Ca2+-dependent modulation of single human cardiac L-type calcium channels by the calcineurin inhibitor cyclosporine

OBJECTIVE: Activity of single L-type calcium channels (LTCC) is enhanced in human failing myocardium (Circulation 98 (1998) 969.), most likely due to impaired dephosphorylation. Protein phosphatase 2B (calcineurin) has recently been shown to be involved in heart failure pathophysiology. We now focus on the regulation of single LTCC by calcineurin that were prevented by Ca(2+)-free experimental conditions in our previous study. METHODS: Single LTCC currents were recorded in myocytes from human atrium and ventricle. Charge carriers were 70 mM Ba(2+), or a mixture of 30 mM Ca(2+) and 60 mM Ba(2+) to facilitate Ca(2+) permeation through recorded channels. The calcineurin inhibitor cyclosporine (10 microM) was used to reveal a putative role for calcineurin in regulation of LTCC. RESULTS: A mixture of Ca(2+) and Ba(2+) as charge carriers allowed for Ca(2+) permeation through recombinant human embryonic kidney cells and native (atrial and ventricular) human cardiac LTCC. With only Ba(2+) as the charge carrier, activities of both ventricular and atrial LTCC were strongly decreased by cyclosporine. In contrast, channel activity remained constant when Ca(2+) permeation was provided. In the presence of thapsigargin and (S)-BayK 8644, cyclosporine here even increased channel activity. CONCLUSIONS: We propose a dual cyclosporine effect on human cardiac LTCC. A non-specific inhibitory effect prevails with Ba(2+) permeation but can be compensated or overcome by a specific Ca(2+)-dependent stimulation with Ca(2+) permeation. More complete restoration of physiological Ca(2+) movements (e.g., Ca(2+) release from sarcoplasmic reticulum) will help to define even more precisely the involvement of calcineurin in regulation of human cardiac LTCC.     

A comparison of standard PCNL and staged retrograde FURS in pelvis stones over 2 cm in diameter: a prospective randomized study

The aim of the study was to compare percutaneous nephrolithotomy (PCNL) and staged retrograde flexible ureteroscopy (FURS) methods used in the treatment of kidney stones of 2 cm or more in diameter. The study comprised a total of 60 patients with a diagnosis of kidney pelvic stones more than 2 cm in diameter, for whom surgery was planned between January 2013 and January 2014. The patients were randomly allocated to two groups as staged retrograde FURS (Group A) and PCNL (Group B). Comparison of the groups was made with respect to operating time, number of procedures, total treatment time, length of hospital stay, stone-free rates and complications according to the Clavien–Dindo classification. In Group A, the total operating time of multiple sessions was 114.46 min. In Group B, a single session of PCNL was applied to all patients and the mean operating time was 86.8 min (p = 0.014). Mean total treatment time was 2.01 weeks in Group A and 1 week in Group B (p < 0.01). The mean total hospitalization time was 3.66 days in Group A and 3.13 days in Group B (p = 0.037). At the end of the sessions, clinically insignificant residual fragments were observed in ten patients of Group A and one patient of Group B (p = 0.03). No statistically significant difference was determined between the groups in terms of stone-free rates or complications. Although current technology with FURS is effective on large kidney stones, it has no superiority to PCNL due to the need for multiple sessions and long treatment time.     

Thrombus aspiration during primary percutaneous coronary intervention associated with reduced platelet activation

Objectives:

To determine the effect of thrombectomy on platelet function in patients undergoing primary percutaneous coronary intervention (PPCI) for ST segment elevation myocardial infarction (STEMI).

Methods:

This retrospective study included 413 consecutive STEMI patients who underwent PPCI between March 2012 and September 2013 at Kartal Kosuyolu High Specialty Education and Research Hospital, Istanbul, Turkey that were assigned to the thrombus aspiration (TA) group or the non-TA group. Platelet count and mean platelet volume (MPV) were obtained at baseline and 24 hours (h), 48 h, and 72 h post PPCI.

Results:

Baseline MPV was similar in both groups, whereas the baseline platelet count was higher in the TA group (p=0.42 and p=0.002). The platelet count was higher in the TA group 24 h post PPCI (p=0.02), but was similar in both groups 48 h and 72 h post PPCI (p=0.18 and p=0.07). The MPV 48 h and 72 h post PPCI was higher in the non-TA group than in the TA group (8.4 ± 1.3 fL versus 8.7 ± 1.6 fL [p=0.04] and 8.5 ± 1.1 fL versus 8.9 ± 1.5 fL [p=0.04]).

Conclusion:

Thrombectomy reduced platelet activity via removal of thrombi from the coronary arteries in patients undergoing PPCI for STEMI.In acute ST-segment elevation myocardial infarction (STEMI), the main initiating factor is atherosclerotic plaque rupture or erosion, then platelets become activated and aggregated leading to acute coronary artery occlusion.1 Primary percutaneous coronary intervention (PPCI) is the standard treatment in patients with STEMI.2 In recent years, implementation of adjunctive mechanical and pharmacological therapies during PPCI, including manual thrombus aspiration (TA), has improved myocardial reperfusion and clinical outcome in STEMI patients.3-5 In daily practice, thrombectomy devices are used to remove thrombi or to prevent embolization of thrombi and plaque during PPCI.6 Platelet volume is a marker of platelet activation and is measured via mean platelet volume (MPV).7 An increase in MPV can occur in cases of acute myocardial ischemia, acute myocardial infarction, coronary atherosclerosis,8,9 and early stent thrombosis (ST).10 The Percutaneous Coronary Intervention in Acute Myocardial Infarction (TAPAS) study5 showed that TA therapy during PPCI decreases mortality and reinfarction rate.5 We speculate that the good results obtained with TA therapy are not only related to improved tissue perfusion but also may be related to reduced platelet activation. Therefore, the present study aimed to determine the effect of thrombectomy on platelet function and ST in patients undergoing PPCI for STEMI.     

Gemcitabine alone versus combination of gemcitabine and cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: a retrospective analysis of multicenter study

The majority of patients with pancreatic cancer is of advanced disease. Several randomized Phase II and III trials suggest that the combination of gemcitabine and cisplatin (GemCis) response rates were higher than Gemcitabine (Gem) alone, however the trials were not enough powered to indicate a statistically significant prolongation of survival in patients with advanced pancreatic adenocarcinoma. The aim of this retrospective multicenter study is to evaluated the efficiency of Gem alone versus GemCis in patients with locally advanced and/or metastatic pancreatic adenocarcinoma .A total of 406 patients, from fourteen centers were evaluated retrospectively. All patients received Gem or GemCis as first-line treatment between September 2005 to March 2011. Primary end of this study were to evaluate the toxicity, clinical response rate, progression-free survival (PFS) and overall survival (OS) between the arms. There were 156 patients (M: 98, F: 58) in Gem arm and 250 patients (M: 175, F: 75) in the combination arm. Gemcitabin arm patients older than the combination arm ( median 63 vs 57.5, p=0.001). In patients with the combination arm had a higher dose reduction (25.2% vs 11.3%, p=0.001) and dose delay (34% vs 16.8%, p=0.001). Among patients with the combination and Gemcitabin arm gender, diabetes mellitus, performance status, cholestasis, grade, stage did not have a statistically difference (p>0.05). Clinical response rate to the combination arm was higher than the Gem arm (69.0% vs 49.7%, p=0.001). PFS was more favorable in the GemCis arm than Gem alone, but the difference did not attain statistical significance (8.9 vs 6.0, p=0.08). OS was not significantly superior in the GemCis arm (12.0 vs 10.2, p>0.05). Grade III-IV hematologic and nonhematologic toxicity were higher in the combination arm. PFS was more favorable in the GemCis arm than Gem alone, but the difference did not attain statistical significance. OS was not significantly superior in the GemCis arm.     

Catheter ablation of ventricular tachycardias using remote magnetic navigation: a consecutive case-control study

Remote Magnetic Navigation for VT Ablation. Background: This study aimed to compare acute and late outcomes of VT ablation using the magnetic navigation system (MNS) to manual techniques (MAN) in patients with (SHD) and without (NSHD) structural heart disease. Methods: Ablation data of 113 consecutive patients (43 SHD, 70 NSHD) with ventricular tachycardia treated with catheter ablation at our center were analyzed. Success rate, complications, procedure, fluoroscopy, and ablation times, and recurrence rates were systematically recorded for all patients. Results: A total of 72 patients were included in the MNS group and 41 patients were included in the MAN group. Patient age, gender, and right ventricular and left ventricular VT were equally distributed. Acute success was achieved in 59 patients in the MNS group (82%) versus 27 (66%) patients in the MAN group (P = 0.046). Overall procedural time (177 ± 79 vs 232 ± 99 minutes, P < 0.01) and mean patient fluoroscopy time (27 ± 19 vs 56 ± 32 minutes, P < 0.001) were all significantly lower using MNS. In NSHD pts, higher acute success was achieved with MNS (83,7% vs 61.9%, P = 0.049), with shorter procedure times (151 ± 57 vs 210 ± 96, P = 0.011), whereas in SHD‐VT these were not significantly different. No major complications occurred in the MNS group (0%) versus 1 cardiac tamponade and 1 significantly damaged ICD lead in the MAN group (4.9%, NS). After follow‐up (20 ± 11 vs 20 ± 10 months, NS), VT recurred in 14 pts (23.7%) in the MNS group versus 12 pts (44.4%) in the MAN group (P = 0.047). Conclusions: The use of MNS offers advantages for ablation of NSHD‐VT, while it offers similar efficacy for SHD‐VT. ((J Cardiovasc Electrophysiol, Vol. 23, pp. 948‐954, September 2012)     

nNOS expression in the brain of rats after burn and the effect of the ACE inhibitor captopril

Objective

To investigate the role of endogenous neuronal nitric oxide synthase (nNOS) on brain injury after burn and the effects of the captopril.

Methods

Wistar albino rats (200–250 g) were exposed on the dorsal surface to 90 °C (burn) or 25 °C (sham) water for 10 s. The ACE group was treated with intraperitoneal 10 mg/kg captopril immediately after burn and this treatment was repeated twice daily. At the end of the 24 h brain samples were taken. nNOS was studied in brain areas by immunohistochemistry.

Results

There was no difference between the cerebellar and hypothalamic areas the nNOS expression of all groups. nNOS expression increased in the frontal cortex, striatum and midbrain in the burn group compared to the control group. In the frontal cortex, nNOS expression significantly decreased after ACE inhibitor treatment (p < 0.05). The striatal nNOS of the ACE group significantly increased when compared to the control group (p = 0.001). In the midbrain of the animals, nNOS decreased in the ACE group. Hippocampal nNOS expression did not change after burn and significantly increased after ACE inhibitor therapy (p < 0.05).

Conclusions

Our data showed that the pathophysiological events following burn appear to be related to an acute inflammatory reaction which is associated with nNOS in the frontal cortex, striatum and midbrain, and captopril treatment abrogates the nNOS response in the frontal cortex and midbrain.