Exercise Intolerance in Patients With Heart Failure: JACC State-of-the-Art Review

Exercise intolerance is the cardinal symptom of heart failure (HF) and is of crucial relevance, because it is associated with a poor quality of life and increased mortality. While impaired cardiac reserve is considered to be central in HF, reduced exercise and functional capacity are the result of key patient characteristics and multisystem dysfunction, including aging, impaired pulmonary reserve, as well as peripheral and respiratory skeletal muscle dysfunction. We herein review the different modalities to quantify exercise intolerance, the pathophysiology of HF, and comorbid conditions as they lead to reductions in exercise and functional capacity, highlighting the fact that distinct causes may coexist and variably contribute to exercise intolerance in patients with HF.     

In vitro anti-hepatitis B and SARS virus activities of a titanium-substituted-heteropolytungstate

A structural determined heteropolytungstate, [K₄(H₂O)₈Cl][K₄(H₂O)₄PTi₂W₁₀O₄₀]·NH₂OH 1, has been synthesized and evaluated for in vitro antiviral activities against hepatitis B (HBV) and SARS virus. The identity and high purity of compound 1 were confirmed by elemental analysis, NMR, IR analysis and single-crystal X-ray diffraction. The compound 1, evaluated in HepG 2.2.15 cells expressing permanently HBV, significantly reduced the levels of HBV antigens and HBV DNA in a dose-dependent and time-dependent manner. EC₅₀ values were determined to be 54 μM for HBeAg, 61 μM for HBsAg and 2.66 μM for supernatant HBV DNA, as compared to 1671, 1570, 169 μM, respectively, for the commercially-available hepatitis B drug adefovir dipivoxil (ADV). Intracellular cccDNA, pgRNA and HBcAg were also found to be decreased by compound 1 in a concentration-dependent manner. Cytotoxicity results showed that compound 1 has low toxicity in HepG 2 cells with CC₅₀ value of 515.20 μM. The results indicate that compound 1 can efficiently inhibit HBV replication in HepG 2.2.15 cells line in vitro. Additionally, compound 1 also shows high anti-SARS activity at an EC₅₀ of 7.08 μM and toxicity with a CC₅₀ of 118.6 μM against MDCK cells.     

Influence of salbutamol on the anticonvulsant potency of the antiepileptic drugs in the maximal electroshock-induced seizures in mice

Backgroundβ₂-Adrenergic receptor agonists are widely used agents in the treatment of asthma or preterm labor. Since prevalence of asthma was shown to be higher in patients with epilepsy and modulation of noradrenergic system activity may modify epilepsy course, the aim of the present study was to examine the effect of salbutamol (SALB), one of the most commonly used β₂-adrenergic receptor agonist on the anticonvulsant potency of four classical antiepileptic drugs (AEDs): valproate (VPA), carbamazepine (CBZ), phenytoin (DPH) and phenobarbital (PB) in mice subjected to the maximal electroshock (MES)-induced seizures.MethodsSeizures were caused by a current delivered through ear-clip electrodes. The influence of AEDs and SALB on animals’ motor coordination and memory processes was also evaluated.ResultsSingle SALB injection did not change, whereas 7 days SALB administration decreased seizure threshold in the MES-induced seizures in mice. Moreover, SALB injected ip for 1 day and for 7 days lowered the antiepileptic activity of PB in the MES-induced seizures in mice, but did not change the effect of other analyzed AEDs: VPA, CBZ or DPH. Butoxamine, a selective β₂-adrenergic receptor antagonist, reversed SALB influence on the activity of PB. SALB given alone or in combination with the tested AEDs did not affect animals’ motor performance and memory after both single and 7 days administration.ConclusionsPresented results show that SALB may decrease the antiepileptic efficacy of PB. A special caution is advised to patients with epilepsy receiving β₂-adrenergic receptors agonists in the pharmacotherapy of pulmonary and obstetrical disorders.     

Surfactant phosphatidylcholine metabolism in neonates with meconium aspiration syndrome

OBJECTIVE: Because meconium directly inhibits surfactant function, we sought to determine the effect of meconium on endogenous surfactant synthesis and clearance. STUDY DESIGN: We studied surfactant phosphatidylcholine kinetics with the use of stable isotopes in 11 newborn infants with meconium aspiration syndrome (MAS) who required extracorporeal membrane oxygenation (ECMO). For comparison we studied 6 neonates with persistent pulmonary hypertension (PPHN) on ECMO and 10 term neonates ventilated for non-pulmonary indications and not on ECMO. All patients received a 24-hour [U- 13C]glucose infusion as precursor for the palmitic acid in surfactant phosphatidylcholine. RESULTS: In the meconium group, the maximal 13C-incorporation in phosphatidylcholine (PC) was half of that in controls (0.09 +/- 0.01 vs 0.18 +/- 0.03 atom percent excess [APE], P = .027). There was a trend toward lower surfactant synthesis in the MAS group (3.3 +/- 0.7%/day) and PPHN group (2.6 +/- 0.3%/day) compared with controls 8.0 +/- 2.4%/day, P = .058). Significantly lower PC concentrations in tracheal aspirates were found in the MAS group (4.4 +/- 2.6 mg/mL) and PPHN group (3.6 +/- 2.0 mg/mL) compared with controls (12.8 +/- 2.6 mg/mL, P = .01). Endogenously synthesized surfactant had a similar half-life in all groups, ranging from 63 to 98 hours. CONCLUSION: We conclude that surfactant synthesis is disturbed and that surfactant PC concentrations are low in infants with MAS on ECMO.     

孟鲁司特联合布地奈德福莫特罗治疗重度哮喘的临床研究

目的观察孟鲁司特联合布地奈德福莫特罗治疗重度哮喘的疗效。方法对136例重度哮喘患者进行随机对照研究，分为治疗组68例，对照组68例，治疗组用盂鲁司特联合布地奈德福莫特罗治疗，对照组吸入布地奈德福莫特罗治疗。结果两组治疗4周后，治疗组疗效优于对照组。结论孟鲁司特联合布地奈德福莫特罗治疗重度哮喘的疗效优于单用布地奈德福莫特罗治疗。     

La fatigue musculaire locale après une séance de natation

This experimentally work was carried out on a group of students in physical and sporting education in order to identify the muscular fatigue they feeled after a swimming training.For this purpose, two approach's methods were used: a questionnaire in order better to estimate the characteristics of this kind of fatigue and standardized tests of muscular isometric contraction relating to biceps brachii and quadriceps corresponding to 100, 80, 60 and 40% of their maximum voluntary contraction (MVC).For each of the 12 subjects, it was the matter to realize these tests before a swimming training then to re-realize them in quite identical conditions after the swimming training. Analysis and data processing allowed us to say that the level of producted performances after the swimming training is lower. This fact is very appreciably for performances which require 100 and 80% of MVC, but less significant for efforts corresponding to 40% of this strength.This kind of stating work's test should be used in functional muscular exploration in order to confirm the fatigue and, even, be useful for trying to detect some required qualities specific of one sporting practice.     

Variability and reproducibility of hepatic FDG uptake measured as SUV as well as tissue‐to‐blood background ratio using positron emission tomography in healthy humans

Introduction: To investigate variability and reproducibility of hepatic [¹⁸F]‐2‐fluoro‐2‐deoxy‐d ‐glucose (FDG) uptake in healthy individuals. Methods:  Static images were obtained 70 min after the injection of 160 MBq FDG in six healthy subjects at two occasions with 13 days’ interval. FDG uptake was adjusted for tissue‐to‐blood background ratio (T/B), or measured as standardized uptake value (SUV). Small regions of interest (ROIs) of 10 cm³ in two different hepatic regions were analysed as well as the total liver. Results: Mean SUV was 1·16 ± 0·15 and mean T/B corrected values was 1·87 ± 0·17. The maximal values were 2·70 (SUV) and 4·67 (T/B). Reproducibility was 6·7% for the mean SUV and 0·2% for the max SUV values. The corresponding figures for the T/B corrected mean values were 6·4% and for the max T/B values 13·0%. In general, the small ROIs had a comparable or even lower CV% for SUV values, but a higher CV% for T/B corrected values. Conclusions: In normal subjects hepatic FDG‐uptake is high and homogeneous with a low CV% between days. T/B corrected values are largely comparable to SUV values but not superior, probably due to the standardization of procedures and homogeneity of the subjects. The T/B corrected method is theoretically superior in a more inhomogeneous population or when using different scanners and is shown here to be easy to apply. Small ROIs of 10 cm³ are representative with respect to mean FDG uptake in the total liver and reproducibility, but do not identify the max FDG uptake.     

INFLUENCE OF 3-PPP, A SIGMA RECEPTOR LIGAND, ON THE ANTICONVULSIVE ACTION OF CONVENTIONAL ANTIEPILEPTIC DRUGS

(+)-3-(3-Hydroxyphenyl)-N-(1-propyl)-piperidine (3-PPP; a sigma receptor ligand), administered at 30 mg kg-1, 30 min before the test, significantly decreased the electroconvulsive threshold in mice, being ineffective in lower doses. 3-PPP (20 mg kg-1) diminished the protective activity of diphenylhydantoin, phenobarbital and valproate, but not that of carbamazepine against maximal electroshock. The effect of 3-PPP upon the electroconvulsive threshold and the 3-PPP-induced inhibition of the protective action of antiepileptics was reversed by haloperidol (0.5 mg kg-1). Moreover, 3-PPP did not alter the total and free plasma levels of antiepileptic drugs, so a pharmacokinetic interaction is not probable. The combined treatment of 3-PPP with antiepileptic drugs, providing a 50% protection against maximal electroshock, did not affect motor performance in mice, although resulted in significant long-term memory deficits. Our data indicate that sigma receptor-mediated events may play some role in seizure processes in the central nervous system and can modulate the protective activity of some conventional antiepileptic drugs.     

IPG-Ⅲ阻抗静脉血流仪的研制

本文报道了IPG-Ⅲ阻抗静脉血流仪的研制及临床应用。该仪器检测深静脉血栓等静脉疾患灵敏、可靠、无损伤,可多次重复并操作简便。阻抗静脉血流图与静脉造影符合率达96.4％接近国外同类产品的水平。     

Clinical benefit in Phase-I trials of novel molecularly targeted agents: does dose matter?

Phase-I trials traditionally involve dose-escalation to determine the maximal tolerated dose (MTD). With conventional chemotherapy, efficacy is generally deemed to be dose-dependent, but the same may not be applicable to molecularly targeted agents (MTAs). We analysed consecutive patients included in Phase-I trials at the Royal Marsden Hospital from 5 January 2005 to 6 June 2006. We considered only trials of monotherapy MTAs in which the MTD was defined. Three patient cohorts (A, B, and C) were identified according to the dose received as a percentage of the final trial MTD (0–33%, 34–65%, >66%). Potential efficacy was assessed using the non-progression rate (NPR), that is, complete/partial response or stable disease for at least 3 months by RECIST. A total of 135 patients having progressive disease before enrolment were analysed from 15 eligible trials. Median age was 57 years (20–86); male : female ratio was 1.8 : 1. Cohort A, B, and C included 28 (21%), 22 (16%), and 85 (63%) patients; NPR at 3 and 6 months was 21% and 11% (A), 50% and 27% (B), 31% and 14% (C), respectively, P=0.9. Median duration of non-progression (17 weeks; 95% CI=13–22) was not correlated with the MTD level, P=0.9. Our analysis suggests that the potential for clinical benefit is not confined to patients treated at doses close to the MTD in Phase-I trials of MTAs.