Traumatic brain injury alters synaptic homeostasis: implications for impaired mitochondrial and transport function

This study utilized a unilateral controlled cortical impact model of traumatic brain injury to assess disruptions of synaptic homeostasis following trauma. Adult rats were subjected to a moderate (2 mm) cortical deformation and synaptosomes were prepared from the entire ipsilateral (injured) hemisphere or dissected into different regions (hippocampus, injured cortical area including penumbra, residual hemisphere) at various times postinjury (10 and 30 min, and 1, 6, and 24 h). Synaptosomes from the corresponding regions of the contralateral hemisphere were used as controls to assess alterations in synaptic ATP levels, lipid peroxidation, and glutamate and glucose transport. The results demonstrate significant time-dependent alterations in synaptic homeostasis, which included an immediate reduction in ATP levels, coupled with a significant increase in lipid peroxidation within 30 min postinjury. Lipid peroxidation demonstrated a biphasic response with elevations observed 24 h postinjury, a time at which decreases in glutamate and glucose transport occurred. These results suggest that disruption of synaptic homeostasis is an extremely early event following trauma that should be considered when designing pharmacological interventions.     

Regional alterations in neuronal activity in dystonic hamster brain determined by quantitative cytochrome oxidase histochemistry

The neural mechanisms underlying idiopathic dystonia are currently unknown. Genetic animal models, such as the dt(sz) hamster, a model of idiopathic paroxysmal dystonia, may be helpful to providing insights into the pathophysiology of this common movement disorder. Recent metabolic mapping studies in the hamster model, using 2-deoxyglucose autoradiography, demonstrated altered 2-deoxyglucose uptake in motor areas such as the striatum, ventral thalamic nuclei, red nucleus, and deep cerebellar nuclei, during dystonic attacks. Whereas the 2-deoxyglucose method is thought to reflect mainly acute alterations of synaptic activity, determination of cytochrome oxidase activity has been suggested as a method of choice to examine sustained baseline changes in neuronal activity. Therefore, in the present study quantitative cytochrome oxidase histochemistry was used to identify chronic regional alterations in the absence of dystonic attacks in mutant hamsters. For comparison with recent 2-deoxyglucose studies, cytochrome oxidase activity was also determined during a dystonic attack, which was induced by mild stress. Cytochrome oxidase was determined in 109 brain regions of dystonic hamsters and non-dystonic, age-matched control hamsters. In the absence of a dystonic attack, a tendency to decreased cytochrome oxidase activity was found in most brain regions, possibly due to retarded brain development in mutant hamsters. Significant decreases in cytochrome oxidase activity were found in motor areas and limbic structures, such as hippocampus, piriform cortex, fundus striatum, globus pallidus, substantia nigra pars reticulata, mediodorsal nucleus of the thalamus, ventral pallidum, and interpositus nucleus of the cerebellum. After induction of a dystonic attack, the trend of decreased cytochrome oxidase activity disappeared, except in globus pallidus and interpositus nucleus of the cerebellum. Although the significant alterations in cytochrome oxidase activity in the absence of a dystonic attack were moderate, the data are in line with previous findings in the mutant hamsters, indicating that dysfunctions of the basal ganglia and their output nuclei are involved in the dystonic condition. Altered neural activity in limbic structures, found in the absence of dystonic attacks in mutant hamsters, may contribute to the stress-susceptibility of the animals.     

The contribution of job satisfaction to the transition from acute to chronic low back pain

The goal of this study was to develop an animal model for the study of acute periodontal disease using silk ligatures in combination with a soft diet in eleven purebred beagle dogs. The silk ligatures were placed subgingivally on the mandible second and fourth premolar on one side of the mouth; the opposite side served as a control. Dogs were monitored during the 16-20 weeks of ligature placement, and for 48 weeks after ligature removal. Development of periodontal disease was evaluated by radiopharmaceutical uptake into bone, radiographic evidence of alveolar bone loss, attachment loss, gingival index and prostaglandin level. Bone loss occurred on the ligatured side during the ligature phase of the study. Radiopharmaceutical uptake was correlated with radiographic evidence of bone loss during the ligature phase. No significant bone loss occurred during the post-ligature phase. Progressive periodontal disease was induced during ligature placement. However, a chronic less aggressive form was not sustained by soft diet alone after ligature removal.     

Effects of controlled heat stress on ovarian function of dairy cattle. 1. Lactating cows

The objective of this experiment was to determine the effects of controlled heat stress on ovarian function of lactating dairy cows. Estrus was synchronized (estrus = d 0), and cows were randomly assigned to either heat stress (n = 11; 29 degrees C, 60% relative humidity) or thermoneutral (n = 11; 19 degrees C, 60% relative humidity) treatment. For cows undergoing heat stress, ambient temperature (19 degrees C) was increased from d 11 to 13 of the estrous cycle (3.3 degrees C/d increase) and remained at 29 degrees C until d 21. Beginning on d 11, the growth and regression of ovarian follicles and corpora lutea were measured by using ultrasonography. Blood was collected daily by coccygeal venipuncture for measurement of serum concentrations of progesterone and estradiol. The second wave dominant follicle was more likely to ovulate in cows in the thermoneutral treatment than in cows undergoing heat stress (91 vs. 18% ovulation, respectively). Patterns of follicular growth in cows under-going heat stress were associated with decreased serum estradiol from d 11 to 21 and on the day of luteolysis. The average day of luteolysis was delayed by 9 d in heat-stressed cows. Conclusions were that follicular growth and development and luteolytic mechanisms were compromised in heat-stressed cows; as a result, luteolysis was delayed, and second wave dominant follicles did not ovulate.     

The negative inotropic effect of beta3-adrenoceptor stimulation is mediated by activation of a nitric oxide synthase pathway in human ventricle

Beta1- and beta2-adrenoceptors in heart muscle cells mediate the catecholamine-induced increase in the force and frequency of cardiac contraction. Recently, in addition, we demonstrated the functional expression of beta3-adrenoceptors in the human heart. Their stimulation, in marked contrast with that of beta1- and beta2-adrenoceptors, induces a decrease in contractility through presently unknown mechanisms. In the present study, we examined the role of a nitric oxide (NO) synthase pathway in mediating the beta3-adrenoceptor effect on the contractility of human endomyocardial biopsies. The negative inotropic effects of a beta3-adrenoceptor agonist, BRL 37344, and also of norepinephrine in the presence of alpha- and beta1-2-blockade were inhibited both by a nonspecific blocker of NO, methylene blue, and two NO synthase (NOS) inhibitors, L-N-monomethyl-arginine and L-nitroarginine-methyl ester. The effect of the NOS inhibitors was reversed by an excess of L-arginine, the natural substrate of NOS, but not by D-arginine. Moreover, the effects of the beta3-adrenoceptor agonist on contractility were associated with parallel increases in the production of NO and intracellular cGMP, which were also inhibited by NOS inhibitors. Immunohistochemical staining of human ventricular biopsies showed the expression of the endothelial constitutive (eNOS), but not the inducible (iNOS) isoform of NOS in both ventricular myocytes and endothelial cells. These results demonstrate that beta3-adrenoceptor stimulation decreases cardiac contractility through activation of an NOS pathway. Changes in the expression of this pathway may alter the balance between positive and negative inotropic effects of catecholamines on the heart potentially leading to myocardial dysfunction.     

The metabolism of 3-phenoxybenzoic acid-containing xenobiotic triacylglycerols in vitro by pancreatic, hormone-sensitive and lipoprotein lipases

Two model substrates, rac-1-(3-phenoxy-[ring-14C]benzoyl)-2,3-dipalmitoyl glycerol (1(3PBA)DPG) and sn-2-(3-phenoxy-[ring-14C]benzoyl)-1,3-dipalmitoyl glycerol (2(3PBA)DPG), were compared with tri[1-14C]palmitoylglycerol or tri[9,10(n)-3H]oleoylglycerol as substrates for pancreatic lipase, lipoprotein lipase, and hormone-sensitive lipase. The loss of 3PBA from the sn-2 position was always low because of the positional specificity of the lipases. The loss of 3PBA from the rac-1 position was similarly low with hormone-sensitive lipase (about 7% of the loss of oleate), but higher with pancreatic lipase (about 35% that of oleate) and lipoprotein lipase (about 23% that of oleate). With one exception, more than 50% and up to 80% of the 14C-3PBA was still in the form of a diacylglycerol after incubation with a lipase, whereas free acid or monoacylglycerol forms would have been expected. Lipoprotein lipase acting on 1-(14C-3PBA)DPG produced nearly 70% of its product as nonesterified 3PBA and only 25% as the diacylglycerol. The results suggest that 3PBA-containing xenobiotic triacylglycerols, and the 3PBA-glycerol ester bond in particular, are poorer substrates for lipases than are their natural counterparts, with the result that high proportions of partially digested xenobiotic acylglycerols are produced. The three lipases performed differently with the xenobiotic substrates; this could have consequences for the relative rates of storage and clearance of the xenobiotic triacylglycerols from the body.     

NMDA induces NO release from primary cell cultures of human fetal cerebral cortex

In order to investigate the role of insulin-like growth factors (IGFs) in human ovulation, we evaluated the concentrations of IGF-binding proteins (IGFBPs) in human follicular fluid (FF). The concentrations of IGFBP-1 in the FFs of 15 women undergoing in vitro fertilization and embryo transfer were measured and related to those of 17beta-estradiol (E2), progesterone and androstenedione in the FFs. IGFBP-1 levels in the FFs were positively correlated with those of E2 and progesterone. No correlation was found between the IGFBP-1 and androstenedione levels in FFs. The concentrations of IGFBP-1 were significantly increased in the FFs which contained mature oocytes compared with those of immature oocytes, whereas IGFBP-3 in FFs tended to decrease as oocytes matured. It is suggested that IGFs may play important roles in human preovulatory processes, and that IGFBP-1 may be a valuable biochemical marker in the evaluation of oocytes.     

Bleomycin induces strain-dependent alterations in the pattern of epithelial cell-specific marker expression in mouse lung

To identify potential opsonic targets of Treponema pallidum subsp. pallidum, a treponemal genomic expression library was constructed and differentially screened with opsonic and non-opsonic T. pallidum antisera. This method identified an immunoreactive clone containing an open reading frame encoding a 356 residue protein. Nucleotide sequence analysis demonstrated the translated protein to be a homologue of glycerophosphodiester phosphodiesterase, a glycerol metabolizing enzyme previously identified in Haemophilus influenzae, Escherichia coli, Bacillus subtilis and Borrelia hermsii. Sequence alignment analyses revealed the T. pallidum and H. influenzae enzymes share a high degree of amino acid sequence similarity (72%), suggesting that in T. pallidum this molecule may be surface exposed and involved in IgD binding as is the case with its counterpart in H. influenzae.     

Survivorship of cemented total knee arthroplasty

The survivorship method of analysis was used to compare the failure rate and overall success of 2629 cemented primary total knee arthroplasties during a 22-year period by the senior surgeon. There were 215 Total Condylar prostheses with a polyethylene tibia, 265 of the Posterior Stabilized type with an all polyethylene tibia, 2036 Posterior Stabilized with a metal backed tibial component, 49 Posterior Stabilized with modular augmented components, and 64 with the Constrained Condylar system. Failure was considered revision or planned revision. The Total Condylar series had an average annual failure rate of 0.46% and a 21-year success rate of 90.77%. The Posterior Stabilized prosthesis with an all polyethylene tibia had an average annual rate of failure of 0.38% and a 16-year success rate of 94.10%, and this prosthesis with a metal backed tibial component had an annual failure rate of 0.14% and a 14-year success rate of 98.10%. The Posterior Stabilized series with modular components had an average annual rate of failure of 0.59% and a 10-year success rate of 93.63%. The Constrained Condylar knee series had an average annual failure rate of 0.26% and a 7-year success rate of 98.12%. This review represents a retrospective analysis of consecutive series of cemented, total knee arthroplasties, whose annual failure and success rates were done during differing time spans. The overall success rate was not influenced by gender, age, diagnosis, or percentage of ideal body weight. Failure was considered revision or planned revision. The best and worse case scenarios were calculated for each series. Long term results of cemented, total knee arthroplasty with a relatively conforming articular surface has been shown to be a reliable procedure with excellent survivorship.