Prophylactic intravenous tranexamic acid and thromboembolism in non-cardiac surgery: a systematic review, meta-analysis and trial sequential analysis.

Tranexamic acid is an antifibrinolytic drug that is widely used during surgery, but there are concerns about its thromboembolic effects. We aimed to investigate the effect of prophylactic intravenous tranexamic acid on thromboembolic outcomes in patients undergoing non-cardiac surgery. The MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials were searched. Randomised controlled trials comparing intravenous tranexamic acid with placebo or no treatment in patients undergoing non-cardiac surgery were included. The primary outcome was a composite of peri-operative cardiovascular thromboembolic events, defined as any deep vein thrombosis, pulmonary embolism, myocardial ischaemia/infarction or cerebral ischaemia/infarction. A total of 191 randomised controlled trials (40,621 patients) were included in the review. The primary outcome occurred in 4.5% of patients receiving intravenous tranexamic acid compared with 4.9% of patients in the control group. Our analysis showed that there was no difference between groups for composite cardiovascular thromboembolic events (risk ratio 1.02, 95%CI 0.94-1.11, p = 0.65, I2 0%, n = 37,512). This finding remained robust when sensitivity analysis was performed with continuity correction and in studies with a low risk of bias. However, in trial sequential analysis, our meta-analysis only achieved 64.6% of the required information size. There was no association between intravenous tranexamic acid and seizure rate or mortality rate within 30 days. Intravenous tranexamic acid was associated with a reduced blood transfusion rate compared with control (9.9% vs. 19.4%, risk ratio 0.46, 95%CI 0.41-0.51, p < 0.0001). It was encouraging to see the evidence that the administration of intravenous tranexamic in patients undergoing non-cardiac surgery was not associated with an increased risk of thromboembolic outcomes. However, our trial sequential analysis demonstrated that currently available evidence is not yet sufficient to reach a firm conclusion.

The Effect of Prehospital Epinephrine in Out-of-Hospital Cardiac Arrest: A Systematic Review and Meta-Analysis.

INTRODUCTION: Epinephrine has been recommended for out-of-hospital cardiac arrest (OHCA) resuscitation for nearly one century, but its efficacy and safety remain unclear in the literature. The primary aim of this review was to determine whether epinephrine increases the return of spontaneous circulation in OHCA patients. METHODS: A systematic review and meta-analysis were conducted using the following databases: MEDLINE, EMBASE, and CENTRAL, from their inception until October 2018. All the randomized controlled trials (RCTs) were included. Observational studies, case reports, case series, and non-systematic reviews were excluded. RESULTS: Two trials including 8,548 patients were eligible for inclusion in the data synthesis. In patients who received epinephrine during OHCA, the incidence of return of spontaneous circulation was increased, with an odds ratio (95%CI) of 4.25 (3.79-4.75), P <.001, high-quality of evidence. The number of patients transported to hospital was increased in patients who had prehospital epinephrine, with an odds ratio (95%CI) of 2.31 (2.11-2.53), P <.001, high-quality of evidence. The prehospital use of epinephrine was associated with an increased survival to hospital discharge, the odds ratio (95%CI) being 1.43 (1.10-1.87), P = .008, moderate-quality of evidence. No significant effect was noted on the favorable neurologic state of patient at hospital discharge, with an odds ratio (95%CI) of 1.21 (0.90-1.64), P = .21, moderate-quality of evidence. CONCLUSIONS: This meta-analysis suggests that the prehospital use of epinephrine increases return of spontaneous circulation, transport of patients to hospital, and survival to hospital discharge for OHCA. However, no significant effects on favorable neurologic function at hospital discharge were demonstrated. The general quality of evidence ranged from moderate to high.

The effect of dexmedetomidine on delirium and agitation in patients in intensive care: systematic review and meta-analysis with trial sequential analysis.

Delirium is common in intensive care patients. Dexmedetomidine is increasingly used for sedation in this setting, but its effect on delirium remains unclear. The primary aim of this review was to examine whether dexmedetomidine reduces the incidence of delirium and agitation in intensive care patients. We sought randomised clinical trials in MEDLINE, EMBASE, PubMed and CENTRAL from their inception until June 2018. Observational studies, case reports, case series and non-systematic reviews were excluded. Twenty-five trials including 3240 patients were eligible for inclusion in the data synthesis. In the patients who received dexmedetomidine (eight trials, 1425 patients), delirium was reduced, odds ratio (95%CI) 0.36 (0.26-0.51), p < 0.001 and high quality of evidence. The use of dexmedetomidine was associated with a reduced incidence of agitation, OR (95%CI) 0.34 (0.20-0.59), p < 0.001, moderate quality of evidence. Patients who were randomly assigned to dexmedetomidine had a significantly higher incidence of bradycardia, OR (95%CI) 2.18 (1.46-3.24), p < 0.001, moderate quality of evidence; and hypotension, OR (95%CI) 1.89 (1.48-2.41), p < 0.001, high quality of evidence. We found no evidence of an effect on mortality, OR (95%CI) 0.86 (0.66-1.10), p = 0.23, moderate quality of evidence. The trial sequential analyses for the incidence of delirium, bradycardia and hypotension was conclusive but not for the incidence of agitation and mortality. In summary, this meta-analysis suggests that dexmedetomidine reduces the incidence of delirium and agitation in intensive care patients. The general quality of evidence ranged from moderate to high.

Peri-implant inflammation and marginal bone level changes around dental implants in relation to proximity with and bone level of adjacent teeth.

OBJECTIVES: This retrospective study assessed radiographic bone changes and prevalence of inflammation around teeth and neighbouring implants supporting a single-unit fixed dental prosthesis (FDP), in relation to implant- positioning and characteristics. MATERIAL AND METHODS: Patients with an implant-supported FDP in function for at least 1 year were recruited. The radiographic horizontal and vertical position of the implants were identified. Probing depth (PD), bleeding on probing (BOP) and radiographic bone level around implants and adjacent teeth at the time of placement, prosthesis delivery, and the most recent review were assessed. RESULTS: 98 patients with 195 implants were evaluated for a mean of 37.8 months. Survival rate was 99.6% and success ranged from 31.3% to 91.3% when different success criteria were utilized. Significantly greater interproximal bone loss around teeth and higher prevalence of interproximal peri-implant inflammation occurred when the horizontal distance of BL implants was <1 mm, but not with TL implants. There was no significant impact of the corono-apical positioning of the implants on marginal bone loss. CONCLUSION: Proximity of implants to adjacent teeth of <1 mm leads to increased prevalence of inflammation and interproximal bone resorption at the teeth adjacent to bone level implants.

Continuous infusion vs. intermittent bolus injection of furosemide in acute decompensated heart failure: systematic review and meta-analysis of randomised controlled trials.

Loop diuretics remain a fundamental pharmacological therapy to remove excess fluid and improve symptom control in acute decompensated heart failure. Several recent randomised controlled trials have examined the clinical benefit of continuous vs. bolus furosemide in acute decompensated heart failure, but have reported conflicting findings. The aim of this review was to compare the effects of continuous and bolus furosemide with regard to mortality, length of hospital stay and its efficacy profile in acute decompensated heart failure. All parallel-arm randomised controlled trials from MEDLINE, EMBASE, PubMed and the Cochrane Database of Systematic Reviews from inception until May 2017 were included. Cross-over randomised controlled trials, observational studies, case reports, case series and non-systematic reviews that involved children were excluded. Eight trials (n = 669) were eligible for inclusion. There was no difference between furosemide continuous infusion and bolus administration for all-cause mortality (four studies; n = 491; I2 = 0%; OR 1.65; 95%CI 0.93-2.91; p = 0.08) or duration of hospitalisation (six studies; n = 576; I2 = 71%; mean difference 0.27; 95%CI -1.35 to 1.89 days; p = 0.74). Continuous infusion of intravenous furosemide was associated with increased weight reduction (five studies; n = 516; I2 = 0%; mean difference 0.70; 95%CI 0.12-1.28 kg; p = 0.02); increased total urine output in 24 h (four studies; n = 390; I2 = 33%; mean difference 461.5; 95%CI 133.7-789.4 ml; p < 0.01); and reduced brain natriuretic peptide (two studies; n = 390; I2 = 0%; mean difference 399.5; 95%CI 152.7-646.3 ng.l-1 ; p < 0.01), compared with the bolus group. There was no difference in the incidence of raised creatinine and hypokalaemia between the two groups. In summary, there was no difference between continuous infusion and bolus of furosemide for all-cause mortality, length of hospital stay and electrolyte disturbance, but continuous infusion was superior to bolus administration with regard to diuretic effect and reduction in brain natriuretic peptide.

Effect of nicotine replacement therapy on mortality, delirium, and duration of therapy in critically ill smokers: a systematic review and meta-analysis.

Nicotine replacement therapy is widely used in critically ill smokers and its effect on delirium, mortality and duration of intensive care unit (ICU) admission is unknown. The aims of this review were to determine whether the management of nicotine withdrawal with nicotine replacement therapy reduces delirium, mortality or length of stay in critically ill smokers in ICU. The primary outcome was incidence of author-defined ICU delirium. Secondary outcomes were ICU or hospital mortality, ICU-free days at day 28, and ICU or hospital length of stay. We conducted a systematic review and meta-analysis of the data sources MEDLINE, EMBASE, CINAHL, and the Cochrane Database of Systematic Reviews for randomised controlled trials and observational studies. Clinical trials, observational studies and systematic reviews comparing nicotine replacement therapy with placebo or no treatment were included. Case reports, case series, non-systematic reviews and studies that involved children were excluded. Eight studies were eligible (n=2,636) for inclusion in the data synthesis. In a meta-analysis of observational studies, nicotine replacement therapy was associated with increased delirium (three studies; n=908; I2=0%; finite element method: odds ratio 4.03 [95% confidence interval 2.64, 6.15]; P <0.001). There was no difference in ICU mortality (three studies; n=1,309; P=0.10, I2=44%; finite element method: odds ratio 0.58; 95% confidence intervals 0.31-1.10) and hospital mortality or 28-day ICU-free days. In the absence of high-quality data, nicotine replacement therapy cannot currently be recommended for routine use to prevent delirium or to reduce hospital or ICU mortality in critically ill smokers.

High serum lactate as an adjunct in the early prediction of anastomotic leak following oesophagectomy.

BACKGROUND: Anastomotic leak (AL) following oesophagectomy carries a high mortality and morbidity. Early detection and intervention is required for a successful outcome. We have examined the role of a high postoperative serum lactate in predicting which patients are at risk of developing an anastomotic leak(AL). MATERIALS AND METHODS: All patients who underwent transthoracic oesophagectomy over a 3-year period were identified from a prospectively collected database. Medical records were reviewed to identify the highest serum lactate recorded from blood gas analysis over each 24hr post-operative period. Patients who underwent transhiatal and left thoraco-abdominal oesophagectomies were excluded. Patients who developed a chyle leak were excluded. RESULTS: Of a total of 136 oesophagectomies included for analysis, 18 developed an AL (13.2%). Of these patients, 10 underwent thoracoscopic oesophageal mobilization with cervical anastomosis and the rest an Ivor Lewis procedure. Predictive factors for AL included neoadjuvant chemotherapy (15/18 83.3% vs 55/118 46.6% p = 0.0046) and number of positive lymph nodes (mean 4.2 vs control mean 2.3 p = 0.045). Overall net fluid balance was comparable between the 2 groups, although AL patients received slightly more fluid on Day 3. High lactate levels on days 1-3 were associated with an AL. Using a Day 2 lactate of 1.7 mmol/L, the sensitivity of predicting AL was 72% and specificity 88%. The mean lag time using existing diagnostic modalities was 7.9 days. CONCLUSION: A serum lactate of >1.7 mmol/l on day 2 should raise the possibility of a potential AL. Such patients should be selected for more intensive monitoring, optimization and selective gastroscopy.

Distinct mechanism of small-for-size fatty liver graft injury--Wnt4 signaling activates hepatic stellate cells.

In this study, we aimed to investigate the significance of hepatic stellate cells (HSCs) activation in small-for-size fatty liver graft injury and to explore the underlying molecular mechanism in a rat liver transplantation model. A rat orthotopic liver transplantation model using fatty grafts (40% of fatty changes) and cirrhotic recipients was applied. Intragraft gene expression profiles, ultrastructure features and HSCs activation were compared among the rats received different types of grafts (whole vs. small-for-size, normal vs. fatty). The distinct molecular signature of small-for-size fatty graft injury was identified by cDNA microarray screening and confirmed by RT-PCR detection. In vitro functional studies were further conducted to investigate the direct effect of specific molecular signature on HSCs activation. HSCs activation was predominantly present in small-for-size fatty grafts during the first 2 weeks after transplantation, and was strongly correlated with progressive hepatic sinusoidal damage and significant upregulation of intragraft Wnt4 signaling pathway. In vitro suppression of Wnt4 expression could inhibit HSC activation directly. In conclusion, upregulation of Wnt4 signaling led to direct HSC activation and subsequently induced small-for-size fatty liver grafts injury. Discovery of this distinct mechanism may lay the foundation for prophylactic treatment for marginal graft injury in living donor liver transplantation.

The significance of proline-rich tyrosine kinase2 (Pyk2) on hepatocellular carcinoma progression and recurrence.

Understanding the precise molecular mechanisms that trigger liver cancer cell migration and invasion could develop novel therapeutic strategies targeting cancer cell invasion to increase the sensitivity to current treatment modalities. In the current study, 49 patients with hepatocellular carcinoma (HCC) were included prospectively. Liver tumour and adjacent non-tumour tissues were detected for the expression of Proline-rich tyrosine kinase 2 (Pyk2), focal adhesion kinase (FAK), ezrin and fibronectin at protein and/or gene levels. Correlation between the expressions of Pyk2/FAK with the clinical pathological data was analysed. Protein expression of Pyk2 was also examined in a nude mice orthotopic liver tumour model with higher metastatic potential. There were 59% (29 out of 49) and 57% (28 out of 49) of HCC patients with higher levels of Pyk2 and FAK protein/gene expression, respectively. We observed a positive correlation between the protein and gene expression levels of Pyk2 and FAK (P=0.000, r=0.875). Overexpression of Pyk2 and FAK was significantly correlated with shorter disease-free survival. Patients with higher levels of Pyk2/FAK had larger tumour size and advanced Edmonson grading. In the animal studies, Pyk2 overexpression was found in infiltrative tumour cells and lung metastatic nodules. In conclusion, overexpression of Pyk2 and FAK was found in nearly 60% of HCC patients and was significantly correlated with poor prognosis. The significance of Pyk2 in HCC invasiveness was confirmed by animal studies.

HIV-1 protein gp120 rapidly impairs memory in chicks by interrupting the glutamate-glutamine cycle.

Learning and memory impairments are frequently observed in patients suffering from AIDS Dementia Complex (ADC). These effects have been linked to the presence of gp120, an HIV viral coat glycoprotein. The present study investigated the possibility that gp120 prevents the uptake of extracellular glutamate by astrocytes, leading to an interruption of the glutamate-glutamine cycle and a subsequent impairment of memory. Ten microliters of 10nM gp120 was bilaterally injected into the region of the intermediate medial mesopallium of day-old chicks at various times before, or after, training using a single-trial passive avoidance task. Gp120 was found to significantly impair memory retention when injected 10-40 min after training. Memory impairments were evident within 5 min of gp120 administration and remained evident 24h later. Further, the amnestic effect of gp120 could be overcome with glutamine or with precursors of glutamate synthesis, but only weakly by glutamate. These results support the conclusion that the amnestic effect of gp120 is due to an impaired uptake of glutamate by astrocytes and a subsequent interruption of glutamine supply to neurones. The data indicate that the glutamate-glutamine cycle may be a useful therapeutic target in the treatment of ADC.

Clinicopathological significance of homeoprotein Six1 in hepatocellular carcinoma.

Tumour recurrence and metastases of hepatocellular carcinoma (HCC) after hepatectomy are the major obstacles of long-term survival. The present study investigated the clinicopathological significance of a possible metastasis regulator Six1 in HCC patients who were undergone hepatectomy. Seventy-two pairs of RNA and 103 pairs of protein from tumour and adjacent nontumour liver tissues of HCC patients were examined. About 85 and 60% of HCC tumour tissues were found to overexpress Six1 mRNA and protein, respectively, compared with nontumour liver tissues. No Six1 protein was detected in HCC nontumour liver tissues and normal liver tissues. Increased Six1 protein expression in HCC patients was significantly correlated with pathologic tumour-node-metastasis (pTNM) stage (P=0.002), venous infiltration (P=0.004) and poor overall survival (P=0.0423). We concluded that Six1 is frequently overexpressed in HCC patients and elevated Six1 protein in HCC patients may be an indication of advanced stage and poor overall survival after hepatectomy.

Rapamycin attenuates liver graft injury in cirrhotic recipient--the significance of down-regulation of Rho-ROCK-VEGF pathway.

To investigate whether rapamycin could attenuate hepatic I/R injury in a cirrhotic rat liver transplantation model, we applied a rat orthotopic liver transplantation model using 100% or 50% of liver grafts and cirrhotic recipients. Rapamycin was given (0.2 mg/kg, i.v.) at 30 min before graft harvesting in the donor and 24 h before operation, 30 min before total hepatectomy and immediately after reperfusion in the recipient. Rapamycin significantly improved small-for-size graft survival from 8.3% (1/12) to 66.7% (8/12) (p = 0.027). It also increased 7-day survival rates of whole grafts (58.3%[7/12] vs. 83.3%[10/12], p = 0.371). Activation of hepatic stellate cells was mainly found in small-for-size grafts during the first 7 days after liver transplantation. Rapamycin suppressed expression of smooth muscle actin, which is a marker of hepatic stellate cell activation, especially in small-for-size grafts. Intragraft protein expression and mRNA levels of vascular endothelial growth factor (VEGF) were down-regulated by rapamycin at 48 h both in whole and small-for-size grafts. Consistently, mRNA levels and protein expression of Rho and ROCK I were decreased by rapamycin during the 48 h after liver transplantation. In conclusion, rapamycin attenuated graft injury in a cirrhotic rat liver transplantation model by suppression of hepatic stellate cell activation, related to down-regulation of Rho-ROCK-VEGF pathway.

Fat-derived hormone adiponectin combined with FTY720 significantly improves small-for-size fatty liver graft survival.

Owing to the discrepancy between organ donation and the demand for liver transplantation, expanding the liver donor pool is of vital importance. However, marginal liver grafts, such as small-for-size and/or fatty grafts, were associated with primary graft nonfunction or poor function. Therefore, novel combination therapies to rescue small-for-size fatty liver grafts should be investigated. In this study, we applied a combination therapy using a fat-derived hormone adiponectin (anti-steatosis) plus immunomodulator FTY720 (anti-inflammatory) in a rat liver transplantation model using small-for-size fatty liver grafts, and investigated the underlying protective mechanism such as anti-steatosis, intra-graft energy metabolism, hepatic microcirculatory changes, cell signaling cascades for survival, apoptosis and inflammation. The current study demonstrated that even a single treatment of adiponectin or FTY720 improved the 7-day graft survival from 0% to 62.5% (p = 0.001). The combination therapy significantly increased the 7-day graft survival rate to 100% by remarkable attenuation of graft steatosis and acute phase inflammatory response, significant activation of cell survival Akt pathway and maintenance of intra-graft adenosine triphosphate metabolism and improvement of hepatic microcirculation. In conclusion, the fat-derived hormone adiponectin combined with FTY720 might be a novel combination drug therapy for prevention of small-for-size fatty liver graft injury.

Inhibition of endogenous carbon monoxide production induces transient retention losses in the day-old chick when trained using a single trial passive avoidance learning task.

Carbon monoxide (CO) is most often thought of as an exogenous toxin rather than as a possible endogenous nootrope. However, a limited number of studies have suggested that CO is necessary in memory processing for at least some tasks. While nitric oxide (NO) and CO are known activators of guanylyl cyclase (GC), only the effect of NO on GC has been extensively investigated as a mechanism underlying memory processing. The aim of the present study was to determine if inhibition of CO production would have an effect on memory processing. Using chicks trained on a single trial passive avoidance task, inhibition of CO production using zinc (II) deuteroporphyrin IX 2,4-bis ethylene glycol (ZnBG; 5 microM) resulted in two transient retention losses occurring at around 40 and 130 min post-training. The timing of these transient retention losses was similar to those observed following inhibition of GC, using the same species and task in a previous study. This supports the notion that CO is necessary in memory processing for this task and may act through a GC-dependent mechanism. As ZnBG also directly inhibits GC or nitric oxide synthase (NOS) at high concentrations, a second experiment was carried-out to confirm the specificity of ZnBG for heme oxygenase (HO) at the concentration used. The action of ZnBG was challenged with the HO agonist hemin (100 microM) and the transient deficits were abolished. This confirmed that the action of ZnBG on memory was through a CO-related mechanism rather than directly on GC or NOS. In this way the specificity of ZnBG (5 microM) for HO could be confirmed. The results support a role for endogenous CO in memory processing, possibly through activation of GC. In addition, the transient retention losses observed following administration of ZnBG suggest that CO may be necessary for memory retrieval and not formation as previously thought.

Noradrenaline involvement in the memory-enhancing effects of exposure to a complex rhythm stimulus following discriminated passive avoidance training in the young chick.

Previous research in our laboratory has demonstrated a significant memory-enhancing effect of exposure to a complex rhythm stimulus following weakly-reinforced passive avoidance learning in chicks. The aim of this study was to explore whether noradrenaline mediates this process. Chicks were trained on a strongly-reinforced single-trial passive avoidance task involving discrimination between two coloured beads. Intracerebral administration of the protein synthesis blocker, anisomycin, revealed that a phase of memory formation sensitive to arousal levels was extended by approximately 35 min following exposure to the complex rhythm stimulus. Administration of 2,4-dinitrophenol showed that this extension occurred during phase B of intermediate-term memory. Finally, a higher dose of the beta-adrenergic receptor antagonist, propranolol, was required to inhibit long-term memory in the presence of the auditory stimulus than in its absence. These findings suggest that the memory-enhancing effects of the complex rhythm stimulus may be mediated by noradrenaline, possibly via an increase in physiological arousal.

Inhibition of short-term memory formation in the chick by blockade of extracellular glutamate uptake.

Injection of monosodium glutamate (40nmol/hemisphere) into the intermediate hyperstriatum ventrale of the day-old chick inhibits the formation of short-term memory for a single trial learning that discriminates between colours of beads. These experiments showed that an excess of glutamate close to learning could be damaging to memory. In the present experiments we have blocked the normal reuptake of glutamate and suggest that glutamate release plays a role in normal learning. Removal of glutamate, released from presynaptic neurones during learning, is achieved by various neuronal and astrocytic glutamate transporters. By blocking the primarily astrocytic removal of glutamate by the injection of L-aspartic acid beta-hydroxamate, we effectively increased extrasynaptic levels of glutamate and inhibited short-term memory in a similar manner to central injection of 40nmol glutamate per hemisphere. These experiments suggest that glutamate release within 2.5min of the learning experience is an important feature of short-term memory formation.

Three-dimensional pseudospectral modelling of cardiac propagation in an inhomogeneous anisotropic tissue.

Various investigators have used the monodomain model to study cardiac propagation behaviour. In many cases, the governing non-linear parabolic equation is solved using the finite-difference method. An adequate discretisation of cardiac tissue with realistic dimensions, however, often leads to a large model size that is computationally demanding. Recently, it has been demonstrated, for a two-dimensional homogeneous monodomain, that the Chebyshev pseudospectral method can offer higher computational efficiency than the finite-difference technique. Here, an extension of the pseudospectral approach to a three-dimensional inhomogeneous case with fibre rotation is presented. The unknown transmembrane potential is expanded in terms of Chebyshev polynomial trial functions, and the monodomain equation is enforced at the Gauss-Lobatto node points. The forward Euler technique is used to advance the solution in time. Numerical results are presented that demonstrate that the Chebyshev pseudospectral method offered an even larger improvement in computational performance over the finite-difference method in the three-dimensional case. Specifically, the pseudospectral method allowed the number of nodes to be reduced by approximately 85 times, while the same solution accuracy was maintained. Depending on the model size, simulations were performed with approximately 18-41 times less memory and approximately 99-169 times less CPU time.

Inhibition of guanylate cyclase and protein kinase G impairs retention for the passive avoidance task in the day-old chick.

Nitric oxide (NO) is a highly labile chemical messenger which has previously been implicated in memory processes in a variety of learning paradigms and species. However, there is only limited evidence to suggest which enzymes are acted upon by NO during the formation of memory. The present study investigates the role of guanylate cyclase (GC) and protein kinase G (PKG) in a form of passive avoidance learning known to be dependent on nitric oxide activity. It was determined that in vivo pharmacological inhibition of GC using either 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one or 6-anilino-5,8-quinolinedione resulted in two transitory memory retention deficits centred around 40 and 120 min posttraining, respectively. In contrast, inhibition of PKG with N-[2-(methylamino)ehtyl]-5-isoquinoline-sulfornamide hydrochloride (H-8) resulted in a single temporary retention loss centered at 120 min posttraining. These temporary retention losses appear to be specific to memory since they were dose-dependent and could not be explained by nonspecific performance effects. Further, these results suggest that these agents inhibit memory retrieval rather than formation, since memory is subsequently available. The current findings indicate that guanylyl cyclase mediates two memory retrieval processes, the latter of which appears to be PKG-dependent. In contrast, since inhibition of NO results in a permanent retention loss, it is suggested that NO is required for memory formation through GC-independent processes.

Calibrated single-plunge bipolar electrode array for mapping myocardial vector fields in three dimensions during high-voltage transthoracic defibrillation.

Mapping of the myocardial scalar electric potential during defibrillation is normally performed with unipolar electrodes connected to voltage dividers and a global potential reference. Unfortunately, vector potential gradients that are calculated from these data tend to exhibit a high sensitivity to measurement errors. This paper presents a calibrated single-plunge bipolar electrode array (EA) that avoids the error sensitivity of unipolar electrodes. The EA is triaxial, uses a local potential reference, and simultaneously measures all three components of the myocardial electric field vector. An electrode spacing of approximately 500 microm allows the EA to be direct-coupled to high-input-impedance, isolated, differential amplifiers and eliminates the need for voltage dividers. Calibration is performed with an electrolytic tank in which an accurately measured, uniform electric field is produced. For each EA, unique calibration matrices are determined which transform potential difference readings from the EA to orthogonal components of the electric field vector. Elements of the matrices are evaluated by least squares multiple regression analysis of data recorded during rotation of the electric field. The design of the electrolytic tank and electrode holder allows the electric field vector to be rotated globally with respect to the electrode axes. The calibration technique corrects for both field perturbation by the plunge electrode body and deviations from orthogonality of the electrode axes. A unique feature of this technique is that it eliminates the need for mechanical measurement of the electrode spacing. During calibration, only angular settings and voltages are recorded. For this study, ten EAs were calibrated and their root-mean-square (rms) errors evaluated. The mean of the vector magnitude rms errors over the set of ten EAs was 0.40% and the standard deviation 0.07%. Calibrated EAs were also tested for multisite mapping in four dogs during high-voltage transthoracic shocks.