PR3-ANCA: A Promising Biomarker in Primary Sclerosing Cholangitis (PSC)

Background and Aims

The only recognized biomarker for primary sclerosing cholangitis (PSC) is atypical anti-neutrophil cytoplasmic antibodies (aANCA), which, in addition to having low sensitivity and specificity, is an indirect immunofluorescence (IIF) test lacking the advantages of high throughput and objectivity. Recent reports have shown that antibodies to proteinase-3 (PR3-ANCA) might add diagnostic value in inflammatory bowel disease (IBD), specifically in ulcerative colitis (UC). As PSC is associated with IBD, the objective of this study was to evaluate the frequency and clinical significance of PR3-ANCA in a large cohort of patients.

Methods

A total of 244 PSC and 254 control [autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), hepatitis C viral infection (HCV), hepatitis B viral infection (HBV), and healthy controls] sera and their clinical correlations were retrospectively analyzed for PR3-ANCA determined by ELISA and a new chemiluminescence immunoassay (CIA). Testing was also performed for aANCA by IIF.

Results

When measured by CIA, PR3-ANCA was detected in 38.5% (94/244) of PSC patients compared to 10.6% (27/254) controls (p<0.0001). By ELISA, PR3-ANCA was detected in 23.4% (57/244) of PSC patients compared to 2.7% (6/254) controls (p<0.0001). PR3-ANCA in PSC patients was not associated with the presence or type of underlying IBD, and, in fact, it was more frequent in Crohn''s disease (CD) patients with PSC than previously reported in CD alone. PR3-ANCA in PSC measured by CIA correlated with higher liver enzymes.

Conclusion

PR3-ANCA is detected in a significant proportion of PSC patients compared to other liver diseases including PBC and AIH. PR3-ANCA is associated with higher liver enzyme levels in PSC, and is not solely related to underlying IBD.     

Neurological Abnormalities in Full-Term Asphyxiated Newborns and Salivary S100B Testing: The “Cooperative Multitask against Brain Injury of Neonates” (CoMBINe) International Study

Background

Perinatal asphyxia (PA) is a leading cause of mortality and morbidity in newborns: its prognosis depends both on the severity of the asphyxia and on the immediate resuscitation to restore oxygen supply and blood circulation. Therefore, we investigated whether measurement of S100B, a consolidated marker of brain injury, in salivary fluid of PA newborns may constitute a useful tool for the early detection of asphyxia-related brain injury.

Methods

We conducted a cross-sectional study in 292 full-term newborns admitted to our NICUs, of whom 48 suffered PA and 244 healthy controls admitted at our NICUs. Saliva S100B levels measurement longitudinally after birth; routine laboratory variables, neurological patterns, cerebral ultrasound and, magnetic resonance imaging were performed. The primary end-point was the presence of neurological abnormalities at 12-months after birth.

Results

S100B salivary levels were significantly (P<0.001) higher in newborns with PA than in normal infants. When asphyxiated infants were subdivided according to a good (Group A; n = 15) or poor (Group B; n = 33) neurological outcome at 12-months, S100B was significantly higher at all monitoring time-points in Group B than in Group A or controls (P<0.001, for all). A cut-off >3.25 MoM S100B achieved a sensitivity of 100% (CI_5-95%: 89.3%-100%) and a specificity of 100% (CI_5-95%: 98.6%-100%) as a single marker for predicting the occurrence of abnormal neurological outcome (area under the ROC curve: 1.000; CI_5-95%: 0.987-1.0).

Conclusions

S100B protein measurement in saliva, soon after birth, is a useful tool to identify which asphyxiated infants are at risk of neurological sequelae.     

Serotyping of Toxoplasma gondii in Cats (Felis domesticus) Reveals Predominance of Type II Infections in Germany

Background

Cats are definitive hosts of Toxoplasma gondii and play an essential role in the epidemiology of this parasite. The study aims at clarifying whether cats are able to develop specific antibodies against different clonal types of T. gondii and to determine by serotyping the T. gondii clonal types prevailing in cats as intermediate hosts in Germany.

Methodology

To establish a peptide-microarray serotyping test, we identified 24 suitable peptides using serological T. gondii positive (n=21) and negative cat sera (n=52). To determine the clonal type-specific antibody response of cats in Germany, 86 field sera from T. gondii seropositive naturally infected cats were tested. In addition, we analyzed the antibody response in cats experimentally infected with non-canonical T. gondii types (n=7).

Findings

Positive cat reference sera reacted predominantly with peptides harbouring amino acid sequences specific for the clonal T. gondii type the cats were infected with. When the array was applied to field sera from Germany, 98.8% (85/86) of naturally-infected cats recognized similar peptide patterns as T. gondii type II reference sera and showed the strongest reaction intensities with clonal type II-specific peptides. In addition, naturally infected cats recognized type II-specific peptides significantly more frequently than peptides of other type-specificities. Cats infected with non-canonical types showed the strongest reactivity with peptides presenting amino-acid sequences specific for both, type I and type III.

Conclusions

Cats are able to mount a clonal type-specific antibody response against T. gondii. Serotyping revealed for most seropositive field sera patterns resembling those observed after clonal type II-T. gondii infection. This finding is in accord with our previous results on the occurrence of T. gondii clonal types in oocysts shed by cats in Germany.     

High Postoperative Serum Cortisol Level Is Associated with Increased Risk of Cognitive Dysfunction Early after Coronary Artery Bypass Graft Surgery: A Prospective Cohort Study

Context

Stress response induced by surgery is proposed to play an important role in the pathogenesis of postoperative cognitive dysfunction.

Objective

To investigate the association between postoperative serum cortisol level and occurrence of cognitive dysfunction early after coronary artery bypass graft surgery.

Design

Prospective cohort study.

Setting

Two teaching hospitals.

Patients

One hundred and sixth-six adult patients who were referred to elective coronary artery bypass graft surgery from March 2008 to December 2009.

Intervention

None.

Main Outcome Measures

Neuropsychological tests were completed one day before and seven days after surgery. Cognitive dysfunction was defined using the same definition as used in the ISPOCD1-study. Blood samples were obtained in the first postoperative morning for measurement of serum cortisol concentration. Multivariate Logistic regression analyses were performed to assess the relationship between serum cortisol level and occurrence of postoperative cognitive dysfunction.

Results

Cognitive dysfunction occurred in 39.8% (66 of 166) of patients seven days after surgery. Multivariate Logistic regression analysis showed that high serum cortisol level was significantly associated with the occurrence of postoperative cognitive dysfunction (odds ratio [OR] 2.603, 95% confidence interval [CI] 1.371-4.944, P = 0.003). Other independent predictors of early postoperative cognitive dysfunction included high preoperative New York Heart Association functional class (OR 0.402, 95% CI 0.207-0.782, P = 0.007), poor preoperative Grooved Pegboard test score of nondominant hand (OR 1.022, 95% CI 1.003-1.040, P = 0.020), use of penehyclidine as premedication (OR 2.565, 95% CI 1.109-5.933, P = 0.028), and occurrence of complications within seven days after surgery (OR 2.677, 95% CI 1.201-5.963, P = 0.016).

Conclusions

High serum cortisol level in the first postoperative morning was associated with increased risk of cognitive dysfunction seven days after coronary artery bypass graft surgery.     

Concomitant Effects of Ramadan Fasting and Time-Of-Day on Apolipoprotein AI,B, Lp-a and Homocysteine Responses during Aerobic Exercise in Tunisian Soccer Players

Objective

To examine the time-of-day and Ramadan fasting (RF) effects on serum apolipoprotein-AI (Apo-AI) and B (Apo-B), lipoprotein particles-a (Lp-a), high-sensitive C-reactive-protein (hs-CRP), and homocysteine (Hcy) during the Yo-Yo intermittent recovery test (YYIRT).

Design

Performance and biochemical measures were completed at two times-of-day (07:00 and 17:00 h), 1-week before RF (BR), the second week of RF (SWR), and the fourth week of RF (ER).

Setting

For each session, subjects performed the YYIRT, and blood samples were taken before and 3-min after the test for biochemical measures.

Participants

Fifteen soccer players.

Main Outcome Measures

Total distance during the YYIRT, core temperature, body composition, dietary intakes, lipid (HDL-C, LDL-C, Apo-AI, B and Lp-a) and inflammatory (hs-CRP and Hcy) profiles.

Results

Performances during the YYIRT were higher in the evening than the morning BR (P < 0.05), but this fluctuation was not observed during RF. Moreover, LDL-C, ApoB, and Lp-a were stable throughout the daytime BR. However, during RF, they decreased at 17:00 h (P < 0.05). Likewise, HDL-C and Apo-AI increased after the exercise and were higher at 17:00 h BR (P < 0.001). Moreover, these parameters increased during RF (P < 0.01). Furthermore, Hcy and hs-CRP increased during the exercise (P < 0.01) with higher evening levels BR. During ER, the diurnal pattern of Hcy was inversed (P < 0.001).

Conclusions

This study concluded that caloric restriction induced by RF seems to ameliorate lipid and inflammatory markers of cardiovascular health during intermittent exercise performed in the evening.     

Higher Carbohydrate Antigen 125 Levels Are Associated with Increased Risk of Coronary Heart Disease in Elderly Chinese: A Population-Based Case-Control Study

Background

High carbohydrate antigen 125 (CA-125) level was reported to be associated with some cardiac dysfunctions, such as chronic heart failure, but the relationship between CA-125 level and coronary heart disease (CHD) risk remains unclear. The aim of this study was to explore the potential association in a Chinese older population.

Methods

In a population-based case-control study conducted in a Chinese older population, serum CA-125 levels were measured in 1177 diagnosed CHD patients and 3531 age and sex matched control subjects without CHD.

Results

Serum CA-125 level was significantly higher in CHD patients than controls (P < 0.001) with adjustment for age, gender, smoking, drinking, BMI, physical activity, hypertension, dyslipidemia, diabetes mellitus, medication history and family history of CHD and myocardial infarction. CHD risk was doubled (OR: 2.10, 95%CI: 1.69-2.60) among subjects in the highest quartile compared to those in the lowest quartile of CA-125 level (P _trend < 0.001). Furthermore, CA-125 levels were associated with CHD risks in subjects with age over 60 years (OR: 2.19, 95%CI: 1.75-2.73), current smokers (OR: 2.29, 95%CI: 1.50-3.49), current drinkers (OR: 2.35, 95%CI: 1.57-3.53) and subjects with hypertension (OR: 2.04, 95%CI: 1.71-2.43).

Conclusions

Elevated serum CA-125 level might be associated with increased risk of coronary heart disease in the Chinese older population. Further investigations are needed to identify the possible biological role of CA-125 in CHD development in the future.     

The GSTM1 Null Genotype Increased Risk of Gastric Cancer: A Meta-Analysis Based on 46 Studies

Background

Glutathione S-transferases M1 (GSTM1) is an important phase II metabolizing enzyme. The null genotype of GSTM1 causes total loss of GSTM1 enzyme activity and numerous studies have investigated the association between GSTM1 null genotype and gastric cancer risk.

Methods

This meta-analysis was designed to investigate the relationship between GSTM1 null genotype and susceptibility to gastric cancer and assess the influence of Helicobacter pylori infection, smoking, Lauren’s classification, and other factors. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the association strength.

Results

A total of 46 eligible studies were indentified and analyzed in this meta-analysis, including 8138 cases of gastric cancer and 13867 controls. Pooled results showed that the GSTM1 null genotype was associated with a significantly increased risk of gastric cancer (OR=1.217, 95% CI: 1.113-1.331, P_{heterogeneity}<0.001). Sub-group analysis suggested that the significant association was only observed in Asians (OR=1.273, 95%: 1.137-1.426, P_{heterogeneity} = 0.002), but not in Caucasians. The increased risk was found among H. pylori positive population (OR=1.928, 95% CI: 1.028-3.615, P_{heterogeneity}=0.065), while no association was found among H. pylori negative population (OR=0.969, 95% CI: 0.618-1.521, P_{heterogeneity}=0.168). For smoking status, the GSTM1 null genotype increased risk of gastric cancer in both ever-smokers and non-smokers. Source of control, sample size, location of tumor and Lauren’s classification did not modify the association.

Conclusions

In this meta-analysis based on 46 epidemiological studies, we show that the GSTM1 null genotype is associated with an increased risk of gastric cancer among Asians but not among Caucasians. H. pylori infection but not smoking status could modify the association.     

Herpesvirus-Associated Acute Urticaria: An Age Matched Case-Control Study

Background

Acute and recurrent acute urticaria are often associated with multiple factors including infections and recent data suggest a role for herpesviruses.

Objective

To test the null hypothesis, that is, there is no association of herpesvirus infections with urticaria.

Methods

Thirty-seven patients between one month and 15 years of age were age matched to 37 controls who were healthy or had mild acute respiratory infections but without urticaria. Patients and controls were followed for 1 to 6 years. Diagnostic studies included DNA detection by real-time PCR for herpes simplex virus (HSV) types 1 and 2, Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human herpesvirus-6 (HHV-6). Tests for other infections included adenovirus, parvovirus B 19, respiratory syncytial virus, influenza A, Group A streptococci, rotavirus, and parasites.

Results

Specific infections were diagnosed in 26 of 37 cases and among 9 of 37 control children (P=0.0002). Single or concomitant herpesvirus infections occurred in 24 cases and in 4 controls (65% vs 11 %, p=0.0003). Cases had 10 HHV-6 infections, 8 CMV infections, 5 EBV infections, and 4 HSV-1 infections.

Conclusion

Herpesvirus infections are associated with acute or recurrent acute urticaria.     

Inhibiting AKT Phosphorylation Employing Non-Cytotoxic Anthraquinones Ameliorates TH2 Mediated Allergic Airways Disease and Rhinovirus Exacerbation

Background

Severe asthma is associated with T helper (T_H) 2 and 17 cell activation, airway neutrophilia and phosphoinositide-3-kinase (PI3K) activation. Asthma exacerbations are commonly caused by rhinovirus (RV) and also associated with PI3K-driven inflammation. Anthraquinone derivatives have been shown to reduce PI3K-mediated AKT phosphorylation in-vitro.

Objective

To determine the anti-inflammatory potential of anthraquinones in-vivo.

Methods

BALB/c mice were sensitized and challenged with crude house dust mite extract to induce allergic airways disease and treated with mitoxantrone and a novel non-cytotoxic anthraquinone derivative. Allergic mice were also infected with RV1B to induce an exacerbation.

Results

Anthraquinone treatment reduced AKT phosphorylation, hypoxia-inducible factor-1α and vascular endothelial growth factor expression, and ameliorated allergen- and RV-induced airways hyprereactivity, neutrophilic and eosinophilic inflammation, cytokine/chemokine expression, mucus hypersecretion, and expression of T_H2 proteins in the airways. Anthraquinones also boosted type 1 interferon responses and limited RV replication in the lung.

Conclusion

Non-cytotoxic anthraquinone derivatives may be of therapeutic benefit for the treatment of severe and RV-induced asthma by blocking pro-inflammatory pathways regulated by PI3K/AKT.     

Preserved Antigen-Specific Immune Response in Patients with Multiple Sclerosis Responding to IFNβ-Therapy

Background

Interferon-beta (IFNβ) regulates the expression of a complex set of pro- as well as anti-inflammatory genes. In cohorts of MS patients unstratified for therapeutic response to IFNβ, normal vaccine-specific immune responses have been observed. Data capturing antigen-specific immune responses in cohorts of subjects defined by response to IFNβ-therapy are not available.

Objective

To assess antigen-specific immune responses in a cohort of MS patients responding clinically and radiologically to IFNβ.

Methods

In 26 MS patients, clinical and MRI disease activity were assessed before and under treatment with IFNβ. Humoral and cellular immune response to influenza vaccine was prospectively characterized in these individuals, and 33 healthy controls by influenza-specific Enzyme-Linked Immunosorbent Assay (ELISA) and Enzyme Linked Immuno Spot Technique (ELISPOT).

Results

Related to pre-treatment disease activity, IFNβ reduced clinical and radiological MS disease-activity. Following influenza vaccination, frequencies of influenza-specific T cells and concentrations of anti-influenza A and B IgM and IgG increased comparably in MS-patients and in healthy controls.

Conclusions

By showing in a cohort of MS-patients responding to IFNβ vaccine-specific immune responses comparable to controls, this study indicates that antigen-specific immune responses can be preserved under successful IFNβ-therapy.     

The -607C/A Polymorphisms in Interleukin-18 Gene Promoter Contributes to Cancer Risk: Evidence from A Meta-Analysis of 22 Case-Control Studies

Background

Several observational studies have investigated the association between -607 C/A polymorphism of IL-18 gene and cancer risk; however, the results were inconsistent. Therefore, we performed a meta-analysis to derive a more precise estimation of the association to help us better understand the relationship between -607 C/A polymorphism of IL-18 gene promoter and risk of cancer.

Methods

A literature search was carried out using PubMed, EMBASE, and China National Knowledge Infrastructure (CNKI) database between January 1966 and February 2013. Fixed-effect and random-effect models were used to estimate the pooled odds ratio (OR) and the corresponding 95% confidence intervals (CIs).

Results

A total of 22 case-control studies including 4100 cancer cases and 4327 controls contributed to the analysis. Significant association between -607C/A polymorphism in IL-18 gene promoter and cancer risk was observed (CA vs CC:OR =1.221, 95% CI: 1.096, 1.360; P_{heterogeneity}=0.219; AA/CA vs. CC:OR =1.203, 95% CI: 1.057, 1.369; P_{heterogeneity}=0.064). In the subgroup analysis by ethnicity, -607C/A polymorphism significantly increased risk of cancer among Asian population (AA/CA vs. CC:OR =1.197, 95% CI: 1.023,1.401; P_{heterogeneity}=0.088); however, no significant association was found in Caucasian or African population. The -607C/A polymorphism was associated with a significantly increased risk of nasopharyngeal carcinoma (CA vs CC:OR =1.330, 95% CI: 1.029,1.719; P_{heterogeneity}=0.704; AA/CA vs. CC:OR =1.323, 95% CI: 1.037,1.687; P_{heterogeneity}=0.823) and esophageal cancer (AA/CA vs. CC:OR =1.289, 95% CI: 1.002,1.658; P_{heterogeneity}=0.700).

Conclusions

The present meta-analysis suggests that the -607C/A polymorphisms in IL-18 gene promoter is associated with a significantly increased risk of cancer, especially for nasopharyngeal carcinoma and esophageal cancer and in Asian population. More studies with larger sample size, well controlled confounding factors are warranted to validate this association.     

Association between Anti-Ganglionic Nicotinic Acetylcholine Receptor (gAChR) Antibodies and HLA-DRB1 Alleles in the Japanese Population

Background/Aims

Anti-ganglionic nicotinic acetylcholine receptor (gAChR) antibodies are observed in autoimmune diseases, as well as in patients with autoimmune autonomic ganglionopathy. However, the genetic background of anti-gAChR antibodies is unclear. Here, we investigated HLA alleles in autoimmune hepatitis (AIH) patients with or without anti-gAChR antibodies.

Methodology/Principal Findings

Genomic DNA from 260 patients with type-1 autoimmune hepatitis (AIH) were genotyped for HLA-A, B, DRB1, and DQB1 loci. Anti-gAChR antibodies in the sera form AIH patients were measured using the luciferase immunoprecipitation system, and examined allelic association in patients with or without anti-gAChR antibodies.

Methodology/ Methods

We detected anti-α3 or -β4 gAChR antibodies in 11.5% (30/260) of patients with AIH. Among AIH patients there was no significant association between HLA-A, B DQB1 alleles and the positivity for anti-gAChR antibodies. Whereas the HLA-DRB1*0403 allele showed a significantly increased frequency in AIH patients with anti-gAChR antibodies compared with those without anti-gAChR antibodies.

Conclusions/Significance

The frequency of the HLA-DRB1*0403 allele differed among Japanese patients with AIH according to the presence or absence of anti-gAChR antibodies. Our findings suggest that particular HLA class II molecules might control the development of anti-gAChR antibodies in the autoimmune response to gAChR.     

Negative Interference in Serum HBsAg ELISA from Rheumatoid Factors

Background

RF(Rheumatoid factor) is usually thought to cause positive interference in immunoassay. Recently, our study showed that high-concentration RFs caused negative interference as well as positive interference in serum HBsAg(Hepatitis B surface antigen) ELISA(Enzyme-linked immunosorbent assay), but it is unclear that RF causing negative interference is an anomaly produced by a certain ELISA kit or a common property of most of HBsAg ELISA kits.

Methods

Serum models were made by blending HBsAg-positive sera and high- or moderate-concentration RFs sera at the ratio of 1: 9, then one-step and two-step ELISA were adopted to determine HBsAg in serum models.

Results

No matter what kind of kit used, one-step ELISA showed that HBsAg S/CO( sample/cut off) values in serum models were significantly lower than original values. Bivariate correlations tests showed decline rates of HBsAg S/CO Values were not associated to serum RF concentrations ranging from 288 to 3560 IU/mL. HBsAg converted to be negative in 69.80% serum models with original-value ranging from 1.00 to 10.00, and in 2.68% serum models with higher original-value. RF causing decline of HBsAg S/CO value provided by one-step ELISA was more obvious than that provided by two-step ELISA.

Conclusions

It is concluded that susceptibility of all HBsAg ELISA assays to interference from RF, leading to predominantly lower and in some cases "false-negative" results, and moreover, the lower the original HBsAg S/CO Value, the higher the false-negative rate.     

Two Functional Variants of IRF5 Influence the Development of Macular Edema in Patients with Non-Anterior Uveitis

Objective

Interferon (IFN) signaling plays a crucial role in autoimmunity. Genetic variation in interferon regulatory factor 5 (IRF5), a major regulator of the type I interferon induction, has been associated with risk of developing several autoimmune diseases. In the current study we aimed to evaluate whether three sets of correlated IRF5 genetic variants, independently associated with SLE and with different functional roles, are involved in uveitis susceptibility and its clinical subphenotypes.

Methods

Three IRF5 polymorphisms, rs2004640, rs2070197 and rs10954213, representative of each group, were genotyped using TaqMan® allelic discrimination assays in a total of 263 non-anterior uveitis patients and 724 healthy controls of Spanish origin.

Results

A clear association between two of the three analyzed genetic variants, rs2004640 and rs10954213, and the absence of macular edema was observed in the case/control analysis (P _FDR=5.07E-03, OR=1.48, CI 95%=1.14-1.92 and P _FDR=3.37E-03, OR=1.54, CI 95%=1.19-2.01, respectively). Consistently, the subphenotype analysis accordingly with the presence/absence of this clinical condition also reached statistical significance (rs2004640: P=0.037, OR=0.69, CI 95%=0.48-0.98; rs10954213: P=0.030, OR=0.67, CI 95%=0.47-0.96), thus suggesting that both IRF5 genetic variants are specifically associated with the lack of macular edema in uveitis patients.

Conclusion

Our results clearly showed for the first time that two functional genetic variants of IRF5 may play a role in the development of macular edema in non-anterior uveitis patients. Identifying genetic markers for macular edema could lead to the possibility of developing novel treatments or preventive therapies.     

Association of VEGF Gene Polymorphisms with Diabetic Retinopathy: A Meta-Analysis

Background

Studies on the association of vascular endothelial growth factor (VEGF) gene -460T/C and -2578C/A polymorphisms with diabetic retinopathy (DR) have reported conflicting results. The aim of the present study was to assess the association by using meta-analysis.

Methods

A systematic search of electronic databases (PubMed, EMBASE, Elsevier Science Direct, ISI Web of Science, CBM, CNKI and VIP) was carried out until Sept 18, 2013. The pooled odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were used to assess the strength of the association.

Results

Eleven studies (-460T/C: 6 studies including 932 cases and 722 controls; -2578C/A: 6 studies including 1,071 cases and 1,137 controls) were involved in this meta-analysis. Significant association was found for -460T/C polymorphism (C versus T: OR=1.48, 95%CI=1.07–2.05, P=0.02; TC+CC versus TT: OR=1.78, 95%CI=1.02–3.12, P=0.04; CC versus TT+TC: OR=1.76, 95%CI=1.10–2.81, P=0.02), but not for -2578C/A polymorphism (P>0.05). Similar results were found in the subgroup analysis.

Conclusions

This meta-analysis demonstrates that DR is associated with VEGF gene -460T/C polymorphism, but not -2578C/A polymorphism. Further case-control studies based on larger sample size are still needed, especially for -2578C/A polymorphism.     

Impact of the Phosphatidylinositide 3-Kinase Signaling Pathway on the Cardioprotection Induced by Intermittent Hypoxia

Background

Exposure to intermittent hypoxia (IH) may enhance cardiac function and protects heart against ischemia-reperfusion (I/R) injury. To elucidate the underlying mechanisms, we developed a cardioprotective IH model that was characterized at hemodynamic, biochemical and molecular levels.

Methods

Mice were exposed to 4 daily IH cycles (each composed of 2-min at 6-8% O₂ followed by 3-min reoxygenation for 5 times) for 14 days, with normoxic mice as controls. Mice were then anesthetized and subdivided in various subgroups for analysis of contractility (pressure-volume loop), morphology, biochemistry or resistance to I/R (30-min occlusion of the left anterior descending coronary artery (LAD) followed by reperfusion and measurement of the area at risk and infarct size). In some mice, the phosphatidylinositide 3-kinase (PI3K) inhibitor wortmannin was administered (24 µg/kg ip) 15 min before LAD.

Results

We found that IH did not induce myocardial hypertrophy; rather both contractility and cardiac function improved with greater number of capillaries per unit volume and greater expression of VEGF-R2, but not of VEGF. Besides increasing the phosphorylation of protein kinase B (Akt) and the endothelial isoform of NO synthase with respect to control, IH reduced the infarct size and post-LAD proteins carbonylation, index of oxidative damage. Administration of wortmannin reduced the level of Akt phosphorylation and worsened the infarct size.

Conclusion

We conclude that the PI3K/Akt pathway is crucial for IH-induced cardioprotection and may represent a viable target to reduce myocardial I/R injury.     

Pharmacodynamic Consequences of Administration of VLA-4 Antagonist CDP323 to Multiple Sclerosis Subjects: A Randomized,Double-Blind Phase 1/2 Study

Background

Lymphocyte inhibition by antagonism of α4 integrins is a validated therapeutic approach for relapsing multiple sclerosis (RMS).

Objective

Investigate the effect of CDP323, an oral α₄-integrin inhibitor, on lymphocyte biomarkers in RMS.

Methods

Seventy-one RMS subjects aged 18–65 years with Expanded Disability Status Scale scores ≤6.5 were randomized to 28-day treatment with CDP323 100 mg twice daily (bid), 500 mg bid, 1000 mg once daily (qd), 1000 mg bid, or placebo.

Results

Relative to placebo, all dosages of CDP323 significantly decreased the capacity of lymphocytes to bind vascular adhesion molecule-1 (VCAM-1) and the expression of α₄-integrin on VCAM-1–binding cells. All but the 100-mg bid dosage significantly increased total lymphocytes and naive B cells, memory B cells, and T cells in peripheral blood compared with placebo, and the dose-response relationship was shown to be linear. Marked increases were also observed in natural killer cells and hematopoietic progenitor cells, but only with the 500-mg bid and 1000-mg bid dosages. There were no significant changes in monocytes. The number of samples for regulator and inflammatory T cells was too small to draw any definitive conclusions.

Conclusions

CDP323 at daily doses of 1000 or 2000 mg induced significant increases in total lymphocyte count and suppressed VCAM-1 binding by reducing unbound very late antigen-4 expression on lymphocytes.

Trial Registration

ClinicalTrials.gov NCT00726648.     

Aliskiren Attenuates Steatohepatitis and Increases Turnover of Hepatic Fat in Mice Fed with a Methionine and Choline Deficient Diet

Background & Aims

Activation of the renin-angiotensin-system is known to play a role in nonalcoholic steatohepatitis. Renin knockout mice manifest decreased hepatic steatosis. Aliskiren is the first direct renin inhibitor to be approved for clinical use. Our study aims to evaluate the possible therapeutic effects and mechanism of the chronic administration of aliskiren in a dietary steatohepatitis murine model.

Methods

Male C57BL/6 mice were fed with a methionine and choline-deficient (MCD) diet to induce steatohepatitis. After 8 weeks of feeding, the injured mice were randomly assigned to receive aliskiren (50 mg_·kg^-1 per day) or vehicle administration for 4 weeks. Normal controls were also administered aliskiren (50 mg_·kg^-1 per day) or a vehicle for 4 weeks.

Results

In the MCD mice, aliskiren attenuated hepatic steatosis, inflammation and fibrosis. Aliskiren did not change expression of lipogenic genes but increase turnover of hepatic fat by up-regulating peroxisome proliferator-activated receptor α, carnitine palmitoyltransferase 1a, cytochrome P450-4A14 and phosphorylated AMP-activated protein kinase. Furthermore, aliskiren decreased the hepatic expression of angiotensin II and nuclear factor κB. The levels of oxidative stress, hepatocyte apoptosis, activation of Kupffer cells and hepatic stellate cells, and pro-fibrotic markers were also reduced in the livers of the MCD mice receiving aliskiren.

Conclusions

Aliskiren attenuates steatohepatitis and fibrosis in mice fed with a MCD diet. Thus, the noted therapeutic effects might come from not only the reduction of angiotensin II but also the up-regulation of fatty acid oxidation-related genes.     

Interaction of Central and Peripheral Factors during Repeated Sprints at Different Levels of Arterial O2 Saturation

Purpose

To investigate the interaction between the development of peripheral locomotor muscle fatigue, muscle recruitment and performance during repeated-sprint exercise (RSE).

Method

In a single-blind, randomised and cross-over design, ten male team-sport athletes performed two RSE (fifteen 5-s cycling sprints interspersed with 25 s of rest; power self-selected) in normoxia and in acute moderate hypoxia (F_IO₂ 0.138). Mechanical work, total electromyographic intensity (summed quadriceps electromyograms, RMS_sum) and muscle (vastus lateralis) and pre-fontal cortex near-infrared spectroscopy (NIRS) parameters were calculated for every sprint. Blood lactate concentration ([Lac^-]) was measured throughout the protocol. Peripheral quadriceps fatigue was assessed via changes in potentiated quadriceps twitch force (ΔQ_tw,pot) pre- versus post-exercise in response to supra-maximal magnetic femoral nerve stimulation. The central activation ratio (Q_CAR) was used to quantify completeness of quadriceps activation.

Results

Compared with normoxia, hypoxia reduced arterial oxygen saturation (-13.7%, P=0.001), quadriceps RMS_sum (-13.7%, P=0.022), Q_CAR (-3.3%, P=0.041) and total mechanical work (-8.3%, P=0.019). However, the magnitude of quadriceps fatigue induced by RSE was similar in the two conditions (ΔQ_tw,pot: -53.5% and -55.1%, P=0.71). The lower cycling performance in hypoxia occurred despite similar metabolic (muscle NIRS parameters and blood [Lac^-]) and functional (twitch and M-wave) muscle states.

Conclusion

Results suggest that the central nervous system regulates quadriceps muscle recruitment and, thereby, performance to limit the development of muscle fatigue during intermittent, short sprints. This finding highlights the complex interaction between muscular perturbations and neural adjustments during sprint exercise, and further supports the presence of pacing during intermittent sprint exercise.