Model for injury to the foreleg of the Thoroughbred racehorse

A discussion is presented of contributing factors to the injury to the foreleg of the Thoroughbred racehorse. The critical part of the step is taken to be the first 10-20 ms after ground contact as the hoof slides forward and stops. Large nonaxial loads associated with the deceleration of the hoof are shown to arise. Results of accelerometer measurements on the hoof of a horse running at racing speed are presented as well as mechanical properties of the racing surface. The mechanical properties of the track surface, the type of shoe, and the degree of fatigue of the horse all work together to determine the level of risk.     

Influence of mass transfer and surface ligand heterogeneity on quantitative BIAcore binding data. Analysis of the interaction of NC10 Fab with an anti-idiotype Fab'

The interaction of monovalent Fab fragments of NC10, an antiviral neuraminidase antibody, and the anti-idiotype antibody 3-2G12 has been used as a model system to demonstrate experimentally the influence of non-ideal binding effects on BIAcore binding data. Because the association rate constant for these two molecules was found to be relatively high (about 5 x 10(5) M-1 S-1), mass transfer was recognised as a potential source of error in the analysis of the interaction kinetics. By manipulation of the flow rate and the surface density of the immobilised ligand, however, the magnitude to this error was minimised. In addition, the application of site-specific immobilisation procedures was found to improve considerably the correlation of experimental binding data to the ideal 1:1 kinetic model such that the discrepancy between experimental and fitted curves was within the noise range of the instrument. Experiments performed to measure the equilibrium constant (KD) in solution resulted in a value of similar magnitude to those obtained from the ratio of the kinetic rate constants, even those measured with a heterogeneous ligand or with a significant mass transfer component. For this system, the experimental complexities introduced by covalent immobilisation did not lead to large errors in the KD values obtained using the BIAcore.     

Antinociceptive analogs of orphanin FQ/nociceptin(1-11)

The presence of pairs of basic amino acids within the sequence of orphanin FQ/nociceptin (OFQ/N) peptide, the endogenous ligand for the ORL1/KOR-3 receptor, has raised the possibility that processing might generate pharmacologically important truncated peptides, including OFQ/N(1-11). OFQ/N(1-11) is pharmacologically active in vivo with a potency comparable to OFQ/N. Several tyrosine-containing analogs of OFQ/N(1-11) have been synthesized and examined for antinociceptive activity. Like OFQ/N(1-11), [Tyr1]OFQ/N(1-11), [Tyr10]OFQ/N(1-11) and [IodoTyr10]OFQ/N(1-11) given supraspinally in mice were antinociceptive in the tailflick assay in mice. The tyrosine analogs showed similar potencies as OFQ/N(1-11) but longer durations of action. This response was readily reversed by the opioid antagonist naloxone despite poor affinities for these analogs at opioid receptors. Another compound, [Tyr11]OFQ/N(1-11) was highly epileptogenic, inducing naloxone-sensitive seizures in greater than 50% of the mice tested at doses comparable to those examined with the other analogs. These results indicate that it is possible to make analgesic OFQ/N(1-11) analogs. The activity of [IodoTyr10]OFQ/N(1-11) suggests that it may prove useful as a radioligand in exploring potential OFQ/N(1-11) binding sites.     

Decompensation of pressure-overload hypertrophy in G alpha q-overexpressing mice

BACKGROUND: Receptor-mediated activation of myocardial Gq signaling is postulated as a biochemical mechanism transducing pressure-overload hypertrophy. The specific effects of Gq activation on the functional and morphological adaptations to pressure overload are not known. METHODS AND RESULTS: To determine the effects of intrinsic myocyte G alpha q signaling on the left ventricular hypertrophic response to experimental pressure overload, transgenic mice overexpressing G alpha q specifically in the heart (G alpha q-25) and nontransgenic siblings underwent microsurgical creation of transverse aortic coarctation and the morphometric, functional, and molecular characteristics of these pressure-overloaded hearts were compared at increasing times after surgery. Before aortic banding, isolated G alpha q-25 ventricular myocytes exhibited contractile depression (depressed +dl/dt and -dl/dt) and G alpha q-25 hearts showed a pattern of fetal gene expression similar to the known characteristics of nontransgenic pressure-overloaded mice. Three weeks after transverse aortic banding, G alpha q-25 left ventricles hypertrophied to a similar extent (approximately 30% increase) as nontransgenic mice. However, whereas nontransgenic mice exhibited concentric left ventricular remodeling with maintained ejection performance (compensated hypertrophy), G alpha q-25 left ventricles developed eccentric hypertrophy and ejection performance deteriorated, ultimately resulting in left heart failure (decompensated hypertrophy). The signature hypertrophy-associated progress of fetal cardiac gene expression observed at baseline in G alpha q-25 developed after aortic banding of nontransgenic mice but did not significantly change in aortic-banded G alpha q-25 mice. CONCLUSIONS: Intrinsic cardiac myocyte G alpha q activation stimulates fetal gene expression and depresses cardiac myocyte contractility. Superimposition of the hemodynamic stress of pressure overload on G alpha q overexpression stimulates a maladaptive form of eccentric hypertrophy that leads to rapid functional decompensation. Therefore G alpha q-stimulated cardiac hypertrophy is functionally deleterious and compromises the ability of the heart to adapt to increased mechanical load. This finding supports a reevaluation of accepted concepts regarding the mechanisms for compensation and decompensation in pressure-overload hypertrophy.     

Gene expression in brain during cuprizone-induced demyelination and remyelination

When C57BL/6J mice, 8 weeks of age, received 0.2% Cuprizone in their diet, extensive demyelination in corpus callosum was detectable after 3 weeks, and there was massive demyelination by 4 weeks. As expected, the accumulation of phagocytically active microglia/macrophages correlated closely with demyelination. When Cuprizone was removed from the diet, remyelination was soon initiated; after 6 weeks of recovery, myelin levels were near-normal and phagocytic cells were no longer prominent. Steady-state levels of mRNA for myelin-associated glycoprotein, myelin basic protein, and ceramide galactosyltransferase were already profoundly depressed after 1 week of Cuprizone exposure and were only 10-20% of control values after 2 weeks. Unexpectedly, upregulation of mRNA for these myelin genes did not correlate with initiation of remyelination but rather with accumulation of microglia/macrophages. After 6 weeks of exposure to Cuprizone, mRNA levels were at control levels or higher-in the face of massive demyelination. This suggests that in addition to effecting myelin removal, microglia/macrophages may simultaneously push surviving oligodendroglia or their progenitors toward myelination.     

Green tea polyphenols block endotoxin-induced tumor necrosis factor-production and lethality in a murine model

The effects of arginine on cell proliferation and subsequent T helper (Th) 1 and Th 2 cytokine synthesis by murine Peyer's patch (PP) Th cells in vitro and the influence of arginine on the induction of antigen-specific mucosal and systemic immune responses in vivo were examined. When the PP T cells were stimulated with the anti-alpha beta T cell receptor (TCR) antibody in the presence of different concentrations of arginine, a higher proliferative response was observed in the culture with an optimal concentration of arginine compared with that with a minimum amount of this amino acid. The concentration of cytokines in the supernatant, the number of cytokine-producing cells and the cytokine-specific mRNA expression of PP T cells were also increased in a dose-dependent fashion. Furthermore, when mice fed on an arginine-supplemented liquid diet were orally immunized with tetanus toxoid plus cholera toxin as a mucosal adjuvant, a higher level of antigen-specific fecal IgA was observed when compared with the response in mice fed on an arginine-free diet. Taken together, these results suggest that arginine enhanced antigen-specific mucosal immune response resulting from the supporting activation of cell proliferation and subsequent cytokine synthesis of PP Th cells.     

Visual marking of moving objects: a role for top-down feature-based inhibition in selection

Recently, the authors presented evidence that new items can be prioritized for selection by the top-down attentional inhibition of old stimuli already in the field (visual marking; D. G. Watson & G. W. Humphreys, 1997). In this article the authors assess whether this inhibition extends to moving old items and test an alternative account of visual marking. Six experiments showed that old moving items could be inhibited provided they did not undergo abrupt property changes. Further, and in contrast to effects with static stimuli, the marking of old moving stimuli was based on inhibition applied at the level of a whole feature map, rather than at their locations. The results also rule out an alternative account of visual marking based on the top-down weighting of dynamic or static processing pathways.     

Extensive direct-tandem organization of a long repeat DNA sequence on the Y chromosome of chinook salmon (Oncorhynchus tshawytscha)

A long repetitive DNA sequence (OtY8) has been cloned from male chinook salmon and its genomic organization has been characterized. The repeat has a unit length of 8 kb and is present approximately 300 times per diploid male nucleus. All internal fragments within the 8-kb repeat segregate from father to son, suggesting that the entire repeat unit is located on the Y chromosome. The organization of this sequence into an 8-kb repeat unit is restricted to the Y chromosome, as are several male-specific repeat subtypes identified on the basis of restriction-site variation. The repeat possesses only weak internal sequence similarities, suggesting that OtY8 has not arisen by duplication of a smaller repeat unit, as is the case for other long tandem arrays found in eukaryotes. Based on a laddered pattern arising from partial digestion of genomic DNA with a restriction enzyme which cuts only once per repeat unit, this sequence is not dispersed on the Y chromosome but is organized as a head-to-tail tandem array. Pulse-gel electrophoresis reveals that the direct-tandem repeats are organized into at least six separate clusters containing approximately 12 to 250 copies, comprising some 2.4 Mb of Y-chromosomal DNA in total. Related sequences with nucleotide substitutions and DNA insertions relative to the Y-chromosomal fragment are found elsewhere in the genome but at much lower copy number and, although similar sequences are also found in other salmonid species, the amplification of the repeat into a Y-chromosome-linked tandem array is only observed in chinook salmon. The OtY8 repetitive sequence is genetically tightly associated with the sex-determination locus and provides an opportunity to examine the evolution of the Y chromosome and sex determination process in a lower vertebrate.     

Lipid lowering in a multidisciplinary clinic compared with primary physician management

OBJECTIVE: This study analyzed questionnaire items that address complaints about sleep from the National Vietnam Veterans Readjustment Study, a nationally representative sample of the 3.1 million men and women who served in Vietnam. This study compared the frequency of nightmares and difficulties with sleep onset and sleep maintenance in male Vietnam theater veterans with male Vietnam era veteran and male civilian comparison subjects. It focused on the role of combat exposure, nonsleep posttraumatic stress disorder (PTSD) symptoms, comorbid psychiatric and medical disorder, and substance abuse in accounting for different domains of sleep disturbance. METHOD: The authors undertook an archival analysis of the National Vietnam Veterans Readjustment Study database using correlations and linear statistical models. RESULTS: Frequent nightmares were found exclusively in subjects diagnosed with current PTSD at the time of the survey (15.0%). In the sample of veterans who served in Vietnam (N = 1,167), combat exposure was strongly correlated with frequency of nightmares, moderately correlated with sleep onset insomnia, and weakly correlated with disrupted sleep maintenance. A hierarchical multiple regression analysis showed that in Vietnam theater veterans, 57% of the variance in the frequency of nightmares was accounted for by war zone exposure and non-sleep-related PTSD symptoms. Alcohol abuse, chronic medical illnesses, panic disorder, major depression, and mania did not predict the frequency of nightmares after control for nonsleep PTSD symptoms. CONCLUSIONS: Frequent nightmares appear to be virtually specific for PTSD. The nightmare is the domain of sleep disturbance most related to exposure to war zone traumatic stress.     

Effects of 6alpha-methylprednisolone acetate on an equine osteochondral fragment exercise model

OBJECTIVE: To determine effects of intra-articularly administered 6alpha-methylprednisolone acetate (MPA) in exercised horses with carpal osteochondral fragmentation. ANIMALS: 18 horses: 3 groups of 6 each. PROCEDURE: An osteochondral (chip) fragment was created in 1 randomly chosen middle carpal joint of each horse. Polyionic fluid (PF) was injected into both middle carpal joints of horses in the control group. In horses of the MPA-control group, MPA was injected into the middle carpal joint without an osteochondral fragment; a similar volume of PF was injected into the contralateral middle carpal joint. In the MPA-treated group of horses, 100 mg of MPA was injected into the middle carpal joint containing the osteochondral fragment; a similar volume of PF was injected into the contralateral joint. Injections were administered on postsurgical days 14 and 28, and horses were exercised on a high-speed treadmill for 8 weeks, starting on postsurgical day 15. RESULTS: Clinical improvement in degree of lameness was not associated with MPA administration. Joints that contained an osteochondral fragment and were treated with MPA had lower prostaglandin E2 concentration in synovial fluid, and lower scores for intimal hyperplasia and vascularity in synovial membrane, compared with PF-treated joints. However, articular cartilage erosion and morphologic lesions suggested possible deleterious effect of intra-articular MPA administration. CONCLUSIONS: Some beneficial effects of MPA administration on synovial fluid and synovial membrane were identified; however, the deleterious findings contrast with those associated with triamcinolone acetonide used in a similar model, but agree with other results of MPA administration in normal and abnormal joints.