Increased risk of epilepsy in patients registered in the Swedish Dementia Registry.

BACKGROUND AND PURPOSE: Data on epilepsy in dementia, particularly on its risk factors, are scarce. Confounding comorbidities and the rising incidence of epilepsy in older age have hampered studies in this field. The occurrence and risk factors for epilepsy in the Swedish Dementia Registry (SveDem), a large cohort of patients with dementia, have been examined. METHODS: Information on epilepsy and seizure-related diagnoses, comorbidities and survival were extracted for all individuals in SveDem (n = 81 192) and three randomly selected age- and gender-matched controls from the population register, excluding all with a dementia diagnosis (n = 223 933). The risk of epilepsy following dementia diagnosis was estimated with Kaplan-Meier curves, and Cox proportional hazard modelling was used to identify risk factors and adjust for comorbidities. RESULTS: A diagnosis of epilepsy was found more frequently amongst dementia patients [4.0%, 95% confidence interval (CI) 3.8-4.1] than controls (1.9%, 95% CI 1.9-2.0). The risk of incident epilepsy after dementia was 2.1% (95% CI 1.9-2.3) at 5 years and 4.0% (95%CI 3.4-4.6) at 10 years, compared to 0.8% (95% CI 0.8-0.8) and 1.6% (95% CI 1.4-1.8) respectively for controls. The risk was greatest for early-onset Alzheimer's disease. In multivariate analysis, dementia was associated with a hazard ratio of 2.52 (95% CI 2.31-2.74) for epilepsy. Young age, male sex, stroke, brain trauma, brain tumour and low Mini-Mental State Examination score significantly increased the risk. CONCLUSIONS: Dementia, particularly young-onset Alzheimer's disease, increases the risk of subsequent epilepsy. Further studies are needed to determine optimal management and the impact of epilepsy on prognosis.

Risk of epilepsy after a single seizure in multiple sclerosis.

BACKGROUND AND PURPOSE: The 2014 International League Against Epilepsy clinical definition of epilepsy allows diagnosis after a single unprovoked seizure if the 10-year recurrence risk exceeds 60%. Multiple sclerosis (MS) carries an increased risk of epilepsy, but the risk after a first seizure is unknown. We aimed to investigate the risk of epilepsy in patients with MS who had suffered a first seizure. METHODS: We cross-referenced data from the Swedish MS register with the national patient register for 15 810 patients with MS and 43 635 controls and included 289 patients with MS and 222 controls with a first diagnosis of seizure or status epilepticus (SE) without prior epilepsy or presumed symptomatic aetiology. Kaplan-Meier curves were used to estimate the risk of epilepsy. RESULTS: The 10-year risk of epilepsy was 51.4% [95% confidence interval (CI), 44.0-58.9] for patients with MS and 41.3% (95% CI, 33.5-49.1) for controls. The risk was 46.1% (95% CI, 35.3-56.9) for patients with relapsing-remitting MS and 60.7% (95% CI, 46.6-74.8) for patients with secondary progressive MS. For patients with MS with SE, the 10-year risk of epilepsy was 85.9% (95% CI, 67.9-100). CONCLUSIONS: Our data indicate that patients with relapsing-remitting MS have a similar risk as controls of developing epilepsy after a single seizure. Patients with secondary progressive MS could run a greater risk of subsequent epilepsy, but our data do not indicate a risk that, with certainty, exceeds the threshold specified by the International League Against Epilepsy. Patients with SE have a high risk of epilepsy, possibly motivating diagnosis and treatment.

Randomized controlled trials of antiepileptic drugs for the treatment of post-stroke seizures: A systematic review with network meta-analysis.

OBJECTIVE: To determine the best available evidence on the efficacy and tolerability of antiepileptic drugs (AEDs) used to treat poststroke seizures and epilepsy. METHODS: MEDLINE, Embase, CENTRAL, ClinicalTrials.gov and Opengrey.eu were searched for RCTs of AEDs used to treat post-stroke epilepsy. The following outcomes were considered: seizure freedom; occurrence of adverse effects (AEs); withdrawal for AEs. The methodological quality was assessed according to the Cochrane Handbook for Systematic Reviews of Interventions. Adjusted indirect comparisons were made between each AED using controlled-release carbamazepine (CR-CBZ) as common comparator. RESULTS: Only 2 RCTs were included, one comparing levetiracetam (LEV) with CR-CBZ and the other comparing lamotrigine (LTG) with CR-CBZ. No significant difference was found in seizure freedom between either LEV or LTG and CR-CBZ. Occurrence of AEs were lower for LEV and LTG than for CR-CBZ. Indirect comparisons showed no difference between LEV and LTG for seizure freedom (OR 0.86; 95%CI: 0.15-4.89). Occurrence of AEs was higher for LEV than for LTG (OR 6.87; 95%CI: 1.15-41.1). For withdrawal rates due to AEs, we found a large width and asymmetrical distribution of confidence intervals around the obtained OR of 10.8 (95% CI: 0.78-149.71). CONCLUSIONS: Direct and indirect comparisons did not find a difference in seizure freedom between the various AEDs, probably because of the small number of patients included. LEV and LTG appears better tolerated than CR-CBZ and LEV seems associated with more AEs than LTG. Further studies are required to provide robust evidence on efficacy and tolerability of AEDs for treating poststroke epilepsy.

Triiodothyronine improves left ventricular function without oxygen wasting effects after global hypothermic ischemia.

Cardiopulmonary bypass results in a "euthyroid sick" state. Recently, interest has focused on the relationship between low serum triiodothyronine levels and postoperative cardiovascular hemodynamics. The present study was undertaken to more clearly define the acute effects of triiodothyronine on myocardial mechanics and energetics after hypothermic global ischemia using an ex-vivo canine heart preparation to model the clinical condition. Experiments were performed on isolated hearts subjected to hyperkalemic arrest with 90 minutes of hypothermic (10 degrees C) ischemia. Isolated hearts were cross-perfused by euthyroid support dogs in which triiodothyronine levels spontaneously decreased by 65% to 75% (p < 0.01) after the initiation of cross-perfusion. In nine heart preparations, triiodothyronine (Triostat) was given as a bolus dose (0.2 micrograms/kg) after 1 hour of baseline data collection with a subsequent measurable rise in serum triiodothyronine levels (p < 0.01). In six postischemic hearts, reverse triiodothyronine was given as a 0.2 micrograms/kg bolus. Triiodothyronine was also administered to a group of eight nonischemic, continuously perfused isolated hearts. Intrinsic myocardial contractility was assessed by analysis of the preload recruitable stroke work area, energetic efficiency from the myocardial oxygen consumption-pressure-volume area relationship, and coronary vascular resistance from analysis of coronary flow and perfusion pressure. Acute administration of triiodothyronine to postischemic hearts improved the preload recruitable stroke work area from 9.5 +/- 1.42 to 14.9 +/- 2.03 x 10(7) erg/ml, a 56% increase from baseline (p < 0.001), but had no effect on the preload recruitable stroke work area of the nonischemic hearts. The inotropic response resulting from triiodothyronine treatment did not alter the myocardial oxygen consumption-pressure-volume area relationship. Triiodothyronine treatment was associated with significantly decreased coronary resistance and increased coronary flow through a range of diastolic loading conditions in the postischemic hearts. The biologically inactive thyroid hormone metabolite reverse triiodothyronine was without effect on any of the measured parameters. On the basis of these results, we conclude that the low triiodothyronine state of cardiopulmonary bypass can be reproduced in this isolated heart model and that acute triiodothyronine treatment results in a unique inotropic action manifest only in the postischemic reperfused myocardium and is accomplished without oxygen wasting effects.

The effects of amrinone versus dobutamine on myocardial mechanics and energetics after hypothermic global ischemia.

The effects on the postischemic myocardium of amrinone and dobutamine were studied in canine hearts that underwent 90 minutes of hypothermic (10 degrees C) arrested ischemia. In an isolated heart preparation cross-circulated by a support dog, left ventricular pressure-volume loops were collected under a constant afterload based on a mock circulatory system and a range of preload conditions controlled by a computerized servo volume pump. Dobutamine (0, 5, 10, 15 micrograms/kg per minute) and amrinone (0, 0.75, 1.5, 3.0 mg/kg) were tested in this order based on the weights of the support dogs in eight experiments. Changes in intrinsic myocardial contractility were analyzed as percent increases in the preload recruitable stroke work area from baselines. Dobutamine exhibited significant dose-related increases in the preload recruitable stroke work area. Amrinone did not produce significant increases in preload recruitable stroke work area at 0.75 mg/kg; amrinone's inotropic effect was equivalent to dobutamine, 5 micrograms/kg per minute at 1.5 mg/kg, and at the maximum dose (3.0 mg/kg) it was equivalent to dobutamine, 10 micrograms/kg per minute. The myocardial energetic efficiency was determined from the analysis of the myocardial oxygen consumption-pressure volume area relationship. The y intercept represents the basal metabolic oxygen requirement of the unloaded beating heart, and the slope is inversely proportional to the rate of energy conversion for increasing loading conditions. Dobutamine significantly increased the y intercepts, but it had no effects on the slopes. These changes demonstrate reduced myocardial efficiencies that are consistent with previous reports. Amrinone (0.75 and 1.50 mg/kg) did not result in change of the y intercepts and the slopes of myocardial oxygen consumption-pressure-volume area relationship from baseline conditions. The y intercept was increased with amrinone (3.0 mg/kg), although still not significantly higher than baseline and not to the extents of the dobutamine group. Dobutamine did not have any primary effect on coronary resistance, while amrinone significantly reduced coronary resistance in all loading conditions at 1.5 and 3.0 mg/kg. This study demonstrates that the inotropic effects of amrinone tested under this constant afterload preparation were lower than those of dobutamine. Amrinone has a superior profile of myocardial efficiency on the postischemic myocardium since it does not produce the oxygen-wasting effects of the traditional inotropic agents such as the beta agonists. This benefit, together with amrinone's coronary dilating effects, critically improves the supply/demand ratio that may be of importance in certain clinical situations.

Superiority of the University of Wisconsin solution over simple crystalloid for extended heart preservation. A study of left ventricular pressure-volume relationship.

To compare the effects of the University of Wisconsin solution with those of an extracellular crystalloid solution, Krebs-Ringer bicarbonate, as cardiac preservation media, we studied 35 adult dogs in an isolated heart preparation. Four groups of seven hearts were preserved in University of Wisconsin solution for 6 or 12 hours or in Krebs-Ringer bicarbonate solution for 6 or 12 hours. An additional group of seven hearts with no ischemia was used for a control group. In the four preservation groups, hearts were arrested by electrolyte solution (Normosol with potassium chloride, 20 mEq/L, added, 4 degrees C), flushed with 200 ml of the preservation solution, and then stored in the same solution at 1 degree to 2 degrees C. The hearts were mounted on an isolated heart preparation equipped with a computer-controlled servo-pump system that used a mock arterial system to modulate the aortic input impedance presented to the left ventricle. Left ventricular pressure-volume loops were measured on-line for 2 hours of reperfusion with autologous warm oxygenated blood. Elastance was derived from the end-systolic pressure-volume relationship, and diastolic compliance was derived from the end-diastolic pressure-volume relationship. The total left ventricular performance was assessed by the preload recruitable stroke work area, the slope, and its x-intercept, all of which derived from the stroke work (pressure-volume area)-end-diastolic volume relationship. Extended global ischemia had more deleterious effects on the end-diastolic than the end-systolic pressure-volume relationship. In confirmation with other studies, elastance did not accurately reflect the level of ventricular contractile dysfunction because of the significant amount of diastolic dysfunction. The preservation of myocardial systolic and diastolic functions, as demonstrated by the preload recruitable stroke work area and diastolic compliance, was better in the University of Wisconsin solution groups than in the Krebs-Ringer bicarbonate solution groups after 6 and 12 hours of preservation. In addition, 6 hours of preservation with University of Wisconsin solution maintained normal systolic and diastolic functions as compared with those of the control group. Preservation with University of Wisconsin solution prevented any myocardial edema formation; by contrast, this was significantly increased after 12 hours in Krebs-Ringer bicarbonate solution. Groups preserved with University of Wisconsin solution had less reperfusion injury as evidenced by the release of coronary sinus creatine kinase during reperfusion; they also had improved oxygen use during reperfusion.(ABSTRACT TRUNCATED AT 400 WORDS)

Myocardial reperfusion injury. Platelet-activating factor stimulates polymorphonuclear leukocyte hydrogen peroxide production during myocardial reperfusion.

To study the roles of platelet-activating factor, polymorphonuclear leukocytes, and oxygen free radicals in myocardial reperfusion injury, we subjected 10 sheep to 90 minutes of mid-left anterior descending coronary artery followed by 6 hours of reperfusion. Stainings with gentian violet and tetratriphenyl ammonium chloride demonstrated 20% +/- 3% of the left ventricular mass at risk for ischemia, of which 75% +/- 10% underwent infarction. Coronary sinus blood was assayed for platelet-activating factor and neutrophil hydrogen peroxide production before and during coronary occlusion and during reperfusion. Platelet-activating factor was isolated by column chromatography and lipid extraction and quantified by radioimmunoassay. Neutrophil hydrogen peroxide production was measured by a 2',7'-dichlorofluorescein flow-cytometric assay. Platelet-activating factor was elevated to 899 +/- 210 pg/ml at 15 minutes of reperfusion, compared with the preocclusion level of 271 +/- 55 pg/ml and coronary occlusion level of 359 +/- 64 pg/ml (p less than 0.05; analysis of variance). Neutrophil hydrogen peroxide production, measured on a relative fluorescence scale, was also elevated to a level of 141 +/- 27 at 1 hour of reperfusion, compared with the preocclusion level of 103 +/- 6 and the coronary occlusion level of 114 +/- 13 (p less than 0.01; analysis of variance). Both of these parameters returned toward baselines at the end of 6 hours of reperfusion. Histologic examination revealed infiltration of polymorphonuclear leukocytes into the interstitium of the reperfused myocardium. Neutrophils isolated from unoperated and healthy sheep demonstrated a graded dose response in hydrogen peroxide production when stimulated by purified platelet-activating factor in vitro. These findings suggest that platelet-activating factor is released in the coronary circulation and is a mediator of oxygen free radical production in polymorphonuclear leukocytes during myocardial reperfusion.

On-line acquisition, analysis and presentation of neurophysiological data based on a personal microcomputer system.

A microcomputer based system is described for the acquisition, averaging, displaying, analysis and storage of electrophysiological (EPSP and post-stimulus histogram) data. The system consists of commercially available hardware (IBM-PC AT compatible, 80286 or 80386 based microcomputer, Burr-Brown analog-to-digital (A/D) converter), a custom built interface module, and a combination of commercially available and custom built software packages. The software operates within a Microsoft Windows environment and is comprised of custom built data acquisition and review modules which are linked to Microsoft's Excel program. The system is capable of four channel A/D conversion of EPSP's at a sampling frequency of up to 10 KHz (50 KHz single channel), the averaging of data including the addition and subtraction of various channels, the graphical display of data, the extraction of various data parameters, and the transfer of data to an Excel spreadsheet. The spreadsheet allows for the development of mathematical formulas for statistical analysis of data and presentation of the results in graphical form. Finally, data can easily be output to a laser printer or plotter. A sample experiment, illustrating system operation, is presented.

Effects of shaving methods and intraoperative irrigation on suppurative mediastinitis after bypass operations.

To investigate the effects of the hair removal methods and intraoperative irrigation on suppurative mediastinitis after cardiopulmonary bypass operations, 1,980 consecutive adult patients over a 2-year period in our institution were prospectively randomized to manual shaving versus electrical clipping of hair before the skin incision, and to povidone-iodine solution (0.5%) versus saline solution mediastinal and subcutaneous irrigation before wound closure. The overall incidence of suppurative mediastinitis was 0.86% (17/1,980). The infectious rate was significantly higher in the manually shaven (13/990) than in the electrically clipped patients (4/990) with an odds ratio of 3.25 (95% confidence interval, 1.11 to 9.32; p = 0.024). It was also higher in the povidone-iodine group (11/990) than in the saline group (6/990), although the difference was not statistically significant (p = 0.16). Fourteen patients were treated with operative debridement with closed tube irrigation, with one failure requiring a conversion to an open wound. Two patients were successfully treated with primary open wound procedures followed by delayed muscular flap closures, and 1 patient succumbed to rapid and profound sepsis soon after open drainage. We conclude that electrical clipping is superior to manual shaving in the prevention of suppurative mediastinitis. The routine use of povidone-iodine (0.5%) irrigation was of no benefit in this study and may increase the incidence of infection due to its known suppressive effects on local leukocytes and fibroblasts. Furthermore, operative debridement with closed tube irrigation was successful in treating the majority of cases in this series.

Effects of temperature and flow rate on regional blood flow and metabolism during cardiopulmonary bypass.

Eleven dogs were subjected to a 150-minute period of cardiopulmonary bypass that consisted of a high-flow, normothermic phase, a high-flow, hypothermic phase, a low-flow, hypothermic phase, and then a high-flow, rewarming phase. Regional blood flow and oxygen consumption to the brain, intestines, kidney, and hind limb were determined at baseline and at 10-minute intervals during cardiopulmonary bypass. Blood flow to the carotid artery, superior mesenteric artery, and renal artery declined significantly with hypothermic cardiopulmonary bypass whereas blood flow to the femoral artery increased significantly. Although total body oxygen consumption returned to baseline values at the end of the rewarming phase, oxygen consumption for these regions differed somewhat from their baseline values. We conclude that blood flow during hypothermic cardiopulmonary bypass is shunted to skeletal muscle, particularly with high pump flows. Additionally, the return of total body oxygen consumption to baseline after rewarming is not necessarily reflected at the regional level.

Evaluation of an extraaortic counterpulsation device in severe cardiac failure.

A valveless, single-orifice polyurethane ventricle with a maximum stroke volume of 60 mL was implanted on the brachiocephalic artery just above the aortic arch in sheep (n = 14) to act as an extraaortic counterpulsation device. In parallel, an intraaortic balloon was placed in the descending thoracic aorta. Both devices were pneumatically driven with an intraaortic balloon pump console that was gated by the electrocardiogram to provide aortic diastolic augmentation at a stroke volume of 40 mL. To compare the efficacy of counterpulsation for each device during severe cardiac failure, biventricular block was induced by continuous infusion of esmolol (100 to 600 micrograms.kg-1.min-1), titrated to reduce aortic flow and pressure to less than 75% of baseline. Pulsatile coronary and aortic flows were recorded with ultrasonic flow probes placed around their respective vessels. Aortic root and left ventricular pressures were recorded using micromanometers. The enhancement of hemodynamic variables for both devices were compared for optimal timing conditions, which were defined as inflation set just before the dicrotic notch and deflation bordering on isovolumetric systole. The extraaortic counterpulsation device was able to significantly augment aortic and coronary flows while simultaneously decreasing left ventricular tension time index and aortic end-diastolic pressure (p less than 0.02). The intraarotic balloon pump was able to significantly reduce only tension time index (p less than 0.002) to a lesser extent that the extraaortic counterpulsation device. All analysis was performed with the paired-samples t test. The extraaortic counterpulsation device greatly improves the myocardial oxygen supply-consumption ratio of the left ventricle by increasing diastolic coronary flow and reducing left ventricular wall tension during systole.(ABSTRACT TRUNCATED AT 250 WORDS)

Ischemic tolerance of the arrested heart during warm cardioplegia.

Normothermic blood cardioplegia has recently generated interest as an alternative method of myocardial protection during cardiopulmonary bypass (CPB) surgery. One disadvantage is the obligatory interruption of coronary flow during the distal coronary anastomosis. This study was designed to determine the safe normothermic ischemic time of the arrested and decompressed heart. Under normothermic CPB (37 degrees C), initial cardioplegic arrest was induced with 750 cc of warm (37 degrees C) hyperkalemic blood cardioplegia in 21 adult dogs. The heart then received warm blood cardioplegia either continuously (50 cc/min), every 5 min (250 cc each) or every 10 min (350 cc each) for a total equivalent ischemic time of 30 min (n = 7 in each group). Left ventricular pressure-volume (PV) loops were measured by micromanometer and conductance (volume) catheters before, at 60 and 90 min after aortic cross-clamping. Systolic function was measured as the preload recruitable stroke work area derived from the stroke work-end diastolic volume relationship, and the diastolic stiffness constant (k) was derived from the exponential diastolic PV relationship. The q5 min group sustained minor deterioration in diastolic function while its systolic function was well maintained during recovery. There were significant reductions in both the diastolic and systolic functions in the q10 min group. The maximum drops in the septal wall pH during aortic cross-clamping were 0.05 +/- 0.02 (not significant), 0.19 +/- 0.06 (P < 0.05), and 0.40 +/- 0.09 (P < 0.01) for the continuous, q5 min and q10 min groups, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

A closed-loop control scheme for intraaortic balloon pumping.

The beneficial hemodynamic effects of IABP are critically dependent on balloon timing relative to the diastolic phase of the cardiac cycle. A microprocessor-based controller has been developed to implement real-time automation of IABP using P-R intervals to regulate balloon deflation and systolic time intervals to trigger balloon inflation in a semi-automatic fashion. Experiments were performed on anesthetized open-chest dogs. Simultaneous measurement of aortic pressure and flow, coronary flow, and left ventricular pressure were recorded. Muscle segment lengths in normal and ischemic border zones were also measured from implanted pairs of endocardial ultrasonic dimension gages. P-waves were obtained from atrial cardiograms, and heart sounds were detected using a special filtering circuit. Both signals were input together with ECG to automate IABP timing. Systolic time intervals were calculated in real-time. IABP efficacy was assessed from changes in aortic flow, coronary flow, tension time index, end diastolic pressure, and the endocardial viability ratio. Comparisons were made between automated and manual timing set by a certified technician. Results indicate that automated timing yielded equivalent hemodynamic enhancement with greater ease of adjustment. A closed-loop control scheme is proposed which allows complete automatic device operation and the capability to rapidly achieve the optimum of any directly measurable hemodynamic variable.

Optimal storage period for extended heart preservation with the University of Wisconsin Solution. A study of the left ventricular pressure-volume relationship.

To define the optimal and safe storage period in the use of the University of Wisconsin Solution (UWS) for extended heart preservation, 34 adult canine hearts were preserved under static and hypothermic conditions for 6, 12, 18, and 24 hours. A group of 10 hearts were used as a control of the preparation used in the study. Left ventricular functions were assessed in an isolated heart preparation equipped with a computerized servo-pump to measure the pressure-volume relationship. The systolic, diastolic and total ventricular performance were derived from the end-systolic pressure-volume relationship, end diastolic pressure-volume pressure relationship, and the stroke work-end diastolic volume relationship, respectively. Myocardial water content and coronary resistance during reperfusion were also analyzed. The study revealed that UWS was able to maintain normal levels of systolic and diastolic functions, and consequently normal level of total ventricular performance after 6 hours of storage. There was a reduction of diastolic function while the systolic function was still well maintained after 12 hours of preservation. The results after 12 hours were poor. There was no increase in the myocardial water content for up to 24 hours of storage; however, the coronary resistance during reperfusion significantly increased in the 18-hour group and the 24-hour group. The findings suggest that UWS may extend the safe period of myocardial preservation beyond the traditional 4 hours of storage closer to 12 hours of storage.

An automated system for the analyses of temporal speech patterns: description of the hardware and software.

A system (WELMAR II) is described for analyzing time patterns of speech on small computers. Temporal speech patterning refers to the pacing of the sounds and silences that make up a stream of speech. The system is particularly useful for research involving clinical populations since it has been shown that speech rhythms are sensitive to interpersonal influence, to dimensions of personality, and to psychological pathology.

The synaptic protein encoded by the gene Slc10A4 suppresses epileptiform activity and regulates sensitivity to cholinergic chemoconvulsants.

The expanding number of disease-causing dysfunctions of synaptic proteins illustrates the importance of investigating newly discovered proteins involved in neuronal transmission. The gene Slc10A4 encodes a recently described carrier protein present in pre-synaptic terminals of cholinergic and monoaminergic neurons. The biological significance of this recently described transporter protein is currently unknown. We here investigated whether absence of the Slc10a4 protein has any impact on function of the cholinergic system. We first investigated the sensitivity of Slc10a4 null mice to cholinergic stimulus in vitro. In contrast to wild type mice, gamma oscillations occurred spontaneously in hippocampal slices from Slc10a4 null mice. Furthermore, moderate treatment of Slc10a4 null slices with the cholinergic agonist carbachol induced epileptiform activity. In vivo, 3-channel EEG measurements in freely behaving mice revealed that Slc10a4 null mice had frequent epileptiform spike-activity before treatment, and developed epileptic seizures, detected by EEG and accompanied by observable behavioral components, more rapidly after injection of the cholinergic agonist pilocarpine. Similar results were obtained on non-operated mice, as evaluated by behavioral seizures and post mortem c-Fos immunohistochemistry. Importantly, Slc10a4 null mice and wild type control mice were equally sensitive to the glutamatergic chemoconvulsant kainic acid, demonstrating that absence of Slc10a4 led to a selective cholinergic hypersensitivity. In summary, we report that absence of the recently discovered synaptic vesicle protein Slc10a4 results in increased sensitivity to cholinergic stimulation.

Compositional analysis of a modified University of Wisconsin solution for extended myocardial preservation. A study of the left ventricular pressure-volume relation.

BACKGROUND: The University of Wisconsin solution (UW) has been shown to be superior to the use of traditional types of simple crystalloids in extended heart preservation. This study was designed to determine the necessity of four potentially redundant components in UW. MATERIALS AND METHODS: Forty canine hearts (n = 8 in each group) were preserved for 6 hours under hypothermic (1-2 degrees C), nonperfused conditions in unmodified UW, UW with an extracellular or reversed composition of sodium and potassium (UW-E), UW with chloride instead of lactobionate (UW-L), UW without raffinose (UW-R), and UW without hydroxyethyl starch (UW-HS). The left ventricular functions were assessed in an isolated heart preparation equipped with a computerized servo-volume pump to measure the pressure-volume relation. The systolic function was expressed in elastance derived from the end-systolic pressure-volume relation, and total ventricular performance was expressed in preload recruitable stroke work area derived from the stroke work-end-diastolic volume relation. Diastolic compliance was derived from the end-diastolic pressure-volume pressure relation. The results were compared with a control group with no ischemia. There was no significant deterioration in left ventricular systolic contractile functions as demonstrated by the analysis of elastance and the preload recruitable stroke work area in any of the modifications of UW. However, significant deterioration in the diastolic compliance occurred in the UW-E and UW-HS groups. A similar trend was found in the UW-L group, although it was not statistically significant, whereas the diastolic compliance was preserved in the UW-R group. CONCLUSIONS: The intracellular electrolyte composition and the hydroxyethyl starch are important in the preservation of left ventricular diastolic function, whereas the omission of raffinose was inconsequential. The replacement of lactobionate by chloride had less untoward functional effects compared with studies of other solid organ preservation.

The effects of warm versus cold blood cardioplegia on endothelial function, myocardial function, and energetics.

BACKGROUND: Recent interest in the use of normothermic blood cardioplegia is based on theoretical advantages over the traditional method of hypothermic myocardial protection. This study was designed to compare the effects of warm and cold blood cardioplegia on left ventricular functions and energetics and coronary responsiveness. MATERIALS AND METHODS: Two groups of mongrel dogs (n = 7 each) underwent either normothermic cardiopulmonary bypass (CPB) with continuous warm (37 degrees C) blood cardioplegia or hypothermic (26 degrees C) CPB with a single dose of cold (4 degrees C) blood cardioplegia supplemented with topical cooling during 30 minutes of aortic clamping. There was no deterioration in the endothelium-dependent and -independent coronary relaxation as tested by the infusion of acetylcholine and nitroglycerin after cardioplegic arrest for either group. At 60 minutes of reperfusion, both groups had complete recovery of left ventricular contractility as measured by the preload recruitable stroke work area derived from the measurement of the ventricular pressure (micromanometer catheter) and volume (conductance catheter) relation. The analysis of myocardial energetics in terms of the myocardial oxygen consumption-pressure volume area relation did not reveal any significant changes between the y-intercepts and the slopes of the two groups. CONCLUSIONS: For 30 minutes of aortic cross-clamp time, continuous warm cardioplegia did not provide any benefit over a single injection of cold cardioplegia in coronary endothelial and smooth muscle function, myocardial function, and energetics.

Survival analysis of octogenarian patients with coronary artery disease managed by elective coronary artery bypass surgery versus conventional medical treatment.

BACKGROUND: In view of the increasing age of the U.S. population, the use of coronary artery bypass surgery in the management of the elderly patients with coronary artery disease needs to be better defined. METHODS AND RESULTS: To evaluate the effects of medical and surgical therapy on octogenarian patients with coronary artery disease in our institution, we retrospectively reviewed 177 consecutive octogenarians who underwent cardiac catheterization over a 5-year period. Sixty-five of these patients were found to have significant coronary artery disease without severe valvular disease. Elective coronary artery bypass surgery was performed in 36 patients, whereas 29 patients were continued on maximization of medical therapy and not referred to the surgical service. Left ventricular ejection fractions (LVEF) were similar for the two groups, whereas the surgical patients had slightly higher average number of diseased coronary vessels and slightly higher levels of angina. Univariate survival analysis of 20 variables, including the choice of medical versus surgical treatment and the associated conditions, was performed by Mantel-Cox testing of the paired Kaplan-Meier product limit survival curves stratified by the subgroups of each variable. The variables found to be significant were then included in a multivariate survival analysis using the Cox proportional hazards regression model. The treatment choice, LVEF, level of angina, and presence of any aortic and/or mitral valvular disease at the time of cardiac catheterization were found to be independent prognostic indicators of survival in the follow-up period of 26 +/- 16 months. The 3-year probability of survival rates for the surgical patients and medical patients were 77.4% and 55.2%, respectively (p = 0.0294). The New York Heart Association functional class of the surgical group decreased significantly from a mean preoperative level of 3.4 +/- 0.5 to a mean level of 1.2 +/- 0.6 at the follow-up interview (p < 0.01), whereas it did not significantly change for the medical group from a baseline mean level of 2.8 +/- 1.3 to a mean follow-up level of 2.5 +/- 1.0. CONCLUSIONS: We conclude that coronary artery bypass surgery provided improved long-term survival and functional benefit compared with conventional medical treatment in a small group of octogenarian patients in our institution.

Erythropoietin in cardiac surgery.

Erythropoietin is the primary growth factor for red blood cells. A glycoprotein hormone synthesized by the kidneys, erythropoietin serves to increase red blood cell production in response to tissue hypoxia. It exerts its effect by increasing the numbers of erythroid progenitor cells in the bone marrow, and by increasing the rate at which their development is accomplished. With the introduction of recombinant erythropoietin in 1987, an important pharmacological agent became available for the manipulation of erythropoiesis. While used primarily for the treatment of the anemia of renal failure, recombinant erythropoietin has also shown usefulness in treating other types of anemias in which the endogenous erythropoietin response is insufficient. Perioperative use of the drug grew as a natural extension of this, and erythropoietin has been applied to correct preoperative anemia, augment autologous blood donation, and improve postoperative red cell recovery. Analysis of these perioperative clinical studies reveals success in these areas, but it also reveals that closer attention to the physiology of the natural response, and to the pharmacology of the recombinant product, might significantly improve results. Such an improvement in efficacy is both desirable and necessary when use of the drug is viewed in the setting of today's changing health care environment. By optimizing dosing schedules and targeting the drug to those most at risk for red cell transfusion, recombinant erythropoietin will likely become an important tool in efforts to achieve the elusive goal of bloodless cardiac surgery.