Molecular target discovery for neural repair in the functional genomics era

A comprehensive understanding of the molecular pathways activated by traumatic neural injury is of major importance for the development of treatments for spinal cord injury (SCI). High-throughput gene expression profiling is a powerful approach to reveal genome-wide changes in gene expression during a specific biological process. Microarray analysis of injured nerves or neurons would ideally generate new hypotheses concerning the progression or deregulation of injury- and repair-related biological processes, such as neural scar formation and axon regeneration. These hypotheses should subsequently be tested experimentally and would eventually provide the molecular substrates for the development of novel therapeutics. Over the last decade, this approach has elucidated numerous extrinsic (mostly neural scar-associated) as well as neuron-intrinsic genes that are regulated following an injury. To date, the main challenge is to translate the observed injury-induced gene expression changes into a mechanistic framework to understand their functional implications. To achieve this, research on neural repair will have to adopt the conceptual advances and analytical tools provided by the functional genomics and systems biology revolution. Based on progress made in bioinformatics, high-throughput and high-content functional cellular screening, and in vivo gene transfer technology, we propose a multistep " roadmap" that provides an integrated strategy for molecular target discovery for repair of the injured spinal cord. © 2012 Elsevier B.V

Large and medium-sized pulmonary artery obstruction does not play a role of primary importance in the etiology of sickle-cell disease-associated pulmonary hypertension

Background: Pulmonary hypertension (PHT) occurs in approximately 30% of adult patients with sickle-cell disease (SCD) and is a risk factor for early death. The potential role of pulmonary artery obstruction, whether due to emboli or in situ thrombosis, in the etiology of SCD-related PHT is unknown. Methods: Consecutive SCD patients were screened for PHT (defined as a tricuspid regurgitant jet flow velocity ≥ 2.5 m/s) employing echocardiography and were evaluated for pulmonary artery obstruction with ventilation-perfusion (VQ) scintigraphy. Results: Fifty-three HbSS, 6 HbSβ0-thalassemia, 20 HbSC, and 6 HbSβ+-thalassemia patients were included. The overall prevalence of PHT was 41% in HbSS/HbSβ0-thalassemia patients and 13% in HbSC/HbSβ+-thalassemia patients. High-probability VQ defects (Prospective Investigation of Pulmonary Embolism Diagnosis criteria) were detected in two patients, one of whom had PHT. In HbSS/HbSβ0-thalassemia patients with PHT, 19 patients (86%), 2 patients (9%), and 1 patient (5%) had low-, intermediate-, or high-probability scan results as compared to 30 patients (97%), 1 patient (3%), and 0 patients (0%) in HbSS/HbSβ0-thalassemia patients without PHT (p = 0.31). In HbSC/HbSβ+-thalassemia patients with PHT, 3 patients (100%), 0 patients (0%), and 0 patients (0%) had low-, intermediate-, and a high-probability scan as compared to 19 patients (90%), 1 patient (5%), and 1 patient (5%) in HbSC/HbSβ+-thalassemia patients without PHT (p = 0.86). There were no statistical differences in irregular distribution of the radiopharmaceutical or nonspecific signs associated with PHT between patients with and without PHT. Conclusions: Although small pulmonary artery obstruction cannot be excluded, large to medium-sized pulmonary artery obstruction is an unlikely primary causative factor in SCD-related PHT