A platelet-activating factor antagonist (WEB 2170) preserves endothelium-dependent vasodilatation and prevents development of a neo-intima induced by a periarterial collar in rabbit carotid arteries

Platelet-activating factor (PAF) may be involved in adhesion of leucocytes and migration of cells during vascular remodelling for it is expressed in leucocytes after cytokine priming and is required for cell adhesion. We studied the effects of WEB 2170, a potent PAF antagonist, on the development of an atheroma-like neo-intima induced by a peri-arterial collar in rabbits. Either WEB 2170 (3 mg/kg/day) or vehicle was given by subcutaneous injection once a day for 4 or 9 days, and on day 3 peri-arterial collars were applied to both carotid arteries in all animals. Two or 7 days after implanting the collars vasodilator responses to the endothelium-dependent vasodilator, acetylcholine and the endothelium-independent vasodilator, sodium nitroprusside were studied in isolated artery rings from both groups of rabbits. Neo-intima formation after 7 days (day 10 of treatment) was measured by light microscopy as the ratio of cross-sectional areas of intima and media, and expression of inducible nitric oxide synthase (iNOS) was studied by immunohistochemistry. PAF-induced platelet aggregation ex vivo was inhibited specifically in WEB 2170-treated rabbits. At day 5, acetylcholine-induced vasorelaxation in collared artery rings was markedly impaired as compared to control sections from both vehicle- and WEB 2170-treated rabbits. At day 10, acetylcholine-induced vasorelaxation in collared artery rings from vehicle rabbits was markedly less than in controls, but in WEB 2170-treated rabbits, the acetylcholine response in collared arteries was similar to control sections. Intimal thickening was much reduced in WEB 2170-treated rabbits, ratios of intima/media areas being vehicle: 0.21 +/- 0.02 (n = 5) and WEB 2170: 0.07 +/- 0.01 (n = 7; p < 0.01). Immunofluorescence showed expression of iNOS only in the neo-intima of vehicle-treated, collared arteries, but not in the residual neo-intima of WEB 2170-treated, collared arteries. These results suggest that WEB 2170 is effective in preserving endothelial function, prevents the development of neo-intima and blocks iNOS expression in the neo-intima in this model.     

Increase of extracellular glutamate and expression of Fos-like immunoreactivity in the ventral tegmental area in response to electrical stimulation of the prefrontal cortex

Electrical stimulation of the medial prefrontal cortex caused glutamate release in the ventral tegmental area (VTA) of freely moving animals. Cathodal stimulation was given through monopolar electrodes in 0.1-ms pulses at an intensity of 300 microA and frequencies of 4-120 Hz. Glutamate was measured in 10-min perfusate samples by HPLC coupled with fluorescence detection following precolumn derivatization with o-phthaldialdehyde/beta-mercaptoethanol. The stimulation-induced glutamate release was frequency dependent and was blocked by the infusion of the sodium channel blocker tetrodotoxin (10 microM) through the dialysis probe. The stimulation also induced bilateral Fos-like immunoreactivity in ventral tegmental neurons, with a significantly greater number of Fos-positive cells on the stimulated side. These findings add to a growing body of evidence suggesting that the medial prefrontal cortex regulates dopamine release in the nucleus accumbens via its projection to dopamine cell bodies in the VTA.     

Vector manometric study of the sphincter of Oddi in the dog: functional and morphological correlation

BACKGROUND: Clinical use of cyclosporine (CsA) is limited by its known nephrotoxicity. Parathyroid hormone (PTH)-related protein (PTHrP) increases after acute renal ischemia and stimulates proliferation of renal cells in culture. Herein, we have examined whether the renal expression of PTHrP and its PTH/PTHrP receptor is affected by chronic CsA nephrotoxicity. METHODS: Rats were randomly assigned to receive daily intramuscular injections of either CsA (25 mg/kg) or the same volume of the vehicle olive oil (control) for 3 weeks. At this time interval, under ether anesthesia, rat blood and kidneys were obtained for analytical determinations, and total RNA isolation or immunohistochemistry, respectively. RESULTS: Serum urea was 11+/-2 and 6+/-1 mmol/L (P < 0.01) in CsA-treated and control rats, respectively. We found that PTH/PTHrP receptor mRNA was unchanged, but PTHrP mRNA, and also transforming growth factor-beta1 mRNA expression as positive control, was about twofold increased in the kidney of CsA-treated rats. This was accompanied by increased PTHrP immunostaining in renal cortical tubules, associated with tubule vacuolation. CONCLUSION: This study demonstrates an up-regulation of PTHrP, associated with chronic CsA-induced nephrotoxicity. Our findings support a role for PTHrP in the CsA-injured kidney.     

Targeting widespread sites of damage in dystrophic muscle: engrafted macrophages as potential shuttles

Differences between Israeli-born and Soviet-born college students were investigated in relation to their sense of coherence, family functioning and gender. 167 Soviet born and 127 Israeli born college students were compared on the Sense of Coherence scale, the General Functioning Scale of the McMaster FAD, and the scales of cohesiveness and adaptability of the FACES III, as well as on a variety of demographic variables. Results indicated that the stress of migration had a negative effect on the Sense of Coherence. Family functioning was the only variable that added significantly to the explanation of the variance of Sense of Coherence.     

Effects of nitric oxide in cultured prevertebral sympathetic ganglion neurons

The effects of the nitric oxide donor, S-nitrosoacetylpenicillamine (SNAP), were tested on cultured dissociated guinea pig celiac ganglion neurons using whole cell patch-clamp recordings. S-nitrosoacetylpenicillamine induced a concentration- and voltage-dependent inwardly directed shift in holding current (inward current shift) in 89% of neurons. The inward current shift was prevented by pre-treatment with the nitric oxide scavenger reduced hemoglobin and was abolished by intra- or extracellular cesium. The amplitude of the inward current shift was also sensitive to the extracellular potassium concentration. The S-nitrosoacetylpenicillamine-induced inward current shift was mediated by a decrease in calcium-dependent potassium currents (IAHPs); apamin (100 nM), charybdotoxin (10 nM) or tetraethylammonium (5 mM) reduced but did not abolish the amplitude of its inward current shift and a combination of apamin and tetraethylammonium abolished the S-nitrosoacetylpenicillamine-induced inward current response. In the presence of extracellular cobalt, SNAP produced an outward current that was concentration- and voltage-dependent, abolished by reduced hemoglobin and extracellular cesium and reduced by 4-AP (1 mM); in the absence of cobalt, 4-AP increased the SNAP-induced inward current shift. These data indicate that NO exerts dual opposing effects on neuronal potassium conductances, namely an inward current shift mediated through an inhibition of IAHP and induction of an outward current mediated by activation of the potassium delayed rectifier.     

Intrathecal 131I-labeled antitenascin monoclonal antibody 81C6 treatment of patients with leptomeningeal neoplasms or primary brain tumor resection cavities with subarachnoid communication: phase I trial results

We aimed to determine the maximum tolerated dose (MTD) of 131I-labeled 81C6 in patients with leptomeningeal neoplasms or brain tumor resection cavities with subarachnoid communication and to identify any objective responses. 81C6 is a murine IgG monoclonal antibody that reacts with tenascin in gliomas/carcinomas but does not react with normal adult brain. 131I-labeled 81C6 delivers intrathecal (IT) radiation to these neoplasms. This study was a Phase I trial in which patients were treated with a single IT dose of 131I-labeled 81C6. Cohorts of three to six patients were treated with escalating doses of 131I (starting dose, 40 mCi; 20 mCi escalations) on 10 mg 81C6. MTD is defined as the highest dose resulting in serious toxicity in no more than two of six patients. Serious toxicity is defined as grade III/IV nonhematological toxicity or major hematological toxicity. We treated 31 patients (8 pediatric and 23 adult). Eighteen had glioblastoma multiforme. Patients were treated with 131I doses from 40 to 100 mCi. Hematological toxicity was dose limiting and correlated with the administered 131I dose. No grade III/IV nonhematological toxicities were encountered. A partial response occurred in 1 patient and disease stabilization occurred in 13 (42%) of 31 patients. Twelve patients are alive (median follow-up, > 320 days); five are progression free >409 days median posttreatment. The MTD of a single IT administration of 131I-labeled 81C6 in adults is 80 mCi 131I-labeled 81C6. The MTD in pediatric patients was not reached at 131I doses up to 40 mCi normalized for body surface area.