Development of miotic cross-tolerance between pyridostigmine and sarin vapor.

The organophosphorous nerve agent sarin (GB) and the carbamate pyridostigmine bromide (PB) both inhibit acetylcholinesterase (AChE), leading to overstimulation of muscarinic receptors. Both GB and PB produce miosis through stimulation of ocular muscarinic receptors. This study investigated 2 hypotheses: (1) that the miotic response to PB would decrease following repeated injections; and (2) that repeated administration of PB would result in tolerance to the miotic effect of GB vapor. Rats were injected intramuscularly with saline, 0.04 mg/kg, 0.5 mg/kg, or 1.4 mg/kg of PB twice daily for 8 consecutive days. After day 3, animals injected with 1.4 mg/kg PB developed miotic tolerance. Twenty-four (24) h following the final PB injection, the rats were exposed to GB vapor (4.0 mg/m(3)). A similar magnitude of miosis was observed in all groups after GB exposure. However, the rate of recovery of pupil size in animals pretreated with 0.5 and 1.4 mg/kg PB was significantly increased. Twenty (20) h following exposure to GB vapor, the pupils of animals pretreated with 1.4 mg/kg PB had recovered to 77% +/- 4% of their pre-exposure baseline, whereas the saline-injected controls had recovered to only 52% +/- 2% of their pre-exposure baseline. The increased rate of recovery does not appear to be a result of protection of pupillary muscarinic receptors by the higher doses of PB, as there was no longer PB present in the animal at the time of GB exposure. These results demonstrate the development of tolerance to the miotic effect of PB following repeated exposures, and also suggest that cross-tolerance between PB and GB occurs. However, because the magnitude of the response was not reduced, the PB pretreatment and its associated miotic cross-tolerance does not appear to diminish the effectiveness of miosis as a biomarker of acute exposure to nerve agent vapor.     

Validation of a simplified technique for using the POPQ pelvic organ prolapse classification system

Our objective was to determine the inter-examiner agreement of a simplified pelvic organ prolapse quantification (POPQ) exam and to assess its correlation with the standard POPQ exam. This study consists of two parts; both were preformed in a prospective, randomized, blinded fashion on women presenting with complaints attributed to pelvic organ support defects. The first study was done to determine the inter-examiner reliability of a simplified POPQ exam. The simplified POPQ exam is based on the POPQ with similar ordinal staging but with only four points measured instead of nine. Forty-eight women underwent exams by five different investigators. The order of exams was randomized and the examiners were blinded to the results of each other’s findings. The results of these two exams were compared using weighted kappa statistics. The second part of the study was done to determine the inter-system agreement between the simplified vs standard POPQ exam. A group of 49 women were examined by four different investigators: one using the simplified and the other using standard POPQ exams. The order of the exams was randomized and the examiners were blinded to the results of each other’s exam. Kendall’s tau-b statistics were used to determine the inter-system agreement. For the inter-examiner reliability of the POPQ exam, the average age was 60±13 years. The weighted kappa statistics for the inter-examiner reliability of the simplified prolapse classification system were 0.86 for the overall stage, 0.89 and 0.86 for the anterior and posterior vaginal walls, respectively, 0.82 for the apex/cuff, and 0.72 for the cervix. All demonstrate significant agreement. For the inter-system association between the simplified POPQ and standard POPQ, the average age was 61±15 year. The Kendall’s tau-b value for overall stage was 0.90, 0.83, and 0.87 for the anterior and posterior walls respectively, and 0.78 for the cuff/apex and 0.98 for the cervix. There is good inter-examiner agreement of a simplified POPQ classification system and it appears to have good inter-system association with the POPQ.IUGA Standardization of Terminology Committee members: Robert Freeman MD (chairman), Steven Swift, Eckhard Petri MD, Richard J. Scotti MD, and Peter Dwyer MD.     

Transcapillary fluid balance consequences of missing initial lymphatics studied in a mouse model of primary lymphoedema

To investigate the phenotypic consequences of a deranged lymphangiogenesis in relation to tissue fluid accumulation and the possible role of inflammation in the pathogenesis of lymphoedema, we measured determinants of transcapillary fluid filtration and inflammatory mediators in the interstitial fluid in genetically engineered Chy mice, a model for primary congenital lymphoedema (Milroy's disease). Although initial lymphatics were not present in dermis in any of the areas studied (fore paw, hind paw, thigh and back skin) interstitial fluid pressure ( P _if), measured with micropipettes, and tissue fluid volumes were significantly increased only in the areas with visible swelling – the fore and hind paw, whereas interstitial colloid osmotic pressure (COP_if) was increased in all the skin areas examined. A volume load of 15% of body weight resulted in a more pronounced increase in P _if as well as a four-fold increase in interstitial fluid volume in Chy relative to wild-type (wt) mice, showing the quantitative importance of lymphatics for fluid homeostasis during acute perturbations. A similar level of proinflammatory markers in interstitial fluid in early established lymphoedema (3–4 months) in Chy and wt suggests that inflammation does not have a major pathogenetic role for the development of lymphoedema, whereas a reduced level of the immunomodulatory cytokine interleukin (IL)-4 may result in a reduced immunological defence ability and thus lead to the increase in inflammatory cytokines IL-2 and IL-6 observed at a later stage (11–13 months). Our data suggest that primary lymphoedema results in a high interstitial fluid protein concentration that does not induce an interstitial inflammatory reaction per se , and furthermore shows the paramount importance of the initial lymphatics in tissue fluid homeostasis, especially during perturbations of transcapillary fluid balance.     

Application of an augmented reality tool for maxillary positioning in orthognathic surgery – A feasibility study

BACKGROUND: An augmented reality tool for computer assisted surgery named X-Scope allows visual tracking of real anatomical structures in superposition with volume rendered CT or MRI scans and thus can be used for navigated translocation of bony segments. METHODS: In a feasibility study X-Scope was used in orthognathic surgery to control the translocation of the maxilla after Le Fort I osteotomy within a bimaxillary procedure. The situation achieved was compared with the pre-operative situation by means of cephalometric analysis on lateral and frontal cephalograms. RESULTS: The technique was successfully utilized in 5 patients. Maxillary positioning using X-Scope was accomplished accurately within a range of 1mm. The tool was used in all cases in addition to the usual intra-operative splints. A stand-alone application without conventional control does not yet seem reasonable. CONCLUSION: Augmented reality tools like X-Scope may be helpful for controlling maxillary translocation in orthognathic surgery. The application to other interventions in cranio-maxillofacial surgery such as Le Fort III osteotomy, fronto-orbital advancement, and cranial vault reshaping or repair may also be considered.     

Etanercept decreases tumor necrosis factor-α activity in chronic wound fluid

High levels of tumor necrosis factor-alpha (TNF-alpha), a pro-inflammatory cytokine, are present in the wound fluid of chronic nonhealing wounds. This leads to increased inflammation, cytokine expression, and ultimately results in impaired wound healing and tissue destruction. Etanercept is a recombinant fusion protein that consists of the soluble TNF receptor (p75) linked to the Fc portion of human IgG1. It is an effective inhibitor of TNF-alpha and has been shown to provide rapid and sustained improvement in rheumatoid arthritis by acting as a soluble receptor binding TNF-alpha and preventing its proinflammatory activities. Therefore, the aim of this study was to determine whether Etanercept could inhibit TNF-alpha activity in chronic wound fluid. Wound fluid was collected from the venous leg ulcers of 16 different patients. The effect of Etanercept on TNF-alpha activity was evaluated using both a TNF-alpha bioassay and an enzyme-linked immunoassay. Etanercept was found to reduce the cytotoxic effect of chronic wound fluid on L929 fibroblasts by approximately 30% and neutralized TNF-alpha binding in the enzyme-linked immunoassay by up to 80%. Direct application of Etanercept to chronic wounds may therefore reduce the inflammatory activity of TNF-alpha, which could reduce the chronicity of venous leg ulcers and thus aid in the healing of these wounds.