Effects of paraoxonase activity and gene polymorphism on coronary vasomotion

ABSTRACT

Effect of hormone replacement therapy on vasomotor function of the coronary microcirculation in post-menopausal women with medically treated cardiovascular risk factors

Aims The aim of this study was to evaluate the effect of hormone replacement therapy (HRT) on coronary vasomotor function in post-menopausal women (PM) with medically treated cardiovascular risk factors (RFs) in a cross-sectional and a longitudinal follow-up (FU) study. Methods and results Myocardial blood flow (MBF) response to cold pressor testing (CPT) and during pharmacologically induced hyperaemia was measured with positron emission tomography in pre-menopausal women (CON), in PM with HRT and without HRT, and repeated in PM after a mean FU of 24 ± 14 months. When compared with CON at baseline, the endothelium-related change in MBF (ΔMBF) to CPT progressively declined in PM with HRT and without HRT (0.35 ± 0.23 vs. 0.24 ± 0.20 and 0.16 ± 0.12 mL/g/min; P = 0.171 and P = 0.021). In PM without HRT and in those with HRT at baseline but with discontinuation of HRT during FU, the endothelium-related ΔMBF to CPT was significantly less at FU than at baseline (0.05 ± 0.19 vs. 0.16 ± 0.12 and −0.03 ± 0.14 vs. 0.25 ± 0.18 mL/g/min; P = 0.023 and P = 0.001), whereas no significant change was observed in PM with HRT (0.19 ± 0.22 vs. 0.23 ± 0.22 mL/g/min; P = 0.453). Impaired hyperaemic MBFs when compared with CON were not significantly altered from those at baseline exam. Conclusion Long-term administration of oestrogen may contribute to maintain endothelium-dependent coronary function in PM with medically treated cardiovascular RF

Suppressing bladder artifacts in bone SPECT of the pelvis

Objective: Bladder-filling reconstruction artifacts have a detrimental effect on the image quality of pelvic bone single photon emission computed tomography (SPECT). Using a simple protocol consisting of forced diuresis coupled with intravenous (IV) hydration, this study was undertaken to obtain an artifact-free pelvic SPECT after discarding the residual urinary activity. Methods: Thirty patients were enrolled. In group I, pelvic SPECT was performed directly after normal void, whereas in group II, SPECT was preceded by IV injection of 0.5 mg/kg furosemide (maximum 40 mg) coupled with IV infusion of 500 cc of physiologic saline. Bladder-filling reconstruction artifacts were analyzed in group I patients, who had their images reconstructed using both filtered backprojection and iterative algorithms, both qualitatively and quantitatively by means of regions of interest (ROIs) drawn around the artifact-bearing bone areas as well as the corresponding contralateral sites. For group II patients, besides visual analysis, ROIs were placed over the sites corresponding to those of the group I patients. In every patient, total counts of each ROI were normalized to a reference ROI placed over the sacrum, and a ratio was created. Results: Using filtered backprojection, two forms of artifacts were identified in group I patients: first, a streak pattern that extended to the sacro-iliac joint in nine (60%) patients, the hip joint in five (33%), the superior pubic rami in four (27%), the sacrum in three (20%), and the ischium in one (6%); second, a count loss subtype which extended to the hip joints in nine (60%) patients. Corresponding values after iterative reconstruction were two (13%) for the sacro-iliac joint, three (20%) for the hip joint, one (6%) for the superior pubic ramus, and one (6%) for the sacrum. In five (33%) patients, residual count loss artifacts were still identifiable after iterative reconstruction. However in group II, no such effects were observed because the bladder activity reached near background level in 14 (93%) of 15 patients after three successive voids with a 3.5-fold decrease in the mean value of total bladder count in comparison with group I patients. A statistically significant difference was found between artifact- and non-artifact-harboring ROIs in group I whichever the method used for reconstruction, whereas the values of right and left hemi-pelvis ROIs/sacrum in group II were almost identical. Conclusions: Forced diuresis coupled with parenteral hydration facilitates the acquisition of an artifact-free pelvic SPECT. Especially for clinical questions that focus on femoral heads and pubic bones, applying the aforementioned protocol may improve the diagnostic accuracy of pelvic bone SPEC

Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening

Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by the degeneration of alpha motor neurons in the spinal cord, leading to muscular atrophy. SMA is caused by deletions or mutations in the survival motor neuron 1 gene (SMN1). In humans, a nearly identical copy gene, SMN2, is present. Because SMN2 has been shown to decrease disease severity in a dose-dependent manner, SMN2 copy number is predictive of disease severity. To develop a treatment algorithm for SMA-positive infants identified through newborn screening based upon SMN2 copy number. A working group comprised of 15 SMA experts participated in a modified Delphi process, moderated by a neutral third-party expert, to develop treatment guidelines. The overarching recommendation is that all infants with two or three copies of SMN2 should receive immediate treatment (n = 13). For those infants in which immediate treatment is not recommended, guidelines were developed that outline the timing and appropriate screens and tests to be used to determine the timing of treatment initiation. The identification SMA affected infants via newborn screening presents an unprecedented opportunity for achievement of maximal therapeutic benefit through the administration of treatment pre-symptomatically. The recommendations provided here are intended to help formulate treatment guidelines for infants who test positive during the newborn screening process

Preclinical Evaluation and Dosimetry of [111In]CHX-DTPA-scFv78-Fc Targeting Endosialin/Tumor Endothelial Marker 1 (TEM1)

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Ausbildung in Nuklearmedizin und Zukunftsperspektiven.

peer reviewe

The Australian temperament project: the first 30 years

The Australian Temperament Project (ATP) is a longitudinal study of the psychosocial development of a large and representative sample of Australian children born in the state of Victoria, Australia between September 1982 and January 1983.The study aims to trace the pathways to psychosocial adjustment and maladjustment across the lifespan, and to investigate the contribution of personal, family and environmental factors to development and wellbeing.<br /

CS1 CAR-T targeting the distal domain of CS1 (SLAMF7) shows efficacy in high tumor burden myeloma model despite fratricide of CD8+CS1 expressing CAR-T cells

Despite improvement in treatment options for myeloma patients, including targeted immunotherapies, multiple myeloma remains a mostly incurable malignancy. High CS1 (SLAMF7) expression on myeloma cells and limited expression on normal cells makes it a promising target for CAR-T therapy. The CS1 protein has two extracellular domains - the distal Variable (V) domain and the proximal Constant 2 (C2) domain. We generated and tested CS1-CAR-T targeting the V domain of CS1 (Luc90-CS1-CAR-T) and demonstrated anti-myeloma killing in vitro and in vivo using two mouse models. Since fratricide of CD8 + cells occurred during production, we generated fratricide resistant CS1 deficient Luc90- CS1- CAR-T (ΔCS1-Luc90- CS1- CAR-T). This led to protection of CD8 + cells in the CAR-T cultures, but had no impact on efficacy. Our data demonstrate targeting the distal V domain of CS1 could be an effective CAR-T treatment for myeloma patients and deletion of CS1 in clinical production did not provide an added benefit using in vivo immunodeficient NSG preclinical models

Phase II Open Label Study of Valproic Acid in Spinal Muscular Atrophy

UNLABELLED:Preliminary in vitro and in vivo studies with valproic acid (VPA) in cell lines and patients with spinal muscular atrophy (SMA) demonstrate increased expression of SMN, supporting the possibility of therapeutic benefit. We performed an open label trial of VPA in 42 subjects with SMA to assess safety and explore potential outcome measures to help guide design of future controlled clinical trials. Subjects included 2 SMA type I ages 2-3 years, 29 SMA type II ages 2-14 years and 11 type III ages 2-31 years, recruited from a natural history study. VPA was well-tolerated and without evident hepatotoxicity. Carnitine depletion was frequent and temporally associated with increased weakness in two subjects. Exploratory outcome measures included assessment of gross motor function via the modified Hammersmith Functional Motor Scale (MHFMS), electrophysiologic measures of innervation including maximum ulnar compound muscle action potential (CMAP) amplitudes and motor unit number estimation (MUNE), body composition and bone density via dual-energy X-ray absorptiometry (DEXA), and quantitative blood SMN mRNA levels. Clear decline in motor function occurred in several subjects in association with weight gain; mean fat mass increased without a corresponding increase in lean mass. We observed an increased mean score on the MHFMS scale in 27 subjects with SMA type II (p<or=0.001); however, significant improvement was almost entirely restricted to participants <5 years of age. Full length SMN levels were unchanged and Delta7SMN levels were significantly reduced for 2 of 3 treatment visits. In contrast, bone mineral density (p<or=0.0036) and maximum ulnar CMAP scores (p<or=0.0001) increased significantly. CONCLUSIONS:While VPA appears safe and well-tolerated in this initial pilot trial, these data suggest that weight gain and carnitine depletion are likely to be significant confounding factors in clinical trials. This study highlights potential strengths and limitations of various candidate outcome measures and underscores the need for additional controlled clinical trials with VPA targeting more restricted cohorts of subjects. TRIAL REGISTRATION:ClinicalTrials.gov