challenges associated to this approach, together with solutions researchers have proposed to tackle them. We have structured this review around six lessons that we have learnt from those previous modeling efforts, and that we believe should be carefully considered by researchers wishing to embark in future iPSC-based models of IEMs.

Cationic Carbosilane Dendrimers Prevent Abnormal α-Synuclein Accumulation in Parkinson's Disease Patient-Specific Dopamine Neurons.

Accumulation of misfolded α-synuclein (α-syn) is a hallmark of Parkinson's disease (PD) thought to play important roles in the pathophysiology of the disease. Dendritic systems, able to modulate the folding of proteins, have emerged as promising new therapeutic strategies for PD treatment. Dendrimers have been shown to be effective at inhibiting α-syn aggregation in cell-free systems and in cell lines. Here, we set out to investigate the effects of dendrimers on endogenous α-syn accumulation in disease-relevant cell types from PD patients. For this purpose, we chose cationic carbosilane dendrimers of bow-tie topology based on their performance at inhibiting α-syn aggregation in vitro. Dopamine neurons were differentiated from induced pluripotent stem cell (iPSC) lines generated from PD patients carrying the LRRK2G2019S mutation, which reportedly display abnormal accumulation of α-syn, and from healthy individuals as controls. Treatment of PD dopamine neurons with non-cytotoxic concentrations of dendrimers was effective at preventing abnormal accumulation and aggregation of α-syn. Our results in a genuinely human experimental model of PD highlight the therapeutic potential of dendritic systems and open the way to developing safe and efficient therapies for delaying or even halting PD progression.

Inhibition of Notch rescues the angiogenic potential impaired by cardiovascular risk factors in epicardial adipose stem cells.

The epicardial adipose tissue (EAT) is a reservoir of adipose-derived stem cells (ASCs), with as yet unknown effects on myocardial and coronary arteries homeostasis. The purpose of this study was to investigate the angiogenic function of epicardial ASCs and their regulation by the common cardiovascular risk factors (CVRFs) affecting heart disease. Epicardial fat was obtained from a rodent model with clustering of CVRFs [Zucker diabetic fatty (ZDF)-Lepr(fa)] rats and from their lean control (ZDF-Crl) littermates without CVRFs, ASCs were isolated, and their function was assessed by proliferation and differentiation assays, flow cytometry, gene expression, and in vivo Matrigel angiogenesis analysis. Epicardial ASCs from both groups showed adipogenic and osteogenic differentiation capacity; however, epicardial ASCs from CVRF animals had a lesser ability to form tubular structures in vitro after endothelial differentiation, as well as a reduced angiogenic potential in vivo compared to control animals. Epicardial ASCs from CVRF rats showed up-regulation of the downstream Notch signaling genes Hes7, Hey1, and Heyl compared with control animals. The inhibition of Notch signaling by conditioning epicardial ASCs from CVRF animals with a γ-secretase inhibitor induced a reduction in Hes/Hey gene expression and rescued their angiogenic function in vivo We report for the first time the impact of CVRF burden on the ASCs of EAT and that the defective function is in part caused by increased Notch signaling. Conditioning ASCs by blocking Notch signaling rescues their angiogenic potential.-Bejar, M. T., Ferrer-Lorente, R., Peña, E., Badimon, L. Inhibition of Notch rescues the angiogenic potential impaired by cardiovascular risk factors in epicardial adipose stem cells.

Systems biology approach to identify alterations in the stem cell reservoir of subcutaneous adipose tissue in a rat model of diabetes: effects on differentiation potential and function.

AIMS/HYPOTHESIS: Autologous progenitor cells represent a promising option for regenerative cell-based therapies. Nevertheless, it has been shown that ageing and cardiovascular risk factors such as diabetes affect circulating endothelial and bone marrow-derived progenitor cells, limiting their therapeutic potential. However, their impact on other stem cell populations remains unclear. We therefore investigated the effects of diabetes on adipose-derived stem cells (ASCs) and whether these effects might limit the therapeutic potential of autologous ASCs. METHODS: A systems biology approach was used to analyse the expression of genes related to stem cell identification in subcutaneous adipose tissue (SAT), the stromal vascular fraction and isolated ASCs from Zucker diabetic fatty rats and their non-diabetic controls. An additional model of type 2 diabetes without obesity was also investigated. Bioinformatic approaches were used to investigate the biological significance of these changes. In addition, functional studies on cell viability and differentiation potential were performed. RESULTS: Widespread downregulation of mesenchymal stem cell markers was observed in SAT of diabetic rats. Gene expression and in silico analysis revealed a significant effect on molecules involved in the maintenance of pluripotency and self-renewal, and on the alteration of main signalling pathways important for stem cell maintenance. The viability and differentiation potential of ASCs from diabetic rats was impaired in in vitro models and in in vivo angiogenesis. CONCLUSIONS/INTERPRETATION: The impact of type 2 diabetes on ASCs might compromise the efficiency of spontaneous self-repair and direct autologous stem cell therapy.

Selective inhibition of sphingosine kinase-1 protects adipose tissue against LPS-induced inflammatory response in Zucker diabetic fatty rats.

Obesity is associated with a state of chronic inflammation. The chemokine (C-C motif) ligand 5 (CCL5) has been proposed to modulate the inflammatory response in adipose tissue (AT). However, the mechanisms underlying CCL5 upregulation in AT remain undefined. The objective of the present study was to evaluate whether the enzyme sphingosine kinase-1 (SK1) would modulate the expression of CCL5 and other inflammatory biomarkers in primary adipocytes and its potential role in lipopolysaccharide (LPS)-induced AT inflammation in a rat model of diabetes. To address this, LPS-stimulated primary adipocytes and 3T3-L1 cells were treated with a SK inhibitor, and the expression of Ccl5 and other CC chemokines were studied. Moreover, the effect of SK1 knockdown on cytokine production was analyzed in 3T3-L1 cells by transfection of SK1-specific small-interfering RNA (siRNA). The anti-inflammatory effects of SK inhibitor in AT were also investigated in vivo using the Zucker lean normoglycemic control (ZLC) rats. LPS treatment stimulated Ccl5, IL-6, pentraxin 3 (Ptx3), and Tnfα mRNA expression in primary adipocytes and 3T3-L1 cells, whereas pharmacologically and siRNA-mediated SK1 inhibition strongly reduced mRNA levels of proinflammatory cytokines in these cells. Similarly, administration of SK inhibitor to ZLC rats prevented the LPS-induced inflammatory response in AT. Our data demonstrate a role for SK1 in endotoxin-induced cytokine expression in adipocytes and suggest that inhibition of SK1 may be a potential therapeutic tool in the prevention and treatment of chronic and common metabolic disorders, including obesity, insulin-resistance, and type 2 diabetes.

Low thymic output, peripheral homeostasis deregulation, and hastened regulatory T cells differentiation in children with 22q11.2 deletion syndrome.

OBJECTIVE: To perform an extensive analysis of the immune status of asymptomatic children with the 22q11.2 deletion syndrome, with special emphasis on the regulatory T cells (Treg) population. STUDY DESIGN: Analysis of thymic function, frequency and absolute counts of immune subsets, and phenotype of Treg were performed in 10 asymptomatic children bearing the 22q11.2 deletion and compared with 12 age-matched, healthy children. RESULTS: Children with 22q11.2 deletion syndrome showed a curtailed thymic output, lower T-cell levels, and a homeostatic deregulation in the CD4 T-cell compartment, characterized by a greater proliferative history in the naïve CD4 T-cell subset. Treg numbers were markedly reduced in children with 22q11.2 deletion syndrome, and remaining Treg showed mostly an activated phenotype. CONCLUSIONS: Reduced thymic output in children with 22q11.2 deletion syndrome could be related with an increased proliferation in the naïve CD4 T-cell compartment and the consequent Treg activation to ensure that T-cell expansion remains under control. Deregulated peripheral homeostasis and loss of suppressive capacity by Treg could compromise the integrity of T-cell immunity during adulthood and play a relevant role in the increased incidence of autoimmune diseases reported in patients with the 22q11.2 deletion syndrome.

Synergistic activity profile of carbosilane dendrimer G2-STE16 in combination with other dendrimers and antiretrovirals as topical anti-HIV-1 microbicide.

Polyanionic carbosilane dendrimers represent opportunities to develop new anti-HIV microbicides. Dendrimers and antiretrovirals (ARVs) acting at different stages of HIV replication have been proposed as compounds to decrease new HIV infections. Thus, we determined the potential use of our G2-STE16 carbosilane dendrimer in combination with other carbosilane dendrimers and ARVs for the use as topical microbicide against HIV-1. We showed that these combinations obtained 100% inhibition and displayed a synergistic profile against different HIV-1 isolates in our model of TZM.bl cells. Our results also showed their potent activity in the presence of an acidic vaginal or seminal fluid environment and did not activate an inflammatory response. This study is the first step toward exploring the use of different anionic carbosilane dendrimers in combination and toward making a safe microbicide. Therefore, our results support further studies on dendrimer/dendrimer or dendrimer/ARV combinations as topical anti-HIV-1 microbicide. FROM THE CLINICAL EDITOR: This paper describes the first steps toward the use of anionic carbosilane dendrimers in combination with antivirals to address HIV-1, paving the way to further studies on dendrimer/dendrimer or dendrimer/ARV combinations as topical anti-HIV-1 microbicides.

The effects of acute exercise on food intake and appetite in adolescents with and without obesity: A systematic review and meta-analysis.

This systematic review and meta-analysis synthesized evidence pertaining to consummatory and appetitive responses to acute exercise in children and adolescents with and without obesity (5-18 years). Articles reporting on supervised, controlled trials of any modality, duration, or intensity with laboratory-measured food intake were found using MEDLINE, EMBASE, and Cochrane up to July 2023. Differences between conditions in laboratory energy and macronutrient intake, appetite sensations, and food reward were quantitatively synthesized using random-effects meta-analyses. Thirty-five studies were eligible for the systematic review of energy intake, consisting of 60 distinct intervention arms with lean (n = 374) and overweight/obesity participants (n = 325; k = 51 eligible for meta-analysis). Study quality as indicated by the Effective Public Healthy Practice Project tool was rated as low and moderate risk of bias for 80% and 20% of studies, respectively. Acute exercise had no significant effect on energy intake during an ad libitum test meal (mean difference [MD] = -4.52 [-30.58, 21.54] kcal, p = .729). Whilst absolute carbohydrate intake was lower after exercise (23 arms; MD = -6.08 [-11.26, -0.91] g, p = .023), the proportion of carbohydrate was not (30 arms; MD = -0.62 [-3.36, 2.12] %, p = .647). A small elevation in hunger (27 arms; MD = 4.56 [0.75, 8.37] mm, p = .021) and prospective food consumption (27 arms; PFC; MD = 5.71 [1.62, 9.80] mm, p = .008) was observed post-exercise, but not immediately prior to the test meal (Interval: Mdn = 30 min, Range = 0-180). Conversely, a modest decrease in explicit wanting for high-fat foods was evident after exercise (10 arms; MD = -2.22 [-3.96, -0.47] mm, p = .019). Exercise intensity (p = .033) and duration (p = .013) moderated food intake only in youth with overweight/obesity, indicating lower intake at high intensity and short duration. Overall, acute exercise does not lead to compensation of energy intake or a meaningful elevation of appetite or food reward and might have a modest benefit in youth with overweight/obesity if sufficiently intense. However, conclusions are limited by substantial methodological heterogeneity and the small number of trials employing high-intensity exercise, especially in youth with overweight/obesity.

Time-restricted eating and supervised exercise for improving hepatic steatosis and cardiometabolic health in adults with obesity: protocol for the TEMPUS randomised controlled trial.

INTRODUCTION: Metabolic dysfunction-associated steatotic liver disease is a major public health problem considering its high prevalence and its strong association with extrahepatic diseases. Implementing strategies based on an intermittent fasting approach and supervised exercise may mitigate the risks. This study aims to investigate the effects of a 12-week time-restricted eating (TRE) intervention combined with a supervised exercise intervention, compared with TRE or supervised exercise alone and with a usual-care control group, on hepatic fat (primary outcome) and cardiometabolic health (secondary outcomes) in adults with obesity. METHODS AND ANALYSIS: An anticipated 184 adults with obesity (50% women) will be recruited from Granada (south of Spain) for this parallel-group, randomised controlled trial (TEMPUS). Participants will be randomly designated to usual care, TRE alone, supervised exercise alone or TRE combined with supervised exercise, using a parallel design with a 1:1:1:1 allocation ratio. The TRE and TRE combined with supervised exercise groups will select an 8-hour eating window before the intervention and will maintain it over the intervention. The exercise alone and TRE combined with exercise groups will perform 24 sessions (2 sessions per week+walking intervention) of supervised exercise combining resistance and aerobic high-intensity interval training. All participants will receive nutritional counselling throughout the intervention. The primary outcome is change from baseline to 12 weeks in hepatic fat; secondary outcomes include measures of cardiometabolic health. ETHICS AND DISSEMINATION: This study was approved by Granada Provincial Research Ethics Committee (CEI Granada-0365-N-23). All participants will be asked to provide written informed consent. The findings will be disseminated in scientific journals and at international scientific conferences. TRIAL REGISTRATION NUMBER: NCT05897073.

The subcutaneous adipose tissue reservoir of functionally active stem cells is reduced in obese patients.

It has been demonstrated that the adipose tissue, a highly functional metabolic tissue, is a reservoir of mesenchymal stem cells. The potential use of adipose-derived stem cells (ADSCs) from white adipose tissue (WAT) for organ repair and regeneration has been considered because of their obvious benefits in terms of accessibility and quantity of available sample. However, the functional capability of ADSCs from subjects with different adiposity has not been investigated. It has been our hypothesis that ADSCs from adipose tissue of patients with metabolic syndrome and high adiposity may be functionally impaired. We report that subcutaneous WAT stromal vascular fraction (SVF) from nonobese individuals had a significantly higher number of CD90+ cells than SVF from obese patients. The isolated ADSCs from WAT of obese patients had reduced differentiation potential and were less proangiogenic. Therefore, ADSCs in adipose tissue of obese patients have lower capacity for spontaneous or therapeutic repair than ADSCs from nonobese metabolically normal individuals.

Platelets derived from the bone marrow of diabetic animals show dysregulated endoplasmic reticulum stress proteins that contribute to increased thrombosis.

OBJECTIVE: Patients with diabetes mellitus have an increased risk of suffering atherothrombotic syndromes and are prone to clustering cardiovascular risk factors. However, despite their dysregulated glucose metabolism, intensive glycemic control has proven insufficient to reduce thrombotic complications. Therefore, we aimed to elucidate the determinants of thrombosis in a model of type 2 diabetes mellitus with cardiovascular risk factors clustering. METHODS AND RESULTS: Intravital microscopy was used to analyze thrombosis in vivo in Zucker diabetic fatty rats (ZD) and lean normoglycemic controls. Bone marrow (BM) transplants were performed to test the contribution of each compartment (blood or vessel wall) to thrombogenicity. ZD showed significantly increased thrombosis compared with lean normoglycemic controls. BM transplants demonstrated the key contribution of the hematopoietic compartment to increased thrombogenicity. Indeed, lean normoglycemic controls transplanted with ZD-BM showed increased thrombosis with normal glucose levels, whereas ZD transplanted with lean normoglycemic controls-BM showed reduced thrombosis despite presenting hyperglycemia. Significant alterations in megakaryopoiesis and platelet-endoplasmic reticulum stress proteins, protein disulfide isomerase and 78-kDa glucose-regulated protein, were detected in ZD, and increased tissue factor procoagulant activity was detected in plasma and whole blood of ZD. CONCLUSIONS: Our results indicate that diabetes mellitus with cardiovascular risk factor clustering favors BM production of hyperreactive platelets with altered protein disulfide isomerase and 78-kDa glucose-regulated protein expression that can contribute to increase thrombotic risk independently of blood glucose levels.

Serum angiopoietin-2 level as a predictor of tumor invasiveness in patients with hepatocellular carcinoma.

BACKGROUND: Because hepatocellular carcinoma (HCC) has important angiogenic activity, the expression of angiopoietin-2 (Ang-2) may have a pathogenic role. The information about the influence of serum Ang-2 (sAng-2) in patients with HCC is scarce. AIMS: The aim was to assess the association between sAng-2 levels and characteristics of tumor and liver disease in patients with HCC. METHODS: sAng-2 concentrations in peripheral (sAng-2-P) and hepatic (sAng-2-H) veins were analyzed by ELISA in 33 patients with chronic liver disease who underwent a splanchnic hemodynamic study. Thirty-two patients received treatment for HCC. RESULTS: The median age was 61 years and 79% were male. Hepatitis C infection (70%) was the main etiology. Most patients were Child-Pugh grade A (72.7%). sAng-2-P and sAng-2-H were well correlated (r = 0.95; p < 0.0001). A significant association was found between sAng-2-H and lobar tumor extension, vascular thrombosis, BCLC staging, infiltrating pattern, abnormal alpha-fetoprotein level, fulfillment of the Milan criteria, and performance of nonsystemic treatment. sAng-2-H also showed a significant correlation with the MELD score (r = 0.49; p = 0.007), albumin (r = -0.63; p < 0.001), and HVPG (r = 0.44; p = 0.02). Eleven patients received treatment with radiofrequency ablation and eight with transarterial chemoembolization. HCC treatment did not influence the sAng-2 concentration while the necrosis response to treatment was not influenced by previous sAng-2 levels. CONCLUSIONS: Ang-2 seems to play an important role in the angiogenic processes of HCC and its serum levels are associated with tumor characteristics and invasive behavior. Our results suggest that Ang-2 is not related with treatment response and its level is not modified by treatment.

Serum level of soluble vascular cell adhesion molecule in patients with hepatocellular carcinoma and its association with severity of liver disease.

BACKGROUND: VCAM-1 (soluble vascular cell adhesion molecule-1) plays a role in liver angiogenesis. Hepatocellular carcinoma (HCC) has important angiogenic activity, so expression of VCAM-1 may be pathogenic. AIM: To assess the association between serum VCAM-1 (sVCAM-1) levels and features of tumour and liver disease in patients with and without HCC, and to study the influence of HCC treatment on sVCAM-1 levels. MATERIAL AND METHODS: Concentrations in peripheral (sVCAM-1-P) and hepatic (sVCAM-1-H) veins were analysed using ELISA in 134 consecutive patients with chronic liver disease between May 2004 and February 2006, who underwent a splanchnic haemodynamic study. Of these patients, 58 had HCC. RESULTS: sVCAM-1-P and sVCAM-1-H were well correlated in both groups. No association was found between sVCAM-1-H and tumour features. No differences were observed in sVCAM-1-H between HCC and non-HCC cirrhotic patients. There was a significant linear association between Child-Pugh stage and sVCAM-1-H in HCC-patients (Child-Pugh A [2,485 ± 1,294 ng/mL] vs. Child-Pugh B [3,408 ± 1,338 ng/mL] vs. Child-Pugh C [4,096 ± 862 ng/mL]; p = 0.007). Seven non-cirrhotic HCC patients had a significantly lower sVCAM-1-H than cirrhotic HCC patients. Treatment of HCC leads to an increase in sVCAM-1-H levels although this was not associated with the necrosis response to treatment. CONCLUSIONS: sVCAM-1 levels are more closely associated with the severity of underlying liver disease than with the presence of HCC. sVCAM-1 levels are not associated with tumour features or invasiveness; therefore, sVCAM-1 does not seem to play an important role in the angiogenic processes of HCC.

Endometrial whole metabolome profile at the receptive phase: influence of Mediterranean Diet and infertility.

Introduction: Several metabolite classes have been identified in human endometrium, including lipids, nucleotides, amino acids, organic acids, and sugars. The first studies suggest the importance of metabolites in endometrial functions, as imbalance in uterine metabolites has been associated with low implantation rate and endometriosis. Nevertheless, most of studies have put emphasis on specific metabolite classes, and we lack the knowledge of the whole metabolome composition in human uterus. Further, a healthy dietary pattern has been shown to potentially protect against different endometrial dysfunctions and is a potential modulator of metabolomic composition and, consequently, the intrauterine microenvironment. The Mediterranean Diet (MD), characterized by a high intake of fruits, vegetables, cereals, nuts, legumes, fish, and olive oil, and a low consumption of meat, dairy products, and processed foods, has been associated with a wide range of benefits for health. Indeed, the MD pattern has displayed a beneficial role in endometriosis management and fertility; however, the relationship between the MD and the endometrial metabolome is still unknown. In our study, we set out to analyze receptive-phase endometrial metabolome profiles among women with infertility and their associations with MD. Methods: The study included women with male factor infertility (n=8), unexplained infertility (n=10), recurrent implantation failure (n=14), and endometriosis (n=13). The endometrial metabolome was analyzed with ultrahigh-performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS). The MD adherence of the participants was assessed using the 14-point MEDAS questionnaire of adherence to the MD. Results: We provide the whole metabolome profile of the endometrium, where 925 different metabolites were identified. Among these metabolites, lipids comprised the largest part, where polyunsaturated fatty acids (PUFAs) prevailed. Women with endometriosis and recurrent implantation failure were found to have lower levels of PUFAs compared to women with male factor and unexplained infertility (i.e., no clear endometrial alterations), identifying a metabolome profile associated with infertility diagnoses where altered endometrial functions are suspected. Moreover, MD adherence seemed to be associated with the endometrial metabolomic profile in a manner dependent on the health status of the uterus. Conclusion: The study findings provide insight into the molecular background of female infertility and lead to identification of potential molecular biomarkers and possibilities for modulating the endometrial microenvironment and, thereby, endometrial functions involved in embryo implantation and infertility.

Preterm neonates show marked leukopenia and lymphopenia that are associated with increased regulatory T-cell values and diminished IL-7.

INTRODUCTION: Current advances in neonatology have improved survival among preterm and low-birth-weight infants. However, the risk of neonatal death in preterm infants is much greater than in full-term neonates and is frequently associated with infections. METHODS: Little is known about the immune status of preterm neonates; therefore, we analyzed the frequency and absolute counts of different immune populations in 211 cord blood samples taken from very-preterm to full-term neonates. RESULTS: We found that absolute counts of all the immune subsets analyzed (i.e., monocytes, granulocytes, B cells, natural killer (NK) cells, CD4(+), and CD8(+) T cells) were markedly lower in preterm infants than in full-term infants. Surprisingly, we observed that regulatory T cells (Tregs) were the only cell subset that did not decrease in preterm infants, and their frequency was even higher than in full-term infants. DISCUSSION: Tregs are crucial to maternal-fetal tolerance, but their suppressive role could be also implicated in the leukopenia observed in preterm infants. We did not observe differences in thymic function, but we found that plasma levels of interleukin (IL)-7 and the frequency of its receptor were significantly decreased in preterm infants. Our results could help to identify leukopenia and to implement immune therapies that significantly diminish mortality in preterm neonates.

Oral immunotherapy in hen's egg-allergic children increases a hypo-proliferative subset of CD4+ T cells that could constitute a marker of tolerance achievement.

BACKGROUND: Food allergy affects a significant number of children and its prevalence, and persistence is undergoing an important increase in the last years. Specific oral tolerance induction (SOTI) is a promising therapy for food allergy. However, little is known about the immune mechanisms implicated in the desensitization to allergens. Our purpose was to study which immune parameters are modified during the process of tolerance achievement with the goal of identifying markers of tolerance induction. METHODS: We performed an extensive immune analysis in 19 allergic children following SOTI with hen's egg before and after the immunotherapy. Changes in lymphocyte subpopulations and serum cytokines were identified in children with desensitization achievement. RESULTS: Sixteen children achieved complete tolerance to egg, and the immune analysis reveals that desensitization was accompanied in all the cases by a significant decrease in the percentage and absolute counts of effector-memory CD4+ T cells (T(EM) ) and a marked increase in the absolute counts of a subset of CD4(+) CD38(+) CD45RO(-) cells. Additionally, we also observed a marked reduction in the plasma levels of different Th1 and Th2 cytokines after tolerance achievement. CONCLUSIONS: Acquisition of tolerance in children after oral immunotherapy is accompanied by a decrease in the T(EM) population and the increase in a particular subset of CD4+ T cells with a hypo-proliferative and non-reactive phenotype. This hypo-proliferative subset of cells could constitute a marker of the development of oral tolerance, and the study of this subset could contribute to the better understanding of the immune responses in allergic subjects.

Sustained virological response to interferon-α plus ribavirin decreases inflammation and endothelial dysfunction markers in HIV/HCV co-infected patients.

OBJECTIVES: Hepatitis C virus (HCV) antiviral therapy might lead to decreased chronic immune activation and endothelial dysfunction associated with cardiovascular risk. The aim was to evaluate the effect of HCV eradication on serum markers of inflammation and endothelial dysfunction markers in HIV/HCV co-infected patients. METHODS: We carried out a retrospective study of 69 HIV/HCV co-infected patients on interferon (IFN)-α plus ribavirin. In addition, 47 HIV-infected subjects were selected as a control group. A sustained virological response (SVR) was defined as an undetectable HCV viral load up to 24 weeks after the end of treatment. Tumour necrosis factor (TNF) receptor-1 (TNF-R1), soluble E-selectin (sE-selectin), soluble P-selectin (sP-selectin), soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1) were measured using a multiplex immunoassay kit. RESULTS: HIV/HCV co-infected patients had higher values of soluble TNF-R1 (sTNF-R1), sE-selectin and sICAM-1 than HIV mono-infected patients (P < 0.05). SVR patients had a decrease in sTNF-R1, sP-selectin, sE-selectin and sICAM-1 during anti-HCV treatment (P < 0.05) and, at the end of treatment, SVR patients had lower values of sTNF-R1, sE-selectin and sVCAM-1 than non-responder patients (P < 0.05), although the values of sTNF-R1, sP-selectin, sE-selectin and sICAM-1 remained higher than in HIV mono-infected patients (P < 0.05). Moreover, we found a significant positive relationship between an increase in sTNF-R1 and increases in sP-selectin, sE-selectin and sICAM-1 during anti-HCV therapy. CONCLUSIONS: Chronic hepatitis C infection induces alterations of markers of inflammation and endothelial dysfunction. Eradication of HCV, following IFN-α and ribavirin therapy, reduces immune activation as well as markers of inflammation and endothelial dysfunction.

Can serum hyaluronic acid replace simple non-invasive indexes to predict liver fibrosis in HIV/Hepatitis C coinfected patients?

BACKGROUND: Hyaluronic acid (HA) serum levels correlate with the histological stages of liver fibrosis in hepatitis C virus (HCV) monoinfected patients, and HA alone has shown very good diagnostic accuracy as a non-invasive assessment of fibrosis and cirrhosis. The aim of this study was to evaluate serum HA levels as a simple non-invasive diagnostic test to predict hepatic fibrosis in HIV/HCV-coinfected patients and to compare its diagnostic performance with other previously published simple non-invasive indexes consisting of routine parameters (HGM-1, HGM-2, Forns, APRI, and FIB-4). METHODS: We carried out a cross-sectional study on 201 patients who all underwent liver biopsies and had not previously received interferon therapy. Liver fibrosis was determined via METAVIR score. The diagnostic accuracy of HA was assessed by area under the receiver operating characteristic curves (AUROCs). RESULTS: The distribution of liver fibrosis in our cohort was 58.2% with significant fibrosis (F≥2), 31.8% with advanced fibrosis (F≥3), and 11.4% with cirrhosis (F4). Values for the AUROC of HA levels corresponding to significant fibrosis (F≥2), advanced fibrosis (F≥3) and cirrhosis (F4) were 0.676, 0.772, and 0.863, respectively. The AUROC values for HA were similar to those for HGM-1, HGM-2, FIB-4, APRI, and Forns indexes. The best diagnostic accuracy of HA was found for the diagnosis of cirrhosis (F4): the value of HA at the low cut-off (1182 ng/mL) excluded cirrhosis (F4) with a negative predictive value of 99% and at the high cut-off (2400 ng/mL) confirmed cirrhosis (F4) with a positive predictive value of 55%. By utilizing these low and high cut-off points for cirrhosis, biopsies could have theoretically been avoided in 52.2% (111/201) of the patients. CONCLUSIONS: The diagnostic accuracy of serum HA levels increases gradually with the hepatic fibrosis stage. However, HA is better than other simple non-invasive indexes using parameters easily available in routine clinical practice only for the diagnosing of cirrhosis.

The Spanish HIV BioBank: a model of cooperative HIV research.

BACKGROUND: The collection of samples from HIV-infected patients is the beginning of the chain of translational research. To carry out quality research that could eventually end in a personalized treatment for HIV, it is essential to guarantee the availability, quality and traceability of samples, under a strict system of quality management. METHODS: The Spanish HIV BioBank was created with the objectives of processing, storing and providing distinct samples from HIV/AIDS patients, categorized according to strictly defined characteristics, free of charge to research projects. Strict compliance to ethical norms is always guaranteed. RESULTS: At the moment, the HIV BioBank possesses nearly 50,000 vials containing different prospective longitudinal study sample types. More than 1,700 of these samples are now used in 19 national and international research projects. CONCLUSION: The HIV BioBank represents a novel approach to HIV research that might be of general interest not only for basic and clinical research teams working on HIV, but also for those groups trying to establish large networks focused on research on specific clinical problems. It also represents a model to stimulate cooperative research among large numbers of research groups working as a network on specific clinical problems. The main objective of this article is to show the structure and function of the HIV BioBank that allow it to very efficiently release samples to different research project not only in Spain but also in other countries.