After injury to the adult central nervous system (CNS), numerous cytokines and growth factors are released that contribute to reactive gliosis and extracellular matrix production. In vitro examination of these cytokines revealed that the presence of transforming growth factor-beta1 (TGF-beta1) and epidermal growth factor (EGF) greatly increased the production of several chondroitin sulfate proteoglycans (CSPG) by astrocytes. Treatment of astrocytes with other EGF-receptor (ErbB1) ligands, such as TGF-alpha and HB-EGF, produced increases in CSPG production similar to those observed with EGF. Treatment of astrocytes, however, with heregulin, which signals through other members of the EGF-receptor family (ErbB2, ErbB3, ErbB4), did not induce CSPG upregulation. The specificity of activation through the ErbB1 receptor was further verified by using a selective antagonist (AG1478) to this tyrosine kinase receptor. Western blot analysis of astrocyte supernatant pre-digested with chondroitinase ABC indicated the presence of multiple core proteins containing 4-sulfated or 6-sulfated chondroitin. To identify some of these CSPGs, Western blots were screened using antibodies to several known CSPG core proteins. These analyses showed that treatment of astrocytes with EGF increased phosphacan expression, whereas treatment with TGF-beta1 increased neurocan expression. Reverse transcription-polymerase chain reaction (RT-PCR) was used to examine the expression of these molecules in vivo, which result in increased expression of TGF-beta1, EGF-receptor, neurocan, and phosphacan after injury to the brain. These data begin to elucidate some of the injury-induced growth factors that regulate the expression of CSPGs which could be targeted in the future to modulate CSPG production after injury to the central nervous system.

Background: The effect of home-based exercise training on neurovascular control in heart failure patients is unknown. Aims: To test the hypothesis that home-based training would maintain the reduction in muscle sympathetic nerve activity (MSNA) and forearm vascular resistance (FVR) acquired after supervised training. Methods and results: Twenty-nine patients (54 T 1.9 years, EF < 40%) were randomised into two groups: untrained control (n = 12) and exercise trained (n = 17). Both groups underwent assessment of Quality of Life (QoL), MSNA, and forearm blood flow. The exercise group underwent a 4-month supervised training program followed by 4 months of home-based training. After the initial 4 months of training, patients in the exercise group showed a significant increase in peak VO 2 and reduction in MSNA, compared to the untrained group, but this was not maintained during 4 months of home-based training. In contrast, the decrease in FVR (56 T 3 vs. 46 T 4 vs. 40 T 2 U, p = 0.008) and the improvement in QOL that were achieved during supervised training were maintained during home-based training. Conclusions: Home-based training following supervised training is a safe strategy to maintain improvements in QoL and reduction in FVR in chronic heart failure patients, but is an inadequate strategy to maintain fitness as estimated by peak VO 2 or reduction in neurohumoral activation.

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Heart failure (HF) is, after cirrhosis, the second-most common cause of ascites. Serum B-type natriuretic peptide (BNP) plays an important role in the diagnosis of HF. Therefore, we hypothesized that BNP would be useful in the differential diagnosis of ascites. Consecutive patients with new onset ascites were prospectively enrolled in this crosssectional study. All patients had measurements of serum-ascites albumin gradient (SAAG), total protein concentration in ascitic fluid, serum, and ascites BNP. We enrolled 218 consecutive patients with ascites resulting from HF (n 5 44), cirrhosis (n 5 162), peritoneal disease (n 5 10), and constrictive pericarditis (n 5 2). Compared to SAAG and/or total protein concentration in ascites, the test that best discriminated HF-related ascites from other causes of ascites was serum BNP. A cutoff of >364 pg/mL (sensitivity 98%, specificity 99%, and diagnostic accuracy 99%) had the highest positive likelihood ratio (168.1); that is, it was the best to rule in HF-related ascites. Conversely, a cutoff £ 182 pg/mL had the lowest negative likelihood ratio (0.0) and was the best to rule out HF-related ascites. These findings were confirmed in a 60-patient validation cohort. Conclusions: Serum BNP is more accurate than ascites analyses in the diagnosis of HFrelated ascites. The workup of patients with new onset ascites could be streamlined by obtaining serum BNP as an initial test and could forego the need for diagnostic paracentesis, particularly in cases where the cause of ascites is uncertain and/or could be the result of HF. (HEPATOLOGY 2014;59:1043-1051 See Editorial on Page 751A scites secondary to heart failure (HF) is, after cirrhosis, the second-most common cause of ascites. 1 The pathophysiology of ascites in both HF and cirrhosis is hepatic sinusoidal hypertension, and therefore the serum-ascites albumin gradient (SAAG) is greater than 1.1 g/dL in both conditions. 2 Because the hepatic sinusoids are normal (leaky, i.e., without significant collagen deposition in the space of Disse) in HF and are abnormal in cirrhosis (less leaky as a result of capillarization of sinusoids), 3 ascites total protein content is higher in HF-related ascites than in cirrhotic ascites and has been used to help in the differential diagnosis between these two entities, with a ascites protein level of >2.5 mg/dL suggesting the presence of ascites related to HF. However, a significant number of cases are still misclassified. 2,4 Even the Abbreviations: ASE, American Society of Echocardiography; BNP, B-type natriuretic peptide; CLD, chronic liver disease; HF, heart failure; HVPG, hepatic venous pressure gradient; INR, international normalized ratio; IQR, interquartile range; LR, likelihood ratio; NPV, negative predictive value; NT-proBNP, N-terminal proBNP; PH, portal hypertension; PPV, positive predictive value; SAAG, serum-ascites albumin gradient; STARD, Standards for reporting Studies of Diagnostic Accuracy; US, ultrasound.From the

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OBJECTIVETo assess the effect of two hypoglycemic drugs on ischemic preconditioning (IPC) patients with type 2 diabetes and coronary artery disease (CAD).RESEARCH DESIGN AND METHODSWe performed a prospective study of 96 consecutive patients allocated into two groups: 42 to group repaglinide (R) and 54 to group vildagliptin (V). All patients underwent two consecutive exercise tests (ET1 and ET2) in phase 1 without drugs. In phase 2, 1 day after ET1 and -2, 2 mg repaglinide three times daily or 50 mg vildagliptin twice daily was given orally to patients in the respective group for 6 days. On the seventh day, 60 min after 6 mg repaglinide or 100 mg vildagliptin, all patients underwent two consecutive exercise tests (ET3 and ET4).RESULTSIn phase 1, IPC was demonstrated by improvement in the time to 1.0 mm ST-segment depression and rate pressure product (RPP). All patients developed ischemia in ET3; however, 83.3% of patients in group R experienced ischemia earlier in ET4, without significant improvement in RPP, indicating the cessation of IPC (P < 0.0001). In group V, only 28% of patients demonstrated IPC cessation, with 72% still having the protective effect (P < 0.0069).CONCLUSIONSRepaglinide eliminated myocardial IPC, probably by its effect on the KATP channel. Vildagliptin did not damage this protective mechanism in a relevant way in patients with type 2 diabetes and CAD, suggesting a good alternative treatment in this population.

SummaryObjective: The objective of this study was to evaluate the effect of polymorphism S447X on plasma lipids of patients with premature coronary artery disease (CAD).Methods: Plasma lipids and genotypes were determined in 2 groups: 313 patients with premature CAD (<55 years of age) and 150 controls without CAD.Results: Frequency of the S447X polymorphism was 18% in patients with CAD and 23% in the control group. The S447X polymorphism of lipoprotein lipase is related to a decrease in plasma triglyceride concentrations in male patients with CAD, but this correlation is not observed in female patients. Conclusion:The presence of the S447X lipoprotein lipase polymorphism was not associated with the incidence of CAD.