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1.  Survival and echocardiographic data in dogs with congestive heart failure caused by mitral valve disease and treated by multiple drugs: A retrospective study of 21 cases 
The Canadian Veterinary Journal  2011;52(11):1219-1225.
This retrospective study reports the survival time [onset of congestive heart failure (CHF) to death from any cause] of 21 dogs with mitral regurgitation (MR) and CHF treated with a combination of furosemide, angiotensin-converting enzyme inhibitor (ACEI, benazepril, or enalapril), pimobendan, spironolactone, and amlodipine. Baseline echocardiographic data: end-systolic and end-diastolic volume indices (ESVI and EDVI), left atrium to aorta ratio (LA/Ao), and regurgitant fraction (RF) are reported. Median survival time (MST) was 430 d. Initial dosage of furosemide (P = 0.0081) and LA/Ao (P = 0.042) were negatively associated with survival. Baseline echocardiographic indices (mean ± standard deviation) were 40.24 ± 16.76 for ESVI, 161.48 ± 44.49 mL/m2 for EDVI, 2.11 ± 0.75 for LA/Ao, and 64.71 ± 16.85% for RF. Combining furosemide, ACEI, pimobendan, spironolactone, and amlodipine may result in long survival times in dogs with MR and CHF. Severity of MR at onset of CHF is at least moderate.
PMCID: PMC3196016  PMID: 22547843
2.  Monitoring of heart failure: comparison of left atrial pressure with intrathoracic impedance and natriuretic peptide measurements in an experimental model of ovine heart failure 
Monitoring of HF (heart failure) with intracardiac pressure, intrathoracic impedance and/or natriuretic peptide levels has been advocated. We aimed to investigate possible differences in the response patterns of each of these monitoring modalities during HF decompensation that may have an impact on the potential for early therapeutic intervention. Six sheep were implanted with a LAP (left atrial pressure) sensor and a CRT-D (cardiac resynchronization therapy defibrillator) capable of monitoring impedance along six lead configuration vectors. An estimate of ALAP (LAP from admittance) was determined by linear regression. HF was induced by rapid ventricular pacing at 180 and 220 bpm (beats/min) for a week each, followed by a third week with daily pacing suspensions for increasing durations (1–5 h). Incremental pacing induced progressively severe HF reflected in increases in LAP (5.9 ± 0.4 to 24.5 ± 1.6 mmHg) and plasma atrial (20 ± 3 to 197 ± 36 pmol/l) and B-type natriuretic peptide (3.7 ± 0.7 to 32.7 ± 5.4 pmol/l) (all P<0.001) levels. All impedance vectors decreased in proportion to HF severity (all P<0.001), with the LVring (left ventricular)-case vector correlating best with LAP (r2=0.63, P<0.001). Natriuretic peptides closely paralleled rapid acute changes in LAP during alterations in pacing (P<0.001), whereas impedance changes were delayed relative to LAP. ALAP exhibited good agreement with LAP. In summary, impedance measured with an LV lead correlates significantly with changes in LAP, but exhibits a delayed response to acute alterations. Natriuretic peptides respond rapidly to acute LAP changes. Direct LAP, impedance and natriuretic peptide measurements all show promise as early indicators of worsening HF. ALAP provides an estimate of LAP that may be clinically useful.
PMCID: PMC2990201  PMID: 20846122
haemodynamics; heart failure; implantable monitor; intrathoracic impedance; left atrial pressure; natriuretic peptide; ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; bpm, beats/min; CRT-D, cardiac resynchronization therapy defibrillator; HF, heart failure; ICU, intensive care unit; LAP, left atrial pressure; ALAP, LAP from admittance; LV, left ventricular; LVEDV, LV end-diastolic volume; MR, mitral valve regurgitation; PAM™, Patient Advisor Module; RA, right atrial; RV, right ventricular; Z, intrathoracic impedance
3.  Alterations in Atrial Electrophysiology and Tissue Structure in a Canine Model of Chronic Atrial Dilatation Due to Mitral Regurgitation 
Circulation  2003;107(20):2615-2622.
Clinically, chronic atrial dilatation is associated with an increased incidence of atrial fibrillation (AF), but the underlying mechanism is not clear. We have investigated atrial electrophysiology and tissue structure in a canine model of chronic atrial dilatation due to mitral regurgitation (MR).
Methods and Results
Thirteen control and 19 MR dogs (1 month after partial mitral valve avulsion) were studied. Dogs in the MR group were monitored using echocardiography and Holter recording. In open-chest follow-up experiments, electrode arrays were placed on the atria to investigate conduction patterns, effective refractory periods, and inducibility of AF. Alterations in tissue structure and ultrastructure were assessed in atrial tissue samples. At follow-up, left atrial length in MR dogs was 4.09±0.45 cm, compared with 3.25±0.28 at baseline (P<0.01), corresponding to a volume of 205±61% of baseline. At follow-up, no differences in atrial conduction pattern and conduction velocities were noted between control and MR dogs. Effective refractory periods were increased homogeneously throughout the left and right atrium. Sustained AF (>1 hour) was inducible in 10 of 19 MR dogs and none of 13 control dogs (P<0.01). In the dilated MR left atrium, areas of increased interstitial fibrosis and chronic inflammation were accompanied by increased glycogen ultrastructurally.
Chronic atrial dilatation in the absence of overt heart failure leads to an increased vulnerability to AF that is not based on a decrease in wavelength.
PMCID: PMC1995672  PMID: 12732604
fibrillation; electrophysiology; tissue
4.  Bioavailability study of fixed-dose tablet versus capsule formulation of amlodipine plus benazepril: A randomized, single-dose, two-sequence, two-period, open-label, crossover study in healthy volunteers 
In the treatment of hypertension, combination therapy is important10 because antihypertensive monotherapy is effective in only 40% of patients worldwide. Amlodipine is a dihydropyridine calcium channel blocker with a slow onset and long duration of action. Benazepril hydrochloride is a prodrug hydrolyzed by esterase to the active metabolite benazeprilat, an angiotensin-converting enzyme inhibitor. In 1995, the US Food and Drug Administration approved the use of a capsule formulation of combination amlodipine-benazepril for hypertension.
The aim of this study was to compare the bioavailability and tolerability10 of the capsule formulation with those of a tablet formulation of combination amlodipine-benazepril in healthy volunteers.
This single-dose, 2-sequence, 2-period, open-label, crossover10 study recruited healthy, adult, male volunteers with normotension. Subjects were randomly assigned to 1 of 2 treatment sequences: a single-dose tablet containing amlodipine 5 mg plus benazepril 10 mg, followed by a single-dose capsule containing the same dose of each drug (AB), or vice versa (BA). The treatment period for each drug consisted of dosing and pharmacokinetic analysis on day 1, followed by pharmacokinetic analysis on days 2 to 7. Treatment periods were separated by a 4-week washout period. For pharmacokinetic analysis, serial blood samples were obtained before dosing and at 20, 40, 60, 80, and 100 minutes and 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 36, 60, 84, 108, 132, and 156 hours after dosing. Tolerability was assessed using subject interview and spontaneous reporting.
Twelve healthy, male, Taiwanese subjects (mean [SD] age, 23.510 [1.7] years) participated in the study. No statistically significant differences inbioavailability were found between the 2 formulations based on the pharmacokinetic measurements of amlodipine and benazeprilat. The rate and extent of absorption of the tablets were found to be comparable to those of the capsules (90% CI, between 80% and 125%). The mean (SD) relative bioavailabilities, as represented by AUC0−∞, of amlodipine and benazeprilat for tablets versus capsules were 1.060 (0.170) versus 0.949 (0.197), respectively. The mean plasma concentration-time profiles of amlodipine and benazeprilat were graphically similar. No adverse effects were observed with either formulation.
The results of this bioavailability comparison study in this 10 population of healthy, male, Taiwanese volunteers suggest that the tablet and capsule formulations of combination amlodipine-benazepril are bioequivalent. Both formulations were well tolerated.
PMCID: PMC3964558
bioequivalence; bioavailability; pharmacokinetics; amlodipinebesylate; benazepril hydrochloride; fixed-dose combination
5.  Latency Associated Peptide Has In Vitro and In Vivo Immune Effects Independent of TGF-β1 
PLoS ONE  2008;3(4):e1914.
Latency Associated Peptide (LAP) binds TGF-β1, forming a latent complex. Currently, LAP is presumed to function only as a sequestering agent for active TGF-β1. Previous work shows that LAP can induce epithelial cell migration, but effects on leukocytes have not been reported. Because of the multiplicity of immunologic processes in which TGF-β1 plays a role, we hypothesized that LAP could function independently to modulate immune responses. In separate experiments we found that LAP promoted chemotaxis of human monocytes and blocked inflammation in vivo in a murine model of the delayed-type hypersensitivity response (DTHR). These effects did not involve TGF-β1 activity. Further studies revealed that disruption of specific LAP-thrombospondin-1 (TSP-1) interactions prevented LAP-induced responses. The effect of LAP on DTH inhibition depended on IL-10. These data support a novel role for LAP in regulating monocyte trafficking and immune modulation.
PMCID: PMC2288562  PMID: 18392110
6.  Endoplasmic Reticulum Stress-Induced JNK Activation Is a Critical Event Leading to Mitochondria-Mediated Cell Death Caused by β-Lapachone Treatment 
PLoS ONE  2011;6(6):e21533.
β-lapachone (β-lap) is a bioreductive agent that is activated by the two-electron reductase NAD(P)H quinone oxidoreductase 1 (NQO1). Although β-lap has been reported to induce apoptosis in various cancer types in an NQO1-dependent manner, the signaling pathways by which β-lap causes apoptosis are poorly understood.
Methodology/Principal Findings
β-lap-induced apoptosis and related molecular signaling pathways in NQO1-negative and NQO1-overexpressing MDA-MB-231 cells were investigated. Pharmacological inhibitors or siRNAs against factors involved in β-lap-induced apoptosis were used to clarify the roles played by such factors in β-lap-activated apoptotic signaling pathways. β-lap leads to clonogenic cell death and apoptosis in an NQO1- dependent manner. Treatment of NQO1-overexpressing MDA-MB-231 cells with β-lap causes rapid disruption of mitochondrial membrane potential, nuclear translocation of AIF and Endo G from mitochondria, and subsequent caspase-independent apoptotic cell death. siRNAs targeting AIF and Endo G effectively attenuate β-lap-induced clonogenic and apoptotic cell death. Moreover, β-lap induces cleavage of Bax, which accumulates in mitochondria, coinciding with the observed changes in mitochondria membrane potential. Pretreatment with Salubrinal (Sal), an endoplasmic reticulum (ER) stress inhibitor, efficiently attenuates JNK activation caused by β-lap, and subsequent mitochondria-mediated cell death. In addition, β-lap-induced generation and mitochondrial translocation of cleaved Bax are efficiently blocked by JNK inhibition.
Our results indicate that β-lap triggers induction of endoplasmic reticulum (ER) stress, thereby leading to JNK activation and mitochondria-mediated apoptosis. The signaling pathways that we revealed in this study may significantly contribute to an improvement of NQO1-directed tumor therapies.
PMCID: PMC3127577  PMID: 21738692
7.  Amlodipine Fatality in an Infant with Postmortem Blood Levels 
Journal of Medical Toxicology  2012;8(2):179-182.
Amlodipine is a dihydropyridine calcium channel blocker used in the treatment of hypertension and angina pectoris. Toxic effects reported from amlodipine include hypotension, reflex tachycardia, metabolic acidosis, and pulmonary edema. We report a rare fatality in an infant after ingestion of amlodipine with benazepril, with postmortem blood concentrations.
Case report
An 11-month-old, 10.88-kg boy ingested 10 to 45 mg amlodipine with 40 to 180 mg benazepril. No action was taken initially because the parents believed only one or two capsules had been ingested. A later count revealed a maximum of nine capsules missing. The child was observed at home and vomited once with possible capsule fragments. Forty-five minutes post-ingestion, the child was noted to be suddenly unresponsive and was brought the local emergency department by a private vehicle. Upon arrival (90 min post-ingestion), the child was unresponsive with the following vital signs HR 133 bpm, BP 67/42 mmHg, respiratory rate 40/min, and temperature 97.5°F. Pertinent abnormal laboratory values were HCO3 13 mmol/l and glucose 302 mg/dl. The child was placed on oxygen via a non-rebreather mask and was intubated 45 min post-arrival. The patient became progressively bradycardic, and 55 min after arrival, the patient was in asystole with no palpable blood pressure. Resuscitation measures included chest compressions, epinephrine atropine, sodium bicarbonate, and calcium gluconate. Rescue insulin therapy was begun with 4 units IVP followed by 10 units per hour. Resuscitation efforts persisted for 1 h without success. An autopsy revealed pulmonary edema and no gross or microscopic evidence of natural disease. Stomach contents revealed food matter with small white fragments. Analysis of postmortem heart blood showed amlodipine 1,300 ng/ml (therapeutic <20 ng/ml). Benazepril levels were not available.
We believe this is the first reported fatality in an infant from amlodipine. While benazepril may have contributed, ACE inhibitors have not been previously associated with rapid cardiovascular collapse.
Small doses of amlodipine (0.9 to 4.1 mg/kg) may produce rapid and fatal cardiovascular collapse in an infant.
PMCID: PMC3550251  PMID: 22271567
Amlodipine; Postmortem; Infant; Overdose
8.  The Effect of Amlodipine Alone and in Combination with Atenolol on Bowel Habit in Patients with Hypertension: An Observation 
ISRN Gastroenterology  2010;2011:757141.
The prevalence of hypertension increases with advancing age. The management of hypertension especially in the elderly has its own limitations. Verapamil is not recommended in the elderly on account of high incidences of troublesome constipation. Amlodipine has become very popular with the cardiologists and general physicians. Survey of literature has not yielded any citation where the troublesome effect of amlodipine on the gastrointestinal tract has been reported. In an experimental study on isolated rabbit intestine we have demonstrated that amlodipine dose-dependently inhibit the spontaneous activity of the intestinal tract. With this background the present observational study was planned. A total of 100 hypertensive patients were included in the present study. Fifty patients were on amlodipine alone and 50 patients on combination of amlodipine and atenolol. The main parameter analyzed was the frequency and consistency of stool before and after intake of drug. The relative risk (RR) of developing constipation was 4.00 with 95% CI 0.8930 to 17.917 in amlodipine alone group. From this study it can be concluded that the relative risk of developing constipation is 4 times more in patients who are taking amlodipine alone as compared to those patients who are on combination of amlodipine and atenolol.
PMCID: PMC3168527  PMID: 21991529
9.  Valsartan addition to amlodipine is more effective than losartan addition in hypertensive patients inadequately controlled by amlodipine 
This study evaluated the effects on blood pressure (BP) of valsartan 160 mg or losartan 100 mg addition to amlodipine 5 mg in hypertensive patients.
221 patients with inadequately controlled BP (DBP ≥ 90 mmHg) after 4 weeks of treatment with amlodipine 5 mg were randomized to receive losartan/amlodipine combination therapy or valsartan/amlodipine combination therapy for 4 weeks in a cross-over study design. At the end of the wash-out period and of each treatment period, clinic and ambulatory BP measurements were recorded.
166 patients completed the study. Both combination treatments induced a greater ambulatory BP reduction than did monotherapy. However, the further mean reductions in BP versus monotherapy were significantly greater with the valsartan/amlodipine combination (SBP/DBP: −7.9 ± 3.4/−6.5 ± 2.6 mmHg for 24-hour, −8.0 ± 3.4/−6.6 ± 2.7 mmHg for daytime; −7.7 ± 3.3/−6.4 ± 2.7 mmHg for nighttime) than with the losartan/amlodipine combination (SBP/DBP: −5.5 ± 2.8/−4.2 ± 2.1 mmHg for 24-hour, −5.7 ± 2.9/−4.4 ± 2.2 mmHg for daytime; −4.8 ± 2.8/−3.7 ± 2.2 mmHg for nighttime; P < 0.01 vs valsartan/amlodipine). The incidence of adverse events with valsartan/amlodipine (8%) and losartan/amlodipine (9%) was lower than that observed with amlodipine monotherapy (17%; P < 0.05 vs combinations).
Valsartan 160 mg plus amlodipine 5 mg produced greater BP reductions than losartan 100 mg plus amlodipine 5 mg.
PMCID: PMC2835558  PMID: 20234783
angiotensin receptor blocker; ambulatory blood pressure monitoring; valsartan; losartan; amlodipine; combination therapy
10.  Impact of Micellar Vehicles on in situ Intestinal Absorption Properties of Beta-Lapachone in Rats 
The aim of the present study was to examine the effect of micellar systems on the absorption of beta-lapachone (b-lap) through different intestinal segments using a single-pass rat intestinal perfusion technique. B-lap was solubilized in mixed micelles composed of phosphatidylcholine and sodium deoxycholate, and in sodium lauryl sulfate (SLS)-based conventional micelles. Both mixed micelles and SLS micelles improved the in situ permeability of b-lap in all intestinal segments tested although the mixed micellar formulation was more effective in increasing the intestinal absorption of b-lap. The permeability of b-lap was greatest in the large intestinal segments. Compared with SLS micelles, the effective permeability coefficient values measured with mixed micelles were 5- to 23-fold higher depending on the intestinal segment. Our data suggest that b-lap should be delivered to the large intestine using a mixed micellar system for improved absorption.
PMCID: PMC3579111  PMID: 23440944
Beta-lapachone; Mixed micelles; Permeability; Single-pass intestinal perfusion
11.  The Effect of Airway Pressure Release Ventilation on Pulmonary Catheter Readings: Specifically Pulmonary Capillary Wedge Pressure in a Swine Model 
Background. Airway pressure release ventilation (APRV) is a mode of mechanical ventilation that theoretically believed to improve cardiac output by lowering right atrial pressure. However, hemodynamic parameters have never been formally assessed. Methods. Seven healthy swine were intubated and sedated. A baseline assessment of conventional ventilation (assist control) and positive end-expiratory pressure (PEEP) of 5 cm H2O was initiated. Ventilator mode was changed to APRV with incremental elevations of CPAP-high from 10 to 35 cm H2O. After a 3-to-5-minute stabilization period, measurements of hemodynamic parameters (PCWP, LAP, and CVP) were recorded at each level of APRV pressure settings. Results. Increasing CPAP caused increased PCWP and LAP measurements above their baseline values. Mean PCWP and LAP were linearly related (LAP = 0.66∗PCWP + 4.5 cm H2O, R2 = 0.674, and P < .001) over a wide range of high and low CPAP values during APRV. With return to conventional ventilation, PCWP and LAP returned to their baseline values. Conclusion. PCWP is an accurate measurement of LAP during APRV over variable levels of CPAP. However, PCWP and LAP may not be accurate measurements of volume when CPAP is utilized.
PMCID: PMC3049321  PMID: 21403912
12.  An Implantable Left Atrial Pressure Sensor Lead Designed for Percutaneous Extraction Using Standard Techniques 
An implantable left atrial pressure (LAP) monitoring system for guiding the management of patients with advanced heart failure has the potential to require extraction, particularly in the setting of infection. The LAP sensor lead was designed to be suitable for ease of percutaneous extraction using standard techniques for extracting pacemaker and defibrillator leads. The clinical experience, to date, with percutaneous extraction of the LAP sensor lead is presented.
A total of 82 patients underwent successful implantation of the LAP sensor lead using transseptal catheterization. Five patients of the 82 patients during a cumulative follow-up period of 267 patient-years (median of 2.9 years/patient) underwent percutaneous extraction using manual traction with a locking stylet and/or an excimer laser sheath to bore through adhesions. The distal fixation anchors of the LAP sensor lead are designed to fold forward during extraction so that the sensor module can easily separate from the interatrial septum.
Percutaneous extraction of the LAP sensor lead was accomplished successfully in all five patients with no embolic events, vascular tears, perforations, or other complications requiring surgical intervention. Manual traction alone was sufficient to detach the LAP sensor lead from the interatrial septum in all cases. Use of the excimer laser sheath was needed in selected cases to bore through scar tissue within the venous insertion site, but not within the heart.
The extraction of the LAP sensor lead was accomplished safely using standard techniques and equipment for percutaneously extracting pacemaker and defibrillator leads.
PMCID: PMC3666087  PMID: 23448187
lead extraction; pacemaker infection; left atrial pressure monitoring
13.  Therapeutic effect of low-dose imatinib on pulmonary arterial hypertension in dogs 
The Canadian Veterinary Journal  2013;54(3):255-261.
This was a pilot study to determine the effectiveness of low-dose imatinib therapy for hemodynamic disturbances, including pulmonary arterial hypertension (PAH), and clinical manifestations caused by chronic heart failure in dogs. Six client-owned dogs with PAH were administered imatinib mesylate orally, 3 mg/kg body weight q24h, for 30 d. Physical examination, blood biochemical tests, radiography, and Doppler echocardiography were performed prior to imatinib administration and again 30 days after administration. Clinical scores were significantly reduced after imatinib treatment. Systolic pulmonary arterial pressure, heart rate, maximum tricuspid regurgitation velocity, left atrium/aorta ratio, right and left ventricular Tei indexes, early diastolic transmitral flow wave/mitral annulus velocity ratio, and plasma atrial natriuretic peptide concentration decreased significantly after therapy. Diastolic blood pressure, stroke volume, cardiac output, and left ventricular fractional shortening increased significantly after therapy. These results indicate that low-dose imatinib therapy was effective for heart failure in dogs with PAH.
PMCID: PMC3573631  PMID: 23997262
14.  A Dynamic Heart System to Facilitate the Development of Mitral Valve Repair Techniques 
Annals of biomedical engineering  2009;37(4):651-660.
The development of a novel surgical tool or technique for mitral valve repair can be hampered by cost, complexity, and time associated with performing animal trials. A dynamically pressurized model was developed to control pressure and flowrate profiles in intact porcine hearts in order to quantify mitral regurgitation and evaluate the quality of mitral valve repair.
A pulse duplication system was designed to replicate physiological conditions in explanted hearts. To test the capabilities of this system in measuring varying degrees of mitral regurgitation, the output of eight porcine hearts was measured for two different pressure waveforms before and after induced mitral valve failure. Four hearts were further repaired and tested. Measurements were compared with echocardiographic images.
For all trials, cardiac output decreased as left ventricular pressure was increased. After induction of mitral valve insufficiencies, cardiac output decreased, with a peak regurgitant fraction of 71.8%. Echocardiography clearly showed increases in regurgitant severity from post-valve failure and with increased pressure.
The dynamic heart model consistently and reliably quantifies mitral regurgitation across a range of severities. Advantages include low experimental cost and time associated with each trial, while still allowing for surgical evaluations in an intact heart.
PMCID: PMC3890103  PMID: 19224369
Dynamic heart model; Mitral regurgitation; Mitral valve repair
15.  Myocardial mechanics in aortic and mitral valvular regurgitation: the concept of instantaneous impedance as a determinant of the performance of the intact heart 
Journal of Clinical Investigation  1968;47(4):867-883.
The effects on myocardial mechanics of acute, artificial aortic and mitral regurgitation were studied in the dog to determine the manner in which the changes in load induced by valvular regurgitation alter ventricular performance. With mitral and aortic regurgitant volumes of approximately the same magnitude as the forward stroke volume, immediate increases occurred in total stroke volume, left ventricular enddiastolic pressure, and peak ejection velocity, whereas contractility remained unchanged. Although calculated myocardial fiber tension rose, the rate of decline of tension during ejection was accelerated with regurgitation due to the more rapid decrease in ventricular size. Average tension therefore decreased relative to average pressure. As a consequence of the increased fiber length and this unloading, contractile element velocity, work, and power were increased. Despite unchanged contractility of the myocardium, the ejection fraction rose with both aortic and mitral regurgitation.
When regurgitant beats were compared with control beats at a constant end-diastolic volume, ventricular stroke volume, work, power, and ejection fraction, as well as contractile element velocity, work, and power consistently increased. Thus, reduction of instantaneous impedance to ejection allowed the ventricle to empty further, reducing ventricular wall tension with a resultant increase in the velocity of shortening. External energy output was increased despite unchanged contractility and diastolic fiber length. It is concluded that the impedance to ejection and myocardial fiber tension during ejection govern the velocity and extent of contractile element shortening, and hence affect stroke volume, peak aortic flow rate, and ejection fraction. The alterations of ventricular function accompanying valvular regurgitation can be explained by an evaluation of the effects of these lesions on the instantaneous impedance to left ventricular ejection.
PMCID: PMC297236  PMID: 5641623
16.  Comparative value of transthoracic and transoesophageal echocardiography before balloon dilatation of the mitral valve 
British Heart Journal  1992;68(5):493-497.
Objective—To assess the relative merits of transthoracic and transoesophageal echocardiography before balloon dilatation of the mitral valve.
Design—Transthoracic and transoesophageal echocardiograms were prospectively performed in 35 patients being considered for balloon dilatation of the mitral valve. Echocardiograms were analysed for image quality, the assessment of valve morphology, the detection of left atrial thrombus, and the assessment of mitral regurgitation and other valvar pathology.
Patients—35 consecutive patients with symptomatic dominant mitral stenosis.
Interventions—30 eventually underwent balloon dilatation of the mitral valve by the Inoue technique. Five patients had mitral valve replacement.
Main outcome measures—Echocardiographic and surgical detection of left atrial thrombus and successful, uncomplicated balloon dilatation of the mitral valve.
Results—Left atrial thrombus was detected in 1/35 patients by transthoracic studies compared with 6/35 from transoesophageal studies. Otherwise both techniques gave comparable results. Thrombus was confirmed at mitral valve replacement in five patients. Successful dilatation of the mitral valve was performed in 30 patients.
Conclusions—Transthoracic echocardiography is a useful screening procedure but transoesophageal echocardiography is mandatory before balloon dilatation of the mitral valve for the detection of left atrial thrombus.
PMCID: PMC1025195  PMID: 1467036
17.  Alterations in the Helicoverpa armigera Midgut Digestive Physiology after Ingestion of Pigeon Pea Inducible Leucine Aminopeptidase 
PLoS ONE  2013;8(9):e74889.
Jasmonate inducible plant leucine aminopeptidase (LAP) is proposed to serve as direct defense in the insect midgut. However, exact functions of inducible plant LAPs in the insect midgut remain to be estimated. In the present investigation, we report the direct defensive role of pigeon pea inducible LAP in the midgut of Helicoverpa armigera (Lepidoptera: Noctuidae) and responses of midgut soluble aminopeptidases and serine proteinases upon LAP ingestion. Larval growth and survival was significantly reduced on the diets supplemented with pigeon pea LAP. Aminopeptidase activities in larvae remain unaltered in presence or absence of inducible LAP in the diet. On the contrary, serine proteinase activities were significantly decreased in the larvae reared on pigeon pea LAP containing diet as compared to larvae fed on diet without LAP. Our data suggest that pigeon pea inducible LAP is responsible for the degradation of midgut serine proteinases upon ingestion. Reduction in the aminopeptidase activity with LpNA in the H. armigera larvae was compensated with an induction of aminopeptidase activity with ApNA. Our findings could be helpful to further dissect the roles of plant inducible LAPs in the direct plant defense against herbivory.
PMCID: PMC3786982  PMID: 24098675
18.  Addition of Aliskiren to Angiotensin Receptor Blocker Improves Ambulatory Blood Pressure Profile and Cardiorenal Function Better than Addition of Benazepril in Chronic Kidney Disease 
An altered ambulatory blood pressure (BP) and heart rate (HR) profile is related to chronic kidney disease (CKD) and cardiorenal syndrome. In this study, we examined the effects of aliskiren, when added to angiotensin II type 1 receptor blockers, on ambulatory BP and cardiorenal function in CKD. Thirty-six hypertensive CKD patients were randomly assigned to the aliskiren add-on group (n = 18) or the benazepril add-on group (n = 18). Ambulatory BP and cardiorenal function parameters were measured at baseline and 24 weeks after treatment. Compared with the benazepril group, nighttime systolic BP variability in the aliskiren group was lower after treatment. Albuminuria was decreased in the aliskiren group, but not in the benazepril group. In addition, left ventricular mass index (LVMI) was significantly lower in the aliskiren group than in the benazepril group after treatment. In the aliskiren group, multivariate linear regression analysis showed an association between changes in albuminuria and changes in nighttime systolic BP. Furthermore, there were associations between changes in LVMI and changes in daytime HR variability, as well as between changes in LVMI and changes in plasma aldosterone concentration. These results suggest that aliskiren add-on therapy may be beneficial for suppression of renal deterioration and pathological cardiac remodeling through an improvement that is effected in ambulatory BP and HR profiles.
PMCID: PMC3759864  PMID: 23887656
albuminuria; ambulatory blood pressure; direct renin inhibitor; left ventricular hypertrophy; hypertension (kidney)
19.  Long-term prehypertension treatment with losartan effectively prevents brain damage and stroke in stroke-prone spontaneously hypertensive rats 
Prehypertension has been associated with adverse cerebrovascular events and brain damage. The aims of this study were to investigate i) whether short- and long-term treatments with losartan or amlodipine for prehypertension were able to prevent blood pressure (BP)-linked brain damage, and ii) whether there is a difference in the effectiveness of treatment with losartan and amlodipine in protecting BP-linked brain damage. In the present study, prehypertensive treatment with losartan and amlodipine (6 and 16 weeks treatment with each drug) was performed on 4-week-old stroke-prone spontaneously hypertensive rats (SHRSP). The results showed that long-term (16 weeks) treatment with losartan is the most effective in lowering systolic blood pressure in the long term (up to 40 weeks follow-up). Additionally, compared with the amlodipine treatment groups, the short- and long-term losartan treatments protected SHRSP from stroke and improved their brains structurally and functionally more effectively, with the long-term treatment having more benefits. Mechanistically, the short- and long-term treatments with losartan reduced the activity of the local renin-angiotensin-aldosterone system (RAAS) in a time-dependent manner and more effectively than their respective counterpart amlodipine treatment group mainly by decreasing AT1R levels and increasing AT2R levels in the cerebral cortex. By contrast, the amlodipine treatment groups inhibited brain cell apoptosis more effectively as compared with the losartan treatment groups mainly through the suppression of local oxidative stress. Taken together, the results suggest that long-term losartan treatment for prehypertension effectively protects SHRSP from stroke-induced brain damage, and this protection is associated with reduced local RAAS activity than with brain cell apoptosis. Thus, the AT1R receptor blocker losartan is a good candidate drug that may be used in the clinic for long-term treatment on prehypertensive populations in order to prevent BP-linked brain damage.
PMCID: PMC3896471  PMID: 24337406
prehypertension; losartan; amlodipine; stroke-prone spontaneously hypertensive rats
20.  Excellent Tolerance to Cilnidipine in Hypertensives with Amlodipine - Induced Edema 
Ankle edema is a common adverse effect of amlodipine, an L-type calcium channel blocker (CCB). Cilnidipine is a newer L/N-type CCB, approved for treatment of essential hypertension.
This study was designed to determine whether cilnidipine can produce resolution of amlodipine-induced edema while maintaining adequate control of hypertension.
Materials and Methods:
A prospective study was performed on 27 patients with essential hypertension with amlodipine-induced edema. Concomitant nephropathy, cardiac failure, hepatic cirrhosis, or other causes of edema, and secondary hypertension were excluded by appropriate tests. Amlodipine therapy was substituted in all the cases with an efficacy-equivalent dose of cilnidipine. Clinical assessment of ankle edema and measurement of bilateral ankle circumference, body weight, blood pressure, and pulse rate were performed at onset of the study and after 4 weeks of cilnidipine therapy.
At completion of the study, edema had resolved in all the patients. There was a significant decrease in bilateral ankle circumference and body weight (P < 0.001). There was no significant change in mean arterial blood pressure and pulse rate.
Therapy with cilnidipine resulted in complete resolution of amlodipine-induced edema in all the cases without significant worsening of hypertension or tachycardia. Cilnidipine is an acceptable alternative antihypertensive for patients with amlodipine-induced edema.
PMCID: PMC3560139  PMID: 23378956
Ankle edema; Calcium channel blocker; Cilnidipine; Hypertension; L/N-type calcium channel
21.  Lamina-associated polypeptide 2α regulates cell cycle progression and differentiation via the retinoblastoma–E2F pathway 
The Journal of Cell Biology  2006;173(1):83-93.
Lamina-associated polypeptide (LAP) 2α is a nonmembrane-bound LAP2 isoform that forms complexes with nucleoplasmic A-type lamins. In this study, we show that the overexpression of LAP2α in fibroblasts reduced proliferation and delayed entry into the cell cycle from a G0 arrest. In contrast, stable down-regulation of LAP2α by RNA interference accelerated proliferation and interfered with cell cycle exit upon serum starvation. The LAP2α-linked cell cycle phenotype is mediated by the retinoblastoma (Rb) protein because the LAP2α COOH terminus directly bound Rb, and overexpressed LAP2α inhibited E2F/Rb-dependent reporter gene activity in G1 phase in an Rb-dependent manner. Furthermore, LAP2α associated with promoter sequences in endogenous E2F/Rb-dependent target genes in vivo and negatively affected their expression. In addition, the expression of LAP2α in proliferating preadipocytes caused the accumulation of hypophosphorylated Rb, which is reminiscent of noncycling cells, and initiated partial differentiation into adipocytes. The effects of LAP2α on cell cycle progression and differentiation may be highly relevant for the cell- and tissue-specific phenotypes observed in laminopathic diseases.
PMCID: PMC2063793  PMID: 16606692
22.  Effect of left atrial compliance on pulmonary artery pressure: a case report 
Left ventricular diastolic dysfunction, with secondary atrial pressure elevation, is a well-known concept. On the contrary, effect of left atrial compliance on pulmonary pressure is rarely considered.
Case presentation
We report the echocardiographic case of a 9-year-old child who presented severe rheumatic mitral valve regurgitation with a giant left atrium, in contrast to a normal artery pulmonary pressure, testifying of the high left atrial compliance.
Left atrial compliance is an important determinant of symptoms and pulmonary artery pressure in mitral valve disease.
PMCID: PMC1557539  PMID: 16901350
23.  Non invasive evaluation of cardiomechanics in patients undergoing MitrClip procedure 
In the last recent years a new percutaneous procedure, the MitraClip, has been validated for the treatment of mitral regurgitation. MitraClip procedure is a promising alternative for patients unsuitable for surgery as it reduces the risk of death related to surgery ensuring a similar result. Few data are present in literature about the variation of hemodynamic parameters and ventricular coupling after Mitraclip implantation.
Hemodynamic data of 18 patients enrolled for MitraClip procedure were retrospectively reviewed and analyzed. Echocardiographic measurements were obtained the day before the procedure (T0) and 21 ± 3 days after the procedure (T1), including evaluation of Ejection Fraction, mitral valve regurgitation severity and mechanism, forward Stroke Volume, left atrial volume, estimated systolic pulmonary pressure, non invasive echocardiographic estimation of single beat ventricular elastance (Es(sb)), arterial elastance (Ea) measured as systolic pressure • 0.9/ Stroke Volume, ventricular arterial coupling (Ea/Es(sb) ratio). Data were expressed as median and interquartile range. Measures obtained before and after the procedure were compared using Wilcoxon non parametric test for paired samples.
Mitraclip procedure was effective in reducing regurgitation. We observed an amelioration of echocardiographic parameters with a reduction of estimated systolic pulmonary pressure (45 to 37,5 p = 0,0002) and left atrial volume (110 to 93 p = 0,0001). Despite a few cases decreasing in ejection fraction (37 to 35 p = 0,035), the maintained ventricular arterial coupling after the procedure (P = 0,67) was associated with an increasing in forward stroke volume (60,3 to 78 p = 0,05).
MitraClip is effective in reducing mitral valve regurgitation and determines an amelioration of hemodynamic parameters with preservation of ventricular arterial coupling.
PMCID: PMC3651274  PMID: 23642140
Mitraclip; Ventricular arterial coupling; Cardiomechanic
24.  CCAAT/Enhancer-binding Protein β Inhibits Proliferation in Monocytic Cells by Affecting the Retinoblastoma Protein/E2F/Cyclin E Pathway but Is Not Directly Required for Macrophage Morphology* 
The Journal of Biological Chemistry  2011;286(26):22716-22729.
Monocytic differentiation is orchestrated by complex networks that are not fully understood. This study further elucidates the involvement of transcription factor CCAAT/enhancer-binding protein β (C/EBPβ). Initially, we demonstrated a marked increase in nuclear C/EBPβ-liver-enriched activating protein* (LAP*)/liver-enriched activating protein (LAP) levels and LAP/liver-enriched inhibiting protein (LIP) ratios in phorbol 12-myristate 13-acetate (PMA)-treated differentiating THP-1 premonocytic cells accompanied by reduced proliferation. To directly study C/EBPβ effects on monocytic cells, we generated novel THP-1-derived (low endogenous C/EBPβ) cell lines stably overexpressing C/EBPβ isoforms. Most importantly, cells predominantly overexpressing LAP* (C/EBPβ-long), but not those overexpressing LIP (C/EBPβ-short), exhibited a reduced proliferation, with no effect on morphology. PMA-induced inhibition of proliferation was attenuated in C/EBPβ-short cells. In C/EBPβWT macrophage-like cells (high endogenous C/EBPβ), we measured a reduced proliferation/cycling index compared with C/EBPβKO. The typical macrophage morphology was only observed in C/EBPβWT, whereas C/EBPβKO stayed round. C/EBPα did not compensate for C/EBPβ effects on proliferation/morphology. Serum reduction, an independent approach known to inhibit proliferation, induced macrophage morphology in C/EBPβKO macrophage-like cells but not THP-1. In PMA-treated THP-1 and C/EBPβ-long cells, a reduced phosphorylation of cell cycle repressor retinoblastoma was found. In addition, C/EBPβ-long cells showed reduced c-Myc expression accompanied by increased CDK inhibitor p27 and reduced cyclin D1 levels. Finally, C/EBPβ-long and C/EBPβWT cells exhibited low E2F1 and cyclin E levels, and C/EBPβ overexpression was found to inhibit cyclin E1 promoter-dependent transcription. Our results suggest that C/EBPβ reduces monocytic proliferation by affecting the retinoblastoma/E2F/cyclin E pathway and that it may contribute to, but is not directly required for, macrophage morphology. Inhibition of proliferation by C/EBPβ may be important for coordinated monocytic differentiation.
PMCID: PMC3123039  PMID: 21558273
C/EBP Transcription Factor; Cell Differentiation; E2F Transcription Factor; Macrophage; Retinoblastoma (Rb); C/EBP beta; Cyclin E; Monocyte; Morphology; Proliferation
25.  β-Lapachone Significantly Increases the Effect of Ionizing Radiation to Cause Mitochondrial Apoptosis via JNK Activation in Cancer Cells 
PLoS ONE  2011;6(10):e25976.
β-lapachone (β-lap), has been known to cause NQO1-dependnet death in cancer cells and sensitize cancer cells to ionizing radiation (IR). We investigated the mechanisms underlying the radiosensitization caused by β-lap.
Methodology/Principal Findings
β-lap enhanced the effect of IR to cause clonogenic cells in NQO1+-MDA-MB-231 cells but not in NQO1−-MDA-MB-231 cells. β-lap caused apoptosis only in NQO1+ cells and not in NQO1− cells and it markedly increased IR-induced apoptosis only in NQO1+ cells. Combined treatment of NQO1+ cells induced ROS generation, triggered ER stress and stimulated activation of ERK and JNK. Inhibition of ROS generation by NAC effectively attenuated the activation of ERK and JNK, induction of ER stress, and subsequent apoptosis. Importantly, inhibition of ERK abolished ROS generation and ER stress, whereas inhibition of JNK did not, indicating that positive feedback regulation between ERK activation and ROS generation triggers ER stress in response to combined treatment. Furthermore, prevention of ER stress completely blocked combination treatment-induced JNK activation and subsequent apoptotic cell death. In addition, combined treatment efficiently induced the mitochondrial translocation of cleaved Bax, disrupted mitochondrial membrane potential, and the nuclear translocation of AIF, all of which were efficiently blocked by a JNK inhibitor. Caspases 3, 8 and 9 were activated by combined treatment but inhibition of these caspases did not abolish apoptosis indicating caspase activation played a minor role in the induction of apoptosis.
β-lap causes NQO1-dependent radiosensitization of cancer cells. When NQO1+ cells are treated with combination of IR and β-lap, positive feedback regulation between ERK and ROS leads to ER stress causing JNK activation and mitochondrial translocation of cleaved Bax. The resultant decrease in mitochondrial membrane leads to translocation of AIF and apoptosis.
PMCID: PMC3188568  PMID: 21998736

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