Effect of voxelotor on cardiopulmonary testing in youths with sickle cell anemia in a pilot study

Background

Individuals with sickle cell anemia (SCA) exhibit decreased exercise capacity. Anemia limits oxygen-carrying capacity and affects cardiopulmonary fitness. The drug voxelotor raises hemoglobin in SCA. We hypothesized that voxelotor improves exercise capacity in youths with SCA.

Methods

In a single-center, open-label, single-arm, longitudinal interventional pilot study (NCT04581356), SCA patients aged 12 and older, stably maintained on hydroxyurea, were treated with 1500 mg voxelotor daily, and performed cardiopulmonary exercise testing before (CPET#1) and after voxelotor (CPET#2). A modified Bruce Protocol was performed on a motorized treadmill, and breath-by-breath gas exchange data were collected. Peak oxygen consumption (peak VO₂), anaerobic threshold, O₂ pulse, VE/VCO₂ slope, and time exercised were compared for each participant. The primary endpoint was change in peak VO₂. Hematologic parameters were measured before each CPET. Patient Global Impression of Change (PGIC) and Clinician Global Impression of Change (CGIC) surveys were collected.

Results

Ten hemoglobin SS patients aged 12–24 completed the study. All demonstrated expected hemoglobin rise, with average +1.6 g/dL (p = .003) and P₅₀ left shift of average −11 mmHg (p < .0001) with decreased oxygen off-loading at low pO₂. The change in % predicted peak VO₂ from CPET#1 to CPET#2 ranged from −12.8% to +11.3%, with significant improvement of more than 5% in one subject, more than 5% decrease in five subjects, and insignificant change of less than 5% in four subjects. All 10 CGIC and seven of 10 PGIC responses were positive.

Conclusion

In a plot study of 10 youths with SCA, voxelotor treatment did not improve peak VO₂ in 9 out of 10 patients.     

Clinical outcomes and complication profile of total hip arthroplasty after lumbar spine fusion: a meta-analysis and systematic review

European Spine Journal - Hip and spine pathology can alter the biomechanics of spino-pelvic mobility. Lumbar spine fusions can reduce the mobility of the lumbar spine and therefore result in...     

A functional neuroimaging study of motivation and executive function

Executive functions, such as working memory, must intersect with functions that determine value for the organism. Functional imaging work in humans and single-unit recordings in non-human primates provide evidence that PFC might integrate motivational context with working memory. With functional magnetic resonance imaging (fMRI), we addressed the question of motivation and working memory, using a trial-related design in an object-working memory task. The design permitted the analysis of BOLD signal at separate stages, corresponding to encoding, maintenance, and retrieval. Subjects were motivated by a financial incentive during the task, such that they could gain a high or a low reward. The two different levels of reward also entailed greater or lesser risk of losing money for incorrect responses. In the high, relative to the low, reward condition, subjects shifted response bias, and showed a trend to greater sensitivity. We found main effects in fMRI BOLD signal for reward, which overlapped with BOLD effects for maintenance of information, in the right superior frontal sulcus and bilateral intraparietal sulcus. We also found an interaction between reward and retrieval from working memory in the right dorsolateral prefrontal cortex. Main effects of load and reward occurred in adjacent regions of the ventrolateral PFC during retrieval. The data demonstrate that when subjects perform a simple working memory task, financial incentives motivate performance and interact with some of the same neural networks that process various stages of working memory. Areas of overlap and interaction may integrate information about value, or they may represent a general effect of motivation increasing neural effort.     

B cell receptor-independent stimuli trigger immunoglobulin (Ig) class switch recombination and production of IgG autoantibodies by anergic self-reactive B cells

In both humans and animals, immunoglobulin (Ig)G autoantibodies are less frequent but more pathogenic than IgM autoantibodies, suggesting that controls over Ig isotype switching are required to reinforce B cell self-tolerance. We have used gene targeting to produce mice in which hen egg lysozyme (HEL)-specific B cells can switch to all Ig isotypes (SWHEL mice). When crossed with soluble HEL transgenic (Tg) mice, self-reactive SWHEL B cells became anergic. However, in contrast to anergic B cells from the original nonswitching anti-HEL x soluble HEL double Tg model, self-reactive SWHEL B cells also displayed an immature phenotype, reduced lifespan, and exclusion from the splenic follicle. These differences were not related to their ability to Ig class switch, but instead to competition with non-HEL-binding B cells generated by VH gene replacement in SWHEL mice. When activated in vitro with B cell receptor (BCR)-independent stimuli such as anti-CD40 monoclonal antibody plus interleukin 4 or lipopolysaccharide (LPS), anergic SWHEL double Tg B cells proliferated and produced IgG anti-HEL antibodies as efficiently as naive HEL-binding B cells from SWHEL Ig Tg mice. These results demonstrate that no intrinsic constraints to isotype switching exist in anergic self-reactive B cells. Instead, production of IgG autoantibodies is prevented by separate controls that reduce the likelihood of anergic B cells encountering BCR-independent stimuli. That bacteria-derived LPS could circumvent these controls may explain the well-known association between autoantibody-mediated diseases and episodes of systemic infection.     

Neuropeptide Y Attenuates Stress‐Induced Bone Loss Through Suppression of Noradrenaline Circuits

Chronic stress and depression have adverse consequences on many organ systems, including the skeleton, but the mechanisms underlying stress‐induced bone loss remain unclear. Here we demonstrate that neuropeptide Y (NPY), centrally and peripherally, plays a critical role in protecting against stress‐induced bone loss. Mice lacking the anxiolytic factor NPY exhibit more anxious behavior and elevated corticosterone levels. Additionally, following a 6‐week restraint, or cold‐stress protocol, Npy‐null mice exhibit three‐fold greater bone loss compared to wild‐type mice, owing to suppression of osteoblast activity. This stress‐protective NPY pathway acts specifically through Y2 receptors. Centrally, Y2 receptors suppress corticotropin‐releasing factor expression and inhibit activation of noradrenergic neurons in the paraventricular nucleus. In the periphery, they act to control noradrenaline release from sympathetic neurons. Specific deletion of arcuate Y2 receptors recapitulates the Npy‐null stress response, coincident with elevated serum noradrenaline. Importantly, specific reintroduction of NPY solely in noradrenergic neurons of otherwise Npy‐null mice blocks the increase in circulating noradrenaline and the stress‐induced bone loss. Thus, NPY protects against excessive stress‐induced bone loss, through Y2 receptor‐mediated modulation of central and peripheral noradrenergic neurons. © 2014 American Society for Bone and Mineral Research.     

Association of rs11190870 near LBX1 with adolescent idiopathic scoliosis in East Asians: a systematic review and meta-analysis

Background contextThe rs11190870 single nucleotide polymorphism in the 3'-flanking region of the LBX1 gene has been implicated in the etiology of adolescent idiopathic scoliosis (AIS). A thorough appraisal of the evidence supporting this association has not been previously attempted.PurposeTo provide a comprehensive assessment and synthesis of the currently available evidence on the association between rs11190870 and AIS.Study designA systematic review and meta-analysis.MethodsThis review followed the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. PubMed (MEDLINE), EMBASE, Scopus, and HuGE Literature Finder databases were systematically searched through November 2013 to identify relevant studies following a sensitive strategy. Summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using the fixed-effect inverse variance model for allelic (T vs. C) and genotypic comparisons.ResultsMeta-analysis of four studies conducted in East Asian populations (n=3,215 AIS cases and n=15,347 controls) found a highly statistically significant and robust association between rs11190870 and AIS. Comparison of summary ORs indicated a codominant model effect of the T allele. Carriers of the TC and TT genotypes were 69% (OR=1.69, 95% CI: 1.48–1.94, p<.001) and 162% (OR=2.62, 95% CI: 2.28–3.02, p<.001), respectively, more likely to have AIS compared with carriers of the CC genotype.ConclusionsBased on a comprehensive analysis of the currently available evidence, rs11190870 is likely a susceptibility variant for AIS in East Asians. Further investigation of this association is necessary in other populations.     

Distribution of polycyclic aromatic hydrocarbons concentrations simultaneously obtained in gas,rainwater and particles

This study reported the distribution of polycyclic aromatic hydrocarbons (PAHs) concentrations simultaneously obtained in gas/rain/particle in rain event from 2010 to 2012 in Osaka, Japan. A sampling method for rain and the materials of a rain collector were also surveyed. Benzene and a glass bottle were used to prevent the decrease of PAHs in rainwater. The average concentration of Σ9PAHs in rainwater ranged between 17.49 and 646.52 ng dm^?3. The mean ratio of these Σ9PAHs in gas versus particles was 77.9 and 68.3 % during rain and no rain, respectively. During rain, the PAHs in particles were scavenged by rain and were incorporated via washout by collision with each other. Therefore, the ratio of PAHs in rainwater was similar to that in particles. The low molecular weight LMW-PAHs from gas were recognized as being dissolved in rain but did not affect the ratio of PAHs in rain. Four rings PAH were dominant in gas/rain/particles. The seasonal variation of Σ9PAHs in rainwater was reported and discussed, and the PAHs levels during the winter and spring were higher compared with that of summer and autumn. Furthermore, the sampling method of PAHs in snow is also developed.