A genome-wide Drosophila epithelial tumorigenesis screen identifies Tetraspanin 29Fb as an evolutionarily conserved suppressor of Ras-driven cancer.

Oncogenic mutations in the small GTPase Ras contribute to ~30% of human cancers. However, Ras mutations alone are insufficient for tumorigenesis, therefore it is paramount to identify cooperating cancer-relevant signaling pathways. We devised an in vivo near genome-wide, functional screen in Drosophila and discovered multiple novel, evolutionarily-conserved pathways controlling Ras-driven epithelial tumorigenesis. Human gene orthologs of the fly hits were significantly downregulated in thousands of primary tumors, revealing novel prognostic markers for human epithelial tumors. Of the top 100 candidate tumor suppressor genes, 80 were validated in secondary Drosophila assays, identifying many known cancer genes and multiple novel candidate genes that cooperate with Ras-driven tumorigenesis. Low expression of the confirmed hits significantly correlated with the KRASG12 mutation status and poor prognosis in pancreatic cancer. Among the novel top 80 candidate cancer genes, we mechanistically characterized the function of the top hit, the Tetraspanin family member Tsp29Fb, revealing that Tsp29Fb regulates EGFR signaling, epithelial architecture and restrains tumor growth and invasion. Our functional Drosophila screen uncovers multiple novel and evolutionarily conserved epithelial cancer genes, and experimentally confirmed Tsp29Fb as a key regulator of EGFR/Ras induced epithelial tumor growth and invasion.

Twenty-four-hour time dependency of clopidogrel effects in patients with acute coronary syndromes: The CiCAD-Study.

Long-term evidence shows an increased risk of cardiovascular events in the morning hours and recent studies in aspirin-treated patients have shown increased platelet reactivity at the end of the dosing interval. Similar pharmacodynamic analyses of adenosine-diphosphate (ADP) receptor inhibitors are scarce. We therefore investigated changes in clopidogrel-dependent platelet function and activation over 24 h and whether enhanced platelet turnover might explain diurnal variability of platelet function and activation. Twenty-one patients after acute coronary syndromes (ACS) on maintenance doses of clopidogrel (75 mg) and aspirin (100 mg) Once per day (OD) were included. Blood was collected at five time points in 24 h. Platelet function and activation was analyzed by vasodilator-stimulated phosphoprotein-phosphorylation (VASP-P), Verify Now, multiple electrode aggregometry (MEA), and platelet PAC-1 and P-selectin (P-sel) expression. Additionally, platelet count, mean platelet volume (MPV), and reticulated platelet fraction (RPF) were analyzed. There was significant diurnal variability of clopidogrel effects as documented with VASP-P, Verify Now, and PAC-1 and P-sel (all p < 0.05), whereas MEA did not differ over 24 h. Neither MPV nor RPF varied significantly over 24 h. In patients with high RPF, platelet function and activation was significantly higher in all assays, compared to patients with low RPF (all p < 0.05). However, the changes over time in low versus high RPF groups were similar. ADP-dependent platelet function and activation recovers significantly at the end of the 24-h dosing interval in patients with ACS on a maintenance dose of clopidogrel and aspirin. Although platelet function and activation is increased in patients with higher RPF, platelet turnover might not explain the observed diurnal variability.

Integrated Strategy for Use of Positron Emission Tomography in Nonhuman Primates to Confirm Multitarget Occupancy of Novel Psychotropic Drugs: An Example with AZD3676.

Positron emission tomography (PET) is widely applied in central nervous system (CNS) drug development for assessment of target engagement in vivo. As the majority of PET investigations have addressed drug interaction at a single binding site, findings of multitarget engagement have been less frequently reported and have often been inconsistent with results obtained in vitro. AZD3676 [N,N-dimethyl-7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl) benzofuran-2-carboxamide] is a novel combined serotonin (5-hydroxytryptamine) 5-HT1A and 5-HT1B receptor antagonist that was developed for the treatment of cognitive impairment in Alzheimer's disease. Here, we evaluated the properties of AZD3676 as a CNS drug by combining in vitro and ex vivo radioligand binding techniques, behavioral pharmacology in rodents, and PET imaging in nonhuman primates. Target engagement in the nonhuman primate brain was assessed in PET studies by determination of drug-induced occupancy using receptor-selective radioligands. AZD3676 showed preclinical properties consistent with CNS drug potential, including nanomolar receptor affinity and efficacy in rodent models of learning and memory. In PET studies of the monkey brain, AZD3676 inhibited radioligand binding in a dose-dependent manner with similar affinity at both receptors. The equally high affinity at 5-HT1A and 5-HT1B receptors as determined in vivo was not predicted from corresponding estimates obtained in vitro, suggesting more than 10-fold selectivity for 5-HT1A versus 5-HT1B receptors. These findings support the further integrated use of PET for confirmation of multitarget occupancy of CNS drugs. Importantly, earlier introduction of PET studies in nonhuman primates may reduce future development costs and the requirement for animal experiments in preclinical CNS drug development programs.

AZD1080, a novel GSK3 inhibitor, rescues synaptic plasticity deficits in rodent brain and exhibits peripheral target engagement in humans.

Abnormal tau phosphorylation resulting in detachment of tau from microtubules and aggregation are critical events in neuronal dysfunction, degeneration, and neurofibrillary pathology seen in Alzheimer's disease. Glycogen synthase kinase-3ß (GSK3ß) is a key target for drug discovery in the treatment of Alzheimer's disease and related tauopathies because of its potential to abnormally phosphorylate proteins and contribute to synaptic degeneration. We report the discovery of AZD1080, a potent and selective GSK3 inhibitor that demonstrates peripheral target engagement in Phase 1 clinical studies. AZD1080 inhibits tau phosphorylation in cells expressing human tau and in intact rat brain. Interestingly, subchronic but not acute administration with AZD1080 reverses MK-801-induced deficits, measured by long-term potentiation in hippocampal slices and in a cognitive test in mice, suggesting that reversal of synaptic plasticity deficits in dysfunctional systems requires longer term modifications of proteins downstream of GSK3ß signaling. The inhibitory pattern on tau phosphorylation reveals a prolonged pharmacodynamic effect predicting less frequent dosing in humans. Consistent with the preclinical data, in multiple ascending dose studies in healthy volunteers, a prolonged suppression of glycogen synthase activity was observed in blood mononuclear cells providing evidence of peripheral target engagement with a selective GSK3 inhibitor in humans.

How much are clinical fMRI reports influenced by standard postprocessing methods? An investigation of normalization and region of interest effects in the medial temporal lobe.

Recent evidence has indicated that standard postprocessing methods such as template-based region of interest (ROI) definition and normalization of individual brains to a standard template may influence final outcome of functional magnetic resonance imaging investigations. Here, we provide the first comprehensive investigation into whether ROI definition and normalization may also change the clinical interpretation of patient data. A series of medial temporal lobe epilepsy patients were investigated with a clinical memory paradigm and individually delineated as well as template-based ROIs. Different metrics for activation quantification were applied. Results show that the application of template-based ROIs can significantly change the clinical interpretation of individual patient data. This relates to sensitivity for brain activation and hemispheric dominance. We conclude that individual ROIs should be defined on nontransformed functional data and that use of more than one metric for activation quantification is beneficial.

Influence of dabigatran on pro-inflammatory cytokines, growth factors and chemokines - Slowing the vicious circle of coagulation and inflammation.

AIMS: Blood coagulation is one of the most important host-defending mechanisms in vivo by maintaining the blood pressure after injury. However, besides maintaining homeostasis, blood coagulation and the contributing factors are directly linked to pathological conditions, such as thromboembolism and inflammation, leading to cardiovascular diseases, among others. As anti-inflammatory drugs may reduce cardiovascular events, we hypothesized in this study that the direct thrombin inhibitor dabigatran may reduce cytokine, growth factor and chemokine expression in vitro. MAIN METHODS: Initially, human whole blood was incubated in tubes for serum, EDTA plasma, and heparinized plasma. Furthermore, human PBMCs were isolated and incubated under different culture conditions, including the treatment with human serum or thrombin, respectively. The effect of the oral anticoagulant dabigatran on pro-inflammatory cytokines, growth factors and chemokines was investigated by ELISA. KEY FINDINGS: Conditioned serum resulted in a significant alteration of the secretome's protein levels after 24 h. However, solely ANG showed a dose-dependent increment by the addition of serum (79.8 ± 9.2 ng/mL) in comparison to baseline (0.2 ± 0.2 ng/mL), as it was in trend for thrombin treatment. Furthermore, the pre-treatment of PBMCs with different doses of dabigatran significantly lowered supernatant protein levels measured. Moreover, dabigatran was shown to decrease most notably the growth factor and chemokine levels in the PBMC's secretome that were treated with 200 ng/mL thrombin in a dose-dependent manner. SIGNIFICANCE: In conclusion, novel oral anticoagulants, such as dabigatran, could help to reduce not only procoagulatory effects in inflammatory conditions but could also reduce proinflammatory stimuli via reduced expression of cytokines and chemokines.

Increased levels of cocaine and amphetamine regulated transcript in two animal models of depression and anxiety.

The neurobiological bases of mood disorders remain elusive but both monoamines and neuropeptides may play important roles. The neuropeptide cocaine and amphetamine regulated transcript (CART) was shown to induce anxiety-like behavior in rodents, and mutations in the human CART gene are associated with depression and anxiety. We measured CART-like immunoreactivity (-LI) in genetic rat models of depression and anxiety, i.e. the Flinders Sensitive Line (FSL) and rats selected for High Anxiety-related Behavior (HAB) using a radioimmunoassay. CART-LI was significantly increased in the periaqueductal grey in FSL rats, whereas in the HAB strain it was increased in the hypothalamus, both compared with their respective controls. No line-dependent changes were found in the hippocampus, striatum or frontal cortex. Our results confirm human genetic studies indicating CART as a neurobiological correlate of depression and anxiety, and suggest that its differential regulation in specific brain regions may play a role for the behavioral phenotypes.

Nortriptyline mediates behavioral effects without affecting hippocampal cytogenesis in a genetic rat depression model.

A prevailing hypothesis is that neurogenesis is reduced in depression and that the common mechanism for antidepressant treatments is to increase it in adult hippocampus. Reduced neurogenesis has been shown in healthy rats exposed to stress, but it has not yet been demonstrated in depressed patients. Emerging studies now indicate that selective serotonin reuptake inhibitors can, exert behavioral effects without affecting neurogenesis in mice. Here we extend our previous findings demonstrating that the number of BrdU positive cells in hippocampus was significantly higher in a rat model of depression, the Flinders Sensitive Line (FSL) compared to the control strain the Flinders Resistant Line (FRL). We also show that chronic treatment with the tricyclic antidepressant nortriptyline exerts behavioral effects in the Porsolt forced swim test without affecting hippocampal cell proliferation in the FSL model. These results strengthen the arguments against hypothesis of neurogenesis being necessary in etiology of depression and as requisite for effects of antidepressants, and illustrate the importance of using a disease model and not healthy animals to assess effects of potential therapies for major depressive disorder.

Differential effects of olanzapine, haloperidol and risperidone on calcitonin gene-related peptide in the rat brain.

Calcitonin gene-related peptide (CGRP) is a 37 amino acid peptide which acts on central nervous system (CNS) neurons and is involved in activities related to dopamine. These effects of CGRP suggest that the peptide may have a role in pathophysiology and treatment of schizophrenia where dopaminergic system hypoactivity in the frontal cortex and hyperactivity in the subcortical structures have been demonstrated. In this study we measured by radioimmunoassay (RIA) the brain levels of CGRP-like immunoreactivity (CGRP-LI) in rats treated with either classical (haloperidol) or atypical (risperidone and olanzapine) antipsychotic drugs. Both haloperidol and risperidone decreased CGRP-LI in the striatum. Risperidone also decreased CGRP-LI in the occipital cortex. On the other hand, olanzapine increased CGRP-LI in the striatum, the frontal cortex and hypothalamus. The differential effects on CGRP could reflect a different profile of side effects and further suggest that CGRP is involved in CNS functions related to psychiatric disorders.

Escitalopram reduces increased hippocampal cytogenesis in a genetic rat depression model.

Hippocampal neurogenesis is potentially implicated in etiology of depression and as the final common mechanism underlying antidepressant treatments. However, decreased neurogenesis has not been demonstrated in depressed patients and, in animals, reduced cytogenesis was shown in healthy rats exposed to stressors, but, so far, not in models of depression. Here we report that the number of BrdU positive cells in hippocampus was (1) significantly higher in a rat model of depression, the Flinders Sensitive Line (FSL) compared to control FRL, (2) increased in both FSL and FRL following maternal separation, (3) reduced by escitalopram treatment in maternally separated animals to the level found in non-separated animals. These results argue against the prevailing hypothesis that adult cytogenesis is reduced in depression and that the common mechanism underlying antidepressant treatments is to increase adult cytogenesis. The results also point to the importance of using a disease model and not healthy animals for testing effects of potential treatments for human depression and suggest other cellular mechanisms of action than those that had previously been proposed for escitalopram.

Chronic amphetamine treatment reduces NGF and BDNF in the rat brain.

Amphetamines (methamphetamine and d-amphetamine) are dopaminergic and noradrenergic agonists and are highly addictive drugs with neurotoxic effect on the brain. In human subjects, it has also been observed that amphetamine causes psychosis resembling positive symptoms of schizophrenia. Neurotrophins are molecules involved in neuronal survival and plasticity and protect neurons against (BDNF) are the most abundant neurotrophins in the central nervous system (CNS) and are important survival factors for cholinergic and dopaminergic neurons. Interestingly, it has been proposed that deficits in the production or utilization of neurotrophins participate in the pathogenesis of schizophrenia. In this study in order to investigate the mechanism of amphetamine-induced neurotoxicity and further elucidate the role of neurotrophins in the pathogenesis of schizophrenia we administered intraperitoneally d-amphetamine for 8 days to rats and measured the levels of neurotrophins NGF and BDNF in selected brain regions by ELISA. Amphetamine reduced NGF levels in the hippocampus, occipital cortex and hypothalamus and of BDNF in the occipital cortex and hypothalamus. Thus the present data indicate that chronic amphetamine can reduce the levels of NGF and BDNF in selected brain regions. This reduction may account for some of the effects of amphetamine in the CNS neurons and provides evidences for the role of neurotrophins in schizophrenia.

Search for biological correlates of depression and mechanisms of action of antidepressant treatment modalities. Do neuropeptides play a role?

Dysregulation of the monoaminergic systems is likely a sufficient but not a necessary cause of depression. A wealth of data indicates that neuropeptides, e.g., NPY, CRH, somatostatin, tachykinins and CGRP play a role in affective disorders and alcohol use/abuse. This paper focuses on NPY in etiology and pathophysiology of depression. Decreased peptide and mRNA NPY were found in hippocampus of both the genetic, e.g., the FSL strain, and environmental rat models of depression, e.g., chronic mild stress and early life maternal separation paradigms. Rat models of alcoholism also show altered NPY. Furthermore, NPY is also reduced in CSF of depressed patients. Antidepressive treatments tested so far (lithium, topiramate, SSRIs, ECT and ECS, wheel running) increase NPY selectively in rat hippocampus and in human CSF. Moreover, NPY given icv to rat has antidepressive effects which are antagonized by NPY-Y1 blockers. The data support our hypothesis that the NPY system dysregulation constitutes one of the biological underpinnings of depression and that one common mechanism of action of antidepressive treatment modalities may be effects on NPY and its receptors. In a novel paradigm, early life maternal separation was superimposed on "depressed" FSL and control rats and behavioral and brain neurochemistry changes observed in adulthood. The consequences were more deleterious in genetically vulnerable FSL. Early antidepressive treatment modulated the adult sequelae. Consequently, if these data are confirmed, the ethical and medical question that will be asked is whether it is permissible and advisable to consider prophylactically treating persons at risk.

Adult life behavioral consequences of early maternal separation are alleviated by escitalopram treatment in a rat model of depression.

In order to study the gene-environment interaction as well as investigate prophylactic/ameliorative effects of early intervention on development of adult life psychopathology, we superimposed maternal separation on an animal model of depression the Flinders Sensitive Line (FSL) rats and their controls the Flinders Resistant Line (FRL) rats and studied behavior following treatment with escitalopram. Animals were maternally separated for 180 min/day from postnatal day 2 (PND 2) to 14. The control groups were left undisturbed. Treatment with escitalopram or vehicle admixed to food pellets was commenced on PND 43 and continued until PND 73. The Porsolt swim test was carried out on PND 65. Baseline FRL/FSL differences in body weight and swim duration, considered to be an inverse index of depression, were found (p's<0.001). In the FSL, maternal separation further decreased swim duration (p<0.001) while the FRL strain was unaffected. Escitalopram had no effect in FRL, but increased swim duration in both maternally non-separated and separated FSL (p<0.05 and p=0.001; respectively). These results confirm the strain differences between the FSL and FRL and demonstrate that the long-term effects of early life adverse experience will to a significant degree depend on the genetic make-up of an individual. Finally, antidepressant treatment reversed behavioral abnormalities caused by genetic and environmental factors. This study highlights the importance of genetic factors in susceptibility to early life adverse events, and demonstrates the efficiency of early antidepressant treatment in reversing behavioral abnormalities, both those caused by genetic factors and by environmental factors.

Effects of acute and subchronic d-amphetamine on ventral striatal concentrations of neurotensin and neuropeptide Y in rats treated with antipsychotic drugs.

We have reported that acute d-amphetamine increases extracellular concentrations (efflux) of neurotensin-like immunoreactivity (NT-LI) and neuropeptide Y-LI (NPY-LI) in the ventral striatum (VSTR) of freely moving rats, effects that are abolished by chronic administration of haloperidol and risperidone admixed to food pellets. In this study we further investigated the d-amphetamine effects on NT-LI and NPY-LI efflux in VSTR and their content in selected brain regions. Rats received haloperidol, risperidone or vehicle for 30days and saline or d-amphetamine either on days 22-29 and/or day 30. Seven day d-amphetamine administration decreased basal NT-LI and NPY-LI efflux in vehicle-treated rats; pretreatment with haloperidol counteracted these effects, while pretreatment with risperidone had effect only on NT-LI. Acute d-amphetamine after the seven day d-amphetamine increased NT-LI only. Pretreatment with haloperidol or risperidone abolished the effects of acute d-amphetamine on NT-LI and NPY-LI. Acute and seven day d-amphetamine increased NT-LI and NPY-LI contents in striatum; seven day d-amphetamine also increased NT-LI in frontal and occipital cortex and both NT-LI and NPY-LI in hippocampus. Our results suggest that NT and NPY are involved in both the pathophysiology and the therapeutics of schizophrenia.

Effect of chronic olanzapine treatment on nerve growth factor and brain-derived neurotrophic factor in the rat brain.

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are proteins involved in neuronal survival, neurite outgrowth and synapse formation. Recent observations suggest that treatment with typical and atypical antipsychotic drugs affect NGF and BDNF levels in the rat brain. The atypical antipsychotic olanzapine has a low incidence of side effects, such as extrapyramidal and anticholinergic symptoms. Since NGF and BDNF are involved in the regulation of cholinergic, dopaminergic and serotonergic neurons in the central nervous system (CNS) we hypothesized that chronic olanzapine treatment will influence the distribution of NGF and BDNF in the rat brain. To test this hypothesis we administered olanzapine for 29 days in the drinking water at the doses of 3 and 15 mg/kg body weight and measured the levels of NGF and BDNF in the brain of Wistar rats. Olanzapine increased NGF in the hippocampus, occipital cortex and hypothalamus. In contrast, olanzapine decreased BDNF in the hippocampus and frontal cortex. Although the significance of these findings is not clear, a heuristic hypothesis is that olanzapine's clinical effects and a favorable side effect profile are in part mediated by neurotrophins.

Antiplatelet drugs in patients with enhanced platelet turnover: biomarkers versus platelet function testing.

Platelets are key players in atherothrombosis. Antiplatelet therapy comprising aspirin alone or with P2Y12-inhibitors are effective for prevention of atherothrombotic complications. However, there is interindividual variability in the response to antiplatelet drugs, leaving some patients at increased risk of recurrent atherothrombotic events. Several risk factors associated with high on-treatment platelet reactivity (HTPR), including elevated platelet turnover, have been identified. Platelet turnover is adequately estimated from the fraction of reticulated platelets. Reticulated platelets are young platelets, characterised by residual messenger RNA. They are larger, haemostatically more active and there is evidence that platelet turnover is a causal and prognostic factor in atherothrombotic disease. Whether platelet turnover per se represents a key factor in pathogenesis, progression and prognosis of atherothrombotic diseases (with focus on acute coronary syndromes) or whether it merely facilitates insufficient platelet inhibition will be discussed in this state-of-the art review.

Effects of haloperidol and risperidone on neurotensin levels in brain regions and neurotensin efflux in the ventral striatum of the rat.

Neurotensin (NT) may play a role in the pathophysiology of schizophrenia and in the mechanism of action of antipsychotic drugs. Here we studied the effects of a 30-day regimen of haloperidol (1.15 mg/100 g food) and risperidone (1.15 and 2.3 mg/100 g food) on NT-like immunoreactivity (-LI) levels in brain tissue and NT-LI efflux in the ventral striatum (VSTR) of the rat. Haloperidol, but not risperidone, increased NT-LI levels in the striatum. In the occipital cortex, risperidone, but not haloperidol, decreased levels of NT-LI. In the hippocampus and the frontal cortex both haloperidol and risperidone (the higher dose) increased NT-LI levels. In the VSTR, haloperidol and risperidone (the higher dose) decreased NT-LI efflux and abolished the stimulatory effect of d-amphetamine (1.5 mg/kg, s.c.). Thus, changes in NT occur in response to antipsychotic drugs and psychostimulants that may be relevant for the pathophysiology and treatment of schizophrenia.

Chronic antipsychotic treatment selectively alters nerve growth factor and neuropeptide Y immunoreactivity and the distribution of choline acetyl transferase in rat brain regions.

Neuropeptides and neurotrophins play a number of roles in the central nervous system (CNS). Nerve growth factor (NGF), the first characterized member of the family of neurotrophins, influences the synthesis of some neuropeptides, including neuropeptide Y (NPY), a peptide amply expressed in the CNS, interacting with catecholamines and modifying behaviour. In this study we investigated whether antipsychotic treatment affects the constitutive levels of NGF-, NPY- and choline acetyl transferase (ChAT)-like immunoreactivities (-LI) in the CNS. Rats were fed food supplemented with haloperidol (1.15 mg/100 g food), risperidone (1.15 or 2.3 mg/100 g food), or vehicle. After 29 d treatment animals were sacrificed with focused high-energy microwave irradiation for radioimmunoassay (RIA) of NPY-LI, by decapitation for analysis of NGF, and by perfusion for immunocytochemistry. Haloperidol and risperidone elevated NGF-LI concentrations in the hypothalamus but decreased NGF-LI in the striatum and hippocampus. In contrast, antipsychotics did not alter NPY-LI in the striatum. Haloperidol increased NPY-LI concentration in the occipital cortex, while risperidone increased NPY-LI in the occipital cortex, hippocampus, and hypothalamus. Significant decreases in ChAT immunoreactivity in large-size neurons following both haloperidol and risperidone treatments in the septum as well as Meynert's nucleus were observed. Our findings demonstrate that antipsychotic drugs alter the regional brain levels of NGF-LI, NPY-LI and ChAT-LI and raise the possibility that these effects are implicated in their pharmacological and therapeutic properties.

Extracellular levels of NPY in the dorsal hippocampus of freely moving rats are markedly elevated following a single electroconvulsive stimulation, irrespective of anticonvulsive Y1 receptor blockade.

Neuropeptide Y (NPY) has been proposed to play a role in the pathophysiology of depression and also to act as an endogenous anticonvulsant. Repeated administration of electroconvulsive stimulations (ECS) has been shown to induce a long-term increase in hippocampal NPY neurotransmission, while the effects of single ECS are largely unexplored. In this study, we assessed extracellular levels of NPY in the dorsal hippocampus of freely moving rats following a single ECS. We also studied the effect of locally administered BIBP3226, a selective NPY Y1 receptor antagonist with reported anticonvulsant properties, on the duration of the ECS-induced seizure and NPY release in freely moving animals. Our data demonstrate that a single ECS increases extracellular NPY-like immunoreactivity (LI) levels in the dorsal hippocampus, reaching statistical significance 2h following the treatment. KCl transiently and calcium-dependently increased extracellular levels of NPY, suggesting that the measured NPY-LI is derived from functional neurons. Local BIBP3226 perfusion essentially abolished the ECS-induced seizure but had no effect on the basal NPY-LI outflow or on the ECS-induced rise in extracellular NPY levels. Our data are in line with the hypothesis that one mechanism of action of ECS is to release NPY in the hippocampus and suggest that the increase is in itself not associated with anticonvulsant activity but may represent other properties of NPY.

High-degree atrioventricular block in patients with preexisting bundle branch block or bundle branch block occurring during transcatheter aortic valve implantation.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) has become the standard therapy for high-risk and non-operable patients with severe aortic stenosis. However, the procedure involves several adverse effects, such as rhythm and conduction disturbances. Patients with postprocedural left bundle branch block may have an increased mortality risk, whereas patients with preprocedural right bundle branch block display a higher rate of postinterventional bradyarrhythmias. OBJECTIVE: The purpose of this study was to investigate the occurrence of high-degree atrioventricular block (AVB) in patients with preexisting bundle branch block (BBB) or BBB occurring during TAVI. METHODS: In this prospective single-center study, 50 consecutive patients undergoing TAVI with the Medtronic CoreValve Revalving System were included. Of these patients, 17 with preexisting BBB or BBB occurring during TAVI received a primary prophylactic permanent DDD pacemaker, programmed to the SafeR-mode and featuring dual-channel event counters as well as stored intracardiac electrograms. Pacemaker readouts and intracardiac electrograms were analyzed for the occurrence of high-degree AVB. RESULTS: Ten of 17 patients (58.8%) with preexisting BBB or BBB occurring during TAVI developed episodes of high-degree AVB that were immediately terminated due to switch into DDD backup pacing. In 5 of the cases (29.4%), the first documented episode of high-degree AVB occurred after hospital discharge. Mean follow-up period was 578.1 ± 294.9 days. CONCLUSION: Development of high-degree AVB is a common complication in patients with preexisting BBB or BBB occurring during TAVI. Accordingly, intensified monitoring might be reasonable, especially in patients treated with the self-expandable Medtronic CoreValve Revalving System.