Activation of muscarinic receptors elicits inotropic responses in ventricular muscle from rats with heart failure through myosin light chain phosphorylation

Background and purpose:

Muscarinic stimulation increases myofilament Ca²⁺ sensitivity with no apparent inotropic response in normal rat myocardium. Increased myofilament Ca²⁺ sensitivity is a molecular mechanism promoting increased contractility in failing cardiac tissue. Thus, muscarinic receptor activation could elicit inotropic responses in ventricular myocardium from rats with heart failure, through increasing phosphorylation of myosin light chain (MLC).

Experimental approach:

Contractile force was measured in left ventricular papillary muscles from male Wistar rats, 6 weeks after left coronary artery ligation or sham surgery. Muscles were also frozen, and MLC-2 phosphorylation level was quantified.

Key results:

Carbachol (10 µmol·L⁻¹) evoked a positive inotropic response only in muscles from rats with heart failure approximating 36% of that elicited by 1 µmol·L⁻¹ isoproterenol (20 ± 1.5% and 56 ± 6.1% above basal respectively). Carbachol-evoked inotropic responses did not correlate with infarction size but did correlate with increased left ventricular end diastolic pressure, heart weight/body weight ratio and lung weight, primary indicators of the severity of heart failure. Only muscarinic receptor antagonists selective for M₂ receptors antagonized carbachol-mediated inotropic effects with the expected potency. Carbachol-evoked inotropic responses and increase in phosphorylated MLC-2 were attenuated by MLC kinase (ML-9) and Rho-kinase inhibition (Y-27632), and inotropic responses were abolished by Pertussis toxin pretreatment.

Conclusion and implications:

In failing ventricular muscle, muscarinic receptor activation, most likely via M₂ receptors, provides inotropic support by increasing MLC phosphorylation and consequently, myofilament Ca²⁺ sensitivity. Enhancement of myofilament Ca²⁺ sensitivity, representing a less energy-demanding mechanism of inotropic support may be particularly advantageous in failing hearts.     

糖尿病视网膜病变易感性与相关基因多态性研究进展

糖尿病视网膜病变是糖尿病的并发症之一,在糖尿病患者中,有血糖控制不良且病程较长但未发生糖尿病视网膜病变的情况,也有血糖控制良好且病程较短的但发生严重糖尿病视网膜病变的患者。通过大量的流行病学调查发现,糖尿病视网膜病变的发生、发展除了与血糖控制的情况、病程长短等因素有关外,还与每个人的个体差异有关。     

Immunohistochemical analysis of NF‐κB signaling proteins IKKε, p50/p105, p52/p100 and RelA in prostate cancers

Seo SI, Song SY, Kang MR, Kim MS, Oh JE, Kim YR, Lee JY, Yoo NJ, Lee SH. Immunohistochemical analysis of NF‐κB signaling proteins IKKε, p50/p105, p52/p100 and RelA in prostate cancers. APMIS 2009; 117:623–8. Activation of nuclear factor‐kappa B (NF‐κB) signaling is considered an important mechanism in the development of prostate cancers. A recent study revealed that IκB kinase epsilon (IKKε), an activator of NF‐κB, was overexpressed in breast cancers and acted as an oncogene. Expression of NF‐κB members has been reported in prostate cancer tissues, but expression of IKKε has not yet been studied in prostate cancers. In this study, we attempted to explore as to whether expressions of IKKε and NF‐κB members p50/105, p52/p100 and RelA are altered in prostate cancers. We analyzed the expression of IKKε, p50/105, p52/p100 and RelA in 107 prostate adenocarcinoma tissues by immunohistochemistry using a tissue microarray (TMA) method. In the TMA, IKKε is expressed in basal cells, but not in alveolar cells in normal prostate glands. IKKε is expressed in 60.0% of prostate intraepithelial neoplasm (PIN) and 70.1% of the prostate cancers in the cytoplasm. Nuclear immunostainings of NF‐κB members p50/105, p52/p100 and RelA, which are considered activation of NF‐κB signaling, were observed respectively in 28.0%, 18.7% and 37.4% of the cancers. Nuclear staining was detected neither in normal alveolar cells nor in PIN. However, none of the expression of p50/105 nor p52/p100 nor RelA nor IKKε was associated with pathologic characteristics, including size of the cancers, age, Gleason score and stage. The increased cytoplasmic expression of IKKε as well as the increased nuclear expressions of p50/105, p52/p100 and RelA in the prostate cancers compared to normal alveolar cells suggested that overexpression of these proteins may be related to activation of the NF‐κB pathway and might play a role in tumorigenesis of prostate cancers.     

Salvage temozolomide for prior temozolomide responders

BACKGROUND: Temozolomide (TMZ) often is used as adjuvant or first-line therapy for patients with glioma. Because of potential hematologic complications, it usually is discontinued after 12-18 cycles, even in responders. Subsequent salvage therapies are reported to have limited efficacy at the time of disease recurrence. In the current study, the authors assessed the outcome and complications of reusing TMZ at the time of disease recurrence in patients who previously responded to treatment. METHODS: A retrospective review of patients with recurrent/progressive glioma who had a history of response to TMZ and were treated with the same agent at the time of disease recurrence was conducted. RESULTS: Fourteen patients were identified (8 men and 6 women). The median age of the patients was 56 years (range, 25-67 yrs) at the time of diagnosis; 9 patients had glioblastoma, 3 had anaplastic astrocytoma, and 2 patients had low-grade oligodendroglioma. No patient developed disease progression while receiving the initial TMZ treatment. At the time of the initial disease recurrence, 13 patients were readministered TMZ. One patient received TMZ at the time of second disease recurrence. All patients were assessed for radiographic response. Objective response or stable disease was achieved in 6 patients (43%; 95% confidence interval [95% CI], 21-67%) and the 6-month progression-free survival was 36% (95% CI, 16-61%). CONCLUSIONS: TMZ was found to be well tolerated and effective in this setting, suggesting that repeat use of TMZ in previous responders warrants further investigation.     

Prospective analysis of creatine kinase muscle-brain fraction and comparison with troponin T to predict cardiac risk and benefit of an invasive strategy in patients with non-ST-elevation acute coronary syndromes

OBJECTIVE: We sought to determine whether elevation of plasma creatine kinase muscle-brain fraction (CK-MB) would be useful to triage patients with acute coronary syndromes (ACS) to early angiography/revascularization. BACKGROUND: It is unknown whether the measurement of CK-MB is effective for triage to an aggressive management strategy. METHOD: Patients in the Treat Angina With Aggrastat and Determine Cost of Therapy With an Invasive or Conservative Strategy (TACTICS-TIMI) 18 study received aspirin, heparin, and tirofiban for treatment of ACS, were randomized to an invasive or a conservative strategy (angiography/revascularization between 4 and 48 h), and were followed up for a composite end point of death, myocardial infarction, or rehospitalization for ACS.Of 2,220 patients, CK-MB was elevated in 826 (37%). Of the patients with negative CK-MB, troponin T was elevated in 361 (31.2%). Event rates at 30 and 180 days were twice as high in patients with elevated CK-MB than in patients without elevated CK-MB. Both groups had similar benefit from an invasive strategy; there was no evidence of interaction between CK-MB elevation and strategy on the composite end point at 30 or 180 days. When patients were stratified according to both CK-MB and troponin status, there was evidence of a benefit in the invasive strategy among patients who were CK-negative but troponin-positive (odds ratios [95% confidence interval]: 0.13 [0.04 to 0.39] at 30 days and 0.29 [0.16 to 0.52] at 180 days). CONCLUSION: Patients with minimal amounts of recent onset myonecrosis but elevated risk as indicated by CK-MB and troponin, respectively, benefit most from invasive management. Determination of troponin levels yielded significant information regarding triage to an invasive strategy, particularly in CK-MB-negative patients.     

Relationship between baseline white blood cell count and degree of coronary artery disease and mortality in patients with acute coronary syndromes: a TACTICS-TIMI 18 (Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy- Thrombolysis in Myocardial Infarction 18 trial)substudy

OBJECTIVES: This study was designed to determine the relationship between baseline white blood cell (WBC) count and angiographic and clinical outcomes in patients with unstable angina (UA)/non-ST-segment elevation myocardial infarction (NSTEMI) and to see if WBC count was a significant predictor of outcomes independent of other biomarkers. BACKGROUND: Inflammation has been shown to play a role in atherosclerosis and acute coronary syndromes. METHODS: We evaluated the relationship between baseline WBC count, other baseline variables and biomarkers, angiographic findings, and clinical outcomes in 2,208 patients in the Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction 18 (TACTICS-TIMI 18) trial. RESULTS: Higher baseline WBC counts were associated with lower Thrombolysis In Myocardial Infarction (TIMI) flow grades (p = 0.0045) and TIMI myocardial perfusion grades (p = 0.03) as well as a greater extent of coronary artery disease (CAD) (p < 0.0001). A higher baseline WBC count was predictive of higher six-month mortality, ranging from 1.5% to 3.6% to 5.1% for patients with low, intermediate, and high WBC counts, respectively (p = 0.0017). In a multivariable proportional hazards model, patients with a low C-reactive protein (CRP) but an elevated WBC remained at significantly higher risk of death at six months (hazard ratio [HR] 4.3, p = 0.049), and patients with a high CRP were at even higher risk (HR 8.6, p = 0.004). conclusions: In patients with UA/NSTEMI, elevations in a simple, widely available blood test, the WBC count, were associated with impaired epicardial and myocardial perfusion, more extensive CAD, and higher six-month mortality. After adjustment for traditional risk factors and other biomarkers, assessment of two inflammatory markers, WBC count and CRP, can be used to stratify patients across an eightfold gradation of six-month mortality risk.