Comparison of nociceptive effects produced by intrathecal administration of mGluR agonists

The present study examined the mGluR subtypes involved in (1S, 3R)-ACPD-induced spontaneous nociceptive behaviours (SNB) by administering the following selective agonists by the intrathecal (i.t.) route: (RS)-DHPG, trans-ADA (Group I; mGluR1/5 and mGluR5, respectively), (1S, 3S)-ACPD, (2R, 4R)-APDC (Group II), and L-AP4 (Group III). (RS)-DHPG administration induced SNB that were of significantly greater intensity and longer duration than those induced by an equal dose of (1S, 3R)-ACPD. No other agonists produced SNB, except (1S, 3S)-ACPD, which may be attributable to a nonselective action at mGluR1. Intrathecal treatment with the mGluR antagonist (+)-MCPG or the NMDA antagonist D-AP5 prior to (RS)-DHPG administration dose-dependently reduced SNB. It is suggested that a possible interaction between NMDA and mGluR1 is a critical event in the maintenance of persistent nociception.     

Differential TNF secretion by wound fibroblasts compared to normal fibroblasts in response to LPS

Fibroblasts cultured from wound sites have been shown to have an altered phenotype compared to normal dermal fibroblasts and are generally regarded as target cells of the cytokine response at sites of injury. This study was undertaken to determine whether wound fibroblasts can contribute to proinflammatory cytokine production in wounds and, in particular, whether they are capable of secreting TNF. Wound fibroblasts were cultured from polyvinyl alcohol sponges implanted subcutaneously for 2 weeks in Balb/c mice. Fibroblasts harvested from the skin and subcutaneous tissue of untreated mice served as a control population of cells. All cells were passaged at least twice and then stimulated with a dose range of LPS. Supernatants were harvested 8 hr following stimulation and TNF was assayed using a standard L929 cell-killing assay. There was a significant TNF response to LPS by wound fibroblasts, evident as early as 4 hr following exposure to LPS and associated with an upregulation of TNF mRNA. Normal dermal fibroblasts did not secrete any measurable amounts of TNF in response to LPS. The results indicate that wound fibroblasts generate a brisk TNF response to stimulation with LPS, in contrast to normal subcutaneous fibroblasts. These data reveal an additional unique property of wound-harvested fibroblasts and suggest a possible contributing mechanism to disordered wound healing in the face of infection or conditions characterized by excessive fibrosis.     

Nitric oxide-related vasoconstriction in lungs perfused with red cell lysate

The present study in isolated rat lungs demonstrates that nitric oxide gas (.NO, 70 nM) added to the perfusate containing a small amount of hemolysate [175 microliters of lysed red blood cells (RBC) per 50 ml of Earle's balanced salt solution (EBSS)] triggered profound and sustained vasoconstriction. Vasoconstriction was not observed when .NO was added to lungs perfused with washed intact rat or human RBC or with oxyhemoglobin (Hgb 20 microM). The presence of hemolysate in the perfusate also caused vasoconstriction in response to n-acetylcysteine (50 microM), glutathione (10(-4) M), or ascorbic acid (10(-4) M) and potentiated greatly the vasoconstrictor response to 5 mM KCl. Not only .NO, but also nitroprusside (SNP) or L-arginine and paradoxically three .NO synthesis inhibitors, including N-monomethyl L-arginine, L-NAME, and nitroblue tetrazolium, which have different mechanisms of action, each caused in the presence of hemolysate large vasoconstrictive responses. Hemolysate itself enhanced O2 consumption by slices of lung; no effects of this dose of .NO on lung slice respiration were seen in the absence of hemolysate. Both Hgb and hemolysate lowered perfusate cGMP levels to the same degree suggesting that the vasoconstrictive response was not due to unique effects of hemolysate on guanylyl cyclase. Addition of superoxide dismutase (SOD) and catalase (CAT) to the hemolysate containing perfusate, or addition of a cyclooxygenase or 5-lipoxygenase inhibitor, virtually abolished the .NO induced vasoconstriction. The latter data are consistent with the concept that exposure of the vasculature to hemolysate may result in the formation of peroxynitrite. However, SOD and CAT did not abolish the pulmonary vasoconstriction induced by L-arginine or by NAC. Our data indicate that hemolysate has profound effects on lung vessel tone regulation and on lung tissue mitochondrial function, yet the precise molecular mechanisms responsible for the action of hemolysate are likely to be very complex.     

Design and analysis of a control system for an optical delay-line circuit used as reconfigurable gain equalizer

The design and analysis of a control system for a coherent two-port lattice-form optical delay-line circuit used as reconfigurable gain equalizer is presented. The design of the control system, which is based on a real device model and a least-square optimization method, is described in detail. Analysis on a five-stage device for the 32 possible solutions of phase parameters showed that, for some filter characteristics, the variations in power dissipation can vary up to a factor of 2. Furthermore, the solution selection has influence on the optimization result and number of iterations needed. A sensitivity analysis of the phase parameters showed that the allowable error in the phase parameters should not exceed a standard deviation of /spl pi//500 in order to achieve a total maximal absolute accuracy error not greater than approximately 0.6 dB. A five-stage device has been fabricated using planar lightwave circuit technology that uses the thermooptic effect. Excellent agreement between simulations and measurements has been achieved.     

Multideterminant role of calcium in hippocampal synaptic plasticity

Hippocampal CA1 cells possess several varieties of long-lasting synaptic plasticity: two different forms of long-term potentiation (LTP) and at least one form of long-term depression (LTD). All forms of synaptic plasticity are induced by afferent activation, all involve Ca2+ influx, all can be blocked by Ca2+ chelators, and all activate Ca(2+)-dependent mechanisms. The question arises as how different physiological responses can be initiated by activation of the same second messenger. We consider two hypotheses which could account for these phenomena: voltage-dependent differences in cytosolic Ca2+ concentration acting upon Ca2+ substrates of differing Ca2+ affinities and compartmentalization of the Ca2+ and its substrates.     

Molecular mechanisms of glomerular injury in rat experimental membranous nephropathy (Heymann nephritis)

The molecular pathogenesis of human membranous nephropathy (MN) is unknown, despite the relatively high incidence and severity of this glomerular immune disease. Heymann nephritis (HN) in rats is considered an instructive experimental model of MN. This study summarizes current molecular aspects of two key events common to both MN and HN, i.e., formation of characteristic subepithelial immune deposits in the glomerular basement membrane (GBM), and development of glomerular capillary wall damage resulting in proteinuria. In HN, the antigenic targets of immune deposit-forming antibodies were identified in cell membranes of glomerular epithelial cells as a 515-kd glycoprotein (megalin, or gp330), which is a polyspecific receptor related to the low-density lipoprotein receptor family, and an associated 44-kd protein (receptor associated protein, RAP). One epitope was recently narrowed to 14 amino acids in RAP, and several others on megalin/gp330 are under investigation. Proteinuria requires formation of the complement C5b-9 membrane attack complex, which is presumably triggered by antibodies directed against lipid antigens that associate with immune deposit-forming megalin/gp330 immune complexes. Sublytic C5b-9 attack on glomerular epithelial cells causes upregulation of expression of the NADPH oxidoreductase enzyme complex by glomerular cells, which is translocated to their cell surfaces, similar to activated neutrophil granulocytes in the respiratory burst reaction. Subsequently, reactive oxygen species (ROS) are produced locally, which reach the GBM matrix. Here formation of lipid peroxidation (LPO) adducts is found, preferentially on monomeric and dimerized NCl domains of covalently crosslinked Type IV collagen. These structural changes within the GBM could be of functional relevance because treatment with the potent LPO-antagonist probucol reduces proteinuria by < 80%. Intact or fragmented apoprotein E-containing lipoproteins were identified as potential sources of the polyunsaturated lipids required for the production of LPO adducts. Lipoproteins accumulate within immune deposits and show signs of oxidative damage, similar to oxidized LDL within atherosclerotic lesions. Collectively, the results obtained so far in HN permit the compilation of a sequence of events, linking formation of immune deposits with proteinuria. However, despite this relatively detailed knowledge of pathogenic events in HN, the bridge to human NM remains to be built.     

Fretting corrosion and the reliability of multicontact connector terminals

The harsh operating environment of the automotive application makes the semi-permanent connector susceptible to intermittent high contact resistance which eventually leads to failure. Fretting corrosion is often the cause of these failures. However, laboratory testing of sample contact materials produces results that do not correlate with commercially tested connectors. A multicontact (M-C) reliability model is developed to bring together the fundamental studies and studies conducted on commercially available connector terminals. It is based on fundamental studies of the single contact interfaces and applied to commercial multicontact terminals. The model takes into consideration firstly, that a single contact interface may recover to low contact resistance after attaining a high value and secondly, that a terminal consists of more than one contact interface. For the connector to fail, all contact interfaces have to be in the failed state at the same time.     

Braking electric-powered wheelchairs: effect of braking method, seatbelt, and legrests

PURPOSE: The aim was to investigate the significance of lymph node micrometastases in Dukes Stages A and B colorectal cancer. METHODS: Archival specimens were examined from 147 patients (96 colon, 51 rectum; 44 Stage A, 103 Stage B) who had surgery between 1987 and 1994. One lymph node section from each node (colon, 1-11; median, 4; rectum, 1-15; median, 3) was examined with use of an anticytokeratin antibody. RESULTS: Forty-seven (32 percent) patients had micrometastases. At follow-up in June 1996, 23 patients had died of cancer or with known tumor relapse, after a median time of 28 (range, 5-67) months; 8 of 47 (17 percent) patients had micrometastases, 15 of 100 (15 percent) did not. No statistically significant differences were observed according to micrometastases when the results were analyzed with respect to Dukes stage or survival time. The median survival time of living patients with micrometastases was 48 (range, 18-97) months, and for patients without micrometastases, 48 (range, 19-111) months. Six of 96 living patients had a tumor relapse; three of these displayed micrometastases. CONCLUSION: Lymph node micrometastases are not a useful prognostic marker in Dukes Stages A and B and do not imply different strategies for additional therapy or follow-up.     

Reversible inactivation of the medial septum or nucleus basalis impairs working memory in rats: a dissociation of memory and performance

Lidocaine-induced inactivation of the medial septum immediately after training or prior to testing in a delay radial-arm maze task produced deficits in spatial working memory that reflected impaired acquisition of the task. Injection of lidocaine into the nucleus basalis magnocellularis produced a profile of behavioral changes that indicated that temporary inactivation of this structure impaired the behavioral expression of information already stored in working memory. This appears to reflect an impairment in processes that are required for performance (i.e., attention, motivation, sensorimotor function) of the task but not for retrieval of stored information. Site-specific inactivation of the basal forebrain should help to reveal the involvement of its component structures in different aspects of cognitive function.     

Carotid artery balloon test occlusion: combined clinical evaluation and xenon-enhanced computed tomographic cerebral blood flow evaluation without patient transfer or balloon reinflation: technical note

OBJECTIVE: Clinical evaluation was combined with xenon-enhanced computed tomographic (CT) cerebral blood flow (CBF) evaluation during carotid artery balloon test occlusion (BTO), without patient transfer from the angiography suite to the CT scanner or balloon reinflation. TECHNIQUE: Thirteen patients underwent carotid artery BTO. Placement of temporary occlusion balloons was performed with patients positioned on the CT scanner table. If neurological testing revealed no changes within 10 minutes after balloon inflation, patients were positioned within the CT scanner gantry for xenon-enhanced CT CBF evaluation. CBF evaluations were begun 12 to 15 minutes after balloon inflation and required 8 minutes for completion. After completion of CBF evaluation, neurological testing continued during 30 minutes of arterial occlusion. RESULTS: One patient did not tolerate BTO, with the development of reversible hemiparesis. Reliable CBF data were not obtained because of patient motion in one case. Eleven patients clinically tolerated BTO and completed CBF evaluation. For five patients, xenon-enhanced CT scanning revealed no regions with CBF of less than 30 ml/100 g/min. For four patients, xenon-enhanced CT scanning revealed small regions with CBF of less than 30 ml/100 g/min within the anterior frontal lobe on the occluded side. For two patients, ipsilateral CBF decreased dramatically during BTO, with CBF in many regions of less than 30 ml/100 g/min and in some of less than 20 ml/100 g/min. CONCLUSION: Xenon-enhanced CT CBF evaluation can be combined with clinical testing during BTO without patient transfer, balloon reinflation, or increases in the duration of the procedure. We recognize that the value of CBF evaluation during BTO remains to be proven; our technique does, however, eliminate abbreviated clinical neurological evaluation, patient transfer, and balloon reinflation, which were previously associated with the use of xenon-enhanced CT CBF evaluation during carotid artery BTO.