Optogenetic and Chemogenic Control of Pain Signaling: Molecular Markers.

Pain is a complex experience that involves physical, emotional, and cognitive aspects. This review focuses specifically on the physiological processes underlying pain perception, with a particular emphasis on the various types of sensory neurons involved in transmitting pain signals to the central nervous system. Recent advances in techniques like optogenetics and chemogenetics have allowed researchers to selectively activate or inactivate specific neuronal circuits, offering a promising avenue for developing more effective pain management strategies. The article delves into the molecular targets of different types of sensory fibers such as channels, for example, TRPV1 in C-peptidergic fiber, TRPA1 in C-non-peptidergic receptors expressed differentially as MOR and DOR, and transcription factors, and their colocalization with the vesicular transporter of glutamate, which enable researchers to identify specific subtypes of neurons within the pain pathway and allows for selective transfection and expression of opsins to modulate their activity.

Acute dopamine receptor blockade in substantia nigra pars reticulata: a possible model for drug-induced Parkinsonism.

Dopamine (DA) depletion modifies the firing pattern of neurons in the substantia nigra pars reticulata (SNr), shifting their mostly tonic firing toward irregularity and bursting, traits of pathological firing underlying rigidity and postural instability in Parkinson's disease (PD) patients and animal models of Parkinsonism (PS). Drug-induced Parkinsonism (DIP) represents 20-40% of clinical cases of PS, becoming a problem for differential diagnosis, and is still not well studied with physiological tools. It may co-occur with tardive dyskinesia. Here we use in vitro slice preparations including the SNr to observe drug-induced pathological firing by using drugs that most likely produce it, DA-receptor antagonists (SCH23390 plus sulpiride), to compare with firing patterns found in DA-depleted tissue. The hypothesis is that SNr firing would be similar under both conditions, a prerequisite to the proposal of a similar preparation to test other DIP-producing drugs. Firing was analyzed with three complementary metrics, showing similarities between DA depletion and acute DA-receptor blockade. Moreover, blockade of either nonselective cationic channels or Cav3 T-type calcium channels hyperpolarized the membrane and abolished bursting and irregular firing, silencing SNr neurons in both conditions. Therefore, currents generating firing in control conditions are in part responsible for pathological firing. Haloperidol, a DIP-producing drug, reproduced DA-receptor antagonist firing modifications. Since acute DA-receptor blockade induces SNr neuron firing similar to that found in the 6-hydroxydopamine model of PS, output basal ganglia neurons may play a role in generating DIP. Therefore, this study opens the way to test other DIP-producing drugs. NEW & NOTEWORTHY Dopamine (DA) depletion enhances substantia nigra pars reticulata (SNr) neuron bursting and irregular firing, hallmarks of Parkinsonism. Several drugs, including antipsychotics, antidepressants, and calcium channel antagonists, among others, produce drug-induced Parkinsonism. Here we show the first comparison between SNr neuron firing after DA depletion vs. firing found after acute blockade of DA receptors. It was found that firing in both conditions is similar, implying that pathological SNr neuron firing is also a physiological correlate of drug-induced Parkinsonism.

Muscarinic presynaptic modulation in GABAergic pallidal synapses of the rat.

The external globus pallidus (GPe) is central for basal ganglia processing. It expresses muscarinic cholinergic receptors and receives cholinergic afferents from the pedunculopontine nuclei (PPN) and other regions. The role of these receptors and afferents is unknown. Muscarinic M1-type receptors are expressed by synapses from striatal projection neurons (SPNs). Because axons from SPNs project to the GPe, one hypothesis is that striatopallidal GABAergic terminals may be modulated by M1 receptors. Alternatively, some M1 receptors may be postsynaptic in some pallidal neurons. Evidence of muscarinic modulation in any of these elements would suggest that cholinergic afferents from the PPN, or other sources, could modulate the function of the GPe. In this study, we show this evidence using striatopallidal slice preparations: after field stimulation in the striatum, the cholinergic muscarinic receptor agonist muscarine significantly reduced the amplitude of inhibitory postsynaptic currents (IPSCs) from synapses that exhibited short-term synaptic facilitation. This inhibition was associated with significant increases in paired-pulse facilitation, and quantal content was proportional to IPSC amplitude. These actions were blocked by atropine, pirenzepine, and mamba toxin-7, suggesting that receptors involved were M1. In addition, we found that some pallidal neurons have functional postsynaptic M1 receptors. Moreover, some evoked IPSCs exhibited short-term depression and a different kind of modulation: they were indirectly modulated by muscarine via the activation of presynaptic cannabinoid CB1 receptors. Thus pallidal synapses presenting distinct forms of short-term plasticity were modulated differently.

Precision therapy for a medically actionable ATP1A3 variant from a genomic medicine program in an underserved population.

BACKGROUND: Genomic medicine is revolutionizing the diagnosis of rare diseases, but the implementation has not benefited underrepresented populations to the same degree. Here, we report the case of a 7-year-old boy with hypotonia, global developmental delay, strabismus, seizures, and previously suspected mitochondrial myopathy. This proband comes from an underrepresented minority and was denied exome sequencing by his public insurance. METHODS: After informed consent was obtained, buccal cells from the proband were collected and whole exome sequencing was performed. Illumina Dragen and Emedgene software was used to analyze the data at Baylor Genetics. The variants were further intepreted according to ACMG guidelines and the patient's phenotype. RESULTS: Through whole-exome sequencing (WES) under the Community Texome project, he was found to have a heterozygous de novo pathogenic variant in the ATP1A3 gene located on chromosome 19q13. CONCLUSION: In retrospect, his symptomatology matches the known medical conditions associated with the ATP1A3 gene namely Alternating Hemiplegia of Childhood 2 (AHC), a rare autosomal dominant disorder with an incidence of 1 in one million. His single nucleotide variant, (c.2401G>A, p.D801N), is predicted to be damaging. The specific amino acid change p.D801N has been previously reported in ClinVar along with the allelic variant p.D801Y and both are considered pathogenic. The identification of this variant altered medical management for this patient as he was started on a calcium antagonist and has reported no further hemiplegic episodes. This case illustrates the value of implementing genomic medicine for precision therapy in underserved populations.

Bidirectional plasticity in striatonigral synapses: a switch to balance direct and indirect basal ganglia pathways.

There is no hypothesis to explain how direct and indirect basal ganglia (BG) pathways interact to reach a balance during the learning of motor procedures. Both pathways converge in the substantia nigra pars reticulata (SNr) carrying the result of striatal processing. Unfortunately, the mechanisms that regulate synaptic plasticity in striatonigral (direct pathway) synapses are not known. Here, we used electrophysiological techniques to describe dopamine D(1)-receptor-mediated facilitation in striatonigral synapses in the context of its interaction with glutamatergic inputs, probably coming from the subthalamic nucleus (STN) (indirect pathway) and describe a striatonigral cannabinoid-dependent long-term synaptic depression (LTD). It is shown that striatonigral afferents exhibit D(1)-receptor-mediated facilitation of synaptic transmission when NMDA receptors are inactive, a phenomenon that changes to cannabinoid-dependent LTD when NMDA receptors are active. This interaction makes SNr neurons become coincidence-detector switching ports: When inactive, NMDA receptors lead to a dopamine-dependent enhancement of direct pathway output, theoretically facilitating movement. When active, NMDA receptors result in LTD of the same synapses, thus decreasing movement. We propose that SNr neurons, working as logical gates, tune the motor system to establish a balance between both BG pathways, enabling the system to choose appropriate synergies for movement learning and postural support.

Diversity in long-term synaptic plasticity at inhibitory synapses of striatal spiny neurons.

Procedural memories and habits are posited to be stored in the basal ganglia, whose intrinsic circuitries possess important inhibitory connections arising from striatal spiny neurons. However, no information about long-term plasticity at these synapses is available. Therefore, this work describes a novel postsynaptically dependent long-term potentiation (LTP) at synapses among spiny neurons (intrinsic striatal circuitry); a postsynaptically dependent long-term depression (LTD) at synapses between spiny and pallidal neurons (indirect pathway); and a presynaptically dependent LTP at strionigral synapses (direct pathway). Interestingly, long-term synaptic plasticity differs at these synapses. The functional consequences of these long-term plasticity variations during learning of procedural memories are discussed.

Autologous CXCR4+ Hematopoietic Stem Cells Injected into the Scar Tissue of Chronic Myocardial Infarction Patients Normalizes Tissue Contractility and Perfusion.

BACKGROUND: Chronic myocardial infarction (CMI), represents a public health and a financial burden. Since stem cell transplant is used to regenerate cardiac tissue after acute myocardial infarction. AIM OF THE STUDY: To determine if autologous CXCR4 stem cells could restore damaged myocardial tissue in patients with CMI lesions. METHODS: 20 NYHA grade III male patients with CMI defined by clinical, biochemical, ECG and echocardiographic parameters were included. Patients were treated with G-CSF for 6 d before isolating their autologous stem cells from PBMCs. Cell phenotyping was done by cytofluorometry using monoclonal antibodies (anti-CXCR4, -CD34, -48, -117, -133, -Ki67, -SDF1 and CXCR4); CXCR4 cell subpopulations isolated by sorting were adjusted to 1 × 108 cells by subpopulation and injected in a circular pattern into the cicatrix previously defined by echocardiography. RESULTS: Patients were followed for 6 and 12 months. Six months after cell implant improvements in left ventricle ejection fraction (from 33-50%), stress rate values (from -3/-9% to -18/-22%), stress tests (from 4-12 METS), and the quantity of left ventricle affected segments (3-9) disappeared according to the G-SPECT images. 12 months evaluations did not show significant differences. Interestingly, 3 months after cell implant the ECG showed normal electrical activity in 9 patients whereas after 6 months it was normal in all the patients. CONCLUSIONS: These results ratify that locally injected autologous CXCR4+ bone marrow-derived stem cells have a physiological and a clinical impact in patients with CMI.

Experiencia en el cuadro clínico, diagnóstico y tratamiento de COVID-19 / Experience in the clinical picture, diagnosis and treatment of COVID-19 / Experiência no quadro clínico, diagnóstico e tratamento da COVID-19

Resumen: Introducción: La infección por SARS-CoV-2 en Wuhan, China, ocasionó una pandemia de tal magnitud que ha provocado la muerte por neumonía a causa de enfermedad infecciosa por coronavirus 19 (COVID-19) de millones de personas. Nos dimos a la tarea de recolectar todas las características de los pacientes que estuvieron hospitalizados por esta enfermedad en nuestra UCI adultos. Material y métodos: Se realizó un estudio de tipo analítico, descriptivo, observacional y retrospectivo en pacientes con diagnóstico de COVID-19 ingresados en la Unidad de Cuidados Intensivos (UCI) del Hospital Ángeles Clínica Londres en la Ciudad de México, evaluados en el periodo del 23 de marzo de 2020 al 10 de mayo de 2020. Se revisaron los expedientes y se tomaron los datos de los mismos, se describieron variables de tipo demográfico, factores de riesgo, signos y síntomas, tratamiento médico y atención respiratoria. Se revisaron escalas de mortalidad SAPS III, APACHE II, SOFA y CALL-score. Se formaron dos grupos con y sin mortalidad realizándose análisis bivariado y multivariado de las variables significativas. El análisis estadístico se efectuó con el programa SPSS 25. Resultados: En el periodo considerado, 25 expedientes cumplieron con los criterios de inclusión, de ellos la demografía y factores de riesgo, 18 (72%) correspondieron a hombres y siete (38%) a mujeres con una mortalidad de 10 (40%). Los factores de riesgo más frecuentes fueron diabetes mellitus (DM) en siete (38%) pacientes, hipertensión arterial (HAS) en seis (24%), obesidad en cuatro (16%), enfermedad pulmonar obstructiva crónica (EPOC) en uno (4%), tabaquismo en 11 (44%) y alcoholismo en siete (28%). Se encontraron diferencias estadísticamente significativas en los grupos sin mortalidad y con mortalidad, 15 y 10 pacientes, respectivamente, observando las siguientes significancias: glucosa 105 mg/dL (percentil [PE 88]) versus 171 mg/dL (PE 125) p = 0.012, urea 33 mg/dL (PE 22) versus 95 mg/dL (PE 57) p = 0.03, BUN 15.3 mg/dL (PE 11) versus 44.2 mg/dL (PE 26.28) p = 0.04, TGO 32 U/L (PE 24.4) versus 58 U/L (PE 43.8) p = 0.010, DHL 239 U/L (PE 198) 454 U/L (PE 260) p = 0.003, triglicéridos 148 mg/dL (PE 120) versus 187.5 mg/dL (PE 165) p = 0.002, CPK 70 U/L (PE 35) versus 81 U/L (PE 78.25) p = 0.003, ferritina 446 mg/L (PE 238) versus 1,030 mg/L (PE 665) p = 0.007. Se realizó un análisis bivariado con regresión logística binaria, con la variable mortalidad dicotómica, no resultando significativa con esta prueba. Conclusiones: Se entiende que ninguna variable es predominantemente importante para explicar la mortalidad y que se recurre a muchos factores que se conjugan para explicar este desenlace, uno de éstos es la severidad misma del problema respiratorio en que se encuentre el paciente.

Abstract: Introduction: The SARS-CoV-2 infection in Wuhan, China caused a pandemic of such magnitude that it has caused the death of millions of people from pneumonia due to infectious disease caused by coronavirus 19 (COVID-19). We took on the task of collecting all the characteristics of the patients who were hospitalized for this disease in our Adult Intensive Care Unit. Material and methods: An analytical, descriptive, observational and retrospective study was carried out in patients with a diagnosis of COVID-19 admitted to the Intensive Care Unit (ICU) of the Hospital Ángeles Clínica Londres in Mexico City, evaluated in the period of March 23 from 2020 to May 10, 2020. The files were reviewed and the data taken from them, demographic variables, risk factors, signs and symptoms, medical treatment and respiratory care were described. SAPS III, APACHE II, SOFA and CALL-score mortality scales were reviewed. Two groups were formed with and without mortality, performing bivariate and multivariate analyzes of the significant variables. Statistical analysis was performed with the SPSS 25 program. Results: In the period considered, 25 files met the inclusion criteria for them: demographics and risk factors were 18 (72%) corresponding to men and seven (38%) to women. With a mortality of 10 (40%). The most frequent risk factors are diabetes mellitus (DM) in seven (38%), arterial hypertension (SAH) six (24%), obesity four (16%), chronic obstructive pulmonary disease (COPD) one (4%), smoking 11 (44%) and alcoholism seven (28%). Statistically significant differences were found in the groups without mortality and with mortality 15 and 10 patients respectively, observing the following significance: glucose 105 mg/dL (percentil [PE] 88) versus 171 mg/dL (PE 125) p = 0.012, urea 33 mg/dL (PE 22) versus 95 mg/dL (PE 57) p = 0.03, BUN 15.3 mg/dL (PE 11) versus 44.2 mg/dL (PE 26.28) p = 0.04, TGO 32 U/L (PE 24.4) versus 58 U/L (PE 43.8) p = 0.010, DHL 239 U/L (PE 198) 454 U/L (PE 260) p = 0.003, triglycerides 148 mg/dL (PE 120) versus 187.5 mg/dL (PE 165) p = 0.002, CPK 70 U/L (PE 35) versus 81 U/L (PE 78.25) p = 0.003, ferritin 446 mg/L (PE 238) versus 1,030 mg/L (PE 665) p = 0.007. A bivariate analysis with binary logistic regression was performed, with the dichotomous mortality variable, not resulting in this significant test. Conclusions: It is understood that no variable is predominantly important to explain mortality and that many factors are involved that are combined to explain this outcome, one of these being the same severity of the respiratory problem in which the patient is.

Resumo: Introdução: A infecção por SARS-CoV-2 em Wuhan China causou uma pandemia de tal magnitude que causou a morte de milhões de pessoas por pneumonia devido a doença infecciosa causada pelo coronavírus 19 (COVID-19). Assumimos a tarefa de coletar todas as características dos pacientes internados por essa doença em nossa unidade de terapia intensiva adulto. Material e métodos: Realizou-se um estudo analítico, descritivo, observacional e retrospectivo em pacientes com diagnóstico de COVID-19 internados na Unidade de Terapia Intensiva (UTI) do Hospital Ángeles Clínica Londres na Cidade do México, validado para o período de 23 de março de 2020 a 10 de maio de 2020. Os prontuários médicos foram revisados e seus dados coletados, as variáveis do tipo demográficas foram descritas, fatores de risco, sinais e sintomas, tratamento médico e cuidados respiratórios. Foram revisadas as escalas de mortalidade SAPS III, APACHE II, SOFA e CALL-score. Dois grupos foram formados com e sem mortalidade, realizando análises bivariadas e multivariadas das variáveis significativas. A análise estatística foi realizada com o programa SPSS 25. Resultados: No período considerado, 25 prontuários atenderam aos critérios de inclusão para os mesmos: dados demográficos e fatores de risco foram 18 (72%) correspondentes a homens e 7 (38%) a mulheres. Com mortalidade de 10 (40%). Os fatores de risco mais frequentes são diabetes mellitus (DM) em 7 (38%), hipertensão arterial (HAS) 6 (24%), obesidade 4 (16%), doença pulmonar obstrutiva crônica (DPOC) 1 (4%), tabagismo 11 (44%) e alcoolismo 7 (28%). Encontrou-se diferenças estatisticamente significativas nos grupos sem mortalidade e com mortalidade de 15 e 10 pacientes respectivamente, observando a seguinte significância: glicose 105 mg/dL (percentil [PE] 88) versus 171 mg/dL (PE 125) p = 0.012, uréia 33 mg/L (PE 22) versus 95 mg/L (PE 57) p = 0.03, BUN 15.3 mg/L (PE 11) versus 44.2 mg/L (PE 26.28) p = 0.04, TGO 32 U/L (PE 24.4) versus 58 U/L (PE 43.8) p = 0.010, DHL 239 U/L (PE 198) 454 (PE 260) p = 0.003, triglicerídeos 148 mg/dL (PE 120) versus 187.5 mg/dL (PE 165) p = 0.002, CPK 70 U/L (PE 35) versus 81 U/L (PE 78.25) p = 0.003, ferritina 446 mg/L (PE 238) versus 1030 mg/L (PE 665) p = 0.007. Realizou-se análise bivariada com regressão logística binária, com a variável mortalidade dicotômica, não resultando em teste significativo. Conclusões: Entende-se que nenhuma variável é predominantemente importante para explicar a mortalidade e que usamos muitos fatores que se conjugam para explicar esse desfecho, sendo um deles a mesma gravidade do problema respiratório em que o paciente se encontra.

Direct cardiac injection of G-CSF mobilized bone-marrow stem-cells improves ventricular function in old myocardial infarction.

Autologous transplant of bone marrow stem cells (BMSC), although extremely useful after acute myocardial events, has not been evaluated in patients with old (>one-year-old) myocardial infarction. Our aim was to determine if CD34(+)-enriched peripheral-blood cells, obtained by apheresis, injected directly into the severely damaged myocardium of five patients with old myocardial infarction could restore depressed myocardial function. We found that 28 weeks after revascularization and peri-infarction injection of the enriched CD34(+) peripheral mononuclear cells, ventricular hemodynamic parameters that included left ventricular ejection fraction, left ventricular diastolic volume, ventricular systolic volume and left ventricular diastolic diameter approximated normal values and there was no restenosis; two patients have been followed for >52 weeks and their parameters are within normal values. In conclusion, intramyocardial injection of easily obtained CD34(+) enriched peripheral blood cells represent an encouraging procedure for patients with severely scarred and dysfunctional myocardium.

[Stem cell perspectives in myocardial infarctions]. / Perspectivas de las células tallo en infartos del miocardio.

Myocardial infarction is the leading cause of congestive heart failure and death in industrializated countries. The cellular cardiomyoplasty has emerged as an alternative treatment in the regeneration of infarted myocardial tissue. In animals' models, different cellular lines such as cardiomyocites, skeletal myoblasts, embryonic stem cells and adult mesenchymal stem cells have been used, resulting in an improvement in ventricular function and decrease in amount of infarcted tissue. The first three cells lines have disvantages as they are allogenics and are difficult to obtain. The adult mesenchymal stem cells are autologous and can be obtained throught the aspiration of bone marrow or from peripherical circulation, after stimulating with cytokines (G-CSF). The implantation in humans with recent and old myocardial infarction have shown improvements similar to those shown in animal models. These findings encourage the continued investigation in the mechanism of cellular differentiation and implantation methods in infarcted myocardial tissue.

A subpopulation of large granular von Willebrand Ag negative and CD105 positive endothelial cells, isolated from abdominal aortic aneurysms, overexpress ICAM-1 and Fas antigen.

The aim of this work was to determine whether there is a pre-established basal condition of the endothelial cells isolated from aortic abdominal aneurysm that might augment immune effector mechanisms and thus provide us an insight into the possible causes of aneurysm rupture. Endothelial cells isolated from saccular aortic aneurysm fragments were analyzed by cytofluorometry for the expression of different immune response-related molecules. Our results showed that there is a subpopulation of granule-rich, CD105 positive and von Willebrand antigen negative endothelial cells that have an enhanced basal expression of ICAM-1, and Fas antigen, but, interestingly, no apoptotic bodies were detected. Control endothelial cells derived from healthy areas of the same abdominal aortas did not show such enhanced expression. We conclude that in the endothelium that lines abdominal aorta aneurysms there is, at least, one endothelial cell subpopulation with an apparent inhibition of programmed cell death and in a proinflammatory activation status.

Sporadic Hemiplegic Migraine with ATP1A2 and Prothrombin Gene Mutations.

Background. Hemiplegic migraine is a rare type of migraine that may present in children and adolescents. Both familial and sporadic hemiplegic migraines have similar prevalence and clinical characteristics. Patient. We report an adolescent with sporadic hemiplegic migraine who previously had a similar attack in the past and who was initially evaluated for a possible acute ischemic event. Results. Magnetic resonance angiography showed dilatation of the left middle cerebral artery that resolved in a follow-up study. She was also found to have a ATP1A2 (c.2273 G>C) mutation and a heterozygous prothrombin mutation. Conclusions. We suggest that patients with sporadic hemiplegic migraine be tested for both ATP1A2 mutations which in some cases may be pathogenic, and prothrombin mutations which increase the stroke risk for this patient population.

The role of levetiracetam in treatment of seizures in brain tumor patients.

Levetiracetam, trade name Keppra, is a new second generation antiepileptic drug that is being increasingly used in brain tumor patients. In patients suffering with brain tumors, seizures are one of the leading neurologic complications being seen in more than 30% of patients. Unlike other antiepileptic drugs, levetiracetam is proposed to bind to a synaptic vesicle protein inhibiting calcium release. Brain tumor patients are frequently on chemotherapy or other drugs that induce cytochrome P450, causing significant drug interactions. However, levetiracetam does not induce the P450 system and does not exhibit any relevant drug interactions. Intravenous delivery is as bioavailable as the oral medication allowing it to be used in emergency situations. Levetiracetam is an attractive option for brain tumor patients suffering from seizures, but also can be used prophylactically in patients with brain tumors, or patients undergoing neurological surgery. Emerging studies have also demonstrated that levetiracetam can increase the sensitivity of Glioblastoma tumors to the chemotherapy drug temozolomide. Levetiracetam is a safe alternative to conventional antiepileptic drugs and an emerging tool for brain tumor patients combating seizures.

Efficacy and tolerability of intravenous levetiracetam in childrens.

Intractable epilepsy in children poses a serious medical challenge. Acute repetitive seizures and status epilepticus leads to frequent emergency room visits and hospital admissions. Delay of treatment may lead to resistance to the first-line anticonvulsant therapies. It has been shown that these children continue to remain intractable even after acute seizure management with approved Food and Drug Administration (FDA) agents. Intravenous levetiracetam, a second-generation anticonvulsant was approved by the FDA in 2006 in patients 16 years and older as an alternative when oral treatment is not an option. Data have been published showing that intravenous levetiracetam is safe and efficacious, and can be used in an acute inpatient setting. This current review will discuss the recent data about the safety and tolerability of intravenous levetiracetam in children and neonates, and emphasize the need for a larger prospective multicenter trial to prove the efficacy of this agent in acute seizure management.

Neurobehavioral effects of levetiracetam in brain tumor related epilepsy.

The neurobehavioral profile of anti-epileptic drugs (AEDs) has been a recurrent research topic in the scientific literature. As pharmacological treatments for epilepsy continue to evolve, there is a general consensus that newer AEDs have less detrimental side effects in comparison to their older counterparts. Among newer AEDs and epilepsy patients, potential risk for neurobehavioral changes has been reported with levetiracetam (LEV). Conversely, limited data exists regarding the manifestation of this symptomatology in a subgroup of epilepsy patients with brain tumors. The current paper reviews the literature regarding the neurobehavioral profile of LEV in brain tumor related epilepsy and suggestions for future research will be discussed.

Clinical pharmacology and pharmacokinetics of levetiracetam.

Status epilepticus and acute repetitive seizures still pose a management challenge despite the recent advances in the field of epilepsy. Parenteral formulations of old anticonvulsants are still a cornerstone in acute seizure management and are approved by the FDA. Intravenous levetiracetam (IV LEV), a second generation anticonvulsant, is approved by the FDA as an adjunctive treatment in patients 16 years or older when oral administration is not available. Data have shown that it has a unique mechanism of action, linear pharmacokinetics and no known drug interactions with other anticonvulsants. In this paper, we will review the current literature about the pharmacology and pharmacokinetics of IV LEV and the safety profile of this new anticonvulsant in acute seizure management of both adults and children.

Dopaminergic presynaptic modulation of nigral afferents: its role in the generation of recurrent bursting in substantia nigra pars reticulata neurons.

PREVIOUS WORK HAS SHOWN THE FUNCTIONS ASSOCIATED WITH ACTIVATION OF DOPAMINE PRESYNAPTIC RECEPTORS IN SOME SUBSTANTIA NIGRA PARS RETICULATA (SNR) AFFERENTS: (i) striatonigral terminals (direct pathway) posses presynaptic dopamine D(1)-class receptors whose action is to enhance inhibitory postsynaptic currents (IPSCs) and GABA transmission. (ii) Subthalamonigral terminals posses D(1)- and D(2)-class receptors where D(1)-class receptor activation enhances and D(2)-class receptor activation decreases excitatory postsynaptic currents. Here we report that pallidonigral afferents posses D(2)-class receptors (D(3) and D(4) types) that decrease inhibitory synaptic transmission via presynaptic modulation. No action of D(1)-class agonists was found on pallidonigral synapses. In contrast, administration of D(1)-receptor antagonists greatly decreased striatonigral IPSCs in the same preparation, suggesting that tonic dopamine levels help in maintaining the function of the striatonigral (direct) pathway. When both D(3) and D(4) type receptors were blocked, pallidonigral IPSCs increased in amplitude while striatonigral connections had no significant change, suggesting that tonic dopamine levels are repressing a powerful inhibition conveyed by pallidonigral synapses (a branch of the indirect pathway). We then blocked both D(1)- and D(2)-class receptors to acutely decrease direct pathway (striatonigral) and enhance indirect pathways (subthalamonigral and pallidonigral) synaptic force. The result was that most SNr projection neurons entered a recurrent bursting firing mode similar to that observed during Parkinsonism in both patients and animal models. These results raise the question as to whether the lack of dopamine in basal ganglia output nuclei is enough to generate some pathological signs of Parkinsonism.

[Correction of the perpendicular positioning of the Amplatzer device during closure of an ostium secundum atrial septal defect]. / Corrección de la posición perpendicular del oclusor Amplatzer en el cierre percutáneo de la comunicación interauricular ostium secundum.

INTRODUCTION AND OBJECTIVES: Ostium secundum atrial septal defects require closure. Echocardiographic studies have reported that, in 7% of cases, the Amplatzer occluder is orientated perpendicular to the rim of the defect. This article describes the use of an ancillary technique involving a balloon catheter that enables the Amplatzer device to be positioned transversely. METHODS: We report six patients with an ostium secundum atrial septal defect in whom echocardiographic imaging showed that the Amplatzer device was positioned perpendicular to the rim of the defect. To correct the device's orientation, we used an ancillary maneuver that involved placing a balloon catheter at the device's lower edge, thereby inducing it to adopt a transverse position and undergo successful implantation. RESULTS: In all cases, the ancillary balloon catheter technique enabled the device to adopt the correct transverse orientation, thereby facilitating successful implantation. CONCLUSIONS: The ancillary balloon catheter technique is useful for ensuring that Amplatzer devices adopt a transverse orientation when echocardiography shows the device to be persistently orientated perpendicular to the rim of the septal defect.

Perspectivas de las células tallo en infartos del miocardio / Stem cell perspectives in myocardial infarctions

Myocardial infarction is the leading cause of congestive heart failure and death in industrializated countries. The cellular cardiomyoplasty has emerged as an alternative treatment in the regeneration of infarted myocardial tissue. In animals' models, differents cellular lines such as cardiomyocites, sheletal myoblast, embryonic stem cells and adult mesenchymal stem cells has been used, resulting in an improvement in ventricular function and decrease in amount of infarted tissue. The first three cells line have disvantages as they are allogenics and are difficult to obtain. The adult mesenchymal stem cells are autologous and can be obtained throught the aspiration of bone marrow or from peripherical circulation, prior to stimulating with cytokines (G-CSF). The implantation in humans with recent and old myocardial infarction have shown improvements similar to those shown in animal models. These findings encourage the continued investigation in the mechanism of cellular differentiation and implantation metods in infarted myocardial tissue.

El infarto del miocardio es la principal causa de falla cardiaca y muerte en países industrializados. A la fecha, la cardiomioplastia celular ha emergido como una alternativa en la regeneración de infartos miocárdicos. En modelos animales se han utilizado diferentes líneas celulares como cardiomiocitos fetales, mioblastos de músculo esquelético, células tallo embrionarias y células tallo mesenquimales del adulto, con mejoría en la función ventricular y disminución del área de tejido infartado. Las tres primeras líneas celulares tienen desventajas porque son alogénicas y difíciles de obtener. Las células tallo mesenquimales del adulto son autólogas y se pueden obtener de aspirados de médula ósea o de la circulación periférica previa estimulación con citocinas (G-CSF). La implantación de estas células en seres humanos con infartos del miocardio recientes y antiguos han mostrado mejorías similares a los reportes con modelos animales. Estos hallazgos alientan a continuar la investigación clínica y básica en busca de los mecanismos de diferenciación celular y selección de vías de implantación, en tejido miocárdico infartado.