A Comparison of YM-14673, U-50488H, and Nalmefene after Spinal Cord Injury in the Rat

A reproducible spinal cord injury model was used to compare the efficacy of three compounds previously shown to improve neurologic recovery after injury in rats: The thyrotropin releasing hormone (TRH) analogue, YM-14673; the specific κ-opioid agonist, U-50488H; and the opioid antagonist, nalmefene, which has increased activity at κ-receptors. A moderate injury in rats that results in recovery of uncoordinated gross locomotion was made at spinal T9 by rapid displacement (1.1. mm) of the cord. Compounds (or vehicle) were given either by intravenous bolus or by continuous mini-osmotic pump over 7 days, beginning 30 min after the injury as follows: controls (saline), YM-14673 (1 mg/kg bolus), U-50488H (10 mg/kg bolus), U-50488H (0.425 mg/kg/h continuous infusion × 7 days); nalmefene (0.1 mg/kg bolus); and nalmefene (0.021 mg/kg/h continuous infusion × 7 days). Neurologic recovery was assessed for 4 weeks by open-field walking, inclined plane, grid walking, and footprint analysis. The percentage of white matter spared was determined at the lesion epicenter. Only those groups given a bolus of YM-14673, U-50488H, and nalmefene had open-field performance better than the scores of controls. Animals that received a bolus of YM-14673 also scored better than controls on the inclined plane and were more likely than controls to recover sufficiently to be tested by both grid walking and footprint analysis. Improved behavioral recovery was not found in groups that received chronic drug infusion. Histology demonstrated significant sparing of white matter for the YM-14673-treated group compared with controls; groups given a U-50488H and nalmefene bolus showed a trend for greater sparing of white matter. The results confirm a beneficial effect for these compounds and suggest that they may be useful in treatment of clinical spinal cord injury.     

Interleukin-1-induced leukocyte extravasation across rat mesenteric microvessels is mediated by platelet-activating factor

Although our understanding of the molecular interactions that mediate the adhesion of leukocytes to venular endothelial cells has greatly expanded, very little is known about the mechanisms that mediate the passage of leukocytes across the vessel wall in vivo. The aim of the present study was to investigate the role of endogenously formed platelet-activating factor (PAF) in the process of leukocyte extravasation induced by interleukin-1 (IL-1). To determine at which stage of emigration PAF was involved, we studied the behavior of leukocytes within rat mesenteric microvessels by intravital microscopy. Rats were injected intraperitoneally with saline, recombinant rat IL-1 beta (IL-1 beta), or the peptide N-formyl-methionyl-leucyl- phenylalanine (FMLP) 4 hours before the exteriorization of the mesenteric tissue. In animals treated with IL-1 beta there was a significant increase in the number of rolling and adherent leukocytes within venules (20- to 40-micron diameter) and in the number of extravasated leukocytes in the tissue. Pretreatment of rats with the PAF receptor antagonist UK-74,505 had no effect on the leukocyte responses of rolling and adhesion, but significantly inhibited the migration of the leukocytes across the vessel wall induced by IL-1 beta (76% inhibition). A structurally unrelated PAF antagonist, WEB-2170, produced the same effect (64% inhibition). However, in contrast, UK- 74,505 had no effect on the leukocyte extravasation induced by FMLP, indicating selectivity for the response elicited by certain mediators. These results provide the first line of direct evidence for the involvement of endogenously formed PAF in the process of leukocyte extravasation induced by IL-1 in vivo.     

The prognostic value of normal exercise myocardial perfusion imaging and exercise echocardiography: a meta-analysis.

OBJECTIVES: The purpose of this work was to determine the prognostic value of normal exercise myocardial perfusion imaging (MPI) tests and exercise echocardiography tests, and to determine the prognostic value of these imaging modalities in women and men. BACKGROUND: Exercise MPI and exercise echocardiography provide prognostic information that is useful in the risk stratification of patients with suspected coronary artery disease (CAD). METHODS: We searched the PubMed, Cochrane, and DARE databases between January 1990 and May 2005, and reviewed bibliographies of articles obtained. We included prospective cohort studies of subjects who underwent exercise MPI or exercise echocardiography for known or suspected CAD, and provided data on primary outcomes of myocardial infarction (MI) and cardiac death with at least 3 months of follow-up. Secondary outcomes (unstable angina, revascularization procedures) were abstracted if provided. Studies performed exclusively in patients with CAD were excluded. RESULTS: The negative predictive value (NPV) for MI and cardiac death was 98.8% (95% confidence interval [CI] 98.5 to 99.0) over 36 months of follow-up for MPI, and 98.4% (95% CI 97.9 to 98.9) over 33 months for echocardiography. The corresponding annualized event rates were 0.45% per year for MPI and 0.54% per year for echocardiography. In subgroup analyses, annualized event rates were <1% for each MPI isotope, and were similar for women and men. For secondary events, MPI and echocardiography had annualized event rates of 1.25% and 0.95%, respectively. CONCLUSIONS: Both exercise MPI and exercise echocardiography have high NPVs for primary and secondary cardiac events. The prognostic utility of both modalities is similar for both men and women.     

The effect of influenza vaccination on IL2 production in healthy elderly: implications for current vaccination practices.

Age-related senescence of T-cell mediated responses is well recognized. This study was designed to determine how aging affects the T-cell mediated Interleukin 2 (IL2) response to influenza vaccination. A group of healthy elderly individuals were compared to a control group of healthy young adults for their response to the 1990 influenza vaccine. Cultures of peripheral blood mononuclear cells (PBMC) were prepared from venous blood samples taken prevaccination (pre) and 8 and 12 weeks post-vaccination (post). PBMC cultures stimulated with inactivated A/Shanghai/16/89 (contained in the 1990 vaccine) and A/Philippine/2/82 (not contained in the vaccine) were assayed for peak IL2 activity. We find that after influenza vaccination, there was an insignificant increase in IL2 activity when PBMC from the young control group were stimulated with A/Shanghai/16/89 (pre, 5.14 U/mL/10(6) PBMC; post, 6.64 U/mL/10(6) PBMC) but there was a significant increase in IL2 activity when stimulated with A/Phillippine/2/82 (pre, 1.5 U/mL/10(6) PBMC; post, 8.3 U/mL/10(6) PBMC). In similar cultures of PBMC from the elderly group, there was a significant increase in IL2 response to both A/Shanghai/16/89 (pre, 1.6 U/mL/10(6) PBMC; post, 3.5 U/mL/10(6) PBMC) and A/Philippine/2/82 (pre, 0.86 U/mL/10(6) PBMC; post, 8.3 U/mL/10(6) PBMC). Measurements of CD4+/CD8+ populations were not affected by vaccination and were not significantly different in the two groups. Subgroup analysis of the elderly group revealed that previous influenza vaccination in 1989 did not significantly affect IL2 levels measured in the present study. This study shows that in healthy elderly, influenza vaccination effectively restores IL2 activity to normal. There appears to be an age-related decrease in the duration of T-cell memory.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reanalysis of Antisera Specificities and Binding Characteristics of Rat Pituitary Hormone Assays

Rat pituitary hormone radioimmunoassays (RIAs) are widely used in reproductive research, yet data on specificity and binding characteristics of many of the antisera are not widely available. This report characterizes one set of rat antisera supplied by the National Institutes of Health (USA). Rat follicle-stimulating hormone (FSH) and thyrotropin-stimulating hormone (TSH) antisera appear specific, but TSH exhibited significant competition in the rat luteinizing hormone (LH) assay. In addition, statistically significant nonparallelism was demonstrable in all three assay systems. This creates further problems in characterizing antisera cross-reactivity and may make potency estimates for pituitary standards inaccurate.     

Aspects of training in clinical medical sciences in dentistry (human disease): recent graduates' perspectives from a UK dental school

Teaching the management of medical emergencies is an important part of most courses in Clinical Medical Sciences in Dentistry (Human Disease). The aim of this study was to examine which medical emergencies graduates from the School of Dental Sciences at Newcastle University had experienced 1 year after qualification and their perceptions of their ability to assess a patient's fitness for treatment or to manage a medical emergency. The study instrument was a computer readable questionnaire. Very few emergencies had been experienced in general practice at this stage of their career, but all respondents either strongly agreed or agreed that their training had adequately equipped them to assess a patient's medical history and deal with medical emergencies. There were, however, aspects of the course that upon reflection that clearly needed to be addressed, including the use of different teachers for aspects of the medical emergency teaching.     

Needle puncture injury causes acute and long‐term mechanical deficiency in a mouse model of intervertebral disc degeneration

Low back pain is a significant socioeconomic burden and intervertebral disc degeneration has been implicated as a cause. A reliable animal model of disc degeneration is necessary to evaluate therapeutics, and functional metrics are essential to quantify their benefit. To this end, needle puncture injuries were created in the caudal intervertebral discs of mice to induce disc degeneration. Compression, torsion, and creep mechanics were assessed both immediately and after eight weeks to distinguish between the effects of injury and the subsequent reparative or degenerative response. Two needle sizes (29 and 26 gauge) were used to determine injury size‐dependence. Compressive stiffness (62%), torsional stiffness (60%), and early damping stiffness (84%) decreased immediately after injury with the large needle (26G). These mechanical properties did not change over time despite structural and compositional changes. At 8 weeks following large needle injury, disc height decreased (37%), nucleus pulposus (NP) glycosaminoglycan content decreased (41%), and NP collagen content increased (45%). The small needle size had no significant effect on mechanics and did not initiate degenerative changes in structure and composition. Thus, the injection of therapeutics into the NP with a minimal needle size may limit damage due to the needle insertion. These findings, along with the wide commercial availability of mouse‐specific biological probes, indicate that the mouse caudal disc model can be a powerful tool for investigating disc degeneration and therapy. © 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 31:1276–1282, 2013