A systematic review and meta-analysis of the prevalence of small fiber pathology in fibromyalgia: Implications for a new paradigm in fibromyalgia etiopathogenesis

Objectives: Fibromyalgia is a condition which exhibits chronic widespread pain with neuropathic pain features and has a major impact on health-related quality of life. The pathophysiology remains unclear, however, there is increasing evidence for involvement of the peripheral nervous system with a high prevalence of small fiber pathology (SFP). The aim of this systematic literature review is to establish the prevalence of SFP in fibromyalgia. Methods: An electronic literature search was performed using MEDLINE, EMBASE, PubMed, Web of Science, CINAHL and the Cochrane Library databases. Published full-text, English language articles that provide SFP prevalence data in studies of fibromyalgia of patients over 18years old were included. All articles were screened by two independent reviewers using a priori criteria. Methodological quality and risk of bias were evaluated using the critical appraisal tool by Munn et al. Overall and subgroup pooled prevalence were calculated by random-effects meta-analysis with 95% CI. Results: Database searches found 935 studies; 45 articles were screened of which 8 full text articles satisfied the inclusion criteria, providing data from 222 participants. The meta-analysis demonstrated the pooled prevalence of SFP in fibromyalgia is 49% (95% CI: 38–60%) with a moderate degree of heterogeneity, (I2= 68%). The prevalence estimate attained by a skin biopsy was 45% (95% CI: 32–59%, I2= 70%) and for corneal confocal microscopy it was 59% (95% CI: 40–78%, I2= 51%). Conclusion: There is a high prevalence of SFP in fibromyalgia. This study provides compelling evidence of a distinct phenotype involving SFP in fibromyalgia. Identifying SFP will aid in determining its relationship to pain and potentially facilitate the development of future interventions and pharmacotherapy

Intravenous immunoglobulin in the treatment of primary trigeminal neuralgia refractory to carbamazepine: a study protocol[ISRCTN33042138]

BACKGROUND: We have recently reported successful treatment of patients with chronic pain syndromes using human pooled intravenous immunoglobulin (IVIG) in a prospective, open-label cohort study. A randomised, placebo controlled, double blinded study is needed to confirm these results. We chose to study patients with carbamazepine resistant primary Trigeminal Neuralgia (rpTN), as these had responded particularly well to IVIG. A protocol involving the use of IVIG in rpTN is complex for three reasons: 1. The effect of IVIG does not follow simple dose-response rules; 2. The response pattern of patients to IVIG was variable and ranged between no effect at all and pain free remission between two weeks and >1 year; 3. TN is characterized by extremely severe pain, for which operative intervention is (if temporarily) helpful in most patients. DESIGN: A placebo controlled, parallel, add-on model was developed and the primary outcome variable defined as the length of time during which patients remain in the study. Study groups are compared using Kaplan-Maier survival analysis. Patients record their response to treatment ("severe, moderate, slight, no pain"). The study coordinator monitors pain diaries. Severe or moderate pain of three days duration will result in termination of the study for that patient. CONCLUSIONS: This study design utilizes a method of survival analysis and is novel in chronic pain research. It allows for both early departure from the study and voluntary crossover upon non-response. It may be applicable to the analysis of IVIG efficacy in other chronic pain syndromes

Spectroscopic studies of carbon containing molecules and their break-up in PISCES-A

We have used the PISCES-A facility in order to study the behavior of carbon containing molecules in a representative plasma with parameters close to that of a tokamak boundary layer, CH{sub 4}, C{sub 2}H{sub 2}, C{sub 2}H{sub 4}, CO, and CO{sub 2} molecules were introduced through a slit aperture into a helium plasma and the radiation from these due to electronic excitation was spectrographically recorded. The imaging of the plasma onto the entrance slit of a 1.33m McPherson optical spectrometer was chosen in such a way that simultaneous information about spectral and spatial distribution of the emission could be obtained by an attached photographic camera and an optical multichannel analyser (OMA). The recorded spectra show that many features in previously obtained spectra from limiters originate -- beside from hydrocarbons -- from carbonoxides, which seem to play a major role in the transport of carbon and oxygen. It was also possible to calibrate the radiation intensity of several molecular bands versus the known molecular influx so that an absolute determination of these fluxes from the wall of a fusion device could be done. Measurements of the attenuation of the individual species were carried out, which describe the penetration of carbon, oxygen, and hydrogen atoms into a discharge by taking into account individual steps in the molecular breakup process. 36 refs., 35 figs

Does Screening for Pain Correspond to High Quality Care for Veterans?

Routine numeric screening for pain is widely recommended, but its association with overall quality of pain care is unclear. To assess adherence to measures of pain management quality and identify associated patient and provider factors. A cross-sectional visit-based study. One hundred and forty adult VA outpatient primary care clinic patients reporting a numeric rating scale (NRS) of moderate to severe pain (four or more on a zero to ten scale). Seventy-seven providers completed a baseline survey regarding general pain management attitudes and a post-visit survey regarding management of 112 participating patients. We used chart review to determine adherence to four validated process quality indicators (QIs) including noting pain presence, pain character, and pain control, and intensifying pharmacological intervention. The average NRS was 6.7. Seventy-three percent of charts noted the presence of pain, 13.9% the character, 23.6% the degree of control, and 15.3% increased pain medication prescription. Charts were more likely to include documentation of pain presence if providers agreed that “patients want me to ask about pain” and “pain can have negative consequences on patient’s functioning”. Charts were more likely to document character of pain if providers agreed that “patients are able to rate their pain”. Patients with musculoskeletal pain were less likely to have chart documentation of character of pain. Despite routine pain screening in VA, providers seldom documented elements considered important to evaluation and treatment of pain. Improving pain care may require attention to all aspects of pain management, not just screening

Simultaneous quantitative assessment of circulating cell-free mitochondrial and nuclear DNA by multiplex real-time PCR

Quantification of circulating nucleic acids in plasma and serum could be used as a non-invasive diagnostic tool for monitoring a wide variety of diseases and conditions. We describe here a rapid, simple and accurate multiplex real-time PCR method for direct synchronized analysis of circulating cell-free (ccf) mitochondrial (mtDNA) and nuclear (nDNA) DNA in plasma and serum samples. The method is based on one-step multiplex real-time PCR using a FAM-labeled MGB probe and primers to amplify the mtDNA sequence of the ATP 8 gene, and a VIC-labeled MGB probe and primers to amplify the nDNA sequence of the glycerinaldehyde-3-phosphate-dehydrogenase (GAPDH) gene, in plasma and serum samples simultaneously. The efficiencies of the multiplex assays were measured in serial dilutions. Based on the simulation of the PCR reaction kinetics, the relative quantities of ccf mtDNA were calculated using a very simple equation. Using our optimised real-time PCR conditions, close to 100% efficiency was obtained from the two assays. The two assays performed in the dilution series showed very good and reproducible correlation to each other. This optimised multiplex real-time PCR protocol can be widely used for synchronized quantification of mtDNA and nDNA in different samples, with a very high rate of efficiency

Chronic Granulomatous Disease; fundamental stages in our understanding of CGD

It has been 50 years since chronic granulomatous disease was first reported as a disease which fatally affected the ability of children to survive infections. Various milestone discoveries from the insufficient ability of patients' leucocytes to destroy microbial particles to the underlying genetic predispositions through which the disease is inherited have had important consequences. Longterm antibiotic prophylaxis has helped to fight infections associated with chronic granulomatous disease while the steady progress in bone marrow transplantation and the prospect of gene therapy are hailed as long awaited permanent treatment options. This review unearths the important findings by scientists that have led to our current understanding of the disease

Do Children Who Move Home and School Frequently Have Poorer Educational Outcomes in Their Early Years at School? An Anonymised Cohort Study

Frequent mobility has been linked to poorer educational attainment. We investigated the association between moving home and moving school frequently and the early childhood formal educational achievement. We carried out a cohort analysis of 121,422 children with anonymised linked records. Our exposure measures were: 1) the number of residential moves registered with a health care provider, and 2) number of school moves. Our outcome was the formal educational assessment at age 6–7. Binary regression modeling was used to examine residential moves within the three time periods: 0 – ,1 year; 1 – ,4 years and 4 – ,6 years. School moves were examined from age 4 to age 6. We adjusted for demographics, residential moves at different times, school moves and birth related variables. Children who moved home frequently were more likely not to achieve in formal assessments compared with children not moving. Adjusted odds ratios were significant for 3 or more moves within the time period 1 –,4 years and for any number of residential moves within the time period 4– ,6 years. There was a dose response relationship, with increased odds ratios with increased frequency of residential moves (2 or more moves at 4–,6 years, adjusted odds ratio 1.16 (1.03, 1.29). The most marked effect was seen with frequent school moves where 2 or more moves resulted in an adjusted odds ratio of 2.33 (1.82, 2.98). This is the first study to examine the relationship between residential and school moves in early childhood and the effect on educational attainment. Children experiencing frequent mobility may be disadvantaged and should be closely monitored. Additional educational support services should be afforded to children, particularly those who frequently change school, in order to help them achieve the expected educational standards

Use of a recombinant Salmonella enterica serovar Typhimurium strain expressing C-Raf for protection against C-Raf induced lung adenoma in mice

BACKGROUND: Serine-threonine kinases of the Raf family (A-Raf, B-Raf, C-Raf) are central players in cellular signal transduction, and thus often causally involved in the development of cancer when mutated or over-expressed. Therefore these proteins are potential targets for immunotherapy and a possible basis for vaccine development against tumors. In this study we analyzed the functionality of a new live C-Raf vaccine based on an attenuated Salmonella enterica serovar Typhimurium aroA strain in two Raf dependent lung tumor mouse models. METHODS: The antigen C-Raf has been fused to the C-terminal secretion signal of Escherichia coli α-hemolysin and expressed in secreted form by an attenuated aroA Salmonella enterica serovar Typhimurium strain via the α-hemolysin secretion pathway. The effect of the immunization with this recombinant C-Raf strain on wild-type C57BL/6 or lung tumor bearing transgenic BxB mice was analyzed using western blot and FACS analysis as well as specific tumor growth assays. RESULTS: C-Raf antigen was successfully expressed in secreted form by an attenuated Salmonella enterica serovar Typhimurium aroA strain using the E. coli hemolysin secretion system. Immunization of wild-type C57BL/6 or tumor bearing mice provoked specific C-Raf antibody and T-cell responses. Most importantly, the vaccine strain significantly reduced tumor growth in two transgenic mouse models of Raf oncogene-induced lung adenomas. CONCLUSIONS: The combination of the C-Raf antigen, hemolysin secretion system and Salmonella enterica serovar Typhimurium could form the basis for a new generation of live bacterial vaccines for the treatment of Raf dependent human malignancies