Calcium- and voltage-driven atrial alternans: Insight from [Ca]i and Vm asynchrony.

Cardiac alternans is defined as beat-to-beat alternations in contraction strength, action potential duration (APD), and Ca transient (CaT) amplitude. Cardiac excitation-contraction coupling relies on the activity of two bidirectionally coupled excitable systems, membrane voltage (Vm ) and Ca release. Alternans has been classified as Vm - or Ca-driven, depending whether a disturbance of Vm or [Ca]i regulation drives the alternans. We determined the primary driver of pacing induced alternans in rabbit atrial myocytes, using combined patch clamp and fluorescence [Ca]i and Vm measurements. APD and CaT alternans are typically synchronized; however, uncoupling between APD and CaT regulation can lead to CaT alternans in the absence of APD alternans, and APD alternans can fail to precipitate CaT alternans, suggesting a considerable degree of independence of CaT and APD alternans. Using alternans AP voltage clamp protocols with extra APs showed that most frequently the pre-existing CaT alternans pattern prevailed after the extra-beat, indicating that alternans is Ca-driven. In electrically coupled cell pairs, dyssynchrony of APD and CaT alternans points to autonomous regulation of CaT alternans. Thus, with three novel experimental protocols, we collected evidence for Ca-driven alternans; however, the intimately intertwined regulation of Vm and [Ca]i precludes entirely independent development of CaT and APD alternans.

Neuropatía múltiple como manifestación clínica de una recidiva de leucemia / Isolated multiple neuropathy as clinical manifestation of leukemia relapse

Introducció La neuroleucemiosis es una rara enfermedad del sistema nervioso periférico producida por la infiltración por células leucémicas. Caso clínico: Presentamos el caso de una paciente de 34 años con antecedente de una leucemia mielomonoblástica aguda en remisión, que presentaba una parálisis progresiva del nervio mediano derecho, del facial bilateral y del peroneal izquierdo. El electromiograma confirmó el diagnóstico de una neuropatía múltiple. La tomografía por emisión de positrones-tomografía computarizada mostró un hipermetabolismo de ambos nervios ciáticos, facial bilateral y mediano derecho. La biopsia de médula ósea confirmó la recidiva de la leucemia, por lo que se inició un nuevo ciclo de quimioterapia con mejoría de los déficits neurológicos. Conclusión: La infiltración del sistema nervioso periférico por células leucémicas puede simular múltiples síndromes neurológicos dependiendo de las estructuras afectadas. La barrera hematonerviosa actúa como defensa de las células leucémicas contra la quimioterapia y el sistema inmunitario, por lo que el sistema nervioso periférico constituye un reservorio de las células leucémicas. Por ello, la neuroleucemia debe considerarse en pacientes con antecedentes de leucemia que presenten síntomas aislados de afectación del sistema nervioso periférico.(AU)

Introduction: Neuroleukemia is a rare disorder of the peripheral nervous system due to leukemic cell infiltration. Case report: We present the case of a 34-year-old patient with history of acute myelomonoblastic leukemia in remission that presented progressive paresis of the right median, bilateral facial, and left peroneal nerves. The electromyogram confirmed the diagnosis of multineuropathy. A PET-CT showed hypermetabolism of both sciatic, facial, and right median nerves. A bone marrow aspirate confirmed the leukemia relapse so a new round of chemotherapy was performed with improvement of the neurological deficit. Conclusion: Peripheral nervous system infiltration by leukemic cells can mimic multiple syndromes depending on the structures involved. The nerve-blood barrier acts as a defense of leukemic cells against chemotherapy and the immune system. Thus, the peripheral nervous system constitutes a reservoir of leukemic cells. Neuroleukemia should be considered in patients with history of acute leukemia who have isolated symptoms of the peripheral nerve.(AU)

Isolated multiple neuropathy as clinical manifestation of leukemia relapse. / Neuropatía múltiple como manifestación clínica de una recidiva de leucemia.

INTRODUCTION: Neuroleukemia is a rare disorder of the peripheral nervous system due to leukemic cell infiltration. CASE REPORT: We present the case of a 34-year-old patient with history of acute myelomonoblastic leukemia in remission that presented progressive paresis of the right median, bilateral facial, and left peroneal nerves. The electromyogram confirmed the diagnosis of multineuropathy. A PET-CT showed hypermetabolism of both sciatic, facial, and right median nerves. A bone marrow aspirate confirmed the leukemia relapse so a new round of chemotherapy was performed with improvement of the neurological deficit. CONCLUSION: Peripheral nervous system infiltration by leukemic cells can mimic multiple syndromes depending on the structures involved. The nerve-blood barrier acts as a defense of leukemic cells against chemotherapy and the immune system. Thus, the peripheral nervous system constitutes a reservoir of leukemic cells. Neuroleukemia should be considered in patients with history of acute leukemia who have isolated symptoms of the peripheral nerve.

TITLE: Neuropatía múltiple como manifestación clínica de una recidiva de leucemia.Introducción. La neuroleucemiosis es una rara enfermedad del sistema nervioso periférico producida por la infiltración por células leucémicas. Caso clínico. Presentamos el caso de una paciente de 34 años con antecedente de una leucemia mielomonoblástica aguda en remisión, que presentaba una parálisis progresiva del nervio mediano derecho, del facial bilateral y del peroneal izquierdo. El electromiograma confirmó el diagnóstico de una neuropatía múltiple. La tomografía por emisión de positrones-tomografía computarizada mostró un hipermetabolismo de ambos nervios ciáticos, facial bilateral y mediano derecho. La biopsia de médula ósea confirmó la recidiva de la leucemia, por lo que se inició un nuevo ciclo de quimioterapia con mejoría de los déficits neurológicos. Conclusión. La infiltración del sistema nervioso periférico por células leucémicas puede simular múltiples síndromes neurológicos dependiendo de las estructuras afectadas. La barrera hematonerviosa actúa como defensa de las células leucémicas contra la quimioterapia y el sistema inmunitario, por lo que el sistema nervioso periférico constituye un reservorio de las células leucémicas. Por ello, la neuroleucemia debe considerarse en pacientes con antecedentes de leucemia que presenten síntomas aislados de afectación del sistema nervioso periférico.

Excitation-contraction coupling and calcium release in atrial muscle.

In cardiac muscle, the process of excitation-contraction coupling (ECC) describes the chain of events that links action potential induced myocyte membrane depolarization, surface membrane ion channel activation, triggering of Ca2+ induced Ca2+ release from the sarcoplasmic reticulum (SR) Ca2+ store to activation of the contractile machinery that is ultimately responsible for the pump function of the heart. Here we review similarities and differences of structural and functional attributes of ECC between atrial and ventricular tissue. We explore a novel "fire-diffuse-uptake-fire" paradigm of atrial ECC and Ca2+ release that assigns a novel role to the SR SERCA pump and involves a concerted "tandem" activation of the ryanodine receptor Ca2+ release channel by cytosolic and luminal Ca2+. We discuss the contribution of the inositol 1,4,5-trisphosphate (IP3) receptor Ca2+ release channel as an auxiliary pathway to Ca2+ signaling, and we review IP3 receptor-induced Ca2+ release involvement in beat-to-beat ECC, nuclear Ca2+ signaling, and arrhythmogenesis. Finally, we explore the topic of electromechanical and Ca2+ alternans and its ramifications for atrial arrhythmia.

Effect of carvedilol on atrial excitation-contraction coupling, Ca2+ release, and arrhythmogenicity.

Carvedilol is an FDA-approved ß-blocker commonly used for treatment of high blood pressure, congestive heart failure, and cardiac tachyarrhythmias, including atrial fibrillation. We investigated at the cellular level the mechanisms through which carvedilol interferes with sarcoplasmic reticulum (SR) Ca2+ release during excitation-contraction coupling (ECC) in single rabbit atrial myocytes. Carvedilol caused concentration-dependent (1-10 µM) failure of SR Ca2+ release. Failure of ECC and Ca2+ release was the result of dose-dependent inhibition of voltage-gated Na+ (INa) and L-type Ca2+ (ICa) currents that are responsible for the rapid depolarization phase of the cardiac action potential (AP) and the initiation of Ca2+-induced Ca2+ release from the SR, respectively. Carvedilol (1 µM) led to AP duration shortening, AP failures, and peak INa inhibition by ~80%, whereas ICa was not markedly affected. Carvedilol (10 µM) blocked INa almost completely and reduced ICa by ~40%. No effect on Ca2+-transient amplitude, ICa, and INa was observed in control experiments with the ß-blocker metoprolol, suggesting that the carvedilol effect on ECC is unlikely the result of its ß-blocking property. The effects of carvedilol (1 µM) on subcellular SR Ca2+ release was spatially inhomogeneous, where a selective inhibition of peripheral subsarcolemmal Ca2+ release from the junctional SR accounted for the cell-averaged reduction in Ca2+-transient amplitude. Furthermore, carvedilol significantly reduced the probability of spontaneous arrhythmogenic Ca2+ waves without changes of SR Ca2+ load. The data suggest a profound antiarrhythmic action of carvedilol in atrial myocytes resulting from an inhibitory effect on the SR Ca2+ release channel.NEW & NOTEWORTHY Here we show that the clinically widely used ß-blocker carvedilol has profound effects on Ca2+ signaling and ion currents, but also antiarrhythmic effects in adult atrial myocytes. Carvedilol inhibits sodium and calcium currents and leads to failure of ECC but also prevents spontaneous Ca2+ release from cellular sarcoplasmic reticulum (SR) Ca2+ stores in form of arrhythmogenic Ca2+ waves. The antiarrhythmic effect occurs by carvedilol acting directly on the SR ryanodine receptor Ca2+ release channel.

[Progressive encephalitis due to anti-DPPX antibodies: a case with good response to treatment with rituximab]. / Encefalitis progresiva por anticuerpos anti-DPPX: un caso con buena respuesta al tratamiento con rituximab.

TITLE: Encefalitis progresiva por anticuerpos anti-DPPX: un caso con buena respuesta al tratamiento con rituximab.

Organic waste as a sustainable feedstock for platform chemicals.

Biorefineries have been established since the 1980s for biofuel production, and there has been a switch lately from first to second generation feedstocks in order to avoid the food versus fuel dilemma. To a lesser extent, many opportunities have been investigated for producing chemicals from biomass using by-products of the present biorefineries, simple waste streams. Current facilities apply intensive pre-treatments to deal with single substrate types such as carbohydrates. However, most organic streams such as municipal solid waste or algal blooms present a high complexity and variable mixture of molecules, which makes specific compound production and separation difficult. Here we focus on flexible anaerobic fermentation and hydrothermal processes that can treat complex biomass as a whole to obtain a range of products within an integrated biorefinery concept.

Long-lasting treatment effect of rituximab in MuSK myasthenia.

OBJECTIVE: Rituximab has emerged as an efficacious option for drug-resistant myasthenia gravis (MG). However, reports published only describe the short-term follow-up of patients treated and little is known about their long-term clinical and immunologic evolution. Our objective was to report the clinical and immunologic long-term follow-up of 17 patients (6 MuSK+MG and 11 AChR+MG) and compare the response between AChR+MG and MuSK+MG patients. METHODS: Myasthenia Gravis Foundation America postintervention status and changes in treatment and antibody titers were periodically determined. Lymphocyte subpopulations, total immunoglobulin, immunoglobulin G (IgG) anti-MuSK subclasses, and anti-tetanus toxoid IgG before and after treatment were also studied. RESULTS: After a mean post-treatment period of 31 months, 10 of the AChR+MG patients improved but 6 of them needed reinfusions. In contrast, all MuSK+MG patients achieved a remission (4/6) or minimal manifestations (2/6) status and no reinfusions were needed. Consequently, in the MuSK+MG group, prednisone doses were significantly reduced and concomitant immunosuppressants could be withdrawn. Clinical improvement was associated with a significant decrease in the antibody titers only in the 6 MuSK+MG patients. At last follow-up MuSK antibodies were negative in 3 of these patients and showed a decrease of over 80% in the other 3. CONCLUSION: In view of the long-lasting benefit observed in MuSK+MG patients, we recommend to use rituximab as an early therapeutic option in this group of patients with MG if they do not respond to prednisone. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that IV rituximab improves the clinical and immunologic status of patients with MuSK+MG.

Antibodies to metabotropic glutamate receptor 5 in the Ophelia syndrome.

OBJECTIVE: To report the metabotropic glutamate receptor 5 (mGluR5) as the autoantigen of antibodies from 2 patients with Hodgkin lymphoma (HL) and limbic encephalopathy (Ophelia syndrome). METHODS: Immunohistochemistry with brain tissue and cultures of rat hippocampal neurons were used to demonstrate antibodies. Immunoprecipitation, mass spectrometry, and mGluR5-null mice served to identify the antigen. HEK293 cells transfected with mGluR5 or mGluR1 were used to determine immunologic crossreactivity. RESULTS: Both patients developed symptoms consistent with limbic encephalopathy; one had MRI findings typical of this disorder and the other had more extensive radiologic involvement, including parietal and occipital cortex. Patients' sera had antibodies that predominantly reacted with the neuropil of hippocampus and cell surface of live hippocampal neurons. Immunoprecipitation from cultured neurons and mass spectrometry demonstrated that the antigen was mGluR5, a receptor involved in processes of learning and memory. The reactivity of patients' sera was abrogated in brain of mGluR5-null mice, further confirming the antibody specificity. Studies with a large number of controls including 2 patients with cerebellar ataxia and mGluR1 antibodies showed that mGluR5 was only identified by sera of the 2 patients with the Ophelia syndrome, and that despite the homology of this receptor with mGluR1 each autoantigen was specific for a distinct syndrome. CONCLUSIONS: Antibodies to mGluR5 should be considered in patients with symptoms of limbic encephalitis and HL (Ophelia syndrome). Recognition of this disorder is important because it can affect young individuals and is reversible.

Analysis of complement and plasma cells in the brain of patients with anti-NMDAR encephalitis.

OBJECTIVES: Most patients with anti-NMDA receptor (NMDAR) encephalitis have intrathecal synthesis of antibodies, which cause a decrease of cell surface and synaptic NMDAR. Antibodies are immunoglobulin G (IgG)1 and IgG3 subtypes and can potentially activate complement. We examined whether complement immunoreactivity and antibody-secreting cells (plasma cells/plasmablasts) are present in the brain of these patients. METHODS: Cultured rat hippocampal neurons were used in an immunocytochemical assay to test whether patients' antibodies can fix complement. Using the same reagents (antibodies to C9neo, C(5b-9), C3), complement immunoreactivity was determined in the brain of 5 patients, the teratoma of 21 patients, and appropriate control tissues. A set of markers for B (CD20), T (CD3, CD4, CD8) and antibody-secreting cells (plasma cells/plasmablasts, CD138) were used to examine the brain inflammatory infiltrates. RESULTS: Patients' antibodies were able to bind complement in vitro, but deposits of complement were not detected in patients' brain. Parallel experiments with teratomas showed that in contrast to the brain, the neural tissue of the tumors contained complement. Analysis of the inflammatory infiltrates in brain samples from autopsy or biopsy performed 3-4 weeks after symptom presentation demonstrated numerous antibody-secreting cells (CD138+) in perivascular, interstitial, and Virchow-Robin spaces, and B and T cells predominantly located in perivascular regions. CONCLUSIONS: Complement-mediated mechanisms do not appear to play a substantial pathogenic role in anti-NMDAR encephalitis. In contrast, there are copious infiltrates of antibody-secreting cells (plasma cells/plasmablasts) in the CNS of these patients. The demonstration of these cells provides an explanation for the intrathecal synthesis of antibodies and has implications for treatment.

Complicaciones neurológicas de los trasplantes / Neurological complications of transplantation

El trasplante de células hematopoyéticas (TCH) y lostrasplantes de órganos han pasado a ser el tratamiento deelección de diversos procesos neoplásicos y no neoplásicos.Las complicaciones neurológicas asociadas a estos tratamientossiguen siendo frecuentes y suelen ser el resultadode la enfermedad de base, los tratamientos inmunosupresoresy la toxicidad de la radioterapia o quimioterapia. En elcaso del TCH la frecuencia y tipo de complicaciones varíancon el tipo de trasplante, autólogo o alogénico. En generallos problemas más frecuentes del TCH y los trasplantes deórganos son las encefalopatías tóxico-metabólicas y las alteracionesneurológicas centrales o periféricas debido a coagulopatías,infecciones y reactivación de procesos autoinmunes.El trastorno linfoproliferativo postrasplante (TLPT)agrupa un espectro de procesos que van desde la hiperplasialinfoide policlonal benigna a los linfomas monoclonales malignos,y suele asociarse al virus de Epstein-Barr. Algunossíndromes que eran poco conocidos o infrecuentes antes dela era de los trasplantes deben tenerse en cuenta en la evaluaciónde las complicaciones neurológicas, incluyendo elsíndrome inflamatorio de reconstitución inmunológica y algunasneuropatías paraneoplásicas relacionadas con el TLPT (AU)

Hematopoietic stem-cell transplantation (HCT) andorgan transplantation have become the standard of care for a number of malignant and non-malignant disorders.Neurological complications associated with these proceduresremain frequent. These complications result from avariety of causes including the underlying disorder, therapiesused for immunosuppression, and toxicities fromradiation or chemotherapy. For HCT the frequency of somecomplications is dependent on whether the transplantis allogenic or autologous. In general, the mainneurological problems of HCT and organ transplantationinclude metabolic and toxic encephalopathies, and centraland peripheral neurological disorders caused by coagulopathy,infections, and autoimmune mechanisms. Theterm post-transplant lymphoproliferative disorder (PTLD)includes a spectrum of disorders ranging from benignpolyclonal lymphoid hyperplasia to malignant monoclonallymphoma, usually related to the Epstein-Barr virus.Some lesser known syndromes such as the immune reconstitutioninflammatory syndrome and paraneoplasticneuropathies related with PTLD are increasingly beingdescribed and need to be considered in the evaluation ofa transplant patient with neurological problems (AU)

[Neurological complications of transplantation]. / Complicaciones neurológicas de los trasplantes.

Hematopoietic stem-cell transplantation (HCT) and organ transplantation have become the standard of care for a number of malignant and non-malignant disorders. Neurological complications associated with these procedures remain frequent. These complications result from a variety of causes including the underlying disorder, therapies used for immunosuppression, and toxicities from radiation or chemotherapy. For HCT the frequency of some complications is dependent on whether the transplant is allogenic or autologous. In general, the main neurological problems of HCT and organ transplantation include metabolic and toxic encephalopathies, and central and peripheral neurological disorders caused by coagulopathy, infections, and autoimmune mechanisms. The term post-transplant lymphoproliferative disorder (PTLD) includes a spectrum of disorders ranging from benign polyclonal lymphoid hyperplasia to malignant monoclonal lymphoma, usually related to the Epstein-Barr virus. Some lesser known syndromes such as the immune reconstitution inflammatory syndrome and paraneoplastic neuropathies related with PTLD are increasingly being described and need to be considered in the evaluation of a transplant patient with neurological problems.

[Breast feeding ; follow up during the puerperium]. / Lactancia materna: seguimiento durante el puerperio.

In a prospective longitudinal study carried out in the Ginecoobstetric Department of the HGZ 6 Cd. Valles S.L.P., from March 1st to July 15th 1995. One hundred patient were evaluated 24 h after puerperium (in hospital), and 20 and 40 days later at home. With the objective to determine the continuity of lactancy, because all mothers were informed and trained about the benefits of human milk. 31% of the pregnancies were cesarean section and 69% vaginal. A lost of continuity was found in 43% at 20 days and 44% at 40 days. The incidence of respiratory and diarrheic diseases were evaluated with mother milk and artificial formulate (No significant p > 0.5%). The reason for ending the lactancy are cultural and behavior distortion about the benefits of human milk, this is necessary to change to enforce the values of this natural resource.