Noradrenergic α1, α2, and ß1receptors mediate VNS-induced theta oscillations.

Although vagal nerve stimulation (VNS) has been employed with success for almost four decades in many central nervous system disturbances, the physiological and pharmacological processes underlying this therapy are still unclear. Searching for central mechanisms of VNS is clinically limited. Hence, in many experiments, VNS technique is tested on the model of laboratory animals. In the present study we proceed with the experiments to verify some central effects of VNS. Specifically, we focussed on the hippocampal formation (HPC) noradrenergic profile which underlines the VNS-induced theta oscillations in anesthetized rats (Broncel et al., 2017; 2021). The effects of noradrenaline (NE) and selective noradrenergic α and ß agonists and antagonists were tested in experiments organized in three stages. Initially, a nonspecific noradrenergic agonist, noradrenaline, was administrated. In the second stage, noradrenergic α and ß agonists were applied. In the last stage, the administration of selected agonists was pretreated by specific antagonists. The results of the present study provide evidence that the selective activation of HPC α1, α2, and ß1 noradrenergic receptors produce the inhibition of VNS-induced theta oscillations. Hippocampal ß2 and ß3 receptors were found not to be involved in the modulation of oscillations produced by the vagal nerve stimulation. The obtained outcomes are discussed in light of the effects of increased exogenous NE and induced release of endogenous NE.

Fractionated doses of gemtuzumab ozogamicin combined with 3 + 7 induction chemotherapy as salvage treatment for young patients with acute myeloid leukemia in first relapse.

Current salvage therapies for relapsed acute myeloid leukemia (AML) are unsatisfactory. We retrospectively evaluated the efficacy and toxicity of fractionated doses of gemtuzumab ozogamicin (GO) combined with a standard 3 + 7 induction regimen in young patients with AML in first relapse. Salvage regimen consisted of GO 3 mg/m² on days 1, 4, and 7; cytarabine, 200 mg/m² on days 1-7; and daunorubicine, 60 mg/m²; or idarubicine, 12 mg/m² on days 1-3. Fourteen patients were treated between April 2008 and April 2011. Median age was 46 years (29-58), median white blood cell count is 3.4 109/L (0.9-19), and median first complete remission (CR) duration is 11 months (1-42). All the patients had previously received high or intermediate doses of cytarabine as consolidation therapy. Salvage treatment was performed as scheduled for the 14 patients, using daunorubicine in 12 patients and idarubicine in two. Overall response rate was 79 % with six CR and five CR with incomplete platelet recovery. Median times to neutrophil (>0.5 109/L) and platelet (>20 109/L) recovery were 29 days (23-32) and 36 days (28-48), respectively. Allogeneic transplantation was performed in the 11 responding patients within a median time of 4 months (3-10). Three mild and one moderate veno-occlusive disease (VOD) occurred after salvage and two moderate VOD after transplantation. Median and 2-year overall survival (OS) were 10 months and 42 %, respectively. For responders, estimated 2-year OS was 53 % (median OS not reached). This salvage regimen seems safe and effective in younger patients with AML in first relapse allowing allogeneic transplantation in CR2 for most patients.

Noradrenergic Profile of Hippocampal Formation Theta Rhythm in Anaesthetized Rats.

The present study was undertaken to identify the noradrenergic receptors underlying the production of hippocampal formation (HPC) type 2 theta rhythm. The experiments were performed on urethanized rats wherein type 2 theta is the only rhythm present. In three independent stages of experiments, the effects of noradrenaline (NE) and selective noradrenergic α and ß agonists and antagonists were tested. We indicate that the selective activation of three HPC noradrenergic receptors, α1, α2 and ß1, induced a similar effect (i.e., inhibition) on type 2 theta rhythm. The remaining HPC ß2 and ß3 noradrenergic receptors do not seem to be directly involved in the pharmacological mechanism responsible for the suppression of theta rhythm in anaesthetized rats. Obtained results provide evidence for the suppressant effect of exogenous NE on HPC type 2 theta rhythm and show the crucial role of α1, α2 and ß1 noradrenergic receptors in the modulation of HPC mechanisms of oscillations and synchrony. This finding is in contrast to the effects of endogenous NE produced by electrical stimulation of the locus coeruleus (LC) and procaine injection into the LC (Broncel et al., 2020).

Which role for rituximab in hairy cell leukemia? Reflections on six cases.

Hairy cell leukemia (HCL) is a rare, chronic, B-cell, lymphoproliferative disorder. Treatment has been revolutionized by the advent of interferon (IFN)-alpha and purine analogs (PA). First-line therapy with PA yields complete response rates of 75-100%, with many long-lasting remissions. In the event of profound neutropenia and/or infectious complications, a short sequence of IFN-alpha may precede PA treatment. Because of the excellent results achieved with PA therapy, the potential role of rituximab (an anti-CD20 monoclonal antibody that is highly effective against most B-cell lymphomas) in HCL has yet to be elucidated. Six HCL cases treated with rituximab are reported herein with a view to elucidating the potential role of the drug in HCL. The indications essentially consist of relapsing or refractory disease, avoiding the cumulative toxicity of PA, consolidation therapy in order to eradicate minimal residual disease, and first-line therapy for patients with contraindications to PA and IFN-alpha.

Effects of locus coeruleus activation and inactivation on hippocampal formation theta rhythm in anesthetized rats.

Previously obtained data suggests that noradrenaline (NE) released from the efferent locus coeruleus (LC) endings in hippocampal formation (HPC) may serve as an important modulating signal involved in the pharmacological mechanisms responsible for the production of type 2 theta rhythm in rats. Hence, two distinct hypotheses were tested in the present study: 1/ if the decrease in HPC level of NE is correlated with the desynchronization of HPC field potential, then the inhibition of LC would be expected to abolish HPC type 2 theta rhythm; 2/ if the increase in HPC NE level is correlated with synchronization of HPC field potential, then the stimulation of LC would be expected to produce type 2 theta. The experiments were performed using an experimental model of HPC type 2 theta rhythm recorded in urethanized rats. It was demonstrated that electrical stimulation of LC produced type 2 theta rhythm whereas procaine injection into LC, in contrast, reversibly abolished type 2 theta. The possible relation of type 2 theta rhythm with some disturbances of Alzheimer disease are addressed.

Vagal nerve stimulation as a promising tool in the improvement of cognitive disorders.

Vagal nerve stimulation (VNS) is known as an effective method of treatment in a number of neurological disorders. The low risk of side effects also makes it useful in clinical trials in other diseases. Branches of the vagal nerve innervate the anatomical structures known to be involved in memory processing. That is why it seems justified that several studies emphasize the impact of VNS on the cognitive and memory function in both healthy volunteers and patients with epilepsy and Alzheimer's disease. Results have shown that VNS can modulate different types of memory depending the protocol of stimulation in non-demented patients after both short term and chronic VNS application. Transcutaneous vagal nerve stimulation (tVNS), which is a non-invasive method of VNS, opens up new perspectives for different clinical applications.

[Hematological disorders and hypereosinophilias]. / Hyperéosinophilies et affections hématologiques.

Hematological disorders are the third cause of hypereosinophilia, after allergic and parasitic diseases. Hematological disorders associated with hypereosinophilias can be classified as clonal, reactive or idiopathic, and recently the improvements of cytogenetic, molecular biology and immunology have allowed to revisit numerous cases previously diagnosed as idiopathic hypereosinophilic syndrome. Reactive eosinophilias are mainly associated with lymphoma or abnormal, often clonal T lymphoid population. Clonal eosinophilia is related either to various myeloid malignancies or to a genuine myeloproliferative disorder from the eosinophile lineage, the so-called chronic eosinophilic leukaemia. Chronic eosinophilic leukaemia can be associated with recurrent genes rearrangements involving PDGFRA, PDGFRB and FGFR1 or with clonal abnormalities not yet categorized. Idiopathic hypereosinophilic syndrome remains an exclusive diagnosis in presence of moderate or severe unexplained eosinophilia with target organ damage. The purpose of the diagnostic work-up of hypereosinophilic syndrome is to evidence either an abnormal T cell population or a clonal haematopoiesis. Imatinib mesylate dramatically improves chronic eosinophilic leukaemias associated with PDGFR abnormalities, while corticosteroids are still the main treatment for the other patients. In a near future, advances could arise from identification of new genes involved in clonal eosinophilia or in alternative therapy such as the anti-IL-5 antibodies.

[Autoimmune hemolytic anemia and immune thrombocytopenia associated with Hodgkin disease: Retrospective monocentric study]. / Cytopénies auto-immunes associées au lymphome de Hodgkin : étude rétrospective monocentrique.

INTRODUCTION: Hodgkin's lymphoma (HL) is less common than non-Hodgkin lymphoma and is rarely associated with autoimmune cytopenia. METHOD: We report a consecutive, monocentric and retrospective series of HL patients diagnosed with concomitant or subsequent autoimmune cytopenia over a period of 8 years. RESULTS: We report 4 out of 84 HL patients (4.8%) diagnosed with autoimmune cytopenia (4 immune thrombocytopenia including 2 Evans' syndromes). They were 4 males (average age 24 years for the 3 youngest, and one over 60 years old). Autoimmune cytopenia revealed lymphoma in 2 patients and occurred after HL treatment in the two other patients (5 and 36 months from the end of chemotherapy) without HL relapse. All cytopenias were resistant to conventional treatments (glucocorticoids, intravenous immune globulin, rituximab) and sensitive to chemotherapy when indicated for HL treatment. CONCLUSION: In our series, the predominance of males, a higher frequency of immune thrombocytopenia than autoimmune hemolytic anemia, the resistance to usual treatments and the efficacy of specific chemotherapy were consistent with the literature. Unexpectedly, patients were young and with nodular sclerosis morphology (vs. mixed cellularity) in 3 of 4 cases.

Peripherally inserted central catheter placement in patients with coagulation disorders: A retrospective analysis.

OBJECTIVE: To assess the safety of peripherally inserted central venous catheter (PICC) placement in patients with altered and uncorrected coagulation parameters or receiving antiplatelet therapy. MATERIALS AND METHODS: Medical charts of all patients with major primary and secondary hemostasis disorders, combined hemostasis disorders or on antiplatelet therapy and who had undergone non-tunneled PICC placement from December 2009 to December 2013, were retrospectively reviewed. A hemostatic disorder was defined as a platelet count (PC)≤50×10(9)/L, an international normalized ratio (INR) ≥ 2, or an activated partial thromboplastin time (aPTT)≥66s, alone or in combination. Underlying hemostasis disorders were not corrected and antiplatelet therapy was not interrupted before PICC placement in any patient. 4, and 5-Fr single and dual lumen PICCs were used. RESULTS: A total of 378 PICCs were placed in 271 patients (180 men and 91 women; mean age=62±13.4years; range, 18-93 years)) with coagulation disorders. Eighty-nine (23%) PICCs were placed in patients who were receiving antiplatelet therapy (aspirin, clopidogrel, rivaroxaban). Thrombocytopenia was noted in 269PICC placements (71%). Among these patients, 23 had disseminated intravascular coagulation. Prolonged INR and aPTT were observed in 42 procedures (11.1%). PICC placement was achieved in all patients, with a mean number of 1.14 attempts. Peripheral venous access was obtained through the basilic and the brachial vein respectively in 295 (79.1%) and 83 (20.9%) of patients. The placements were performed by residents and fellows in 108 (28.5%) and 270 (71.5%) procedures, respectively. No early or late complications were reported after any procedure. No accidental puncture of the brachial artery occurred. CONCLUSION: In patients with severe primary and secondary hemostasis disorders, combined hemostasis disorders or on antiplatelet therapy, PICC placement is a feasible and safe procedure and does not require correction of coagulation parameters or discontinuation of antiplatelet therapy.

Theta-like activity in the limbic cortex in vitro.

The generation of EEG theta rhythm in the mammalian limbic cortex is a prime example of rhythmic activity that involves central mechanisms of oscillations and synchrony. This EEG pattern has been extensively studied since 1938, when Jung and Kornmuller (28) (Eine methodik der ableitung lokalisierter potential schwankingen aus subcorticalen hirnyebieten, Arch. Psychiat. Neruenkr. 109 (1938) 1-30) demonstrated the first theta recordings in the hippocampal formation of rabbits. In 1986 we demonstrated for the first time that bath perfusion of hippocampal slices with the cholinergic agonist, carbachol, resulted in theta-like oscillations. Since this initial demonstration of in vitro theta-like activity, we have carried out a number of experiments in an attempt to answer the following question: what are the similarities between cholinergic-induced in vitro theta-like activity and theta rhythm which naturally occurs in the in vivo preparation. Thus far, our studies have provided strong evidence that theta-like activity recorded in vitro shares many of the physiological and pharmacological properties of theta rhythm observed in vivo.

Theta-like activity in hippocampal formation slices: cholinergic-GABAergic interaction.

Brain slice preparations obtained from the rat were used to study cholinergic GABAergic interaction in mechanisms responsible for production of theta-like activity in hippocampal slices maintained in vitro. Bicuculline, a GABA-A antagonist, applied at 25 microM facilitated the effect of low concentration carbachol (25 microM) in inducing theta-like oscillations. At 100 microM, bicuculline increased the amplitude of carbachol-induced theta-like slow waves. This carbachol-bicuculline induced field potential was antagonized by a muscarinic blocker, atropine sulphate, and a GABA-A agonist, muscimol. These results provide in vitro evidence for cholinergic-GABAergic interaction in the production of hippocampal theta-like slow waves.

Muscarinic (M1) mediation of hippocampal spontaneous theta rhythm in freely moving cats.

The effects of intrahippocampally applied different doses of muscarinic (atropine sulphate, pirenzepine, gallamine) and nicotinic (hexamethonium, mecamylamine) antagonists on the spontaneous theta rhythm in the cat hippocampal formation were investigated. The injections of atropine and pirenzepine abolished spontaneous theta but administration of gallamine did not affect the EEG pattern. The intrahippocampally administered nicotinic blockers, hexamethonium and mecamylamine, were completely ineffective in antagonizing theta waves. The data suggest that the spontaneous theta rhythm in the cat is mediated by the M1 receptor subtype.

Cholinergically-induced theta-like oscillations in the hippocampal formation of freely moving cats.

The present investigation was undertaken to assess the role of the cholinergics in the production of theta (theta) rhythm in the cat hippocampal formation. Intrahippocampal injections of carbachol, muscarine or eserine produced a well synchronized high frequency cholinergic theta activity (HFC) in a range of 5-12 Hz. Subsequent intrahippocampal injection of muscarinic antagonist, atropine sulphate, completely blocked this cholinergic-induced EEG pattern. The nicotinic antagonist, hexamethonium, was without any effect on the cholinergic-induced rhythmical waves. We suggest that HFC may result from the activation of the oscillatory mechanism intrinsic to the cat hippocampal formation.

Muscarinic (M1) mediation of carbachol-induced theta in the cat entorhinal cortex in vitro.

Entorhinal cortex slice preparations obtained from the cat exhibited theta rhythm during perfusion with 50 microM carbachol. The effect of carbachol was antagonized by the muscarinic blocker atropine sulphate, but not by hexamethonium and mecamylamine, which are antagonists of the nicotinic receptor. Further analysis of the pharmacological profile of these carbachol-induced theta oscillations showed that M1 receptor subtype to be involved in mediation of this EEG activity: the theta rhythm was antagonized by the M1 receptor blocker pirenzepine, but was unaffected by gallamine, an antagonist of the M2 receptor subtype.

Kainic acid versus carbachol induced emotional-defensive response in the cat.

The emotional-defensive response (EDR) and accompanied neurotoxic and electroencephalographic (EEG) effects induced by injection of kainic acid (KA, 0.1; 0.2 microgram) into the midbrain periaqueductal grey region (PAG) and antero-medial hypothalamus (AMH) in the cat were examined and compared with EDR and accompanied neurotoxic and EEG effects induced by injection of cholinergic agent, carbachol (CCH), into the same sites. The injections of KA (0.2 microgram) into the PAG induced EDR which closely resembled the defense behavior typically observed after administration of CCH. However, in contrast to CCH-induced EDR, the defensive response induced by KA was found to be accompanied by EEG symptoms of epileptiform activity in the limbic cortex and a massive cell loss in the site of injection. It is proposed that KA-induced EDR and seizure activity may have resulted from the activation of different cell populations localized either in the vicinity of the injection (i.e., PAG region) and in the area remote from the injection loci, the limbic cortex. KA induced activation of PAG neuronal network would trigger the 'local response' (emotional-defensive response) and produce a remote effect-epileptiform activity.

Carbachol-induced rhythmic slow activity (theta) in cat hippocampal formation slices.

Application of the cholinergic agonist, carbachol, produced theta-like rhythmical waveforms, recorded in the stratum moleculare of the dentate gyrus in the cat hippocampal formation slices. This effect of carbachol was antagonized by atropine but not D-tubocurarine. These results provide first direct evidence that the hippocampal formation neuronal network in the cat is capable of producing synchronized slow wave activity when isolated from pulsed rhythmic inputs of the medial septum.

Carbachol-induced theta-like activity in entorhinal cortex slices.

The present study was conducted for two purposes: the first was to evaluate whether activation of cholinergic receptors of the entorhinal cortex in vitro (complete deafferentation) with carbachol (100 microM) was capable of producing theta (theta)-like slow activity. The second purpose was to determine whether carbachol-induced slow waveforms were mediated by muscarinic or nicotinic receptors. We demonstrated that carbachol was capable of producing theta-like slow activity. This activity was not altered by nicotinic antagonists, (+)-tubocurarine and hexametonium. Atropine and scopolamine, in contrast, completely blocked in vitro induced slow waves, indicating entorhinal muscarinic receptors to be actively involved in the mechanism generating cholinergic theta rhythm.

Evidence that activation of in vitro hippocampal theta rhythm only involves muscarinic receptors.

The present study was conducted for two purposes: the first was to evaluate whether activation of nicotinic receptors in the hippocampal formation in vitro (slice) preparation was capable of producing type 2 (atropine-sensitive) theta rhythm. The cholinergic nature and involvement of muscarinic receptors in this type of theta has been previously well documented. The second purpose was to determine whether perfusion of a number of (other) putative neurotransmitters shown to be present in the hippocampal formation could elicit type 1 (atropine-resistant) theta in the slice preparation. Further experiments were conducted to determine if these agents interacted in any manner with cholinergically-induced type 2 theta. Electroencephalic (EEG) theta activity was not induced by nicotine, providing evidence for an exclusive muscarinic receptor involvement in this cholinergically-induced type 2 theta. In addition, theta activity was not elicited by the application of gamma-aminobutyric acid (GABA), glutamate, norepinephrine, dopamine or serotonin. The application of any of these agents did not significantly alter the production of cholinergically-induced theta. These results suggest that type 1 theta originates in regions extrinsic to the hippocampus, or is the result of the interaction of several neurotransmitters on different receptors.

Carbachol-induced EEG 'theta' in hippocampal formation slices: evidence for a third generator of theta in CA3c area.

The topography of carbachol-induced EEG theta activity was studied using the hippocampal formation slice preparation. Systematic tracking with electrodes exhibited two amplitude maxima of cholinergic-induced theta, one located in the stratum oriens of the CA1 pyramidal cells and the other in a region of CA3c pyramidal neurons. In addition, mapping experiments demonstrated EEG theta in the CA3a and CA3b cell body layers, but not in the subicular and parasubicular regions, or the ventral blade of the dentate gyrus. Furthermore, transected slice (trans-slice) preparations used in the present study revealed that the CA3c region could generate carbachol-induced theta independently of CA1 and dentate gyrus generator zones and conversely, CA1 and dentate gyrus areas were capable of generating cholinergic-induced theta rhythm independently of the CA3c region. These results provide strong evidence for 3 independent, anatomically separated generators of theta: one located in the stratum oriens of CA1 neurons, a second in the stratum moleculare of the dentate gyrus and a third one in the region of Ca3c cells. In addition, the results support previous in vivo suggestions that theta rhythm can be either elicited or blocked by cholinergic agents acting on sites within the hippocampal formation.

The development of carbachol-induced EEG 'theta' examined in hippocampal formation slices.

The development of carbachol-induced EEG theta (theta) activity was studied in the CA1 and dentate regions of hippocampal formation slices obtained from neonatal rats (4, 6, 8, 10, 12 and 14 days of age). When perfused with carbachol (50 microM), 4- and 6-day-old hippocampal slices exhibited only short-lasting irregular activity. The initial appearance of carbachol-induced rhythmic waves were observed in slices obtained from 8-day-old rats. From the time that theta appeared at 8 days of age, a steady increase in amplitude and frequency was noted. This observed in vitro developmental pattern of hippocampal theta-rhythm closely resembles the development of theta activity in in vivo preparations.