Rationale,design, and protocol for the prevention of low back pain in the military (POLM) trial (NCT00373009)

Background  

There are few effective strategies reported for the primary prevention of low back pain (LBP). Core stabilization exercises targeting the deep abdominal and trunk musculature and psychosocial education programs addressing patient beliefs and coping styles represent the current best evidence for secondary prevention of low back pain. However, these programs have not been widely tested to determine if they are effective at preventing the primary onset and/or severity of LBP. The purpose of this cluster randomized clinical trial is to determine if a combined core stabilization exercise and education program is effective in preventing the onset and/or severity of LBP. The effect of the combined program will be compared to three other standard programs.     

A Mono-Percoll separation technique improves sperm recovery of normal and male factor specimens when compared with the swim-up technique

The purpose of this study was to determine the effects of asimplified 80% Mono-Percoll sperm separation procedure on bothnormal and male factor semen samples compared with the standardswim-up technique. The parameters examined include sperm concentration,motility and morphology, total motile functional spermatozoaand percentage recovery. Normal patients demonstrated enhancedsperm parameters with the Mono-Percoll compared with the swim-uptechnique for concentration (67x10⁶ versus 42x10⁶/ml, P <0.001), motility (66 versus 59%, P < 0.001), morphology (56versus 49%, P < 0.005) and percentage recovery (60 versus42%, P < 0.005). Male factor patients showed enhanced spermparameters with the Mono-Percoll procedure compared with theswim-up technique for motility (53 versus 42%, P < 0.05)and percentage recovery (54 versus 29%, P < 0.005), withno significant difference in concentration and morphology. Insummary, the Mono-Percoll sperm recovery procedure is significantlybetter than the swim-up technique for male factor patients andpatients with normal sperm parameters.     

Phase I study of temozolomide in paediatric patients with advanced cancer. United Kingdom Children's Cancer Study Group.

A phase I study of temozolomide administered orally once a day, on 5 consecutive days, between 500 and 1200 mg m(-2) per 28-day cycle was performed. Children were stratified according to prior craniospinal irradiation or nitrosourea therapy. Sixteen of 20 patients who had not received prior craniospinal irradiation or nitrosourea therapy were evaluable. Myelosuppression was dose limiting, with Common Toxicity Criteria (CTC) grade 4 thrombocytopenia occurring in one of six patients receiving 1000 mg m(-2) per cycle, and two of four patients treated at 1200 mg m(-2) per cycle. Therefore, the maximum-tolerated dose (MTD) was 1000 mg m(-2) per cycle. The MTD was not defined for children with prior craniospinal irradiation because of poor recruitment. Plasma pharmacokinetic analyses showed temozolomide to be rapidly absorbed and eliminated, with linear increases in peak plasma concentrations and systemic exposure with increasing dose. Responses (CR and PR) were seen in two out of five patients with high-grade astrocytomas, and one patient had stable disease. One of ten patients with diffuse intrinsic brain stem glioma achieved a long-term partial response, and a further two patients had stable disease. Therefore, the dose recommended for phase II studies in patients who have not received prior craniospinal irradiation or nitrosoureas is 1000 mg m(-2) per cycle. Further evaluation in diffuse intrinsic brain stem gliomas and other high-grade astrocytomas is warranted.     

SARS-CoV-2 Infections in Vaccinated and Unvaccinated Populations in Camp Lemonnier,Djibouti, from April 2020 to January 2022

The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has highlighted the disparity between developed and developing countries for infectious disease surveillance and the sequencing of pathogen genomes. The majority of SARS-CoV-2 sequences published are from Europe, North America, and Asia. Between April 2020 and January 2022, 795 SARS-CoV-2-positive nares swabs from individuals in the U.S. Navy installation Camp Lemonnier, Djibouti, were collected, sequenced, and analyzed. In this study, we described the results of genomic sequencing and analysis for 589 samples, the first published viral sequences for Djibouti, including 196 cases of vaccine breakthrough infections. This study contributes to the knowledge base of circulating SARS-CoV-2 lineages in the under-sampled country of Djibouti, where only 716 total genome sequences are available at time of publication. Our analysis resulted in the detection of circulating variants of concern, mutations of interest in lineages in which those mutations are not common, and emerging spike mutations.     

Assessment of Multiplate platelet aggregometry using citrate,heparin or hirudin in Rhesus macaques

Electrical impedance aggregometry (EIA) has gained popularity in clinical and research applications. Nonhuman primates are used to study disease and drug-related mechanisms that affect hemostasis, therefore establishing normal EIA parameters are necessary. The anticoagulants sodium heparin, hirudin and sodium citrate and three agonists, ADP, ASPI, and collagen were evaluated. Whole blood from 12 adult male rhesus macaques was collected to evaluate anticoagulants, sodium heparin, hirudin and sodium citrate using three agonists (ADP, ASPI and collagen), on the Multiplate® 5.0 Analyzer. Platelet function was reported for three parameters: Area under the curve (AUC), aggregation, and aggregation velocity. There was a significant difference in mean AUC between citrate and heparin samples, and citrate and hirudin samples regardless of the agonist used. There was no difference in AUC between heparin and hirudin. ADP-activated samples showed an increase in impedance with hirudin samples compared to citrate. Furthermore, heparin and hirudin out-perform citrate as the anticoagulant for EIA in the macaque. Finally, this study demonstrates the utility of the Multiplate® system in this model and provides important insight into anticoagulant choice when using EIA.     

Dynamic optical imaging of metabolic and NADPH oxidase-derived superoxide in live mouse brain using fluorescence lifetime unmixing

Superoxide is the single-electron reduction product of molecular oxygen generated by mitochondria and the innate immune enzyme complex, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox), and its isoforms. Initially identified as critical to the host defense against infection, superoxide has recently emerged as an important signaling molecule and as a proposed mediator of central nervous system injury in stroke, neurodegenerative conditions, and aging itself. Complete understanding of superoxide in central nervous system disease has been hampered by lack of noninvasive imaging techniques to evaluate this highly reactive, short-lived molecule in vivo. Here we describe a novel optical imaging technique to monitor superoxide real time in intact animals using a fluorescent probe compound and fluorescence lifetime contrast-based unmixing. Specificity for superoxide was confirmed using validated mouse models with enhanced or attenuated brain superoxide production. Application of fluorescence lifetime unmixing removed autofluorescence, further enhanced sensitivity and specificity of the technique, permitted visualization of physiologically relevant levels of superoxide, and allowed superoxide in specific brain regions (e.g., hippocampus) to be mapped. Lifetime contrast-based unmixing permitted disease model-specific and brain region-specific differences in superoxide levels to be observed, suggesting this approach may provide valuable information on the role of mitochondrial and Nox-derived superoxide in both normal function and pathologic conditions in the central nervous system.     

Phospho-CRKL monitoring for the assessment of BCR-ABL activity in imatinib-resistant chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia patients treated with nilotinib

Actual BCR-ABL kinase inhibition in vivo as determined by phospho-CRKL (pCRKL) monitoring has been recognized as a prognostic parameter in patients with chronic myelogenous leukemia treated with imatinib. We report a biomarker sub-study of the international phase I clinical trial of nilotinib (AMN107) using the established pCRKL assay in imatinib-resistant chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia. A minimum dose (200 mg) required for effective BCR-ABL inhibition in imatinib resistant/intolerant leukemia was determined. The pre-clinical activity profile of nilotinib against mutant BCR-ABL was largely confirmed. Substantial differences between peripheral blood baseline pCRKL/CRKL ratios were observed when comparing chronic myeloid leukemia with Ph+ acute lymphoblastic leukemia. Finally, rapid BCR-ABL-reactivation shortly after starting nilotinib treatment was seen in acute lymphoblastic leukemia patients with progressive disease carrying the P-loop mutations Y253H, E255K, or mutation T315I. Monitoring the actual BCR-ABL inhibition in nilotinib treated patients using pCRKL as a surrogate is a means to establish effective dosing and to characterize resistance mechanisms against nilotinib.