bluuebunny/crossref_metadata_2025_split huggingface dataset:
An introduction to multivariate adaptive regression splines
Authors: Friedman Jerome H , Roosen Charles B 
Published: November 2007

Multivariate Adaptive Regression Splines (MARS) is a method for flexible modelling of high dimensional data. The model takes the form of an expansion in product spline basis functions, where the number of basis functions as well as the parameters associated with each one (product degree and knot locations) are automatically determined by the data. This procedure is motivated by recursive partitioning (e.g. CART) and shares its ability to capture high order interactions. However, it has more power and flexibility to model relationships that are nearly additive or involve interactions in at most a few variables, and produces continuous models with continuous derivatives. In addition, the model can be represented in a form that separately identifies the additive contributions and those associated with different multivariable interactions. This paper summarizes the basic MARS algorithm, as well as extensions for binary response, categorical predictors, nested variables and missing values. It presents tips on interpreting the output of the standard FORTRAN implementation of MARS, and provides an example of MARS applied to a set of clinical data.
Investigative Concerns in Demonstrating Reduced Risk from Reversing Left Ventricular Hypertrophy
Authors: Frohlich Edward D. , Aristizabal Dagnovar , Soria Federico , Messerli Franz H. 
Published: November 2007

Background: To demonstrate reduced risk from reversing left ventricular hypertrophy (LVH) in hypertension, one must show that it is independent of blood pressure reduction. Methods and Results: A feasibility study was conducted with 15 patients. The study employed 48-hour Holter recording, exercise treadmill (for ST-segment changes) and, as nec essary, thallium scintigraphy and coronary angiography. All patients were treated for 3 months with quinapril (10 mg) and demonstrated decreased mean arterial pressure (125 ± 3.1 vs 103 ± 1.9 mmHg; P < .01) and left ventricular mass index (125 ± 6.4 vs 104 ± 4.9; P < .02) with preserved left ventricular function. There were no significant changes in these patients with moderate LVH in the incidence of arrhythmias; however, 4 of the 15 patients developed ST-segment changes prior to LVH reversal, and these changes did not recur in 3 patients following reversal of LVH or when pressure was allowed to rise. Conclusions: Ischemic changes, rather than development of arrhythmias, may be of greater value in demonstrating risk reduction with LVH reversal. Nloreover, these preliminary data suggest pitfalls in demonstrating risk reduction after LVH reversal, indicating that more sen sitive and adequate techniques are necessary to show risk reduction from LVH.
Protective Effect of Elastase Inhibition Against Myocardial Dysfunction and Injury Induced by Ischemia and Reperfusion in Isolated Rat Hearts
Authors: Yang B.C. , Williams J.C. , Mehta J.L. 
Published: November 2007

Background: Elastase release has been incriminated in the genesis of reperfusion-induced myocardial dysfunction and injury, and elastase inhibitors have been reported to reduce myocardial dysfunction in dogs subjected to coronary artery occlusion and reperfusion. Methods and Results: To examine if efastase inhibition will modify myocardial dysfunction and injury induced by ischemia and reperfusion in isolated hearts, hearts from male Sprague Dawley rats were subjected to 30 minutes of total ischemia followed by 30 minutes of reper fusion. Ischemia-reperfusion resulted in myocardial dysfunction (increase in coronary perfu sion pressure and decrease in myocardial contraction), injury (measured as creatine kinase release), and lipid peroxidation (myocardial malondialdehyde). Perfusion of hearts with an elastase inhibitor, ICI200,880, protected against myocardial dysfunction, injury and lipid per oxidation following ischcmia-reperfusion. As expected, perfusion with superoxide dismutase protected the hearts against hemodynamic deterioration following ischemia-reperfusion. In in vitro studies, there was no direct effect of ICI200,880 on superoxide anion generation. Conclusions: ICI200,880 seems to exert cardioprotective effects against ischemia-reperfu sion-induced injury and myocurdial dysfunction in isolated buffer-perfused hearts, most likely by an elastase-like protease inhibitory activity.
Reduction of Myocardial Infarct Size in the Rabbit by a Carbohydrate Analog of Sialyl Lewisx
Authors: Kilgore Kenneth S. , Park James L. , Chi Liguo , Musser John H. , Date Vandana , Abbas Saeed , Lucchesi Benedict R. 
Published: November 2007

Background: Available data suggest that the accumulation of neutrophils within the myocardium following an ischemic event plays an important role in the pathogenesis of myocardial ischemia/reperfusion injury. It is of interest, therefore, to develop pharmacologic agents designed to inhibit neutrophil adhesion to the endothelium. Methods and Results: A synthetic carbohydrate analog to the P-selectin ligand sialyl Lewis x (sLex) was evaluated for its ability to protect the myocardium from ischemia/reperfusion injury. Open chest anesthetized rabbits were subjected to 30 minutes occlusion of the left cir cumflex artery followed by 5 hours of reperfusion. Vehicle or sLe x analog (10 mg/kg) was administered intravenously before the onset of reperfusion and every hour during the reper fusion period. Myocardial infarct size in rabbits treated with the sLex analog was significantly reduced when compared to rabbits treated with vehicle (28 ± 9% vs 57 ± 10% of the area at risk, P < .05). The compound did not alter circulating neutrophil counts or myocardial oxy gen demand as determined by the rate-pressure product. Furthermore, neutrophil accumula tion within the ischemic region was decreased by 44% (P < .05) in the hearts of animals receiving sLex analog as compared to vehicle. Conclusions: Carbohydrate derivatives of sLex may be effective in reducing the degree of myocardial injury after ischemia/reperfusion.
The Novel Class III Antiarrhythmic Agent MS-551 Blocks the Cardiac Inward Rectifier With Greater Potency Than Sotalol or E-4031: Possible Relevance to Reverse Use Dependence
Authors: Nakaya Yutaka , Martin Donald K. , Campbell Terence J. 
Published: November 2007

Background: The tendency for the electrophysiologic effect of class III antiarrhythmic agents (action potential prolongation) to be diminished at faster heart rates represents a major drawback of this class of drug and is usually referred to as "reverse use dependence." A novel class III agent, MS-551, has recently been reported to exhibit less reverse use dependence than E-4031. We set out to investigate whether this observation may be due to differential blockade of the inward rectifier current (iK1) by these drugs. Methods and Results: We recorded iK1 using single channel methods and cell attached patch configurations, with standard patch clamp technology. Neither E-4031 nor racemic sotalol in concentrations up to 100 μM had any significant effect on the open probability or kinetics of iK1 channels. MS-551 produced a concentration-dependent reduction in the open probability of i K1 without altering the single-channel conductance. Openings to subconductance levels were abolished in three of six patches in which they had been frequently present in the absence of drug. MS-551 had no effect on mean channel open time but increased the slower component of the closed time. Conclusions: MS-551, unlike E-4031 and sotalol, appears to produce significant blockade of the inwardly rectifying potassium channel at clinically relevant concentrations. We propose that this might provide a partial explanation for the observed differences in their response to rate changes.
Protective Effects of Iganidipine on Morphological and Functional Changes of Arteries in Hypertensive Dahl Rats
Authors: Shirahase Hiroaki , Uehara Yoshio , Kanda Mamoru , Wada Katsuo , Ichikawa Atsuko , Kobayashi Yoshihiko , Funahashi Norio 
Published: November 2007

Background: This study was performed to examine the protective effects of iganidipine, a new water-soluble calcium antagonist, on the morphological and functional changes of arteries in Dahl salt-sensitive (Dahl-S) rats. Methods and Results: Vehicle and iganidipine were administered orally to Dahl-S rats fed a high-salt diet (HSD) for 8 weeks. Aorta, superior mesenteric arteries (SMA), and peri pheral mesenteric arteries (PMA) were examined light-microscopically or electron- microscopically. Relaxant responses of isolated aorta and SMA were recorded isometrically. In rats fed HSD, blood pressure was markedly increased. Light microscopy showed intimal and medial hypertrophy, periarteritis, and narrowed arterial lumen in the PMA. Transmis sion and scanning electron microscopy or light microscopy showed medical thickness in the aorta and SMA and hypertrophy of endothelial cells and dilatation of the subendothelial space only in the aorta. In the SMA, both endothelium-dependent relaxation (EDR) and endothelium-independent relaxations (EIR) were reduced to a similar extent. In the aorta, the EDR was more markedly attenuated than the EIR. Iganidipine at 3 mg/kg/day showed a 24-h sustained hypotensive effect and completely prevented the morphological and func tional changes in both arteries. Iganidipine at 1 mg/kg/day, which lowered blood pressure only for several hours, decreased the injuries in PMA and aortic endothelium and moder ately restored the EDR in the aorta. Iganidipine at 0.3 mg/kg/day had no effects. Conclusions: In Dahl-S rats fed an HSD, iganidipine completely prevented all the changes at a sustained-hypotensive dose and prevented the injuries of PMA and aortic endothelium and the reduction of EDR in the aorta at a nonsustained hypotensive dose. Nonhemody namic effects of iganidipine may be partly involved in its protective effects against arterial injuries.
Angiotensin-Converting Enzyme Inhibition Delays Onset of Glucosuria With Regression of Renal Injuries in Genetic Rat Model of Non-Insulin-Dependent Diabetes Mellitus
Authors: Uehara Yoshio , Hirawa Nobuhito , Numabe Atsushi , Kawabata Yukari , Nagoshi Hiroshi , Negoro Hideyuki , Fujiwara Satoshi , Gomi Tomoko , Ikeda Toshio , Goto Atsuo , Omata Masao 
Published: November 2007

Background: The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is a new genetic model of non-insulin-dependent diabetes mellitus (NIDDM). We investigated whether angiotensin inhibition influences the onset of NIDDM and brings about a regression of renal injury in diabetes mellitus. Methods and Results: Six-week-old OLETF rats were treated with the angiotensin-con verting enzyme (ACE) inhibitors imidapril or enalapril for 16 weeks. Systolic blood pres sure is increased in an age-dependent manner in OLETF rats. In this study, the elevation in systolic blood pressure was dose-dependently reduced by ACE inhibitor treatment. In OLETF rats, plasma concentrations of insulin and glucose increased and the glucosuria occurred at the age of 22 weeks. Simultaneously, OLETF rats exhibited proteinuria and nodular lesions in glomeruli. The ACE inhibitor treatment almost completely reduced glu cosuria, and also decreased plasma concentrations of insulin and glucose in OLETF rats. ACE inhibitor treatment lessened the proteinuria and attenuated morphologically the severity of nodular lesions in OLETF rats. Moreover, increases in plasminogen activator inhibitor 1 (PAI-1) in OLETF rats were reduced by the ACE inhibitor treatment, and the improvement of glomerular lesions was related to decreases of PAI-1 and angiotensin II levels in plasma but not to improvement of glucose metabolism. Conclusions: ACE inhibitors delay onset of NIDDM with attenuation of kidney injury. The regression of kidney lesions is probably due to angiotensin reduction but not to glucose metabolism per se. ACE inhibitor drug therapy may be useful in preventing NIDDM and the subsequent renal injury in patients with NIDDM.
Age-Dependent Changes in the Effects of Amiodarone on Rabbit Cardiac Myocyte Contractions
Authors: Fuhua Chen  , Naim Suhaila , Friedman William F. , Klitzner Thomas S. , Wetzel Glenn T. 
Published: November 2007

Background: Intravenous amiodarone has increasingly been used to control life-threaten ing atrial and ventricular arrhythmias. In addition to its four antiarrhythmic properties, amio darone may have complex effects on intracellular Ca 2+ stores and myocyte contractility. Methods and Results: Contraction amplitude was recorded for cardiac ventricular myo cytes isolated from neonatal and adult rabbits. Sarcoplasmic reticulum (SR) Ca2+ stores were loaded to steady-state levels by a train of eight electric field stimulations. The SR Ca2+ load was quantified by recording the contraction amplitude resulting from the complete depletion of SR Ca2+ stores by exposing the cell to a 1-second pulse of 10 mmol/L caffeine. After the cells were exposed to 1 μmol/L amiodarone for 10 minutes, electrically stimulated contraction amplitudes significantly decreased in both adult and neonatal cells. Caffeine- induced cell contraction amplitudes were not affected by amiodarone in adult ventricular myocytes. By contrast, amiodarone markedly inhibited caffeine-induced contractions in neonatal ventricular myocytes. The inhibitory effect of amiodarone on the caffeine-induced contractions was not replicated by Ca2+ channel blockade with diltiazem. Conclusions: Amiodarone markedly inhibits caffeine-induced contraction in neonatal myo cytes but has no significant effect on adult myocytes. Ca2+ influx through amiodarone-sensitive Ca2+ channels may play a primary role in maintaining SR Ca2+ stores in neonatal heart.
Mechanisms of Hydrogen Peroxide—Induced Increase in Intracellular Calcium in Cardiomyocytes
Authors: Xi Wang  , Takeda Satoshi , Mochizuki Seibu , Jindal Rashi , Dhalla Naranjan S. 
Published: November 2007

Background: Hydrogen peroxide (H2O2) in high concentrations has been implicated in heart dysfunction attributable to ischemia-reperfusion. Although H 2O2 is also known to increase the intracellular concentration of Ca2+ ([Ca2+]i) in cardiomyocytes, the mecha nisms for such a change are not clear. In this study, the sources and mechanisms of increase in [Ca 2+]i caused by high concentrations of H2O 2 in cardiomyocytes were explored. Methods and Results: Cardiomyocytes were isolated from adult male Sprague-Dawley rats. Cell viability was examined by trypan blue exclusion test. [Ca2+] i was measured by employ ing cell suspension at room temperature and Fura-2 fluorescence technique. Incubation of cells with 0.25-1 mmol/L H2O2 increased [Ca 2+]i in a time- and concentration-dependent manner. Catalase attenuated the H2O2-induced increase in [Ca2+] i significantly, whereas mannitol showed no effect. Neither the presence of verapamil, a sarcolemmal Ca2+ channel blocker, nor the removal of Ca2+ from the medium produced any significant reduction in the H2O2-induced increase in [Ca2+] i. Conversely, treatment of cardiomyoctes with stauro sporin, a protein kinase C inhibitor, thapsigargin, a sarcoplasmic reticulum Ca2+-pump aden osine triphosphatase inhibitor, as well as ryanodine, a sarcoplasmic reticulum Ca2+-release channel blocker, markedly prevented the 0.5-mmol/L H2O2-induced increase in [Ca 2+]i. The responses of cardiomyoctes to H2O 2 and other Ca2+-mobilizing agents, such as KCl or aden osine triphosphate, were additive. No changes in cardiomyocyte viability were seen on incu bation with 0.5 and 1 mmol/L H2O2. Perfusion of the isolated heart with H2O2 (0.1-0.5 mmol/L) depressed the left ventricular developed pressure, rate of contraction, and rate of relaxation, whereas the left ventricular end-diastolic pressure was increased. Conclusions: These results indicate that formation of H2O2 under pathophysiological con ditions such as ischemic heart disease may induce changes in Ca2+ homeostasis in cardiomy ocytes and may induce contractile dysfunction. Furthermore, the sarcoplasmic reticulum involving a protein kinase C-mediated mechanism appears to be the main site of action of H 2O2 in cardiomyocytes.
Domoic Acid Attenuates the Adenosonine-5'- Triphosphate-Induced Increase in [Ca2+] i in Adult Cardiomyocytes
Authors: Nijjar Mohinder S. , Pierce Grant N. , Nijjar Satnam S. , Dhalla Naranjan S. 
Published: November 2007

Background: Although domoic acid (DA), a shellfish neurotoxin, carries a negative surface charge at physiological pH like that of adenosine-5'-triphosphate (ATP), very little is known about its cellular effects. In view of the potentially significant role of extracellular ATP as a signaling molecule for increasing the intracellular concentration of Ca2+ ([Ca2+]i), we examined the possibility that DA may interfere with this signal transduction mechanism in the myocardium. Methods and Results: Cardiomyocytes were isolated from rat heart and loaded with Fura-2 to measure the [Ca2+]i. ATP produced a gradual rise in [Ca2+]i, reaching a peak level in 25- 30 seconds and declining thereafter. DA did not affect the [Ca2+]i in cardiomyocytes; however, it diminished the ATP-induced elevation in [Ca2+]i in a concentration-dependent manner. Kainic acid, an analogue of DA, had a similar effect but at a 25-fold higher concentration, whereas glutamate and aspartate did not modify the action of ATP. Well-known inhibitors of L-type voltage-sensitive Ca2+ channels, nifedipine and nicardipine, depressed the ATP- induced increase in [Ca2+ ]i, but DA did not produce additive effects with either of these agents. On the other hand, DA potentiated the KCl-induced increase in [Ca2+]i in quiescent cardiomyocytes and augmented the nicardipine-sensitive Ca2+ transients in electrically stimulated cardiomyocytes. Conclusions: These results suggest that DA may diminish the ATP-induced increase in [Ca 2+]i by inhibiting the ATP interaction with cardiomyocytes in a specific manner.
Nifedipine and Bay K 8644 Induce an Increase of [Ca2+] i and Nitric Oxide in Endothelial Cells
Authors: Berkels Reinhard , Mueller Andreas , Roesen Renate , Klaus Wolfgang 
Published: November 2007

Background: The dihydropyridine-induced vasorelaxation is partly dependent on the endothelium, which does not express L-type calcium channels. Because nitric oxide (NO) is one of the most important endothelium-derived vasorelaxing factors, we investigated how the calcium antagonist nifedipine and the calcium agonist Bay K 8644 modulate intracellu lar calcium and NO formation in porcine endothelial cells.Methods and Results: NO formation of porcine aortic endothelial cell cultures and of native endothelium of intact porcine coronary arteries was measured with an electrochemi cal electrode, and the intracellular concentration of Ca2+[Ca2+]iwas evaluated using the Fura-2 technique. Nifedipine induced a concentration-dependent [0.01-1 μmol/L] increase in [Ca2+]iand NO formation in cultured porcine aortic endothelial cells, and moreover a dose- dependent NO formation in native endothelial cells from intact porcine coronary arteries, which was higher than in cultured cells. This effect was inhibited by N-nitro-L-arginine, a spe cific NO synthase inhibitor. Bay K 8644 caused a [Ca2+]iincrease and NO release in cul tured cells, too, although to a lesser extent. Nifedipine-induced and Bay K 8644-induced [Ca2+]irise could be blocked by removal of extracellular calcium, indicating that a calcium influx may be involved.Conclusions: The calcium antagonist nifedipine as well as the calcium agonist Bay K 8644 cause an increase of [Ca2+]iand NO in porcine endothelium. Therefore, these effects seem to be related to the dihydropyridines as a substance class, which may explain the endothe lial component in dihydropyridine-induced vasorelaxation.
Plasma Tissue Factor Pathway Inhibitor Levels as a Marker for Postoperative Bleeding After Enoxaparin Use in Deep Vein Thrombosis Prophylaxis in Orthopedics and General Surgery
Authors: Hakki Sam I. , Fareed Jawed , Hoppensteadt Debra A. , Abdullah Hani , Camblin John , Nasseri Andrew F. , Hamadeh Ossama , Wright Terry 
Published: November 2007

Low-molecular-weight heparins (LMWH) are widely used as antithrombotic prophylactic pharmaceutical agents in orthopedic and general surgery. Their antithrombotic characteristics are expressed by plasma mediators such as anti- Xa, anti-IIa, and increased release of tissue factor pathway inhibitor (TFPI) from vascular endothelium. The purpose of this clinical research is to study the relation between plasma levels of these mediators and postoperative bleeding. Forty-one consecutive patients undergoing hip or knee ar throplasty (n = 36) and colectomy (n = 5) received the stan dard enoxaparin (a LMWH) dose preoperatively (general sur gery) or immediately postoperatively (orthopedic surgery). Ma jor bleeding was defined as a postoperative drop of ≥ 5 g/dL) of hemoglobin. The authors observed that there was a linear relationship between an increase in free/total TFPI ratio levels and postoperative bleeding. When that ratio increased by >60%, the hemoglobin dropped to >5 g/dL (n = 17). This relationship between free/total TFPI ratio increase and postoperative bleeding was statistically significant ( P < 0.001). Those who did not bleed (hemoglobin drop was less than 5 g/dL) (n = 24) had a ratio increase (if any) of less than 50%. However, the authors did not observe any statistical relation ship between anti-Xa, anti-IIa, or prothrombin time and post operative bleeding in patients receiving LMWH for deep vein thrombosis prophylaxis in orthopedic and general surgery pa tients. The authors recommend a pre- and postoperative ratio level measurement whenever major bleeding is anticipated, as adjustments of LMWH dose or frequency might be necessary.
Stability of mitomycin C in different infusion fluids: Compatibility with heparin and glucocorticosteroids
Authors: Dorr Robert T. , Liddil James D. 
Published: November 2007

Introduction: Mitomycin C (Mutamycin) stability and compatibility was analyzed by reverse-phase high performance liquid chromatography (HPLC).Methods: The drug was reconstituted in sterile water for injection USP, 0.9% sodium chloride for injection USP, 5% dextrose injection USP and lactated Ringer's injection USP. Samples were stored for vari ous times at —20°C, 4°C and 25°C in both glass and plastic (polyvinyl chloride) containers.Results: Mitomycin C was shown to be stable (> 90% remaining for 5 to 7 days at room temperature in nondextrose containing infusion fluids. Greater stability was noted at drug concentrations ≥ 0.4 μg/mL and at reduced temperatures. In 5% dextrose solutions, stability was highly dependent upon pH: 3.4 hours at pH 4.7 and slightly over 24 hours at pH 5.5. Non-linear decomposition in dextrose was due to a slow increase in solution pH after adding mitomycin C. There were no stability differences for glass or plastic containers. Mitomycin was shown to be stable for prolonged periods when mixed with dexametha sone sodium phosphate (T90% > 2 days), with hydro cortisone sodium succinate (T90% > 7 days) or with sodium heparin (T90% > 2 days). Within these times, the concentrations of corticosteroids (measured by HPLC) and heparin (measured by bioassay) did not significantly decline.Conclusions: Mitomycin C demonstrates pro longed stability in nonacidic infusion fluids. Long- term storage in dextrose-containing solutions should be avoided, but short-term admixture with heparin and corticosteroids is feasible.