TNFα Inhibits Schwann Cell Proliferation, Connexin46 Expression, and Gap Junctional Communication

Schwann cell responses to nerve injury are stimulated, in part, by inflammatory cytokines. This study compares changes in the phenotype of cultured Schwann cells after exposure to the cytokine tumor necrosis factor (TNF)-α or the mitogen neu differentiation factor (NDF)-β. TNFα inhibited proliferation in a dose-dependent manner without altering Schwann cell survival. TNFα also reduced both gap junctional conductance and Lucifer yellow dye coupling between Schwann cells. Moreover, both P₀and glial fibrillary acidic protein (GFAP) immunoreactivity were reduced. By contrast, NDFβ initially had little effect on cell division although it reduced junctional coupling within 8 h. However, by 48 h, NDFβ stimulated proliferation with a concomitant increase in coupling. Dividing Schwann cells (BrdU⁺) were preferentially dye coupled compared to nondividing cells, indicating an association between proliferation and coupling. Moreover, cultured Schwann cells expressed connexin46 mRNA and protein, and changes in the levels of the protein correlated with the degree of proliferation and coupling. The data thus provide evidence for cytokine-induced modulation of Schwann cell antigenic phenotype, proliferation, and gap junction properties. These observations suggest that enhanced gap junctional communication among Schwann cells after nerve injury could help to coordinate cellular responses to the injury, and that TNFα may be a signal which terminates proliferation as well as junctional communication.     

Impact of Social Confrontation on Rat CD4 T Cells Bearing Different CD45R Isoforms

The impact of social defeat on lymphocyte subpopulations and T helper subsets was investigated in Long Evans rats. CD4 T helper cell subsets with distinct functional properties and different cytokine profiles can be distinguished by using the mAbs OX-22 (anti-CD45RC) and OX-7 (anti-CD90, Thy1.1). Male intruders were exposed for 2, 6, or 48 h to aggressive resident pairs. All intruders were attacked upon introduction and were defeated as indicated by frequent display of full submissive postures. After 2 and 48 h of confrontation, drastic but differential effects on blood leukocyte numbers, CD4 and CD8a cells, and CD4 subsets were evident. However, after 6 h of confrontation most lymphocyte subset numbers corresponded to baseline levels. Focusing on CD4 subsets after 2 h of confrontation, we demonstrated that only the number of the CD45RC⁻CD90⁻subset declines, whereas neither the number of the CD45RC⁺CD90⁻subset nor the number of the CD45RC⁻CD90⁺subset (recent thymic emigrants) was influenced. Con A stimulation of sorted subsets identified the CD45RC⁻CD90⁻as a poor producer of IFN-γ. The data clearly demonstrate that social factors might differentially influence not only T cell subsets but also T helper cell subsets with distinct cytokine profiles in a possibly time-dependent manner. Such a stress-induced shift toward a CD45RC⁺CD90⁻-dominated milieu may have important consequences in interpreting results obtained from mitogenic stimulation of blood lymphocytes and cytokine production profiles measured after such a stimulation. In addition, a shift toward a CD45RC⁺CD90⁻dominance may modify the type and magnitude of immune response, at least temporarily.     

Practice Functions Necessary for the Delivery of Pharmaceutical Care

Pharmaceutical care is a concept outlining the responsibilities of individual pharmacists to individual patients. Although widely accepted on a philosophical basis, there is a lack of comprehensive information about the functions and responsibilities pharmacists undertake when providing pharmaceutical care. Pharmacy educators and practitioners at the faculty of pharmacy, University of Toronto, developed and informally tested a process that details the practice functions required of pharmacists when providing pharmaceutical care as originally defined.     

GABAergic suppression prevents the appearance and subsequent fatigue of an NMDA receptor-mediated potential in neocortex

We have investigated the regulation of anN-methyl-d-aspartate (NMDA) receptor-mediated synaptic potential by γ-aminobutyric acid (GABA)-mediated inhibition using extracellular and whole-cell voltage clamp recordings in rat auditory cortex in vitro. Single afferent stimulus pulses at low intensity elicited a slow extracellular negativity (Component C) that was mediated by NMDA receptors. At higher intensities, Component C was suppressed by recruitment of GABAergic inhibition. To understand the actions of GABAergic inhibition on Component C, we determined the effects of: (i) paired-pulse stimulation, which depresses GABAergic inhibition; (ii) pharmacological antagonism of GABA receptors; and (iii) afferent stimulation in slices from neonatal rats prior to the development of cortical inhibition. The results indicate that GABAergic inhibition prevents Component C fromoccurring, thereby preventing its reduction upon repeated stimulation. Whole-cell voltage clamp recordings were used to test the hypothesis that GABAergic suppression occurred by way of membrane hyperpolarization. At hyperpolarized holding potentials no NMDA receptor-mediated synaptic current was elicited, even with paired-pulse stimulation. At depolarized holding potentials a significant NMDA synaptic current was elicited despite the presence of GABAergic synaptic currents. We conclude that membrane hyperpolarization by GABAergic inhibition prevents the appearance and subsequent fatigue of an NMDA receptor-mediated synaptic potential. Reduction of inhibition can act as a ‘switch’ to fully release the NMDA potential as frequently as once every 10–20 s.     

A preliminary study into the dental health status of multiple sclerosis patients

Multiple sclerosis (MS) is an inflammatory disease of unknown etiology involving the central nervous system. Since MS affects the whole body, orofacial aspects of the disease must be expected, particularly since loss of muscular coordination may result in a diminished ability to maintain oral hygiene. This preliminary study examined the dental health status of 22 volunteer MS patients. A questionnaire collected data regarding medical and dental histories and socieo-demographic information. Extra- and intra-oral examinations were carried out on all subjects to determine the particular dental treatment needs of this special group. The DMFT and CPITN scores for this group did not indicate that MS patients were more susceptible to dental caries or periodontal disease. However, the prevalence of trigeminal neuralgia and symptoms of TMJ dysfunction in the group studied indicated that these conditions may be manifest in MS patients and warrant further investigations.     

Dexmedetomidine Produces Similar Alterations in the Determinants of Left Ventricular Afterload in Conscious Dogs before and after the Development of Pacing-induced Cardiomyopathy

Background: The authors tested the hypothesis that intravenous dexmedetomidine produces alterations in left ventricular (LV) afterload that are deleterious to cardiac performance in conscious dogs with pacing-induced cardiomyopathy.

Methods: Dogs (n = 8) were fitted with instruments for long-term measurement of LV and aortic blood pressure, aortic blood flow, and subendocardial segment length and received dexmedetomidine (1.25, 2.5, and 5 [micro sign]g/kg) in a cumulative manner before and after 19 +/- 3 (mean +/- SEM) days of rapid LV pacing. LV afterload was measured with aortic input impedance [Zin ([Greek small letter omega]) and quantified with a three-element Windkessel model. Hemodynamics and Zin ([Greek small letter omega]) were assessed under control conditions and 5 and 60 min after administration of each dose.

Results: Dexmedetomidine caused early and late decreases in heart rate, the maximum rate of increase of LV pressure, mean aortic blood flow, and stroke volume in dogs before and after pacing. Dexmedetomidine caused similar early increases in total arterial resistance and decreases in total arterial compliance in dogs before and after pacing. Early dexmedetomidine-induced increases in resistance and decreases in compliance caused similar reductions in mean aortic blood flow in cardiomyopathic compared with healthy dogs. Resistance and compliance returned to control values, and characteristic aortic impedance decreased late after dexmedetomidine in healthy dogs. In contrast, resistance remained elevated late after dexmedetomidine in dogs with dilated cardiomyopathy.     

Massive residual dental cyst: Case report

A case report is presented of a massive residual dental cyst that involved over half an edentulous mandible. Presentation, diagnosis and management of the massive cyst is discussed.     

Serotonergic modulation of spinal ascending activity and sacral reflex activity evoked by pelvic nerve stimulation in cats

Serotonin (5-HT) may be inhibitory to micturition at a spinal level. A potential mechanism of action for serotonergic inhibition of bladder function is a depression of the ascending limb of the supraspinal reflex mediating micturition. Ascending activity evoked by pelvic nerve stimulation was recorded in the thoracic spinal cord of anesthetized cats. For comparison, spinal reflex activity evoked by pelvic nerve stimulation was recorded on the pudendal nerve. The effects of intrathecal administration of serotonergic agents were examined to determine whether spinal and supraspinal responses to bladder afferent activation were modulated by 5-HT. Methysergide (60 nmol), a non-selective serotonergic antagonist, increased ascending activity by 61±7% and depressed spinal reflex activity by 38±6%. Zatosetron (10 nmol), a 5-HT₃ antagonist had a similar effect on both activities (increased by 93±24% and decreased by 77±7%, respectively). The effect on ascending activity of blocking 5-HT₃ receptors was also confirmed with ICS 205930 and MDL 72222. 2-Methyl-5-HT (800 nmol), a 5-HT₃ agonist, depressed ascending activity to 46±9% of control, but enhanced spinal reflex activity by 73±92%. These results demonstrate that stimulation of 5-HT₃ and methysergide-sensitive 5-HT receptors can inhibit ascending activity and facilitate spinal reflex activity elicited by activation of bladder afferents. It is suggested that descending serotonergic pathways may participate in the spinal coordination of urinary continence.