AAV6 mediated Gsx1 expression in neural stem progenitor cells promotes neurogenesis and restores locomotor function after contusion spinal cord injury.

Genomic screened homeobox 1 (Gsx1 or Gsh1) is a neurogenic transcription factor required for the generation of excitatory and inhibitory interneurons during spinal cord development. In the adult, lentivirus (LV) mediated Gsx1 expression promotes neural regeneration and functional locomotor recovery in a mouse model of lateral hemisection spinal cord injury (SCI). The LV delivery method is clinically unsafe due to insertional mutations to the host DNA. In addition, the most common clinical case of SCI is contusion/compression. In this study, we identify that adeno-associated virus serotype 6 (AAV6) preferentially infects neural stem/progenitor cells (NSPCs) in the injured spinal cord. Using a rat model of contusion SCI, we demonstrate that AAV6 mediated Gsx1 expression promotes neurogenesis, increases the number of neuroblasts/immature neurons, restores excitatory/inhibitory neuron balance and serotonergic neuronal activity through the lesion core, and promotes locomotor functional recovery. Our findings support that AAV6 preferentially targets NSPCs for gene delivery and confirmed Gsx1 efficacy in clinically relevant rat model of contusion SCI.

Nkx6.1 enhances neural stem cell activation and attenuates glial scar formation and neuroinflammation in the adult injured spinal cord.

Nkx6.1 plays an essential role during the embryonic development of the spinal cord. However, its role in the adult and injured spinal cord is not well understood. Here we show that lentivirus-mediated Nkx6.1 expression in the adult injured mouse spinal cord promotes cell proliferation and activation of endogenous neural stem/progenitor cells (NSPCs) at the acute phase of injury. In the chronic phase, Nkx6.1 increases the number of interneurons, reduces the number of reactive astrocytes, minimizes glial scar formation, and represses neuroinflammation. Transcriptomic analysis reveals that Nkx6.1 upregulates the sequential expression of genes involved in cell proliferation, neural differentiation, and Notch signaling pathway, downregulates genes and pathways involved in neuroinflammation, reactive astrocyte activation, and glial scar formation. Together, our findings support the potential role of Nkx6.1 in neural regeneration in the adult injured spinal cord.

Diversity of Adult Neural Stem and Progenitor Cells in Physiology and Disease.

Adult neural stem and progenitor cells (NSPCs) contribute to learning, memory, maintenance of homeostasis, energy metabolism and many other essential processes. They are highly heterogeneous populations that require input from a regionally distinct microenvironment including a mix of neurons, oligodendrocytes, astrocytes, ependymal cells, NG2+ glia, vasculature, cerebrospinal fluid (CSF), and others. The diversity of NSPCs is present in all three major parts of the CNS, i.e., the brain, spinal cord, and retina. Intrinsic and extrinsic signals, e.g., neurotrophic and growth factors, master transcription factors, and mechanical properties of the extracellular matrix (ECM), collectively regulate activities and characteristics of NSPCs: quiescence/survival, proliferation, migration, differentiation, and integration. This review discusses the heterogeneous NSPC populations in the normal physiology and highlights their potentials and roles in injured/diseased states for regenerative medicine.

Gsx1 promotes locomotor functional recovery after spinal cord injury.

Promoting residential cells, particularly endogenous neural stem and progenitor cells (NSPCs), for tissue regeneration represents a potential strategy for the treatment of spinal cord injury (SCI). However, adult NSPCs differentiate mainly into glial cells and contribute to glial scar formation at the site of injury. Gsx1 is known to regulate the generation of excitatory and inhibitory interneurons during embryonic development of the spinal cord. In this study, we show that lentivirus-mediated expression of Gsx1 increases the number of NSPCs in a mouse model of lateral hemisection SCI during the acute stage. Subsequently, Gsx1 expression increases the generation of glutamatergic and cholinergic interneurons and decreases the generation of GABAergic interneurons in the chronic stage of SCI. Importantly, Gsx1 reduces reactive astrogliosis and glial scar formation, promotes serotonin (5-HT) neuronal activity, and improves the locomotor function of the injured mice. Moreover, RNA sequencing (RNA-seq) analysis reveals that Gsx1-induced transcriptome regulation correlates with NSPC signaling, NSPC activation, neuronal differentiation, and inhibition of astrogliosis and scar formation. Collectively, our study provides molecular insights for Gsx1-mediated functional recovery and identifies the potential of Gsx1 gene therapy for injuries in the spinal cord and possibly other parts of the central nervous system.

Peak early diastolic mitral annulus velocity by tissue Doppler imaging for the assessment of left ventricular relaxation in subjects with mitral annulus calcification.

AIMS: The aim of this article was to determine whether lateral and septal early diastolic mitral annular velocities (LW-e' and IS-e', respectively) accuracy to reflect left ventricular (LV) relaxation is truly compromised by a limitation of mitral annular motion due to mitral annulus calcification (MAC) and to search for e' surrogates to circumvent this limitation. METHODS AND RESULTS: LW-e', IS-e', and peak early diastolic velocities at the basal-lateral and basal-septal LV segments 2 cm distal to the annulus (LW-e'2 and IS-e'2, respectively) were measured using tissue Doppler imaging (TDI) in 206 consecutive patients referred for echocardiography. Significant MAC (assessed by two-dimensional echocardiography) was present in 57 (28%) subjects. There was a significant reduction in LW-Δe' (LW-e' minus LW-e'2) in subjects with posterior MAC (0.15 ± 1.35 vs. 1.30 ± 1.24 cm/s, P < 0.0001) and a small but not significant reduction in IS-Δe' (IS-e' minus IS-e'2) in subjects with anterior MAC (-0.15 ± 1.04 vs. 0.42 ± 1.56 cm/s, P = 0.07), compared with age-matched no MAC subjects. Potential confusion factors were analysed on multiple regression. The basal segments in which e'2 were measured were free of calcification regardless of MAC. In search for e'2-based surrogates for e', the regression equation [Formula: see text] (R(2) = 0.86, P < 0.0001) was obtained from the first 100 consecutive subjects and validated in the next 49 no MAC subjects (intraclass correlation coefficient 0.96, P < 0.0001). In the septal side, no difference was found between IS-e' and IS-e'2 in the 149 subjects with no MAC (8.5 ± 3.1 vs. 8.5 ± 2.9 cm/s, P = 0.55). CONCLUSION: MAC significantly affected LW-e' (and not significantly IS-e') accuracy to reflect LV relaxation. [Formula: see text] and IS-e'2 as surrogates for LW-e' and IS-e', respectively, may correct this inaccuracy.

Utilidad de los valores del péptido natriurético cerebral frente al control clínico habitual para la monitorización del tratamiento en pacientes con insuficiencia cardiaca / Usefulness of brain natriuretic peptide levels, as compared with usual clinical control, for the treatment monitoring of patients with heart failure

Fundamento y objetivos: La insuficiencia cardiaca crónica sigue teniendo un mal pronóstico, a pesar de los avances en su tratamiento. Es posible que la optimización del tratamiento basada en el control clínico de los pacientes no sea la estrategia más efectiva. El objetivo de nuestro estudio es evaluar la efectividad de una estrategia de adecuación del tratamiento basada en los valores del péptido natriurético cerebral (BNP).Pacientes y métodos: Se han estudiado 60 pacientes consecutivamente dados de alta en un servicio de cardiología de un hospital español con el diagnóstico de insuficiencia cardiaca con clase de la New York Heart Association (NYHA) III o IV, 30 asignados de forma aleatoria a un grupo en el que el ajuste del tratamiento farmacológico se basó en un control clínico (score de Framinghan), y otros 30 a un grupo en el que el ajuste se realizó de acuerdo a los valores plasmáticos de BNP. El tratamiento se ajustó intentando obtener una puntuación clínica <2 en el grupo de control clínico y unos valores plasmáticos de BNP <100pg/ml en el grupo de control por BNP. Los pacientes fueron seguidos durante 16±4 meses.Resultados: Los pacientes controlados mediante el BNP tuvieron unos valores de este marcador menores a lo largo del seguimiento en comparación a los del grupo control. La puntuación clínica fue similar en ambos grupos: media (DE) de 0,42 (0,33) frente a 0,39 (0,63) a los 18 meses. La probabilidad de supervivencia a los 18 meses fue similar (86% en ambos grupos), igual que la probabilidad de no sufrir reingresos por insuficiencia cardiaca (68 frente a 66%) (AU)

Background and objectives: Chronic heart failure continues to have a poor prognosis, in spite of advances made in its therapy. It is uncertain whether symptom-guided therapy optimization is the most effective strategy in this setting. The aim of our study was to evaluate the usefulness of a brain natriuretic peptide (BNP)-guided therapy for the treatment of patients with heart failure. Patients and methods: We carried out a prospective and randomized study including 60 patients consecutively discharged with the diagnosis of heart failure NYHA class III or IV in one cardiology department of a Spanish hospital; 30 patients were randomly assigned to a symptom-guided therapy group based on the clinical Framingham score, and 30 to a BNP-guided therapy group. Therapy was adjusted to obtain a clinical score <2 in the symptom-guided group and BNP levels <100pg/ml in the BNP-guided group. Follow up was 16±4 months. Results: BNP-guided group had lower BNP levels during follow up than had symptom-guided group: 14(20)pg/ml versus 111±71pg/ml at 18 months, p=0.029. Clinical score was similar in both groups: 0.42(0.33) versus 0.39(0.63) at 18 months. Probability of survival (86% in both groups) and probability of being free of readmissions for heart failure (68 versus 66%) at 18 months were similar in both groups. Conclusions: In our experience, in patients with heart failure, BNP-guided therapy did not improve clinical outcomes compared with symptom-guided therapy (AU)

[Usefulness of brain natriuretic peptide levels, as compared with usual clinical control, for the treatment monitoring of patients with heart failure]. / Utilidad de los valores del péptido natriurético cerebral frente al control clínico habitual para la monitorización del tratamiento en pacientes con insuficiencia cardiaca.

BACKGROUND AND OBJECTIVES: Chronic heart failure continues to have a poor prognosis, in spite of advances made in its therapy. It is uncertain whether symptom-guided therapy optimization is the most effective strategy in this setting. The aim of our study was to evaluate the usefulness of a brain natriuretic peptide (BNP)-guided therapy for the treatment of patients with heart failure. PATIENTS AND METHODS: We carried out a prospective and randomized study including 60 patients consecutively discharged with the diagnosis of heart failure NYHA class III or IV in one cardiology department of a Spanish hospital; 30 patients were randomly assigned to a symptom-guided therapy group based on the clinical Framingham score, and 30 to a BNP-guided therapy group. Therapy was adjusted to obtain a clinical score <2 in the symptom-guided group and BNP levels <100pg/ml in the BNP-guided group. Follow up was 16±4 months. RESULTS: BNP-guided group had lower BNP levels during follow up than had symptom-guided group: 14(20)pg/ml versus 111±71pg/ml at 18 months, p=0.029. Clinical score was similar in both groups: 0.42(0.33) versus 0.39(0.63) at 18 months. Probability of survival (86% in both groups) and probability of being free of readmissions for heart failure (68 versus 66%) at 18 months were similar in both groups. CONCLUSIONS: In our experience, in patients with heart failure, BNP-guided therapy did not improve clinical outcomes compared with symptom-guided therapy.

[Percutaneous closure of patent foramen ovale in young patients with cryptogenic stroke: long-term follow-up]. / Cierre percutáneo de foramen oval permeable en pacientes jóvenes con ictus criptogénico: seguimiento a largo plazo.

Percutaneous closure of patent foramen ovale (PFO) has been proposed as a therapeutic option for cryptogenic stroke. The aim of this article was to describe the experience with this treatment at our center. Up until February 2006, percutaneous closure of PFO was carried out in 52 patients who presented with one or more cryptogenic strokes or transient ischemic attacks. The procedure was carried out under anesthesia and was guided by transesophageal echocardiography. The overall success rate was 100%. Transesophageal echocardiography carried out immediately after device implantation found no evidence of right-to-left shunting in 27 patients. During a mean follow-up of 26 months in 49 patients, none presented with a new ischemic episode or with complications attributable to the device. Echocardiographic follow-up showed that the foramen ovale had been completely sealed in all cases.

Cierre percutáneo de foramen oval permeable en pacientes jóvenes con ictus criptogénico: seguimiento a largo plazo / Percutaneous Closure of Patent Foramen Ovale in Young Patients With Cryptogenic Stroke: Long-Term Follow-Up

El cierre percutáneo del foramen oval permeable esuna de las opciones terapéuticas propuestas para el ictuscriptogénico. El objetivo del presente trabajo es describir la experiencia de nuestro centro. Hasta febrero de 2006, se ha tratado con cierre percutáneo de foramen oval permeable a 52 pacientes que habían presentado uno o más ictus o ataques isquémicos transitorios criptogénicos. El procedimiento se realizó con anestesia y guiado por ecocardiografía transesofágica (ETE). La tasa de éxito primario fue del 100%. Inmediatamente tras el implante deldispositivo, en 27 pacientes no se observó paso derechaizquierda por ETE. Tras un seguimiento clínico medio de 26 meses en 49 pacientes, ninguno ha tenido nuevos episodios isquémicos ni complicaciones atribuibles al dispositivo. El seguimiento ecocardiográfico mostró en todos un sellado completo del foramen oval

Percutaneous closure of patent foramen ovale (PFO)has been proposed as a therapeutic option forcryptogenic stroke. The aim of this article was to describe the experience with this treatment at our center. Up until February 2006, percutaneous closure of PFO was carried out in 52 patients who presented with one or more cryptogenic strokes or transient ischemic attacks. The procedure was carried out under anesthesia and was guided by transesophageal echocardiography. Theoverall success rate was 100%. Transesophagealechocardiography carried out immediately after deviceimplantation found no evidence of right-to-left shunting in 27 patients. During a mean follow-up of 26 months in 49 patients, none presented with a new ischemic episode or with complications attributable to the device.Echocardiographic follow-up showed that the foramenovale had been completely sealed in all cases (AU)

Drug-eluting stents for the treatment of bifurcation lesions: a randomized comparison between paclitaxel and sirolimus stents.

BACKGROUND: Drug-eluting stents have been shown to reduce restenosis in many types of lesions. The purpose of this article is to assess the efficacy of sirolimus- and paclitaxel-eluting stents in patients with bifurcation lesions. METHODS: Between June 2003 and October 2004, 205 patients were enrolled in a prospective randomized trial; 103 patients were assigned to sirolimus stents and 102 patients to paclitaxel stents. All patients were treated by provisional T-stenting. RESULTS: There were no differences between groups in terms of age, risk factors, clinical condition, location of the bifurcation lesion, or other technical factors. Angiographic data and immediate results were also similar in both groups. Three patients developed inhospital non-Q-wave acute myocardial infarction (2 from the sirolimus group and 1 from the paclitaxel group). Follow-up angiography was obtained in 109 patients (53%). In the sirolimus group, 5 patients developed restenosis (9%): 1 at the main vessel, 2 at the side branch, and 2 in both branches. In contrast, 16 patients from the paclitaxel group had restenosis (29%): 6 at the main vessel, 5 at the side branch, and 5 in both branches. Target lesion revascularization at 24 +/- 5 months post stenting occurred in 4 patients from the sirolimus group (4%) and in 13 from the paclitaxel group (13%) (P < .05). Late loss at the main vessel in the sirolimus group patients was 0.31 +/- 0.59 versus 0.60 +/- 0.77 mm in patients from the paclitaxel group (P < .05). CONCLUSIONS: Patients with bifurcation lesions treated by sirolimus showed significantly lower rates of late loss, restenosis and target lesion revascularization than patients treated with paclitaxel-eluting stents.