Effects Of Chronic Stimulation Research Articles

Motivational and cognitive predictors of apathy after subthalamic nucleus stimulation in Parkinson's disease.

Postoperative apathy is a frequent symptom in Parkinson's disease patients who have undergone bilateral deep brain stimulation of the subthalamic nucleus. Two main hypotheses for postoperative apathy have been suggested: (i) dopaminergic withdrawal syndrome relative to postoperative dopaminergic drug tapering; and (ii) direct effect of chronic stimulation of the subthalamic nucleus. The primary objective of our study was to describe preoperative and 1-year postoperative apathy in Parkinson's disease patients who underwent chronic bilateral deep brain stimulation of the subthalamic nucleus. We also aimed to identify factors associated with 1-year postoperative apathy considering: (i) preoperative clinical phenotype; (ii) dopaminergic drug management; and (iii) volume of tissue activated within the subthalamic nucleus and the surrounding structures. We investigated a prospective clinical cohort of 367 patients before and 1 year after chronic bilateral deep brain stimulation of the subthalamic nucleus. We assessed apathy using the Lille Apathy Rating Scale and carried out a systematic evaluation of motor, cognitive and behavioural signs. We modelled the volume of tissue activated in 161 patients using the Lead-DBS toolbox and analysed overlaps within motor, cognitive and limbic parts of the subthalamic nucleus. Of the 367 patients, 94 (25.6%) exhibited 1-year postoperative apathy: 67 (18.2%) with 'de novo apathy' and 27 (7.4%) with 'sustained apathy'. We observed disappearance of preoperative apathy in 22 (6.0%) patients, who were classified as having 'reversed apathy'. Lastly, 251 (68.4%) patients had neither preoperative nor postoperative apathy and were classified as having 'no apathy'. We identified preoperative apathy score [odds ratio (OR) 1.16; 95% confidence interval (CI) 1.10, 1.22; P < 0.001], preoperative episodic memory free recall score (OR 0.93; 95% CI 0.88, 0.97; P = 0.003) and 1-year postoperative motor responsiveness (OR 0.98; 95% CI 0.96, 0.99; P = 0.009) as the main factors associated with postoperative apathy. We showed that neither dopaminergic dose reduction nor subthalamic stimulation were associated with postoperative apathy. Patients with 'sustained apathy' had poorer preoperative fronto-striatal cognitive status and a higher preoperative action initiation apathy subscore. In these patients, apathy score and cognitive status worsened postoperatively despite significantly lower reduction in dopamine agonists (P = 0.023), suggesting cognitive dopa-resistant apathy. Patients with 'reversed apathy' benefited from the psychostimulant effect of chronic stimulation of the limbic part of the left subthalamic nucleus (P = 0.043), suggesting motivational apathy. Our results highlight the need for careful preoperative assessment of motivational and cognitive components of apathy as well as executive functions in order to better prevent or manage postoperative apathy.

FTO-mediated m6A modification promotes malignant transformation of gastric mucosal epithelial cells in chronic Cag A+ Helicobacter pylori infection.

Cag A+ Helicobacter pylori chronic infection cause malignant transformation of the human gastric mucosa. N6-methyladenosine (m6A) modifications are the most common and abundant mRNA modifications and one of the pathways affecting tumorigenicity and tumor progression. However, the role of m6A modification in the process of chronic H. pylori infection leading to malignant transformation of gastric mucosa is unclear. In this study, we used Cag A- and Cag A+H. pylori chronic infection to establish cellular models in GES-1 cells and analyzed the cellular morphology, proliferation, apoptosis, invasiveness and tumorigenicity of gastric mucosal epithelial cells. The m6A expression levels of GES-1 cells after chronic infection with Cag A- and Cag A+H. pylori were examined, and modifying effect of FTO (the fat mass and obesity-associated protein) on CD44 was verified by MeRIP-qPCR. Finally, the FTO expression changes and m6A expression levels were further validated in clinical gastric cancer tissues. Chronic Cag A+H. pylori-infected GES-1 cells exhibit altered cell morphology, apoptosis inhibition, abnormal proliferation, enhanced migration, colony formation, and increased stem cell-like properties. Meanwhile, FTO and CD44 expression was enhanced, and FTO may induce malignant transformation of gastric mucosa by regulating CD44 mRNA m6A methylation modifications. We verified the effect of chronic stimulation of Cag A+H. pylori on malignant transformation of gastric mucosal epithelium. revealing the possibility of FTO in promoting malignant transformation of gastric mucosa by modifying CD44 mRNA methylation, suggesting that FTO expression is a potential molecule for malignant transformation of gastric mucosal epithelial cells.

Chronic sacral neuromodulation for pelvic floor dysfunction in children with spina bifida

To estimate the effectiveness of chronic sacral neurostimulation for neurogenic lower urinary tract dysfunction in children with spina bifida. Eight patients with spina bifida and neurogenic lower urinary tract dysfunction underwent surgical treatment. Three patients had detrusor-sphincter dyssynergia and urinary incontinence. Five patients had detrusor overactivity and urine retention. Conservative treatment was failed in all cases. We implanted quadripolar test electrode on the S3 root through Tuohy needle under fluoroscopic control. Test stimulation was ineffective in three children with detrusor overactivity. Five patients with positive response to stimulation underwent implantation of chronic neurostimulation system. We estimated the efficacy of neurostimulation considering symptoms of neurogenic lower urinary tract dysfunction, urinary diary, PAD test and complex urodynamic examination data. Positive clinical effects were observed in 3 patients with detrusor-sphincter dyssynergia and 2 patients with detrusor overactivity. Clinical effect included improvement in urine leakage and higher bladder volume. In patients with urinary retention, we revealed voluntary urination and less number of daily catheterization procedures. In one patient, clinical effect of chronic stimulation regressed within 3 month after surgery. Preliminary results of chronic sacral neuromodulation confirmed its advisability in children with neurogenic lower urinary tract dysfunction. Patients with detrusor-sphincter dyssynergia had better results compared to those with detrusor overactivity.

Chronic stimulation of the serotonergic 5-HT4 receptor modulates amyloid-beta-related impairments in synaptic plasticity and memory deficits in male rats

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by memory decline and impaired hippocampal synaptic plasticity. The serotonin 5-HT4 receptor is involved in learning and memory processes. This study explored the effects of chronic stimulation of 5-HT4R on cognition, memory, long-term potentiation (LTP), paired-pulse ratio (PPR), and neuronal apoptosis in a rat model of amyloid-beta (Aβ)-induced AD.Thirty-five male Wistar rats were randomly divided into three groups as follows: the sham, Aβ, and Aβ + BIMU8 groups. Aβ (6 µg/µl) was administrated by intracerebroventricular (icv) injection. The animals were treated with BIMU8 (1 μg/μL, ICV) as a 5-HT4R agonist for 30 days. Memory and behavioral changes were assessed by the passive avoidance learning, novel object recognition, open field, and elevated plus maze tests. Hippocampal synaptic plasticity was evaluated in the dentate gyrus (DG) in response to the stimulation applied to the perforant pathway. Furthermore, neuronal apoptosis was measured in the hippocampus. Data were analyzed by SPSS version 19 using one-way ANOVA, followed by Tukey’s post hoc test.Aβ induced memory deficits and neuronal loss and inhibited LTP induction. Aβ also increased the normalized PPR. BIMU8 enhanced the slope of the field excitatory postsynaptic potential in LTP and improved cognition behavior. Paired-pulse inhibition or facilitation was not affected by LTP induction in Aβ animals receiving the BIMU8.It can be concluded that the stimulation of the 5-HT4 receptor modulated the Aβ-induced cognition and memory deficits, probably via a decrease in the hippocampal apoptotic neurons and an improvement in the hippocampal synaptic functions without involving its inhibitory interneurons.

CREB regulates the expression of type 1 inositol 1,4,5-trisphosphate receptors.

Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) play a central role in regulating intracellular Ca2+ signals in response to a variety of internal and external cues. Dysregulation of IP3R signaling is the underlying cause for numerous pathological conditions. It is well established that the activities of IP3Rs are governed by several post-translational modifications, including phosphorylation by protein kinase A (PKA). However, the long-term effects of PKA activation on expression of IP3R subtypes remains largely unexplored. In this report, we investigate the effects of chronic stimulation and tonic activity of PKA on the expression of IP3R subtypes. We demonstrate that expression of the type 1 IP3R (IP3R1) is augmented upon prolonged activation of PKA or upon ectopic overexpression of cyclic AMP-response element-binding protein (CREB) without altering IP3R2 and IP3R3 abundance. By contrast, inhibition of PKA or blocking CREB diminished IP3R1 expression. We also demonstrate that agonist-induced Ca2+-release mediated by IP3R1 is significantly attenuated upon blocking of CREB. Moreover, CREB - by regulating the expression of KRAS-induced actin-interacting protein (KRAP) - ensures correct localization and licensing of IP3R1. Overall, we report a crucial role for CREB in governing both the expression and correct localization of IP3R1. This article has an associated First Person interview with the first author of the paper.

Apraxia of Lid Opening in Subthalamic Nucleus Deep Brain Stimulation for Parkinson's Disease-Frequency, Risk Factors and Response to Treatment.

New-onset apraxia of lid opening (ALO) is reported to occur in Parkinson's disease (PD) patients following Deep Brain Stimulation (DBS). There are only few systematic studies on this uncommon disorder of eyelid movements. We aimed to examine the frequency, temporal evolution, predisposing factors and response to treatment, of new-onset ALO in PD patients who underwent bilateral subthalamic nucleus (STN) DBS. We retrospectively reviewed the data of patients who underwent STN DBS at our centre between 1999 and 2017, with a minimum of 2 years of follow up after surgery. New-onset ALO was seen in 17 (9.1%) of the 187 patients after an average of 16.9 months (Range - 6-36 months). Comparison of the groups with and without ALO revealed that ALO occurred more often in older patients, both at the onset of PD symptoms and at surgery and in those with non-tremor dominant subtypes of PD and freezing of gait at baseline. The extent of levodopa dose reduction after surgery and the pre-operative severity of motor symptoms were not risk factors. Response to adjustments of dopaminergic medications and stimulation parameters was ill-sustained or nil. Botulinum toxin therapy resulted in satisfactory improvement in the majority. New-onset ALO is an uncommon phenomenon that manifests months after STN DBS. Development of ALO is likely to be due to the effects of chronic stimulation of basal ganglia-thalamo-cortical or brain stem circuits controlling lid movements in susceptible patients. Botulinum toxin therapy offers relatively better relief of symptoms than other strategies.

Cognitive outcomes following vagus nerve stimulation, responsive neurostimulation and deep brain stimulation for epilepsy: A systematic review

BackgroundThe cognitive impacts of resective surgery for epilepsy have been well-studied. While seizure outcomes for less invasive, neuromodulatory treatments are promising, there is a paucity of data for cognitive outcomes. MethodsMedline, EMBASE, and the Cochrane Library were searched on November 2019. Inclusion criteria were studies reporting cognitive outcomes following chronic (>6 months) vagus nerve stimulation (VNS), deep brain stimulation (DBS) and responsive neurostimulation (RNS) for epilepsy in at least five patients. Studies reporting acute on-off effects of stimulation were also included. Studies were screened, extracted of data, and assessed for bias using the Joanna Briggs Institute Critical Appraisal Tools by two independent reviewers. Prospero ID: CRD42020184432. ResultsOf 8443 studies screened, 29 studies were included. Nineteen investigated the effects of chronic stimulation (11 VNS, 6 DBS, 2 RNS): 10 (53 %) reported no change compared to preoperative baseline; 8 (42 %) reported some improvement in one or more cognitive domain; 1 (5%) reported decline. Ten investigated the effects of acute stimulation (5 VNS, 5 DBS): 3 (30 %) reported no change; 4 reported improvement (40 %); 3 (30 %) reported decline. Eight (28 %) did not report statistical analysis. ConclusionsLong-term cognitive outcomes are at least stable following VNS, DBS and RNS. Acute effects of stimulation are less clear. However, data are limited by number, size, and quality. More robust evidence is needed to properly assess the cognitive effects of each of these treatments.

Relationships between inflammatory and metabolic markers, exercise and body composition in young individuals

Physical exercise may help combat disease and elicits a possible "protective" anti-inflammatory effect on the body. Inflammatory cytokines, C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNFα), along with transcription factor, nuclear factor-kappa B (NFκB) in young (n=16, 21.1±2.1 years) individuals were examined in a cross-sectional descriptive study, to assess the effects of chronic stimulation on their expression and relationship with health parameters. Fasting venous whole blood and lipid levels along with body composition measurements were obtained from young, healthy, endurance-trained NCAA Division III student-athletes and untrained individuals. Assays (ELISA) were conducted to analyze fasting plasma (CRP, IL-6, and TNFα) and isolated lymphocyte NF-κB activation (lymphocytes were isolated from whole blood samples through differential centrifugation and Ficoll-Paque). A Spearman's rank order correlation coefficient was used for associations between variables and a regression analysis was performed to determine which measurement accounted for the inflammation in this young and apparently healthy population. While the inflammatory markers were not associated with each other, CRP levels were associated with body composition and following regression analyses, body fat percentage (P>0.05) was a significant factor for elevated CRP. Chronic physical exercise eliciting lower body fat percentages in young adults may have a positive protective impact through anti-inflammatory status, minimizing disease risk in a young population. Chronic physically active young adult patients may exhibit less inflammation and lower body fat levels which may decrease their risk for chronic disease.

Effect of Chronic Stimulation and Stimulus Level on Temporal Processing by Cochlear Implant Listeners

A series of experiments investigated potential changes in temporal processing during the months following activation of a cochlear implant (CI) and as a function of stimulus level. Experiment 1 tested patients on the day of implant activation and 2 and 6 months later. All stimuli were presented using direct stimulation of a single apical electrode. The dependent variables were rate discrimination ratios (RDRs) for pulse trains with rates centred on 120 pulses per second (pps), obtained using an adaptive procedure, and a measure of the upper limit of temporal pitch, obtained using a pitch-ranking procedure. All stimuli were presented at their most comfortable level (MCL). RDRs decreased from 1.23 to 1.16 and the upper limit increased from 357 to 485 pps from 0 to 2 months post-activation, with no overall change from 2 to 6 months. Because MCLs and hence the testing level increased across sessions, two further experiments investigated whether the performance changes observed across sessions could be due to level differences. Experiment 2 re-tested a subset of subjects at 9 months post-activation, using current levels similar to those used at 0 months. Although the stimuli sounded softer, some subjects showed lower RDRs and/or higher upper limits at this re-test. Experiment 3 measured RDRs and the upper limit for a separate group of subjects at levels equal to 60 %, 80 % and 100 % of the dynamic range. RDRs decreased with increasing level. The upper limit increased with increasing level for most subjects, with two notable exceptions. Implications of the results for temporal plasticity are discussed, along with possible influences of the effects of level and of across-session learning.

The effect of chronic stimulation of serotonin receptor type 7 on recognition, passive avoidance memory, hippocampal long-term potentiation, and neuronal apoptosis in the amyloid β protein treated rat.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory impairment, neuronal death, and synaptic loss in the hippocampus. Long-term potentiation (LTP), a type of synaptic plasticity, occurs during learning and memory. Serotonin receptor type 7 (5-HTR7) activation is suggested as a possible therapeutic target for AD. The aim of the present study was to examine the effects of chronic treatment with the 5-HTR7 agonist, AS19, on cognitive function, memory, hippocampal plasticity, amyloid beta (Aβ) plaque accumulation, and apoptosis in an adult rat model of AD. AD was induced in rats using Aβ (single 1μg/μL intracerebroventricular (icv) injection during surgery). The following experimental groups were included: control, sham-operated, Aβ + saline (1μL icv for 30days), and Aβ + AS19 (1μg/μL icv for 30days) groups. The animals were tested for cognition and memory performance using the novel object recognition and passive avoidance tests, respectively. Next, anesthetized rats were placed in a stereotaxic apparatus for electrode implantation, and field potentials were recorded in the hippocampal dentate gyrus. Lastly, brains were removed and Aβ plaques and neuronal apoptosis were evaluated using Congo red staining and TUNEL assay, respectively. Administration of AS19 in the Aβ rats increased the discrimination index of the novel object recognition test. Furthermore, AS19 treatment decreased time spent in the dark compartment during the passive avoidance test. AS19 also enhanced both the population spike (PS) amplitude and the field excitatory postsynaptic potential (fEPSP) slope evoked potentials of the LTP components. Aβ plaques and neuronal apoptosis were decreased in the AS19-treated Aβ rats. These results indicate that chronic treatment with a 5-HTR7 agonist can prevent Aβ-related impairments in cognition and memory performance by alleviating Aβ plaque accumulation and neuronal apoptosis, hence improving neuronal plasticity. AS19 may be useful as a therapeutic agent for AD.

Testing Effects of Chronic Chemogenetic Neuronal Stimulation on Energy Balance by Indirect Calorimetry.

The fundamental of neuroscience is to connect the firing of neurons to physiological and behavioral outcomes. Chemogenetics enables researchers to control the activity of a genetically defined population of neurons in vivo through the expression of designer receptor exclusively activated by designer drug (DREADD) in specific neurons and the administration of its synthetic ligand clozapine N-oxide (CNO) (Sternson and Roth, 2014). Using stimulatory Gq-coupled DREADD (hM3Dq) in mice, we showed that leptin receptor (LepRb)-expressing neurons in the preoptic area (POA) of the hypothalamus are warm-sensitive neurons that mediate warm-responsive metabolic and behavioral adaptations by reducing energy expenditure and food intake (Yu et al., 2016). We also used DREADD technology to test effects of chronic stimulation of POA LepRb neurons on energy expenditure, food intake, and body weight with the TSE indirect calorimetry system. Here we describe the detailed protocol of how we used indirect calorimetry to study the outcome of chronic stimulation of POA LepRb neurons. This protocol can be adapted to study long-term metabolic and behavioral consequences of other neuronal modulations, with possible modifications to the type of DREADD, duration of CNO treatment, or method of CNO delivery.

Postmortem studies of deep brain stimulation for Parkinson's disease: a systematic review of the literature.

Deep brain stimulation (DBS), arguably the greatest therapeutic advancement in the treatment of Parkinson's disease since dopamine replacement therapy, is now routinely used. While the exact mechanisms by which DBS works still remain unknown, over the past three decades since it was first described, we have gained significant insight into several of the processes involved. Though often overlooked in this regard, increasing numbers of postmortem and autopsy studies are contributing significantly to our understanding. In this manuscript, we review the literature involving the pathological findings from autopsies in patients who have undergone deep brain stimulation surgeries for Parkinson's disease. The major results show that multiple stereotactic targeting methods can be accurate at placing leads in the desired nuclei that help with clinically effective results, that perioperative complications and inaccurate diagnosis as determined by autopsy can lead to suboptimal stimulation effect and that the normal long-term effects of chronic stimulation include fibrosis around the electrodes and a mild immune response. In addition, recent results suggest mechanisms by which DBS might be effective in Parkinson's disease i.e., through rescuing pathological changes in microvasculature and by promoting the proliferation of neural progenitor cells.

Protein Kinase Cα (PKCα) Is Resistant to Long Term Desensitization/Down-regulation by Prolonged Diacylglycerol Stimulation

Sustained activation of PKCα is required for long term physiological responses, such as growth arrest and differentiation. However, studies with pharmacological agonists (e.g. phorbol 12-myristate 13-acetate (PMA)) indicate that prolonged stimulation leads to PKCα desensitization via dephosphorylation and/or degradation. The current study analyzed effects of chronic stimulation with the physiological agonist diacylglycerol. Repeated addition of 1,2-dioctanoyl-sn-glycerol (DiC8) resulted in sustained plasma membrane association of PKCα in a pattern comparable with that induced by PMA. However, although PMA potently down-regulated PKCα, prolonged activation by DiC8 failed to engage known desensitization mechanisms, with the enzyme remaining membrane-associated and able to support sustained downstream signaling. DiC8-activated PKCα did not undergo dephosphorylation, ubiquitination, or internalization, early events in PKCα desensitization. Although DiC8 efficiently down-regulated novel PKCs PKCδ and PKCϵ, differences in Ca(2+) sensitivity and diacylglycerol affinity were excluded as mediators of the selective resistance of PKCα. Roles for Hsp/Hsc70 and Hsp90 were also excluded. PMA, but not DiC8, targeted PKCα to detergent-resistant membranes, and disruption of these domains with cholesterol-binding agents demonstrated a role for differential membrane compartmentalization in selective agonist-induced degradation. Chronic DiC8 treatment failed to desensitize PKCα in several cell types and did not affect PKCβI; thus, conventional PKCs appear generally insensitive to desensitization by sustained diacylglycerol stimulation. Consistent with this conclusion, prolonged (several-day) membrane association/activation of PKCα is seen in self-renewing epithelium of the intestine, cervix, and skin. PKCα deficiency affects gene expression, differentiation, and tumorigenesis in these tissues, highlighting the importance of mechanisms that protect PKCα from desensitization in vivo.

Chronic electroacupuncture of the ST36 point improves baroreflex function and haemodynamic parameters in heart failure rats.

Electroacupuncture (EA) has been used to treat many diseases, including heart failure (HF). This study aimed to evaluate the effects of chronic stimulation in the ST36 acupuncture point on haemodynamic parameters and baroreflex function in rats with HF. Cardiovascular parameters assessed were heart rate (HR), blood pressure (BP), and the reflex cardiovascular response of HR triggered by stimulation of baroreceptors in animals with HF subsequent to acute myocardial infarction (AMI). Male Wistar rats were divided into three groups: Sham Control - animals without HF and without EA; HF Control group - animals with HF and without EA; and HF EA group - animals with HF that received the EA protocol. Six weeks after surgical induction of AMI, the EA protocol (8 weeks, 5 times a week) was performed. The protocol was applied with EA at the ST36 point, frequency of 2 Hz, pulse of 0.3 ms and intensity of 1-3 mA for 30 min. Haemodynamic parameters and baroreceptor function were assessed. There was no difference between groups in the variables HR, systolic blood pressure (SBP) and diastolic blood pressure (DBP), which were evaluated with awake animals (p>0.05). There was an increase in the mean arterial pressure (MAP) in the HF EA group compared to the HF Control group (p<0.05). The maximum gain of the baroreflex heart rate response (Gain) was higher in the HF EA group than the HF Control and Sham Control groups. Chronic EA in the ST36 point increased the MAP and baroreflex sensitivity in rats with HF.

Chronic baclofen desensitizes GABAB-mediated G-protein activation and stimulates phosphorylation of kinases in mesocorticolimbic rat brain

The GABAB receptor is a therapeutic target for CNS and neuropathic disorders; however, few preclinical studies have explored effects of chronic stimulation. This study evaluated acute and chronic baclofen treatments on GABAB-activated G-proteins and signaling protein phosphorylation as indicators of GABAB signaling capacity. Brain sections from rats acutely administered baclofen (5 mg/kg, i.p.) showed no significant differences from controls in GABAB-stimulated GTPγS binding in any brain region, but displayed significantly greater phosphorylation/activation of focal adhesion kinase (pFAKTyr397) in mesocorticolimbic regions (caudate putamen, cortex, hippocampus, thalamus) and elevated phosphorylated/activated glycogen synthase kinase 3-β (pGSK3βTyr216) in the prefrontal cortex, cerebral cortex, caudate putamen, nucleus accumbens, thalamus, septum, and globus pallidus. In rats administered chronic baclofen (5 mg/kg, t.i.d. for five days), GABAB-stimulated GTPγS binding was significantly diminished in the prefrontal cortex, septum, amygdala, and parabrachial nucleus compared to controls. This effect was specific to GABAB receptors: there was no effect of chronic baclofen treatment on adenosine A1-stimulated GTPγS binding in any region. Chronically-treated rats also exhibited increases in pFAKTyr397 and pGSK3βTyr216 compared to controls, and displayed wide-spread elevations in phosphorylated dopamine- and cAMP-regulated phosphoprotein-32 (pDARPP-32Thr34) compared to acutely-treated or control rats. We postulate that those neuroadaptive effects of GABAB stimulation mediated by G-proteins and their sequelae correlate with tolerance to several of baclofen's effects, whereas sustained signaling via kinase cascades points to cross-talk between GABAB receptors and alternative mechanisms that are resistant to desensitization. Both desensitized and sustained signaling pathways should be considered in the development of pharmacotherapies targeting the GABA system.

Alternative right ventricular pacing sites.

The main adverse effect of chronic stimulation is stimulation-induced heart failure in case of ventricular contraction dyssynchrony. Because of this fact, new techniques of stimulation should be considered to optimize electrotherapy. One of these methods is pacing from alternative right ventricular sites. The purpose of this article is to review currently accumulated data about alternative sites of cardiac pacing. Medline and PubMed bases were used to search English and Polish reports published recently. Recent studies report adeleterious effect of long term apical pacing. It is suggested that permanent apical stimulation, by omitting physiological conduction pattern with His-Purkinie network, may lead to electrical and mechanical dyssynchrony of heart muscle contraction. In the long term this pathological situation can lead to severe heart failure and death. Because of this, scientists began to search for some alternative sites of cardiac pacing to reduce the deleterious effect of stimulation. Based on current accumulated data, it is suggested that the right ventricular outflow tract, right ventricular septum, direct His-bundle or biventricular pacing are better alternatives due to more physiological electrical impulse propagation within the heart and the reduction of the dyssynchrony effect. These methods should preserve abetter left ventricular function and prevent the development of heart failure in permanent paced patients. As there is still not enough, long-term, randomized, prospective, cross-over and multicenter studies, further research is required to validate the benefits of using this kind of therapy. The article should pay attention to new sites of cardiac stimulation as abetter and safer method of treatment.

Acute and Chronic Lymphocytic Leukemia Induces Exhaustion and Suppresses Metabolic Reprogramming in T Cell Activation

Background. Cancer cells in both hematopoietic and non-hematopoietic malignancies can suppress anti-tumor immunity by inducing a state of T cell exhaustion and hypo-responsiveness. Indeed, T cells in patients with leukemia, such as chronic lymphocytic leukemia (CLL) and acute lymphocytic leukemia (ALL) express exhaustion markers such as PD-1 or TIM-3 and can be poorly responsive. As a result, the T cells not only fail to engage the leukemic cells, but render the host susceptible to infections. The cause of the T cell defect is not known. We have previously shown that T cell metabolism is tightly regulated and sought here to test if chronic T cell stimulation through leukemic cells in human and murine leukemia modulates T cell metabolism to suppress T cell function.Methods. We established in vitro and in vivo T cell stimulation models using syngeneic pro-B-cell BCR/ABL+ mouse lymphocytic leukemia. We also analyzed freshly collected peripheral blood from 18 CLL patients and from blood or bone marrow aspirates of 3 patients with BCR/ABL+ ALL. Using flow cytometry and radiometric assays, we measured T cell proliferation, IL-2 and IFNγ production, expression of the activation and exhaustion markers CD25, CD71 and PD-1 and changes in T cell glucose metabolism. Lastly, the role of altered glucose uptake was tested using mice with T cell-specific transgenic expression of the glucose transporter 1 (Glut1).Results. Our studies showed that murine and human lymphocytic leukemia induces chronic T cell stimulation and exhaustion as measured by increased expression of PD-1 and TIM-3. Following T cell receptor stimulation, T cells from leukemic mice and human patients had impaired up regulation of surface activation molecules. Production of IL-2 and IFNγ was reduced and proliferation of leukemia-associated T cells was impaired. Importantly, recruitment of key metabolic genes such as Glut1 was inhibited in both murine and human leukemia-associated T cells. The mechanism of T cell exhaustion was unclear, but additionally to the effects of persistent stimulation, T cells expressed inhibitory receptors and inhibitory ligands were found in the leukemic microenvironment. The nutrient profile of conditioned media from leukemia cells was markedly altered, and the conditioned media prevented mouse T cell activation and proliferation. Next we questioned whether altered glucose metabolism contributed to T cell functional defects in lymphoid leukemia. We used mice expressing transgenic Glut1 in T cells to determine the effects of chronic stimulation through leukemia cells on the phenotypes of T cells. These Glut1-transgenic T cells resisted exhaustion and partially maintained function despite the presence of leukemia.Conclusion. Results of our studies indicate that lymphocytic leukemia induces a chronic stimulation leading to T cell exhaustion and impaired T cell function in part through inhibition of glucose metabolism. DisclosuresRathmell:Novartis: Consultancy.

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English

Effect of isoprenaline chronic stimulation on APD restitution and ventricular arrhythmogenesis

BackgroundIsoprenaline (ISO) acts through β-adrenergic receptors to increase the intracellular Ca2+, which has effects on action potential duration (APD) restitution and arrhythmogenesis. Thus, we investigated the effect of chronic stimulation with isoprenaline on APD restitution and ventricular tachyarrhythmias (VA) in the rabbit heart. Methods and resultsRabbits were randomly selected to receive an injection of isoprenaline (ISO group) or an equal volume of 0.9% saline (CTL group). The S1–S2 protocol (n=15) and S1 dynamic pacing (n=15) were performed to construct APD restitution and to induce APD alternans or arrhythmia in 10 sites of Langendorff-perfused hearts. Compared with the same sites in the control group, long-term ISO administration (7 days) shortened the APD90 and the effective refractory period (ERP), and greatly increased the spatial dispersion of APD and ERP (p<0.01). Compared to CTL group, the APD restitution curves were significantly changed (p<0.01) and showed increased spacial dispersion of maximal slope (Smax) among each site in the ISO group (p<0.05). In induction of VA and APD alternans, the threshold of VA and alternans was both decreased in each site of the ISO group. ConclusionChronic stimulation with ISO facilitated VA, possibly through the increased spatial dispersion of APD restitution.

Unilateral subdural motor cortex stimulation improves essential tremor but not Parkinson's disease

Epidural motor cortex stimulation has been reported to be effective in treating some movement disorders. Nevertheless, clinical results have been variable and no double-blinded evaluations have been reported. The aim of this study was to investigate efficacy and safety of unilateral subdural motor cortex stimulation in patients with essential tremor and Parkinson's disease. Six patients with essential tremor and five parkinsonian patients were selected. Craniotomy was performed under local anaesthesia with conscious sedation. A four contact electrode (Resume II model 3587, Medtronic, Inc) was positioned on the motor cortex, after identification of the area with direct monopolar cortical stimulation. Soon after surgery, a variety of different settings of stimulation were assessed using standard rating scales to select the optimal stimulation parameters. The effects of chronic stimulation were evaluated in both groups of patients after 3 months (double-blinded fashion) and 1 year (open fashion). In essential tremor, contralateral hand tremor scores significantly improved (P = 0.04) with stimulation during the double-blinded study, whereas in Parkinson's disease, there were no changes in the OFF medication/on stimulation motor scores compared with off stimulation. At 1 year, tremor was improved by stimulation in two out of three patients with essential tremor available at follow-up, whereas no improvement was observed in the five parkinsonian patients. One parkinsonian patient had a cortical venous infarct. Three other patients had self-limiting seizures with aggressive trials of stimulation in the period of dosage selection. These findings suggest that unilateral subdural motor cortex stimulation may be useful for contralateral hand tremor in selected patients with essential tremor but was not effective in improving parkinsonian signs in our series.