bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamics of the action of dFOXO on adult mortality in Drosophila
Authors: Giannakou Maria E. , Goss Martin , Jacobson Jake , Vinti Giovanna , Leevers Sally J. , Partridge Linda
Published: May 2007

The insulin/insulin growth factor (IGF)‐like signaling (IIS) pathway has a conserved role in regulating lifespan in Caenorhabditis elegans, Drosophila and mice. Extension of lifespan by reduced IIS has been shown in C. elegans to require the key IIS target, forkhead box class O (FOXO) transcription factor, DAF‐16. dFOXO, the Drosophila DAF‐16 orthologue, is also an IIS target, and its overexpression in adult fat body increases lifespan. In C. elegans, IIS acts exclusively during adulthood to determine adult survival. We show here, using an inducible overexpression system, that in Drosophila continuous dFOXO overexpression in adult fat body reduces mortality rate throughout adulthood. We switched the IIS status of the flies at different adult ages and examined the effects of these switches on dFOXO expression and mortality rates. dFOXO protein levels were switched up or down by the inducible expression system at all ages examined. If IIS status is reversed early in adulthood, similar to the effects of another intervention that reduces adult mortality in Drosophila, dietary restriction (DR), there is a complete switch of subsequent mortality rate to that of flies chronically exposed to the new IIS regime. At this age, IIS thus acts acutely to determine risk of death. Mortality rates continued to respond to a switch in IIS status up to 4 weeks of adult age, but not thereafter. However, unlike DR, as IIS status was altered at progressively later ages, mortality rates showed incomplete switching and responded with progressively smaller changes. These findings indicate that alteration of expression levels of dFOXO may have declining effects on IIS status with age, that there could be some process that prevents or lessens the physiological response to a switch in IIS status or that, unlike DR, this pathway regulates aging‐related damage. The decreased mortality and increased lifespan of dFOXO overexpressing flies was uncoupled from any effect on female fecundity and from expression levels of Drosophila insulin‐like peptides in the brain.
A novel role of peroxin PEX6: suppression of aging defects in mitochondria
Authors: Seo Jae‐Gu , Lai Chi‐Yung , Miceli Michael V. , Jazwinski S. Michal
Published: May 2007

Yeast cells become older with each division, but their daughters are born young. Mutational analysis shows that maintenance of this age asymmetry requires segregation of a complement of active mitochondria to daughters and that this process breaks down in older mother cells. This decline has implications for stem cell aging in higher organisms. PEX6, a peroxisome biogenesis gene, has been isolated as a multicopy suppressor of an atp2 age asymmetry mutant. Suppression depended on the presence of particular amino acid residues in Atp2p, and required adenosine triphosphate (ATP) binding and/or ATP hydrolysis activity of Pex6p. Extra copies of PEX6 corrected the deficit in Atp2p in mitochondria in the mutant by improving its import kinetics, resulting in near normal mitochondrial inheritance by daughter cells. The novel function of Pex6p described here may provide insights into peroxisomal and mitochondrial disorders and into metabolic diseases in general.
Expansion of the calcium hypothesis of brain aging and Alzheimer's disease: minding the store
Authors: Thibault Olivier , Gant John C. , Landfield Philip W.
Published: May 2007

Evidence accumulated over more than two decades has implicated Ca2+ dysregulation in brain aging and Alzheimer's disease (AD), giving rise to the Ca2+ hypothesis of brain aging and dementia. Electrophysiological, imaging, and behavioral studies in hippocampal or cortical neurons of rodents and rabbits have revealed aging‐related increases in the slow afterhyperpolarization, Ca2+ spikes and currents, Ca2+ transients, and L‐type voltage‐gated Ca2+ channel (L‐VGCC) activity. Several of these changes have been associated with age‐related deficits in learning or memory. Consequently, one version of the Ca2+ hypothesis has been that increased L‐VGCC activity drives many of the other Ca2+‐related biomarkers of hippocampal aging. In addition, other studies have reported aging‐ or AD model‐related alterations in Ca2+ release from ryanodine receptors (RyR) on intracellular stores. The Ca2+‐sensitive RyR channels amplify plasmalemmal Ca2+ influx by the mechanism of Ca2+‐induced Ca2+ release (CICR). Considerable evidence indicates that a preferred functional link is present between L‐VGCCs and RyRs which operate in series in heart and some brain cells. Here, we review studies implicating RyRs in altered Ca2+ regulation in cell toxicity, aging, and AD. A recent study from our laboratory showed that increased CICR plays a necessary role in the emergence of Ca2+‐related biomarkers of aging. Consequently, we propose an expanded L‐VGCC/Ca2+ hypothesis, in which aging/pathological changes occur in both L‐type Ca2+ channels and RyRs, and interact to abnormally amplify Ca2+ transients. In turn, the increased transients result in dysregulation of multiple Ca2+‐dependent processes and, through somewhat different pathways, in accelerated functional decline during aging and AD.
Malignant pheochromocytoma presenting as a bradyarrhythmia in a dog
Authors: Brown Andrew J. , Alwood Amy J. , Cole Steven G.
Published: May 2007

Objective:To describe a case of atrioventricular block and syncope secondary to systemic hypertension in a dog with malignant pheochromocytoma.

Case Summary:A 13‐year‐old spayed female mixed‐breed dog presented following an acute onset of collapse. The dog was hypertensive and had paradoxical high‐grade second‐degree atrioventricular block with concurrent syncope. Initial emergent therapy included a nitroprusside infusion for the systemic hypertension and vagolytic therapy for the bradyarrhythmia. A left adrenal mass was seen on abdominal ultrasound and was further characterized by MRI. Following medical stabilization with phenoxybenzamine and propantheline, a left adrenalectomy was performed. Histological diagnosis was consistent with a malignant pheochromocytoma. Following tumor removal there has been no further hypertension, atrioventricular block or syncope.

Unique information provided:This is the first documented case of a malignant pheochromocytoma presenting as syncope secondary to hypertension induced atrioventricular block.
The Effect of Surface Roughness on Activation of the Coagulation System and Platelet Adhesion in Rotary Blood Pumps
Authors: Linneweber Jörg , Dohmen Pascal Maria , Kerzscher Ullrich , Affeld Klaus , Nosé Yukihiko , Konertz Wolfgang
Published: May 2007

Abstract:  The surface roughness of left ventricular assist devices (LVADs) is important for the biocompatibility of blood pumps. However, little is known about the effect of surface roughness on the antithrombogenicity of the device. The present study investigated the effect of surface roughness on the activation of the coagulation system and platelet adhesion in an impeller‐type blood pump. Three identical Baylor Gyro 710 centrifugal blood pumps (Baylor College of Medicine, Houston, TX, USA) were manufactured with impeller surface roughness of 0.05, 0.2, and 0.4 µm, respectively, as determined by a stylus profilometer and by scanning electron microscopy. Whole blood was anticoagulated (1‐IU heparin/mL, ACT 250 s) and circulated for 60 min in an artificial circulatory system, simulating LVAD perfusion (5‐L/min flow against 100 mm Hg). Enzyme‐linked immunosorbent assays were developed to quantify fibrinogen‐ and von Willebrand factor (vWf) adsorption as well as platelet adhesion directly on the impellers of the pumps. Levels of prothrombin fragment F1.2 and thrombin–antithrombin (TAT) complex were measured in order to quantify activation of coagulation. Compared with the 0.05‐µm surface, platelet adhesion was 40 and 76% higher on the 0.2‐ and 0.4‐µm surface, respectively (P < 0.01). The evaluation of adsorbed fibrinogen and vWf showed significant higher protein antigen levels on the rougher surfaces (P < 0.01). Furthermore, nonpulsatile perfusion activated the coagulation system. By contrast, the surface roughness had no significant influence on plasma prothrombin F1.2 fragment‐ and TAT concentrations. Antithrombogenicity was significantly reduced in pumps with inferior metal‐finishing quality.
Deformability of Red Blood Cells and Its Relation to Blood Trauma in Rotary Blood Pumps
Authors: Watanabe Nobuo , Sakota Daisuke , Ohuchi Katsuhiro , Takatani Setsuo
Published: May 2007

Abstract:  In this study, mechanical trauma to red blood cells was evaluated by conventional hemolysis test and a newly developed cyclically reversing shear flow generator. The fresh porcine blood obtained from a local slaughterhouse was subjected to the conventional hemolysis test using a commercial centrifugal blood pump for the duration of 8 h. The measurements consisted of (i) plasma‐free hemoglobin based on the standard optical measurement and (ii) the deformability of red blood cells (RBCs) using a cyclically reversing shear flow generator and microscope image acquisition system. The deformability of RBCs was expressed by the L/W value where L and W were the longer and shorter axes of the elongated RBCs' images. Although the plasma‐free hemoglobin level increased with the pumping duration, the L/W remained unchanged for the duration of 8 h of pumping to indicate no alteration in the deformability. It was speculated that (i) although RBCs might have been circulated for so many times through the test pump, after each exposure to mechanical stress, RBCs might have recovered, and net effect due to shear stress‐exposure time might have been small; and (ii) RBCs' deformability might be maintained near normal until sudden burst or membrane rupture, or the hemoglobin might have continuously leaked through the pores of the thinned membrane created by the mechanical stress. The deformability testing under a fluctuating shear flow could be a new method to quantify subhemolytic mechanical damage that has been accumulated in the RBCs' membrane and that may not be assessed by the conventional hemolysis test.
Left Ventricular Pressure–Volume Loop Analysis During Continuous Cardiac Assist in Acute Animal Trials
Authors: Moscato Francesco , Vollkron Michael , Bergmeister Helga , Wieselthaler Georg , Leonard Edward , Schima Heinrich
Published: May 2007

Abstract:  For better understanding of the interaction between left ventricle and continuous cardiac assist, the effect of different working conditions and support levels on left ventricular pressure–volume (PV) loop was investigated in acute animal experiments. A MicroMed‐DeBakey ventricular assist device (MicroMed Cardiovascular Inc., Houston, TX, USA) was implanted in seven healthy sheep (102 ± 20 kg). Measurements of hemodynamic variables were taken with clamped graft, on minimum, medium, and maximum support, and in pump‐off condition (backflow). Each pump condition was studied for different heart rates, central venous pressures, and under pharmacologically altered contractility. End‐systolic and end‐diastolic volume normalized by the body surface area (BSA) (end systolic volume index [ESVI] and end diastolic volume index [EDVI]) showed significant correlation both within each sheep and in the pooled data. The linear regression for the pooled data was ESVI = 0.845 × EDVI − 15.21, R2 = 0.924, P < 0.0001, n = 200. EDVI and stroke volume (SV) normalized by BSA (stroke volume index [SVI]) also showed a lower but significant correlation: SVI =  0.155 × EDVI + 15.21, R2 = 0.291, P < 0.0001, n = 200. An increase of preload due to infusion caused, in the clamped graft condition, an increase in end diastolic volume of 22%, no significant increase in SV, a decrease both of systemic vascular resistance of 30% and ventricular contractility (maximum elastance [Emax] and peak rate of rise of ventricular pressure [dP/dtmax] decreasing 38 and 21%, respectively). PV loop analysis in continuous cardiac assist reveals that the ESVI and the EDVI are strongly correlated and that ESVI varies considerably with preload. SVI becomes slightly dependent on EDVI, which may be due to autoregulatory mechanisms.
Extracorporeal Circulation, Optimized: A Pilot Study
Authors: Agati Salvatore , Ciccarello Giuseppe , Trimarchi Eugenio Santo , Grasso Daniela , Trimarchi Giuseppe , Stefano Salvatore Di , Carmelo Mignosa
Published: May 2007

Abstract:  We designed a pilot study to assess as primary end point the safety and efficacy of a new phosphorylcholine‐coated, closed cardiopulmonary bypass (CPB) system (extracorporeal circulation, optimized [ECC.O], Dideco, Mirandola, Italy). The secondary end point was to compare results with two retrospectively matched cohorts of patients who underwent isolated coronary artery by‐pass graft (CAGB) with nonphosphorylcholine‐bonded circuits and cardiotomy suction (Group II, n = 32) and off‐pump coronary artery by‐pass (OPCAB) (Group III, n = 26). In January 2005, 30 patients (Group I) undergoing first‐time CABG were assigned to the ECC.O group. Five minutes after CPB, initial hematocrit levels were significantly and consistently highest in Group I relative to Group II (Group I, 29.7 ± 4.4 vs. Group II, 22.7 ± 4.1; P < 0.001). Red blood cell transfusion rate was reduced drastically in Group I versus Group II (P < 0.001). High differences were also observed in C‐reactive protein levels at 24 h after surgery (Group I vs. Group II—P < 0.001 and vs. Group III—P < 0.001) and at 72‐h peak value (Group I vs. Group II—P < 0.001 and vs. Group III—P < 0.001). The routine clinical use of the ECC.O system has been demonstrated to be both clinically safe and efficacious. An intensive training program for surgeons, perfusionists, and anesthesiologists is required.
pH 48 h After Onset of Extracorporeal Membrane Oxygenation Is an Independent Predictor of Survival in Patients With Respiratory Failure
Authors: Rega Filip R. , Evrard Veerle , Bollen Hilde , Peeters Geert , Vercaemst Leen , Meuris Bart , Herijgers Paul , Sergeant Paul , Hermans Greet , Vlasselaers Dirk , Meyns Bart
Published: May 2007

Abstract:  Extracorporeal membrane oxygenation (ECMO) is a life‐saving procedure in patients with severe respiratory failure, unresponsive to conventional therapy. We reviewed our series of 70 ECMO runs (April 1997 to December 2005) in patients with respiratory distress, refractory to standard ventilation. Survival at 90 days was 42.7%. Besides age, we found no statistical significant difference in patient demographics or preoperative patient data between survivors and nonsurvivors. Univariate analyses indicated that pH values at 24 and 48 h after onset of ECMO were significantly higher in survivors. In multivariate analysis, age and pH at 48 h remained independent predictors of survival. ECMO in respiratory failure saves lives. No other demographic or preoperative, patient‐related parameter than age was identified as predictor of survival. Although there was no difference in pH at onset of ECMO, blood gas analysis at 48 h revealed pH as an independent predictor of survival.
Primary Extracorporeal Membrane Oxygenation Versus Primary Ventricular Assist Device Implantation in Low Cardiac Output Syndrome Following Cardiac Operation
Authors: Klotz Stefan , Rukosujew Andreas , Welp Henryk , Schmid Christof , Tjan Tonny D.T. , Scheld Hans H.
Published: May 2007

Abstract:  Mechanical support is often the only therapeutic option in low cardiac output (LCO) following cardiac operation using extracorporeal circulation (ECC). However, the question whether primary ventricular assist device (VAD) or primary extracorporeal membrane oxygenation (ECMO) followed by secondary VAD implantation is superior remains unclear. We analyzed the outcome of 183 patients with LCO following ECC. Primary VAD implantation (VAD) was performed on 20 patients and 163 patients underwent ECMO implantation (ECMO). Out of this group, 13 patients received a secondary VAD (ECMO‐VAD). Age was significantly lower in the VAD group, while gender and type of operation were similarly distributed. Thirty‐day mortalities were 50, 75, and 46% (VAD, ECMO, and ECMO‐VAD, respectively; P < 0.05 ECMO vs. VAD and ECMO‐VAD). Survival was best with VAD implantation 1.2 ± 1.2 days following LCO. In conclusion, the outcome of LCO following ECC remains poor. Early VAD support provides best survival. Primary or secondary VAD implantation has no impact on survival.
Kinetics of Group IB and IIA Phospholipase A2 During Low‐Volume Continuous Hemodiafiltration in Severe Acute Pancreatitis
Authors: Suzuki Masaharu , Okahisa Toshiya , Sogabe Masahiro , Iwaki Hiroshi , Okita Yoshio , Ohnishi Yoshiaki , Ito Susumu
Published: May 2007

Abstract:  Continuous hemodiafiltration (CHDF) has been performed for the treatment of severe acute pancreatitis. Phospholipase A2 (PLA2) is one of the important mediators which exacerbate acute pancreatitis, but whether PLA2 can be removed by CHDF is unclear. In this study, the kinetics of group IB and group IIA PLA2 was examined at the first session of low‐volume CHDF in eight patients with severe acute pancreatitis. CHDF was performed using polysulfone hemofilters (surface area: 0.7 m2) at a blood flow rate of 100 mL/min and a filtration and dialysate flow rate of 10 mL/min each. The plasma concentrations of group IB and IIA PLA2 before the start of CHDF were 47.4 ± 52.0 µg/L and 352 ± 390 µg/L, respectively, and did not change significantly. The clearances of group IB and IIA PLA2 achieved by the CHDF circuit 1 h after the start of CHDF were 20.7 ± 11.6 mL/min and 16.7 ± 4.4 mL/min, respectively, with both clearances decreasing significantly with time. The clearance of group IB PLA2 into the waste fluid tended to increase with time; however, the concentrations of group IIA PLA2 in the waste fluid were less than the measurable sensitivity. These results indicate that group IB PLA2 is adsorbed on the hemofilter membrane in preference to being removed into the waste fluid, while group IIA PLA2 is mainly removed by adsorption. However, low‐volume CHDF is not effective at eliminating the group IB and IIA PLA2 plasma concentration.
Long‐term Management of an Implantable Left Ventricular Assist Device Using Low Molecular Weight Heparin and Antiplatelet Therapy: A Possible Alternative to Oral Anticoagulants
Authors: Meuris Bart , Arnout Jozef , Vlasselaers Dirk , Schetz Marie , Meyns Bart
Published: May 2007

Abstract:  Between January 2004 and December 2005, out of 14 patients with decompensated heart failure who were treated with an INCOR left ventricular assist device (Berlin Heart AG, Berlin, Germany), 10 patients were kept on a long‐term regime of low molecular weight heparin (LMWH) and antiplatelet therapy. The treatment objective was bridge‐to‐transplantation. All patients received LMWH in therapeutic doses according to body weight, in combination with daily aspirin 160 mg, clopidogrel 75 mg, and three times dipyridamole 75 mg. Effectiveness of the low molecular weight regime was monitored through measurement of antifactor Xa activity (base and peak levels). Antiplatelet therapy was monitored through weekly platelet function tests. Within this group of 10 patients, six patients successfully received transplants and four patients died, the latest death after 405 days of INCOR support. Causes of death were sepsis, intestinal hemorrhage, acute right ventricular failure, and one major stroke. Long‐term management of INCOR assist devices using a combination of LMWH and antiplatelet therapy is feasible. This treatment strategy can serve as an alternative to oral anticoagulants.
Cleveland Clinic PediPump Lamb Cadaver Fitting Studies
Authors: Cingoz Faruk , Fukamachi Kiyotaka , Ootaki Yoshio , Kamohara Keiji , Akiyama Masatoshi , Ootaki Chiyo , Kopcak Michael W. , Liu Jenny , Noecker Angela , Dudzinski Dave , Smith William A. , Duncan Brian W.
Published: May 2007

Abstract:  We are developing the PediPump, a magnetically suspended, mixed‐flow pump, as an implantable pediatric ventricular assist device (VAD). Lamb cadaver fitting studies were performed to determine the optimal pump location and optimal design of the inflow and outflow conduits for chronic in vivo studies. A prototype of the PediPump right and left ventricular assist devices (RVAD and LVAD, respectively) were implanted via a sternotomy or left thoracotomy in four lamb cadavers (3.7–34.2 kg). Via a sternotomy, the RVAD and LVAD required long inflow cannulas when placed into the right or left thoracic cavities, respectively. Via a left thoracotomy, with both pumps implanted in the left thoracic cavity, the RVAD required a 70° inflow cannula and a bent outflow graft while the LVAD required a 130° inflow cannula and a straight outflow graft. In conclusion, left thoracotomy provided optimal fitting for both LVAD and RVAD for the small lamb model.
Feasibility of a Tiny Centrifugal Blood Pump (TinyPump) for Pediatric Extracorporeal Circulatory Support
Authors: Ohuchi Katsuhiro , Hoshi Hideo , Iwasaki Yasuhiko , Ishihara Kazuhiko , Yoshikawa Masaharu , Ugaki Shinya , Ishino Kozo , Osaki Satoru , Kotani Yasuhiro , Sano Shunji , Takatani Setsuo
Published: May 2007

Abstract:  In this study, the performances of the TinyPump (priming volume 5 mL) system including the pediatric cannulae (Stöckert Pediatric Arterial Cannulae 2.6, 3.0, and 4.0 mm, Stöckert Instruments GmbH, Munich, Germany; Polystan 20‐Fr Venous Catheter, MAQUET GmbH, Rastatt, Germany) and an oxygenator (Terumo Capiox RX05 Baby‐RX, Terumo Cardiovascular Systems Co., Tokyo, Japan) were studied in vitro followed with preliminary ex vivo studies in 20‐kg piglets. In vitro results revealed that the TinyPump system met the requirements for pump speed, pump flow, and pressure drop as extracorporeal circulatory support during open heart surgery and extracorporeal membrane oxygenation (ECMO) in pediatric patients. In 2‐h ex vivo studies using 20‐kg piglets where the blood contacting surface of the TinyPump was coated with a biocompatible phospholipid polymer, the plasma‐free hemoglobin levels remained less than 5.0 mg/dL and no thrombus formation was observed inside the pump. The TinyPump system including the oxygenator and connecting circuits resulted in an overall priming volume of 68 mL, the smallest ever reported. The TinyPump can be a safe option for pediatric circulatory support during open heart surgery and ECMO without requiring blood transfusion.
Development of Miniaturized Mass Flow Meter for an Axial Flow Blood Pump
Authors: Kosaka Ryo , Maruyama Osamu , Nishida Masahiro , Yamane Takashi
Published: May 2007

Abstract:  To grasp the conditions of patients and implantable artificial hearts, it is essential to monitor the blood flow rate continuously and noninvasively. However, it is difficult to monitor the pump flow rate in an implantable artificial heart, because the conventional flow meter is too large to implant into the human body, and the flow estimation method is influenced by changes in the blood characteristics and the pump performance. In particular, the power consumption has neither linearity nor uniqueness with respect to the pump flow rate in an axial flow blood pump. In this research, we develop a prototype miniaturized mass flow meter that uses centrifugal force Fc for discharged patients with an axial flow blood pump. This flow meter measures the Fc corresponding to the mass flow rate, and implements compensation for static pressure. Because the strain gauges are attached outside of the curved tube, this mass flow meter has no blood contact point, resulting in a compact design. To evaluate the measurement accuracy and the tracking performance, the mass flow meter was compared with the conventional ultrasonic flow meter in a mock‐up circulation study. As a result, the measurement error ranging from 0.5 to 5.0 L/min was less than ±10% with respect to the maximum flow rate. The tracking performance of pulsation flow was approximately equivalent to that of the conventional flow meter. These experiments demonstrated that the prototype miniaturized mass flow meter using Fc could accurately measure the mass flow rate continuously and noninvasively.
In Vitro Long‐term Fatigue Endurance of the Secondary “Cement Injection Stem” Hip Prosthesis
Authors: Cristofolini Luca , Erani Paolo , Grupp Thomas , Jansson Volkmar , Viceconti Marco
Published: May 2007

Abstract:  A secondary cementation hip stem (Cement Injection Stem; Aesculap, Tuttlingen, Germany) was designed to reduce the risk of fat embolism, and achieve precise implant position and high‐quality cement mantle. A validated long‐term in vitro simulation was carried out that replicated 24 years of activity of a very demanding patient. Inducible and permanent micromotions were monitored. The cement mantle was sectioned and inspected for signs of fatigue damage. The stem–cement interface was inspected for fretting. Results were compared against previously published results for a conventionally implanted stem with comparable design (Centrament; Aesculap) from which this project was derived. Comparable micromotions were found (slightly larger proximally, in correspondence to the precured centralizer). No sign of fretting was observed. All fatigue damage indicators were comparable or significantly better than those for the conventionally implanted stem. The few cement cracks found were mainly localized in proximity of a proximal drainage hole. It is foreseen that when this detail is optimized, long‐term endurance will further improve.
Intermittent Stops of Shear Reduce the Mechanical Damage of Red Blood Cells
Authors: Mizunuma Hiroshi , Sakai Shirou
Published: May 2007

Abstract:  Continuous and intermittent high shear were loaded to red blood cells in a cone and a plate rheoscope. The mechanical damage to red cells was compared for continuous and intermittent shear. The intermittent shear was achieved by alternately starting and stopping shear repeatedly. In the case of intermittent shear load, red cell damage was suppressed remarkably. To explain this effect, we introduced a phenomenological hemolysis model, which agreed reasonably with the hemolysis tests for intermittent shear flow.
Classification of Physiologically Significant Pumping States in an Implantable Rotary Blood Pump: Effects of Cardiac Rhythm Disturbances
Authors: Karantonis Dean M. , Lovell Nigel H. , Ayre Peter J. , Mason David G. , Cloherty Shaun L.
Published: May 2007

Abstract:  Methods of speed control for implantable rotary blood pumps (iRBPs) are vital for providing implant recipients with sufficient blood flow to cater for their physiological requirements. The detection of pumping states that reflect the physiological state of the native heart forms a major component of such a control method. Employing data from a number of acute animal experiments, five such pumping states have been previously identified: regurgitant pump flow, ventricular ejection (VE), nonopening of the aortic valve (ANO), and partial collapse (intermittent [PVC‐I] and continuous [PVC‐C]) of the ventricle wall. An automated approach that noninvasively detects such pumping states, employing a classification and regression tree (CART), has also been developed. An extension to this technique, involving an investigation into the effects of cardiac rhythm disturbances on the state detection process, is discussed. When incorporating animal data containing arrhythmic events into the CART model, the strategy showed a marked improvement in detecting pumping states as compared to the model devoid of arrhythmic data: state VE—57.4/91.7% (sensitivity/specificity) improved to 97.1/100.0%; state PVC‐I—66.7/83.1% improved to 100.0/88.3%, and state PVC‐C—11.1/66.2% changed to 0.0/100%. With a simplified binary scheme differentiating suction (PVC‐I, PVC‐C) and nonsuction (VE, ANO) states, suction was initially detected with 100/98.5% sensitivity/specificity, whereas with the subsequent improved model, both these states were detected with 100% sensitivity. The accuracy achieved demonstrates the robustness of the technique presented, and substantiates its inclusion into any iRBP control methodology.
Relationship Between Biometric Characteristics and Stem Size of Uncemented Hip Prostheses
Authors: De Clerico Manuela , Bordini Barbara , Stea Susanna , Viceconti Marco , Toni Aldo
Published: May 2007

Abstract:  The authors examined 2329 uncemented hip prosthesis stems (AncaFit stem, Wright Medical Technology, Arlington, TN, USA) implanted between 1996 and 2004 due to primary coxarthrosis. This is the most commonly used stem in the Emilia‐Romagna region, in northern Italy, according to data from the Register of Orthopaedic Prosthetic Implants (RIPO). It is produced in eight sizes for each side. We analyzed the relationship between stem size and anthropometric data. Among the patients, 49.5% were men and 50.5% were women; mean age at surgery was 64.1 years (SD 9.1); mean height was 167 cm (SD 8.4), and mean weight was 75.7 kg (SD 12.7). Multifactorial analysis demonstrated that stem size was influenced by sex, age, and height, but not by weight. Besides this, there was an interaction between sex and age: in women, but not in men, the stem size increased with aging.
Development of Air Micro Bubbles in the Venous Outlet Line: An In Vitro Analysis of Various Air Traps Used for Hemodialysis
Authors: Stegmayr Christofer J. , Jonsson Per , Forsberg Ulf , Stegmayr Bernd G.
Published: May 2007

Abstract:  Venous air traps were tested in vitro with respect to presence of micro bubbles. Three types of venous air traps were measured (Bioline, Bioline GmbH, Luckenwalde, Germany; Gambro, Gambro AB, Lund, Sweden; Fresenius M.C., Fresenius Medical Care AG & Co. KGaA, Bad Homburg, Germany). Measurements (n = 10) were taken for each air trap, fluid flow (50–600 mL/min), and fluid level (high/low). A 1.5‐MHz ultrasound probe was used with an analysis device. The probe was mounted on the outlet line downstream of the venous air trap. A semisynthetic fluid was used to resemble blood viscosity. Occurrences of micro bubbles, without inducing an alarm of the dialysis device, were detected in almost all measurements. The amount of bubbles increased with increasing flow. There were more bubbles with low fluid level compared with high level. The Bioline tubing released the least bubbles in high fluid level. At low level, the Gambro tubing showed the least bubbles at flows 50–400 mL/min, and the Fresenius M.C. tubing showed the least bubbles at flows 400–600 mL/min. High fluid level in the air trap reduced generation of micro bubbles compared to low level, as did lower fluid flow versus high flow. The design of the air trap was also of importance.
Lacosamide: A Review of Preclinical Properties
Authors: Beyreuther Bettina K. , Freitag Joachim , Heers Cara , Krebsfänger Niels , Scharfenecker Ute , Stöhr Thomas
Published: May 2007

Lacosamide (LCM), (SPM 927, (R)‐2‐acetamido‐N‐benzyl‐3‐methoxypropionamide, previously referred to as harkoseride or ADD 234037) is a member of a series of functionalized amino acids that were specifically synthesized as anticonvulsive drug candidates. LCM has demonstrated antiepileptic effectiveness in different rodent seizure models and antinociceptive potential in experimental animal models that reflect distinct types and symptoms of neuropathic as well as chronic inflammatory pain. Recent results suggest that LCM has a dual mode of action underlying its anticonvulsant and analgesic activity. It was found that LCM selectively enhances slow inactivation of voltage‐gated sodium channels without affecting fast inactivation. Furthermore, employing proteomic affinity‐labeling techniques, collapsin‐response mediator protein 2 (CRMP‐2 alias DRP‐2) was identified as a binding partner. Follow‐up experiments confirmed a functional interaction of LCM with CRMP‐2 in vitro. LCM did not inhibit or induce a wide variety of cytochrome P450 enzymes at therapeutic concentrations. In safety pharmacology and toxicology studies conducted in mice, rats, rabbits, and dogs, LCM was well tolerated. Either none or only minor side effects were observed in safety studies involving the central nervous, respiratory, gastrointestinal, and renal systems and there is no indication of abuse liability. Repeated dose toxicity studies demonstrated that after either intravenous or oral administration of LCM the adverse events were reversible and consisted mostly of exaggerated pharmacodynamic effects on the CNS. No genotoxic or carcinogenic effects were observed in vivo, and LCM showed a favorable profile in reproductive and developmental animal studies. Currently, LCM is in a late stage of clinical development as an adjunctive treatment for patients with uncontrolled partial‐onset seizures, and it is being assessed as monotherapy in patients with painful diabetic neuropathy. Further trials to identify LCM's potential in pain and for other indications have been initiated.
MD‐354: What is It Good For?
Authors: Dukat Małgorzata , Glennon Richard A. , Young Shawquia
Published: May 2007

MD‐354 (meta‐chlorophenylguanidine) has been identified as a member of a novel class of 5‐HT3serotonin receptor agonists. MD‐354 is a 5‐HT3receptor partial agonist that has been shown to behave as an agonist in some assays, and as an antagonist in others. MD‐354 also binds at α‐adrenoceptors (ARs) and displays an affinity for α2B‐ARs comparable to its affinity for 5‐HT3receptors. Although devoid of antinociceptive actions following systemic administration alone, MD‐354 markedly enhances the antinociceptive actions of clonidine in the mouse tail‐flick assay without potentiating the sedative side effects of clonidine. Although studies with MD‐354 are still in progress, some pharmacological findings are described here. MD‐354‐related agents may represent drug adjuvants for the relief of severe pain.
Pharmacological Properties, Toxicology and Scientific Rationale for the use of Natalizumab (Tysabri®) in Inflammatory Diseases
Authors: Stüve Olaf , Bennett Jeffrey L.
Published: May 2007

Natalizumab (Tysabri®) was the first adhesion molecule antagonist to make it into clinical trial for patients with multiple sclerosis (MS) and other inflammatory disorders. Natalizumab is a humanized recombinant monoclonal antibody (MAb) that binds to the alpha (α)4 chain of the α4 beta (β)1 (very late activating antigen 4; VLA‐4) and α4β7 integrins. The scientific rationale for natalizumab therapy is the reduction of leukocyte extravasation into peripheral tissues. Natalizumab, like other VLA‐4 antagonists, may also interfere with the activation of T lymphocytes in secondary lymphoid organs and their reactivation in the central nervous system (CNS).

Shortly after its approval for the treatment of relapsing‐remitting MS (RR‐MS), three patients who were treated with natalizumab in the setting of clinical trials developed progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the brain with the polyoma virus JC. It remains to be elucidated why the use of this VLA‐4 antagonist is associated with an increased incidence of PML. Natalizumab was recently reapproved for the treatment of relapsing forms of MS. In this review, we outline the scientific rationale for using natalizumab in MS and other inflammatory disorders. In addition, an overview of pharmacological properties, clinical efficacy, safety, and toxicology of natalizumab is provided.
Levetiracetam: The Profile of a Novel Anticonvulsant Drug—Part I: Preclinical Data
Authors: De Smedt Tim , Raedt Robrecht , Vonck Kristl , Boon Paul
Published: May 2007

The objective of this article was to review and summarize the available reports on the preclinical profile of the novel anticonvulsant drug levetiracetam (LEV). Therefore, a careful search was conducted in the MEDLINE database and combined with guidelines from regulatory agencies, proceedings of professional scientific meetings, and information provided by the manufacturers. This article provides detailed information on the anticonvulsant effects of LEV in various animal models of epilepsy and on its pharmacology in laboratory animals. The mechanism of action of LEV is reviewed, with special regard to its recently discovered binding site, the synaptic vesicle protein 2A. In general, LEV is shown to be a safe, broad‐spectrum anticonvulsant drug with highly beneficial pharmacokinetic properties and a distinct mechanism of action. The clinical studies with LEV will be discussed in the second part of this review article to be published subsequently.
Levetiracetam: Part II, the Clinical Profile of a Novel Anticonvulsant Drug
Authors: De Smedt Tim , Raedt Robrecht , Vonck Kristl , Boon Paul
Published: May 2007

The objective of this article was to review and summarize the available reports on the profile of the novel anticonvulsant drug levetiracetam (LEV) in a clinical setting. Therefore, a careful search was conducted in the MEDLINE database and combined with guidelines from regulatory agencies, proceedings of professional scientific meetings, and information provided by the manufacturers. This article is devoted to the clinical pharmacology and clinical trials of LEV investigating its efficacy and safety as add‐on therapy or monotherapy for various seizure types. Finally, results from postmarketing surveillance of LEV are briefly discussed. In general, LEV is shown to be a safe, broad‐spectrum anticonvulsant drug with highly beneficial pharmacokinetic properties, a favorable long‐term retention rate, and a high responder rate, indicating that LEV is an efficient therapeutic option for the treatment of several types of epilepsy.
Dextromethorphan: A Review of N‐methyl‐d‐aspartate Receptor Antagonist in the Management of Pain
Authors: Siu Anita , Drachtman Richard
Published: May 2007

Dextromethorphan (DM) is a noncompetitive N‐methyl‐d‐aspartate (NMDA) receptor antagonist, which is widely used as an antitussive agent. DM also prevents neuronal damage and modulates pain sensation via noncompetitive antagonism of excitatory amino acids (EAAs). DM has been found to be useful in the treatment of pain in cancer patients and in the treatment of methotrexate‐induced neurotoxicity. Clinical studies with DM in cancer patients are reviewed in this article.
The Pharmacology of Ro 64‐6198, a Systemically Active, Nonpeptide NOP Receptor (Opiate Receptor‐Like 1, ORL‐1) Agonist with Diverse Preclinical Therapeutic Activity
Authors: Shoblock James R.
Published: May 2007

The NOP receptor (formerly referred to as opiate receptor‐like 1, ORL‐1, LC132, OP4, or NOP1) is a G protein–coupled receptor that shares high homology to the classic opioid MOP, DOP, and KOP (mu, delta, and kappa, respectively) receptors and was first cloned in 1994 by several groups. The NOP receptor remained an orphan receptor until 1995, when the endogenous neuropeptide agonist, known as nociceptin or orphanin FQ (N/OFQ) was isolated. Five years later, a group at Hoffmann‐La Roche reported on the selective, nonpeptide NOP agonist Ro 64‐6198, which became the most extensively published nonpeptide NOP agonist and a valuable pharmacological tool in determining the potential of the NOP receptor as a therapeutic target. Ro 64‐6198 is systemically active and achieves high brain penetration. It has subnanomolar affinity for the NOP receptor and is at least 100 times more selective for the NOP receptor over the classic opioid receptors. Ro 64‐6198 ranges from partial to full agonist, depending on the assay. Preclinical data indicate that Ro 64‐6198 may have broad clinical uses, such as in treating stress and anxiety, addiction, neuropathic pain, cough, and anorexia. This review summarizes the pharmacology and preclinical data of Ro 64‐6198.
Cytokine and Chemokine Gene Expression of IL‐1β Stimulated Equine Articular Chondrocytes
Authors: DAVID FLORENT , FARLEY JUDITH , HUANG HONG , LAVOIE JEAN‐PIERRE , LAVERTY SHEILA
Published: May 2007

Objective—To evaluate mRNA expression of several proinflammatory and anti‐inflammatory cytokines and chemokines in equine unstimulated and interleukin‐1β (IL‐1β)‐stimulated chondrocytes.

Study Design—In vitro experiment using equine chondrocyte cultures.

Sample Population—Whole articular cartilage from metacarpophalangeal joints (n=5 horses; 10 fetlocks).

Methods—Chondrocyte monolayer cultures were established from digested adult equine articular cartilage and stimulated with 5 ng/mL of recombinant human IL‐1β. RNA was extracted from the cells 24 hours after stimulation. IL‐1β, IL‐4, IL‐6, IL‐8, tumor necrosis factor‐α (TNF‐α), and ubiquitin (house keeping gene) mRNA expression were investigated by real‐time RT‐PCR.

Results—IL‐1β, IL‐6, and IL‐8 mRNA were expressed in unstimulated chondrocytes from macroscopically normal joints and were significantly up‐regulated after stimulation (5/5 horses). IL‐4 mRNA was not detected in any samples (0/5 horses). TNF‐α mRNA, by comparison, was expressed in 2/5 unstimulated samples and in all stimulated samples but a considerable sample variation in response to IL‐1β stimulation was observed.

Conclusions—Equine chondrocytes express mRNA for several proinflammatory cytokines and chemokines and IL‐1β modulates their expression.

Clinical Relevance—Chondrocytes express proinflammatory cytokines and chemokines capable of modulating a local inflammatory cascade in articular cartilage, which could potentially lead to focal degradation and osteoarthritis.
Does Use of a Jig Influence the Precision of Tibial Plateau Leveling Osteotomy Surgery?
Authors: BELL JONATHAN C. , NESS MALCOLM G.
Published: May 2007

Objective— To compare the precision of tibial plateau leveling osteotomy (TPLO) surgery when performed with or without a jig.

Study Design— Cadaveric study.

Sample Population— Cadaveric, adult greyhound hindlimbs (n=9 pair).

Methods— TPLO (n=18) was performed on each limb pair; 1 with and 1 without use of a jig. Measurements taken from pre‐ and postsurgical radiographs were osteotomy position, tibial plateau angle (TPA), varus‐valgus malalignment, and tibial torsion. The null hypothesis was that TPLO precision was not affected by use of a jig. Student's t‐test was used to investigate differences in TPA, osteotomy location, and frequency and extent of iatrogenic limb malalignment; P<.05 was considered significant.

Results— There were no significant differences in postsurgical TPA, tibial crest thickness, varus‐valgus malalignment, or tibial torsion between TPLOs performed with or without a jig. Osteotomy location was significantly more distal when a jig was used (P=.03).

Conclusions— Jig use did not improve the precision of TPLO surgery.

Clinical Relevance— Performing TPLO without a jig should reduce surgery time, eliminate complications related to placement of the distal jig pin and allow unhindered positioning of the osteotomy.
The Effect of Lidocaine on Postoperative Jejunal Motility in Normal Horses
Authors: MILLIGAN MELISSA , BEARD WARREN , KUKANICH BUTCH , SOBERING TIM , WAXMAN SARAH
Published: May 2007

Objective—To measure the effect of lidocaine on the duration of the migrating myoelectric complex (MMC) and Phases I, II, and III of the MMC, spiking activity of the jejunum, and number of Phase III events when administered postoperatively to normal horses.

Study Design—Nonrandomized cross‐over design.

Methods—Horses were anesthetized and via flank laparotomy 4 silver–silver chloride bipolar electrodes were sutured to the proximal jejunum. Electrical activity was recorded for 6 hours during 3 recording sessions beginning 24, 48, and 72 hours postoperatively. Saline (0.9% NaCl) solution was administered for 3 hours followed by lidocaine administration for 3 hours (1.3 mg/kg bolus intravenously [IV], 0.05 mg/kg/min IV constant rate infusion).

Results—Duration of MMC was unchanged during lidocaine administration (77 minutes—saline versus 105 minutes—lidocaine,P=.16). Durations of Phase I and II were unchanged during lidocaine administration (P=.19 and .056, respectively). Phase III was shorter during lidocaine administration (P=.002). Spiking activity was unchanged at all time periods during lidocaine administration (24 hours—P=.10; 48 hours—P=.95; and 72 hours—P=.12). The number of Phase III events was unchanged over all time periods during lidocaine administration (P=.053).

Conclusions—Duration of MMC, spiking activity, and number of Phase III events was unchanged during lidocaine administration.

Clinical Relevance—Use of lidocaine as a prokinetic agent cannot be supported by this study in normal horses; however, results may differ in clinically affected horses.
Evaluation of Pentosan Polysulfate Sodium in the Postoperative Recovery from Cranial Cruciate Injury in Dogs: A Randomized, Placebo‐Controlled Clinical Trial
Authors: BUDSBERG STEVEN C. , BERGH MARY SARAH , REYNOLDS LISA R. , STREPPA HEATHER K.
Published: May 2007

Objective—To evaluate the efficacy of pentosan polysulfate (PPS) for improving the recovery period and mitigate the progression of osteoarthritis (OA) of the canine stifle after extracapsular stabilization of cranial cruciate ligament (CCL) injuries.

Study Design—Randomized, blinded, placebo‐controlled clinical trial.

Animals—Dogs (n=40) with unilateral CCL instability.

Methods—Each dog had an extracapsular stabilization of the stifle with or without partial meniscectomy. Dogs were divided into 4 groups based on preoperative radiographic assessment and whether a partial meniscectomy was performed. Dogs were randomly assigned to either (3 mg/kg) PPS or placebo treatment in each group, and then injected subcutaneously weekly for 4 weeks. Lameness, radiographic changes, biological marker concentration in blood and urine, and ground reaction forces (GRFs) were collected preoperatively, and at 6, 12, 24, and 48 weeks. Data were analyzed within and between groups using repeated measures ANOVA;P<.05 was considered significant.

Results—No adverse reactions to PPS were reported. Thirty‐nine dogs completed a minimum of 24‐weeks follow‐up and 33 dogs completed 48 weeks. All dogs clinically improved after surgery without differences in lameness score, vertical GRFs, or radiographic progression. Grouped and evaluated only by initial radiographic score, PPS‐treated dogs improved significantly faster in braking GRFs than placebo‐treated dogs. In dogs with partial meniscectomies, urine deoxypyridinoline, and serum carboxy‐propeptide of type II collagen were significantly increased at 6 weeks in placebo‐treated dogs compared with PPS‐treated dogs.

Conclusions—PPS administered after stabilization of the cruciate deficient stifle may prove to be a useful adjunctive treatment option, although further studies are necessary to substantiate this claim.