Motor-evoked potentials in amyotrophic lateral sclerosis: potential implications in detecting subclinical UMN involvement in lower motor neuron phenotype

Journal of Neurology - In amyotrophic lateral sclerosis (ALS), the involvement of lower motor neuron is well defined by electromyography, whereas a reliable marker of upper motor neuron (UMN)...     

Avoidance of stimulation improves engraftment of cultured and retrovirally transduced hematopoietic cells in primates

Recent reports suggest that cells in active cell cycle have an engraftment defect compared with quiescent cells. We used nonhuman primates to investigate this finding, which has direct implications for clinical transplantation and gene therapy applications. Transfer of rhesus CD34(+) cells to culture in stem cell factor (SCF) on the CH-296 fibronectin fragment (FN) after 4 days of culture in stimulatory cytokines maintained cell viability but decreased cycling. Using retroviral marking with two different gene transfer vectors, we compared the engraftment potential of cytokine-stimulated cells versus those transferred to nonstimulatory conditions (SCF on FN alone) before reinfusion. In vivo competitive repopulation studies showed that the level of marking originating from the cells continued in culture for 2 days with SCF on FN following a 4-day stimulatory transduction was significantly higher than the level of marking coming from cells transduced for 4 days and reinfused without the 2-day culture under nonstimulatory conditions. We observed stable in vivo overall gene marking levels of up to 29%. This approach may allow more efficient engraftment of transduced or ex vivo expanded cells by avoiding active cell cycling at the time of reinfusion.     

Retroviral transduction efficiency of G-CSF+SCF-mobilized peripheral blood CD34+ cells is superior to G-CSF or G-CSF+Flt3-L-mobilized cells in nonhuman primates

Gene transfer experiments in nonhuman primates have been shown to be predictive of success in human clinical gene therapy trials. In most nonhuman primate studies, hematopoietic stem cells (HSCs) collected from the peripheral blood or bone marrow after administration of granulocyte colony-stimulating factor (G-CSF) + stem cell factor (SCF) have been used as targets, but this cytokine combination is not generally available for clinical use, and the optimum target cell population has not been systematically studied. In our current study we tested the retroviral transduction efficiency of rhesus macaque peripheral blood CD34(+) cells collected after administration of different cytokine mobilization regimens, directly comparing G-CSF+SCF versus G-CSF alone or G-CSF+Flt3-L in competitive repopulation assays. Vector supernatant was added daily for 96 hours in the presence of stimulatory cytokines. The transduction efficiency of HSCs as assessed by in vitro colony-forming assays was equivalent in all 5 animals tested, but the in vivo levels of mononuclear cell and granulocyte marking was higher at all time points derived from target CD34(+) cells collected after G-CSF+SCF mobilization compared with target cells collected after G-CSF (n = 3) or G-CSF+Flt3-L (n = 2) mobilization. In 3 of the animals long-term marking levels of 5% to 25% were achieved, but originating only from the G-CSF+SCF-mobilized target cells. Transduction efficiency of HSCs collected by different mobilization regimens can vary significantly and is superior with G-CSF+SCF administration. The difference in transduction efficiency of HSCs collected from different sources should be considered whenever planning clinical gene therapy trials and should preferably be tested directly in comparative studies.     

Force-frequency relationship in the echocardiography laboratory: a noninvasive assessment of Bowditch treppe?

BACKGROUND: Estimation of contractility of the left ventricle is an important, and as yet elusive, goal with noninvasive techniques. OBJECTIVE: We sought to assess the feasibility of a totally noninvasive estimation of force-frequency relation (FFR) during exercise stress in the echocardiography laboratory. METHODS: We enrolled 13 healthy control patients (12 men, age 38 +/- 15 years) as group I, and 50 patients (38 men, age 64 +/- 11 years) referred for exercise echocardiography as group II. To build the FFR, the force was determined at each step as the ratio of the systolic pressure (cuff sphygmomanometer)/end-systolic volume index (biplane Simpson's rule/body surface area). The slope of the relationship was calculated with the linear best fit of the FFR. RESULTS: Noninvasive systolic pressure/end-systolic volume ratio was obtained in all patients. The slope of the linear best fit of the force-frequency curve was lower in group II compared with group I (group II = 10.1 +/- 9.3 x 10(-2) vs group I = 14.9 +/- 9.9 x 10(-2) group I, P =.04). By regional wall-motion analysis, 2 subgroups were identified in group II: group IIA (n = 8) had a positive echocardiogram; and group IIB (n = 42) had a negative echocardiogram. The slope of the force-frequency curve was lower in patients with ischemia compared with those without (group IIA = 3.5 +/- 4.2 x 10(-2) vs group IIB = 11.4 +/- 9.5 x 10(-2); P =.012). Heart rate-systolic pressure/end-systolic volume index relation was biphasic, with an initial positive slope and a subsequent negative slope in 1 patient of group I, 4 patients of group IIA, and 15 patients of group IIB (P <.05 vs group I). CONCLUSION: A noninvasive estimation of FFR can be easily determined during exercise echocardiography. This index of global contractility is theoretically appealing for identification of limited contractile reserve and latent global left ventricular dysfunction.     

"Ultrasound comet-tail images": a marker of pulmonary edema: a comparative study with wedge pressure and extravascular lung water

BACKGROUND: Echographic examination of the lung surface may reveal multiple "comet-tail images" originating from water-thickened interlobular septa. These images could be useful for noninvasive assessment of interstitial pulmonary edema. STUDY OBJECTIVE: The purpose of this study was to assess the diagnostic accuracy of lung comet-tail images compared with chest radiography, wedge pressure, and extravascular lung water (EVLW) quantified by the indicator dilution method (PiCCO System, version 4.1; Pulsion Medical Systems; Munich, Germany). METHODS AND PATIENTS: We enrolled 20 patients (mean age, 62.6 +/- 11.5 years [+/- SD]). Patients were studied before, immediately after, and 24 h following cardiac surgery with chest ultrasound, chest radiography, pulmonary artery catheterization, and the PiCCO system. Performing echo scanning (right and left hemithorax, from second to fourth intercostal space, from parasternal to midaxillary line), an individual patient comet score was obtained by summing the number of comets in each scanned space. RESULTS: A total of 60 comparisons were obtained. Significant positive linear correlations were found between comet score and EVLW determined by the PiCCO System (r = 0.42, p = 0.001), between comet score and wedge pressure (r = 0.48, p = 0.01), and between comet score and radiologic lung water score (r = 0.60, p = 0.0001). CONCLUSIONS: The presence and the number of comet-tail images provide reliable information on interstitial pulmonary edema. Therefore, ultrasonography represent an attractive, easy-to-use, bedside diagnostic tool for assessing cardiac function and pulmonary congestion.