Pharmacotherapy for Fibromyalgia

Fibromyalgia (FM) is a chronic disorder characterized by multifocal pain and other associated somatic symptoms including fatigue, insomnia, cognitive/memory problems, and even psychological distress. It appears that 2–4% of the general population suffers from FM. FM negatively impacts the physical functioning of its patients, as evidenced by difficulties with multiple daily activities, as well as affecting emotional health, social functioning, and health related quality of life. This review will discuss the potential theories that possibly contribute to the pathogenesis of FM, although the precise mechanism is unknown. The evolution of the assessment of FM will also be examined, with the waning use of tender point examinations and the appearance of new simple, practical diagnostic criteria. Although non-pharmacologic therapeutic options (exercise, education, cognitive–behavioral therapy) have been shown to be extremely effective in FM, the focus of this article will be on pharmacologic strategies. Non-Food and Drug Administration (FDA) approved as well as FDA approved agents will be presented. Each agent's therapeutic “niche” in FM management will be discussed based on its pharmacologic profile, patient responsiveness, and tolerability. Finally a clinical algorithm will be presented for the step-wise management of pain and other associated symptoms of FM

Environmental Estrogens Alter Early Development in Xenopus laevis

A growing number of environmental toxicants found in pesticides, herbicides, and industrial solvents are believed to have deleterious effects on development by disrupting hormone-sensitive processes. We exposed Xenopus laevis embryos at early gastrula to the commonly encountered environmental estrogens nonylphenol, octylphenol, and methoxychlor, the antiandrogen, p,p-DDE, or the synthetic androgen, 17 alpha-methyltestosterone at concentrations ranging from 10 nM to 10 microM and examined them at tailbud stages (approximately 48 hr of treatment). Exposure to the three environmental estrogens, as well as to the natural estrogen 17 beta-estradiol, increased mortality, induced morphologic deformations, increased apoptosis, and altered the deposition and differentiation of neural crest-derived melanocytes in tailbud stage embryos. Although neural crest-derived melanocytes were markedly altered in embryos treated with estrogenic toxicants, expression of the early neural crest maker Xslug, a factor that regulates both the induction and subsequent migration of neural crest cells, was not affected, suggesting that the disruption induced by these compounds with respect to melanocyte development may occur at later stages of their differentiation. Co-incubation of embryos with the pure antiestrogen ICI 182,780 blocked the ability of nonylphenol to induce abnormalities in body shape and in melanocyte differentiation but did not block the effects of methoxychlor. Our data indicate not only that acute exposure to these environmental estrogens induces deleterious effects on early vertebrate development but also that different environmental estrogens may alter the fate of a specific cell type via different mechanisms. Finally, our data suggest that the differentiation of neural crest-derived melanocytes may be particularly sensitive to the disruptive actions of these ubiquitous chemical contaminants

Solid Rocket Booster (SRB) - Evolution and Lessons Learned During the Shuttle Program

The Solid Rocket Booster (SRB) element integrates all the subsystems needed for ascent flight, entry, and recovery of the combined Booster and Motor system. These include the structures, avionics, thrust vector control, pyrotechnic, range safety, deceleration, thermal protection, and retrieval systems. This represents the only human-rated, recoverable and refurbishable solid rocket ever developed and flown. Challenges included subsystem integration, thermal environments and severe loads (including water impact), sometimes resulting in hardware attrition. Several of the subsystems evolved during the program through design changes. These included the thermal protection system, range safety system, parachute/recovery system, and others. Obsolescence issues occasionally required component recertification. Because the system was recovered, the SRB was ideal for data and imagery acquisition, which proved essential for understanding loads and system response. The three main parachutes that lower the SRBs to the ocean are the largest parachutes ever designed, and the SRBs are the largest structures ever to be lowered by parachutes. SRB recovery from the ocean was a unique process and represented a significant operational challenge; requiring personnel, facilities, transportation, and ground support equipment. The SRB element achieved reliability via extensive system testing and checkout, redundancy management, and a thorough postflight assessment process. Assembly and integration of the booster subsystems was a unique process and acceptance testing of reused hardware components was required for each build. Extensive testing was done to assure hardware functionality at each level of stage integration. Because the booster element is recoverable, subsystems were available for inspection and testing postflight, unique to the Shuttle launch vehicle. Problems were noted and corrective actions were implemented as needed. The postflight assessment process was quite detailed and a significant portion of flight operations. The SRBs provided fully redundant critical systems including thrust vector control, mission critical pyrotechnics, avionics, and parachute recovery system. The design intent was to lift off with full redundancy. On occasion, the redundancy management scheme was needed during flight operations. This paper describes some of the design challenges, how the design evolved with time, and key areas where hardware reusability contributed to improved system level understanding

See Me, Hear Me, Coach Me

The writers describe the implementation of virtual coaching for teachers in Alabama and Pennsylvania. They describe use of bug-in-ear devices, revolutionized by Internet and mobile technology advances, to provide on-the-spot feedback as teachers deliver instruction. They outline lessons learned from virtual coaching initiatives and present research results showing the positive impact of this approach on both teachers and students. They also provide advice for those using this approach on making contact and providing feedback

Role of miRNA-mRNA Interaction in Neural Stem Cell Differentiation of Induced Pluripotent Stem Cells

miRNA regulates the expression of protein coding genes and plays a regulatory role in human development and disease. The human iPSCs and their differentiated progenies provide a unique opportunity to identify these miRNA-mediated regulatory mechanisms. To identify miRNA–mRNA regulatory interactions in human nervous system development, well characterized NSCs were differentiated from six validated iPSC lines and analyzed for differentially expressed (DE) miRNome and transcriptome by RNA sequencing. Following the criteria, moderated t statistics, FDR-corrected p-value ≤ 0.05 and fold change—absolute (FC-abs) ≥2.0, 51 miRNAs and 4033 mRNAs were found to be significantly DE between iPSCs and NSCs. The miRNA target prediction analysis identified 513 interactions between 30 miRNA families (mapped to 51 DE miRNAs) and 456 DE mRNAs that were paradoxically oppositely expressed. These 513 interactions were highly enriched in nervous system development functions (154 mRNAs; FDR-adjusted p-value range: 8.06 × 10−15–1.44 × 10−4). Furthermore, we have shown that the upregulated miR-10a-5p, miR-30c-5p, miR23-3p, miR130a-3p and miR-17-5p miRNA families were predicted to down-regulate several genes associated with the differentiation of neurons, neurite outgrowth and synapse formation, suggesting their role in promoting the self-renewal of undifferentiated NSCs. This study also provides a comprehensive characterization of iPSC-generated NSCs as dorsal neuroepithelium, important for their potential use in in vitro modeling of human brain development and disease

An evaluation of Bradfordizing effects

The purpose of this paper is to apply and evaluate the bibliometric method Bradfordizing for information retrieval (IR) experiments. Bradfordizing is used for generating core document sets for subject-specific questions and to reorder result sets from distributed searches. The method will be applied and tested in a controlled scenario of scientific literature databases from social and political sciences, economics, psychology and medical science (SOLIS, SoLit, USB Köln Opac, CSA Sociological Abstracts, World Affairs Online, Psyndex and Medline) and 164 standardized topics. An evaluation of the method and its effects is carried out in two laboratory-based information retrieval experiments (CLEF and KoMoHe) using a controlled document corpus and human relevance assessments. The results show that Bradfordizing is a very robust method for re-ranking the main document types (journal articles and monographs) in today’s digital libraries (DL). The IR tests show that relevance distributions after re-ranking improve at a significant level if articles in the core are compared with articles in the succeeding zones. The items in the core are significantly more often assessed as relevant, than items in zone 2 (z2) or zone 3 (z3). The improvements between the zones are statistically significant based on the Wilcoxon signed-rank test and the paired T-Test

Imaging Changes after Stereotactic Radiosurgery of Primary and Secondary Malignant Brain Tumors

After radiosurgery of malignant tumors, it can be difficult to discriminate between transient treatment effects, radiation necrosis, and tumor progression on post-treatment imaging. Misinterpretation of an enlarging lesion may lead to inappropriate treatment and contribute to disagreements about treatment efficacy. In an effort to clarify this problem, we reviewed our experience with interpreting post-radiosurgical imaging in patients with malignant primary and secondary brain tumors. We reviewed results of radiosurgery of 30 malignant gliomas and 35 metastatic brain tumors with minimum follow up of 1 year or until death. Of 30 gliomas, 73% were larger a mean of 13 weeks after radiosurgery. Of 35 metatstatic tumors, 22% were larger a mean of 10 weeks after radiosurgery. Eleven had 18 F-fluorodeoxyglucose-positron emission tomography (FDG-PET) of enlarging lesions. Eight showed increased activity with respect to brain; three decreased activity. Of the eight, six predicted incorrectly based upon the patients' subsequent courses (all alive, mean follow up of 27 months), and two correctly, with the patients dying from the imaged lesions 8 and 13 months later. Of the three with FDG uptake less than brain, one patient was alive with 32 weeks of follow up, and two patients died from the imaged lesion 13 and 21 months later. Radiographic enlargement after radiosurgery is common, especially for gliomas. Physicians caring for these patients should be aware of this phenomenon and be cautious in interpreting post-treatment images. MRI appearance may be useful for metastases. FDG-PET seems unreliable. Further evaluation of Tl-201 and HMPAO SPECT or MRS is warranted.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45392/1/11060_2004_Article_393674.pd

The Development of FVIII Inhibitor in Hispanic American Patients with Hemophilia A Critically Impacts Coagulation Potential

Background: Hemophilia A (HA) is caused by deficiencies in plasma-FVIII and heterogeneous factor-VIII-gene mutations that impair intrinsic coagulation amplification. In severe hemophilia A patients (HAPs), FVIII infusions are begun at toddlerhood to prevent hemarthrosis induced crippling. However, approximately 30% of these patients develop FVIII inhibitors. Gain-of-function mutations in the common pathway of coagulation increases coagulation potential and decreases bleeding and FVIII-utilization in HAPs which should decrease FVIII-inhibitor-risk. We identified loss-of-function mutations in this pathway which decrease coagulation-potential as they increase FVIII-inhibitor risk in HAPs. Methods: We screened Mexican-American-pedigrees of the South-Texas-Family-Study (STFS) for protein-altering-variants. Subjects were genotyped using Illumina-exome-24-chip. Protein-altering-variants were analyzed for associations with FII:C, PT, and aPTT. Linear-mixed-model-analyses was performed to estimate trait-heritability and examine single-nucleotide-variations (SNVs) for gene association. Significant associations’ p-values fell below Bonferroni-adjusted significance level. Results: Heritability-estimates for FII:C, aPTT, and PT were highly-significant with p-values of 0.49, 0.49, and 0.54 (for all, pT in the FII-gene (F2)—which encodes 543R\u3eL and has a large effect-size on each trait (for all, pT have lower FII:C levels but correspondingly prolonged aPTT and PT times. Conclusion: We hypothesize that FII-543R\u3eL (Prothrombin-RGV) likely contributes to the high-incidence of FVIII-inhibitor-development in HA-patients of Mexican-ancestry, resulting in higher risk of developing anti-tFVIII-antibodies than patients without the variant. Patients with the RGV variant are likely to bleed more which can require surgery, further increasing the development of FVIII inhibitor development

Increasing physical activity among young children from disadvantaged communities: Study protocol of a group randomised controlled effectiveness trial

Background: Participation in regular physical activity (PA) during the early years helps children achieve healthy body weight and can substantially improve motor development, bone health, psychosocial health and cognitive development. Despite common assumptions that young children are naturally active, evidence shows that they are insufficiently active for health and developmental benefits. Exploring strategies to increase physical activity in young children is a public health and research priority. Methods: Jump Start is a multi-component, multi-setting PA and gross motor skill intervention for young children aged 3–5 years in disadvantaged areas of New South Wales, Australia. The intervention will be evaluated using a two-arm, parallel group, randomised cluster trial. The Jump Start protocol was based on Social Cognitive Theory and includes five components: a structured gross motor skill lesson (Jump In); unstructured outdoor PA and gross motor skill time (Jump Out); energy breaks (Jump Up); activities connecting movement to learning experiences (Jump Through); and a home-based family component to promote PA and gross motor skill (Jump Home). Early childhood education and care centres will be demographically matched and randomised to Jump Start (intervention) or usual practice (comparison) group. The intervention group receive Jump Start professional development, program resources, monthly newsletters and ongoing intervention support. Outcomes include change in total PA (accelerometers) within centre hours, gross motor skill development (Test of Gross Motor Development-2), weight status (body mass index), bone strength (Sunlight MiniOmni Ultrasound Bone Sonometer), self-regulation (Heads-Toes-Knees-Shoulders, executive function tasks, and proxy-report Temperament and Approaches to learning scales), and educator and parent self-efficacy. Extensive quantitative and qualitative process evaluation and a cost-effectiveness evaluation will be conducted. Discussion: The Jump Start intervention is a unique program to address low levels of PA and gross motor skill proficiency, and support healthy lifestyle behaviours among young children in disadvantaged communities. If shown to be efficacious, the Jump Start approach can be expected to have implications for early childhood education and care policies and practices, and ultimately a positive effect on the health and development across the life course