RV Groups Research Articles

Preclinical safety assessment of modified gamma globin lentiviral vector-mediated autologous hematopoietic stem cell gene therapy for hemoglobinopathies.

Previously, we reported the development of a human Aγ-globin gene lentivirus (LV), GbG, which expresses high levels of HbF to correct the sickle cell anemia (SCA) phenotype in the Berkeley SCA mouse model, and then modified the γ-globin gene by substituting glycine at codon 16 with aspartic acid in the Aγ-globin gene to generate GbGM LV. In the present study, we evaluated the long-term safety of human Aγ-globin gene carrying GbGM LV in wild-type mice after primary and secondary transplants of GbGM-modified hematopoietic stem cells (HSC) over 18 months. The safety of the GbGM bone marrow transplant was assessed by monitoring the effects on body weight, hematology, histopathology, malignancy formation, and survival. Mice transplanted with Mock-transduced and spleen focus forming virus (SFFV) γ-retroviral vector (RV)-transduced HSC served as negative and positive controls, respectively. The mean donor-cell engraftment was comparable across Mock, GbGM LV, and SFFV RV groups. There were no significant differences in body weight, clinical signs, immunophenotype, or histopathology in the GbGM-treated mice compared to controls. Four SFFV RV-treated mice, but none of the GbGM-treated mice, developed donor-derived, vector-positive lymphomas as demonstrated by flow cytometry analysis and in situ hybridization. These results highlight the safety of the administration of GbGM LV-modified HSC with long-term follow-up after primary and secondary transplants in mice. This data supported the initiation of phase 1/2 first-in-human SCA clinical trial in the United States.

Edaravone Confers Neuroprotective, Anti-inflammatory, and Antioxidant Effects on the Fetal Brain of a Placental-ischemia Mouse Model.

Reduced uterine perfusion pressure (RUPP) is a well-established model which mimics many clinical features of preeclampsia (PE). Edaravone is a free radical scavenger with neuroprotective, antioxidant and anti-inflammatory effects against different models of cerebral ischemia. Therefore, we aimed to elucidate the different potential mechanisms through which PE affects fetal brain development using our previously established RUPP-placental ischemia mouse model. In addition, we investigated the neuroprotective effect of edaravone against the RUPP-induced fetal brain development alterations. On gestation day (GD) 13, pregnant mice were divided into four groups; sham (SV), edaravone (SE), RUPP (RV), and RUPP+edaravone (RE). SV and SE groups underwent sham surgeries, however, RV and RE groups were subjected to RUPP surgery via bilateral uterine ligation. Edaravone (3mg/kg) was injected via tail i.v. injection from GD 14-18. The fetal brains from different groups were collected on GD 18 and subjected to further investigations. The results showed that RUPP altered the structure of fetal brain cortex, induced neurodegeneration, increased the expression of the investigated pro-inflammatory markers; TNF-α, IL-6, IL-1β, and MMP-9. RUPP resulted in microglial and astrocyte activation in the fetal brains, inaddition to upregulation of Hif-1α and iNOS. Edaravone conferred a neuroprotective effect via alleviating the inflammatory response, restoring the neuronal structure and decreasing oxidative stress in the developing fetal brain. In conclusion, RUPP-placental ischemia mouse model could be a useful tool to further understand the underlying mechanisms of PE-induced child neuronal alterations. Edaravone could be a potential adjuvant therapy during PE to protect the developing fetal brain. The current study investigated the effects of a placenta-induced ischemia mouse model using reduced uterine perfusion pressure (RUPP) surgery on the fetal brain development and the potential neuroprotective effects of the drug edaravone. The study found that the RUPP model caused neurodegeneration and a pro-inflammatory response in the developing fetal brain, as well as hypoxia and oxidative stress. However, maternal injection of edaravone showed a strong ability to protect against these detrimental effects and target multiple pathways associated with neuronal damage. The current study suggests that the RUPP model could be useful for further study of the impact of preeclampsia on fetal brain development and that edaravone may have potential as a therapy for protecting against this damage.

Long term survival of antenatally diagnosed functionally single ventricle congenital heart disease

Abstract Funding Acknowledgements Type of funding sources: None. Background Antenatal diagnosis of single ventricle congenital heart disease (CHD) allows prenatal counselling, better parental preparation and support as well as improved perinatal management. Expectant parents frequently ask about likely outcomes and expected longer term survival. Our aim is to review the survival of antenatally diagnosed single ventricle CHD presenting at our institutions between January 2000 and July 2022. Methods Retrospective data was collected from the fetal cardiac and paediatric cardiology databases. Maternal data, fetal cardiac diagnosis, postnatal cardiac diagnosis and management were collected for each patient. The outcomes were separated into 2 groups – Cohort 1 (CO1) [2000 to 2007] and Cohort 2 (CO2) [2008 to 2022]. Results A total of 495 fetuses were diagnosed with single ventricle CHD in the 21 years and 7 months period, with outcomes illustrated in Table 1. For the small LV group with intention to treat at birth, there was 46% survival at over 10 years for the CO1 group and 69% survival at over 10 years for CO2 group. There was however no significant difference in the survival between the CO1 and CO2 groups (log rank test p=0.12). For the small RV group with intention to treat at birth, there was 71% survival at over 10 years for the CO1 group and 91% survival at over 10 years for CO2 group. There was significant difference in the survival between the CO1 and CO2 groups (log rank test p=0.03). No analysis was made for the unspecified hypoplasia as the numbers were too small. Conclusions For both the antenatal small LV and small RV groups, the termination rate and compassionate care option remained unchanged between both cohorts. Overall, there has been improvement in the survival for the antenatal small LV and RV groups with intention to treat. This is likely due to improved perinatal management with detailed management plan and designated delivery at tertiary neonatal hospital close to the cardiac surgical centre, improved surgical expertise and experience, improved cardiac intensive care management as well as availability of ECMO for the sicker patients. In the antenatal small LV groups, although there has been improvement in survival, this is not yet statistically significant due to more complex patients with more co-morbidity being accepted for surgery. Whereas for the antenatal small RV groups, we see statistically significant improvement with survival reaching 90% at 10 years, due to increased use of non-surgical intervention like ductal stenting over conventional BT shunts which carry higher morbidity and mortality risk. Our survival outcomes are comparable with other published data across the world.

CDX-301 prevents radiation-induced dysregulation of miRNA expression and biogenesis

Risks of radiation exposure necessitate the development ofradioprophylactic drugs. We have reported the efficacy of CDX-301, a recombinantly developed human protein form of Fms-related tyrosine kinase 3 ligand (Flt3L), as a radioprophylactic and radiomitigatory agent. Here, we performed global microRNA profiling to further understand the mechanism of action of CDX-301. We find that CDX-301 administration 24h prior to total body irradiation prevents radiation-induced dysregulation of microRNA biogenesis and expression in murine serum and spleen samples in a time- and tissue-dependent manner. Further analysis shows that activation of the HOTAIR regulatory pathway has a prominent function in radiation-induced injury responses, which is inhibited by pre-treatment with CDX-301. Moreover, CDX-301 attenuates radiation-induced dysregulation of several cellular functions such as inflammatory and immune responses. In corroboration, we also find that pre-treatment with CDX-301 restores the expression of bone marrow aplasia markers and inflammatory cytokines and growth factors, as well as the expression of genes associated with MAP kinase and TGF-β pathways that are altered by radiation. Our findings provide new insights into CDX-301-mediated molecular and cellular mechanisms and point to a possible novel radioprotective drug for the prevention of irradiation-induced injury and hematopoietic acute radiation syndrome.

Nasopharyngeal microbiota in hospitalized children with Bordetella pertussis and Rhinovirus infection

Despite great advances in describing Bordetella pertussis infection, the role of the host microbiota in pertussis pathogenesis remains unexplored. Indeed, the microbiota plays important role in defending against bacterial and viral respiratory infections. We investigated the nasopharyngeal microbiota in infants infected by B. pertussis (Bp), Rhinovirus (Rv) and simultaneously by both infectious agents (Bp + Rv). We demonstrated a specific nasopharyngeal microbiome profiles for Bp group, compared to Rv and Bp + Rv groups, and a reduction of microbial richness during coinfection compared to the single infections. The comparison amongst the three groups showed the increase of Alcaligenaceae and Achromobacter in Bp and Moraxellaceae and Moraxella in Rv group. Furthermore, correlation analysis between patients’ features and nasopharyngeal microbiota profile highlighted a link between delivery and feeding modality, antibiotic administration and B. pertussis infection. A model classification demonstrated a microbiota fingerprinting specific of Bp and Rv infections. In conclusion, external factors since the first moments of life contribute to the alteration of nasopharyngeal microbiota, indeed increasing the susceptibility of the host to the pathogens' infections. When the infection is triggered, the presence of infectious agents modifies the microbiota favoring the overgrowth of commensal bacteria that turn in pathobionts, hence contributing to the disease severity.

Cardiac Natriuretic Peptide Profiles in Chronic Hypertension by Single or Sequentially Combined Renovascular and DOCA-Salt Treatments.

The involvement of natriuretic peptides was studied during the hypertrophic remodeling transition mediated by sequential exposure to chronic hemodynamic overload. We induced hypertension in rats by pressure (renovascular) or volume overload (DOCA-salt) during 6 and 12 weeks of treatment. We also studied the consecutive combination of both models in inverse sequences: RV 6 weeks/DS 6 weeks and DS 6 weeks/RV 6 weeks. All treated groups developed hypertension. Cardiac hypertrophy and left ventricular ANP gene expression were more pronounced in single DS than in single RV groups. BNP gene expression was positively correlated with left ventricular hypertrophy only in RV groups, while ANP gene expression was positively correlated with left ventricular hypertrophy only in DS groups. Combined models exhibited intermediate values between those of single groups at 6 and 12 weeks. The latter stimulus associated to the second applied overload is less effective than the former to trigger cardiac hypertrophy and to increase ANP and BNP gene expression. In addition, we suggest a correlation of ANP synthesis with volume overload and of BNP synthesis with pressure overload-induced hypertrophy after a prolonged treatment. Volume and pressure overload may be two mechanisms, among others, involved in the differential regulation of ANP and BNP gene expression in hypertrophied left ventricles. Plasma ANP levels reflect a response to plasma volume increase and volume overload, while circulating BNP levels seem to be regulated by cardiac BNP synthesis and ventricular hypertrophy.

Characterization of Hippocampal Histomorphology Following R. vomitoria Root Extract Treatment

Rauwolfia vomitoria Afzel. is an antipsychotic plant used by several African communities in the management of psychiatric conditions with good outcomes. Concerns about its dosages on brain activity lead to this investigation of its action on the hippocampal microstructure. Twenty-four adult male Wistar rats of average weight 200 g, were assigned into four groups (n = 6): control; 200, 300 and 400 mg/kg body weight of RV root bark extract, respectively. The administration was once daily, and orally for seven days. Daily observation of the animals was done till on day eight when they were sacrificed after deep anaesthesia. Each brain was processed for histology and immunohistochemical studies. Animals in the 200, 300 and 400 mg/kg RV groups appeared generally dull and drowsy, and barely fed. Their hippocampal histology showed neuronal atrophy and karyorrhexis, with no difference in cell count, although the pyramidal cell numbers decreased in the 300 and 400 mg/kg RV groups. Neuron-specific enolase decreased in the 400 mg/kg RV group, while neurofilament decreased in all test groups. Glial fibrillary acidic protein expression and density increased in the 200 and 300 mg/kg RV groups, but not the 400 mg/kg RV group, all compared with the control group. The given doses of RV root bark extract in adult Wistar rats showed sedative activities with hippocampal histopathological changes, which may not be reversible, thereby leading to the hippocampal functional deficit.

P987 Comprehensive systolic right ventricular longitudinal strain analysis in congenital heart disease patients with different right ventricular loading conditions

Abstract Background Right ventricular (RV) function is recognized as a prognostic factor in congenital heart disease (CHD). Speckle tracking analysis might reveal subclinical systolic dysfunction. Accurate assessment of global (GLS) and regional strain measurements of the RV remain challenging. We previously introduced a novel four-view approach with all RV walls visualized in their long axis from one apical view using 2D multi-plane-transthoracic echocardiographic (TTE) iRotate mode. Aims To extensive evaluate GLS of the entire RV using iRotate echocardiography in CHD patients with different RV loading conditions compared with healthy subjects. Methods and Results One-hundred forty-two CHD patients with different RV loading conditions were recruited from the outpatient clinic and compared with 89 age, gender and BSA matched healthy controls. CHD patients were divided in 5 groups: 42 patients with volume overloaded (VO)RV (at least moderate pulmonary or tricuspid regurgitation (TR) and/or an atrium septum defect), 16 patients with pressure overloaded (PO) RV (defined as TR velocity > 2.8 m/s), 34 patients who met both criteria for volume and pressure overloaded RV (P + VO), 30 patients with systemic RV and 27 with normal RV loading conditions. TAPSE and Fractional area change (FAC%) were significantly lower in all CHD subgroups vs healthy controls (p < 0.05). Within the CHD group, TAPSE, FAC% and TDI S` did not differentiate systemic RV from PO RV, whereas RV function was significantly better in RV VO and RV VO + PO compared with systemic RV. GLS was significantly lower in patients with CHD compared with healthy subjects. Within the CHD groups, GLS values of systemic RV were lower (p < 0.05), but no significant difference could be observed between the other subpulmonic RV loading conditions (Figure). Conclusion Comprehensive RV function analysis reveals decreased RV function in all CHD subgroups compared with healthy subjects. GLS showed RV systolic function to be the worst in the systemic RV but however could not differentiate between subpulmonic RV groups confirming the load independent functional analysis capacity of GLS. Abstract P987 Figure.

Vitamin E supplementation and caloric restriction promotes regulation of insulin secretion and glycemic homeostasis by different mechanisms in rats.

Vitamin E and caloric restriction have antioxidant effects in mammals. The aim of this study was to evaluate effects of vitamin E supplementation and caloric restriction upon insulin secretion and glucose homeostasis in rats. Male Wistar rats were distributed among the following groups: C, control group fed ad libitum; R, food quantity reduction of 40%; CV, control group supplemented with vitamin E [30 mg·kg-1·day-1]; and RV, food-restricted group supplemented with vitamin E. The experiments ran for 21 days. Glucose tolerance and insulin sensitivity was higher in the CV, R, and RV groups. Insulin secretion stimulated with different glucose concentrations was lower in the R and RV groups, compared with C and CV. In the presence of glucose and secretagogues, insulin secretion was higher in the CV group and was lower in the R and RV groups. An increase in insulin receptor occurred in the fat pad and muscle tissue of groups CV, R, and RV. Levels of hepatic insulin receptor and phospho-Akt protein were higher in groups R and RV, compared with C and CV, while muscle phospho-Akt was increased in the CV group. There was a reduction in hepatic RNA levels of the hepatocyte growth factor gene and insulin degrading enzyme in the R group, and increased levels of insulin degrading enzyme in the CV and RV groups. Thus, vitamin E supplementation and caloric restriction modulate insulin secretion by different mechanisms to maintain glucose homeostasis.

Echogenic intracardiac foci and fetal cardiac anomalies: A review of cases from a tertiary care center in China.

To investigate the relationship between the location of echogenic intracardiac foci (EIFs) and fetal cardiac anomalies in our patient population. We performed a retrospective study of the clinical files of fetuses who underwent an echocardiographic examination at our fetal cardiac medical center from August 2010 to August 2016. Fetuses were grouped by EIF location (left ventricle [LV], right ventricle [RV], or bilateral ventricles [BVs]). The maternal age, reason for referral, and cardiac anomalies in the three groups were analyzed. We enrolled 2647 fetuses with an EIF. Of these, 2498 (94.4%) were in the LV group, while 45 (1.7%) and 104 (3.9%) were in the RV and BV groups, respectively. Aneuploidy was found in 3 fetuses, and all of these had a left-sided EIF. Cardiac anomalies were found in 93/2498 (3.7%) fetuses with a left-sided EIF, 5/45 (11.1%) of those with a right-sided EIF, and 3/104 (2.9%) of those with bilateral EIFs. The prevalence of congenital heart disease was significantly higher in fetuses with a right-sided EIF than in those with left-sided or bilateral EIFs (P < .05). Right-sided EIFs were more frequently associated with fetal cardiac anomalies than were left-sided or bilateral EIFs.

Vitamin E and caloric restriction promote hepatic homeostasis through expression of connexin 26, N-cad, E-cad and cholesterol metabolism genes

Connexins (Cx) and cadherins are responsible for cell homeostasis. The Cx activity is directly related to cholesterol. The present work investigates whether vitamin E, with or without caloric restriction (CR), alters the mRNA expression of Cx26, Cx32, Cx43, N-cadherins (N-cads), E-cadherins (E-cads) and alpha-smooth muscle actin (α-SMA), and evaluates their relation to cholesterol metabolism in rat liver. Animals were divided into different groups: control with ad libitum diet (C), control+vitamin E (CV), aloric restriction with intake to 60% of group C (CR), and the intake of group CR+vitamin E (RV). There were increases of manganese superoxide dismutase (Mn-SOD) and glutathione S-transferase mu 1, indicating antioxidant effects of CR and vitamin E. An increase of nitric oxide in the CR group was in agreement with the Mn-SOD data. Supplementation with vitamin E, with or without CR, upregulated the expression of Cx26 mRNA and increased low-density lipoprotein cholesterol (LDL-c) in the CV group. Reductions of Cx32 and Cx43 were associated with lower LDL-c. Increases in Hmgcr and low-density lipoprotein receptor (LDLr) in the CV and RV groups could be explained by the effect of vitamin E. A reduction of LDLr in the CR group was due to the reduced dietary intake. Increases in cadherins in the CV, CR and RV groups were indicative of tissue maintenance, which was also supported by increases of α-SMA in groups CV and RV. Finally, vitamin E, with or without CR, increased Cx26, probably modulated by expression of the Hmgcr and LDLr genes. This suggests important relationship of Cxs and cholesterol metabolism genes.

Effect of exogenous emulsifier on growth performance, fat digestibility, apparent metabolisable energy in broiler chickens

This research was done to evaluate the effect of a commercial exogenous emulsifier (polyethylene glycol ricinoleate (PEGR)) with high hydrophilic-to-lipophilic balance (HLB) supplementation to broiler chicken diets on growth performance, digestibility of fat and apparent metabolisable energy (AME) content in week 1, 3 and 5. A total of 360 one-day-old male Cobb broiler chicks were assigned in groups of 30 to 12 battery cages. The chicks were randomly assigned to two dietary treatments, with 6 replicate cages per treatment. The diets were either standard broiler starter and finisher, with rice bran oil (RBO) as supplemented fat source or similar diets + 0.05% emulsifier (RBOV). Feed intakes of RBOV groups significantly increased compared to those of RBO groups from week 2 till 4 while body weights of RBOV diets significantly increased in week 4 and 5. Both RBOV and RBO groups had similar FCR except for week 5. Addition of this strongly hydrophilic emulsifier showed no significant difference in fat digestibility of both RC and RV groups but higher AME was noted for the treatment than for the control groups at week 5. Therefore, supplementing the exogenous emulsifier into a broiler diet enriched with rice bran oil improved body weight and AME content at week 5 with minimal effect on fat digestibility

Recombinant Bivalent Fusion Protein rVE Induces CD4+ and CD8+ T-Cell Mediated Memory Immune Response for Protection Against Yersinia enterocolitica Infection.

Studies investigating the correlates of immune protection against Yersinia infection have established that both humoral and cell mediated immune responses are required for the comprehensive protection. In our previous study, we established that the bivalent fusion protein (rVE) comprising immunologically active regions of Y. pestis LcrV (100–270 aa) and YopE (50–213 aa) proteins conferred complete passive and active protection against lethal Y. enterocolitica 8081 challenge. In the present study, cohort of BALB/c mice immunized with rVE or its component proteins rV, rE were assessed for cell mediated immune responses and memory immune protection against Y. enterocolitica 8081. rVE immunization resulted in extensive proliferation of both CD4 and CD8 T cell subsets; significantly high antibody titer with balanced IgG1: IgG2a/IgG2b isotypes (1:1 ratio) and up-regulation of both Th1 (TNF-α, IFN-γ, IL-2, and IL-12) and Th2 (IL-4) cytokines. On the other hand, rV immunization resulted in Th2 biased IgG response (11:1 ratio) and proliferation of CD4+ T-cell; rE group of mice exhibited considerably lower serum antibody titer with predominant Th1 response (1:3 ratio) and CD8+ T-cell proliferation. Comprehensive protection with superior survival (100%) was observed among rVE immunized mice when compared to the significantly lower survival rates among rE (37.5%) and rV (25%) groups when IP challenged with Y. enterocolitica 8081 after 120 days of immunization. Findings in this and our earlier studies define the bivalent fusion protein rVE as a potent candidate vaccine molecule with the capability to concurrently stimulate humoral and cell mediated immune responses and a proof of concept for developing efficient subunit vaccines against Gram negative facultative intracellular bacterial pathogens.

Rhinovirus-induced VP1-specific Antibodies are Group-specific and Associated With Severity of Respiratory Symptoms

BackgroundRhinoviruses (RVs) are a major cause of common colds and induce exacerbations of asthma and chronic inflammatory lung diseases. MethodsWe expressed and purified recombinant RV coat proteins VP1-4, non-structural proteins as well as N-terminal fragments of VP1 from four RV strains (RV14, 16, 89, C) covering the three known RV groups (RV-A, RV-B and RV-C) and measured specific IgG-subclass-, IgA- and IgM-responses by ELISA in subjects with different severities of asthma or without asthma before and after experimental infection with RV16. FindingsBefore infection subjects showed IgG1>IgA>IgM>IgG3 cross-reactivity with N-terminal fragments from the representative VP1 proteins of the three RV groups. Antibody levels were higher in the asthmatic group as compared to the non-asthmatic subjects. Six weeks after infection with RV16, IgG1 antibodies showed a group-specific increase towards the N-terminal VP1 fragment, but not towards other capsid and non-structural proteins, which was highest in subjects with severe upper and lower respiratory symptoms. InterpretationOur results demonstrate that increases of antibodies towards the VP1 N-terminus are group-specific and associated with severity of respiratory symptoms and suggest that it may be possible to develop serological tests for identifying causative RV groups.

225: Developmental programming of adult disease: the role of DNA methylation in genes responsible for antioxidant enzymes

gain, fetal weights, placental weights or number of pups between the RV and control groups. Treatment with RV had no significant effect on baseline myometrial contractility nor on contractility after indomethacin or nifedipine treatment. CONCLUSION: Unlike its effect on vascular smooth muscle, resveratrol does not seem to affect myometrial contractility nor potentiate the effect of tocolytics in pregnant mice.

Shared and Group-Specific Features of the Rotavirus RNA Polymerase Reveal Potential Determinants of Gene Reassortment Restriction

Rotaviruses (RVs) are nonenveloped, 11-segmented, double-stranded RNA viruses that are major pathogens associated with acute gastroenteritis. Group A, B, and C RVs have been isolated from humans; however, intergroup gene reassortment does not occur for reasons that remain unclear. This restriction might reflect the failure of the viral RNA-dependent RNA polymerase (RdRp; VP1) to recognize and replicate the RNA of a different group. To address this possibility, we contrasted the sequences, structures, and functions of RdRps belonging to RV groups A, B, and C (A-VP1, B-VP1, and C-VP1, respectively). We found that conserved amino acid residues are located within the hollow center of VP1 near the active site, whereas variable, group-specific residues are mostly surface exposed. By creating a three-dimensional homology model of C-VP1 with the A-VP1 crystallographic data, we provide evidence that these RV RdRps are nearly identical in their tertiary folds and that they have the same RNA template recognition mechanism that differs from that of B-VP1. Consistent with the structural data, recombinant A-VP1 and C-VP1 are capable of replicating one another's RNA templates in vitro. Nonetheless, the activity of both RdRps is strictly dependent upon the presence of cognate RV core shell protein A-VP2 or C-VP2, respectively. Together, the results of this study provide unprecedented insight into the structure and function of RV RdRps and support the notion that VP1 interactions may influence the emergence of reassortant viral strains.

Long-term effects of resveratrol supplementation on suppression of atherogenic lesion formation and cholesterol synthesis in apo E-deficient mice

Atherosclerosis is a chronic inflammatory disease of the arteries resulting from interactions between lipids, monocytes, and arterial wall cells. The effects of resveratrol supplements (RV, 0.02% and 0.06% each, w/w) with regard to the modulation of lipid profiles, cholesterol synthesis, and anti-atherogenesis were examined in apo E-deficient (apo E−/−) mice fed a normal diet. The concentration of total-cholesterol (total-C) and LDL-cholesterol (LDL-C) in plasma was significantly lower in the resveratrol-supplemented groups compare to the control group over the entire experimental period. The plasma HDL-C concentration was significantly elevated, and the ratio of HDL-C/total-C was significantly higher in the CF and RV groups than in the control group. Plasma paraoxonase (PON) activity was significantly higher in the 0.06% resveratrol group. The hepatic HMG-CoA reductase (HMGR) activity was significantly lower in the clofibrate and resveratrol groups than in the control group. Resveratrol supplements attenuated the presence of atherosclerotic lesions and periarterial fat deposition in the apo E−/− mice. The presence of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in atherosclerotic vessels was diminished in the resveratrol-supplemented apo E−/− mice. These results provide new insight into the anti-atherogenic and hypocholesterolemic properties of resveratrol in apo E−/− mice that were fed a normal diet.

Systemic ventricular morphology-associated increased QRS duration compromises the ventricular mechano-electrical and energetic properties long-term after the Fontan operation

Objectives To evaluate the impact of systemic ventricular (SV) morphology on mechano-electrical interaction (MEI) and compare the results with clinical profiles in Fontan patients. Background Abnormal ventricular MEI causes systolic dysfunction of the right and left ventricles (RV, LV). Methods We evaluated serial changes (up to 15 years post-Fontan operation) in QRS duration (QRS-d, ms), catheterization-based hemodynamics and SV performance in 77 patients and compared them with 36 referents. Results Preoperative QRS-d was wider in the Fontan patients (86 ± 14 vs. 64 ± 9, p < 0.001) and steadily increased for the next 15 years (107 ± 25 vs. 85 ± 9, p < 0.001). QRS-d was wider in non-LV type SV patients than those with LV morphology ( p < 0.05) with a positive association with age at repair ( p < 0.001). SV contractility (Ees) improved in the RV and LV groups ( p < 0.05), during the next 10-year Ees, ventriculoarterial coupling (Ea/Ees) and ventricular efficiency (SW/PVA) were superior in the LV group. QRS-d and its long-term change correlated with the corresponding SV volume and change ( p < 0.01), respectively, while the immediate postoperative volume reduction did not result in the QRS-d shortening. QRS-d correlated with Ees, Ea/Ees, SW/PVA, and peak oxygen uptake (VO 2) ( p < 0.001) and QRS-d was one of the main determinants of peak VO 2 ( r = − 0.48, p < 0.001). Conclusions SV morphology-associated wide QRS-d compromises the MEI as well as energetic properties long-term after the Fontan operation, especially in non-LV type patients.

Regional difference in ischaemia-induced myocardial interstitial noradrenaline and acetylcholine releases

Knowledge of the regional differences in myocardial interstitial noradrenaline (NA) and acetylcholine (ACh) levels during ischaemia would be important to understand the abnormality of neuronal environment surrounding the ischaemic heart. Using a cardiac microdialysis technique, we compared ischaemia-induced changes in the myocardial interstitial NA and ACh levels among three groups of anesthetized cats: the anterior free wall of the left ventricle (ANT group, n = 7; the left anterior descending coronary artery was occluded), the posterior free wall of the left ventricle (POST group, n = 6; the left circumflex coronary artery was occluded), and the right ventricle (RV group, n = 6; the right coronary artery was occluded). The maximum NA level was not different between the ANT and POST groups but was significantly lower in the RV group ( P < 0.01) [70 nM (SD 37), 106 nM (SD 99), and 7 nM (SD 10), respectively]. The maximum ACh level was not different between the ANT and POST groups but was significantly lower in the RV group ( P < 0.05) [16 nM (SD 7), 20 nM (SD 15), and 6 nM (SD 2), respectively]. In contrast, there were no significant differences in NA or ACh release in response to a local administration of ouabain (10 mM) among the ANT, POST, and RV groups ( n = 6 each). In conclusion, the regional difference of the ischaemic effects, rather than the regional difference in the functional distributions of sympathetic and vagal efferent nerve terminals, might contribute to the lower levels of ischaemia-induced NA and ACh releases in the RV group.

Role of Etiology on the Clinical and Nutritional Outcomes of Acute Diarrhea

244 male infants were admitted for studies on dietary therapy of acute diarrhea. All patients had complete history and physical exams, anthropometrics, and extensive laboratory tests, including stool studies for virus, bacteria and parasites and metabolic balance studies. Rehydration and replacement of ongoing losses were carried out following WHO guidelines. Feeding was started after 4-8 hours rehydration. Antibiotics were given for proven Shigella or Campylobacter. Giardia was treated on day 7. Treatment failures defined as recurrence of dehydration, and severe or prolonged diarrhea, were treated individually. Patients were grouped by etiological agent to compare initial presentation and clinical and nutritional outcomes. Covariance analysis was used to correct the effect of confounding variables not associated to etiology; then discrete and continuous variables were compared by chi square and ANOVA, respectively. Patients were divided in 6 groups: ETEC: 31(13%), EPEC: 29(12%), RV: 23(9%), other bacteria: 24(10%), mixed infections: 70(29%) and no pathogens: 67 (27%). Diarrhea duration before admission was longer in the EPEC group and shorter in RV patients, who also had more vomiting, dehydration and acidosis. There were no differences in frequency of failures according to etiology. Diarrhea duration was shorter for the RV group and longer with the ETEC group. Stool output was higher for the RV and mixed groups and lower for the “none” group on the first 2 days. Likewise, nitrogen, fat, carbohydrate and energy absorption and nitrogen retention were lower for the RV, other, and mixed groups during the first 2 days. Begining on day 3 there were no differences among the etiological groups regarding stool volume and nutrient absorption. Neither there were differences regarding changes in weight, skin fold thickness or serum albumin, from day 1 to day 7. Conversely, weight and skin folds increments correlated strongly with total energy intake.