PubMed · 7029158
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M R Gaspar. 1981. Arterial aneurysms.. https://pubmed.ncbi.nlm.nih.gov/7029158/
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Hypothalamic-pituitary-adrenal (HPA) responses to stress are initiated by parvicellular neurosecretory neurons in the medial parvicellular (mp) part of the paraventricular hypothalamic nucleus (PVH), which express corticotropin-releasing factor (CRF), among other neuropeptides. We have used an approach guided by patterns of stress-induced Fos expression to explore the manner in which anatomically and phenotypically defined components of the mpPVH respond to acute vs. repeated restraint stress. Hormonal indices of HPA activation in animals exposed to the last of 14 daily repeated restraint sessions were significantly lower than those in rats receiving a single restraint episode. Although this habituation was paralleled by global decrements in activation patterns across all PVH compartments, clear spatial-temporal differences in recruitment profiles were noted between dorsal and ventral aspects of the mpPVH. Thus, acute restraint provoked a biphasic Fos induction, which occurred first within the mpPVH and in an adjoining population of somatostatinergic cells in the periventricular region and only later within other aspects of the PVH. By contrast, Fos responses of habituated animals were monophasic and focused decisively within a discrete ventral aspect of the mpPVH. The ventral population was identified as comprising neurons that express CRF and/or enkephalin and, to a lesser extent, growth hormone-releasing factor. These results indicate a lack of homogeneity among stress-responsive parvicellular neurosecretory neurons and suggest that distinct complements of CRF cells may be preferentially involved in initiating HPA responses to acute stress and sustaining them in the repeated condition.
Visilizumab is a humanized anti-CD3 monoclonal antibody characterized by a mutated IgG2 isotype, lack of binding to Fcgamma-receptors, and ability to induce apoptosis selectively in activated T cells. To test pharmacokinetics, safety, and immunosuppressive activity of visilizumab, 17 patients with glucocorticoid-refractory acute graft-versus-host disease (GVHD) were enrolled in a phase 1 study. Six patients were given 7 doses of visilizumab (0.25 or 1.0 mg/m(2)) on days 1, 3, 5, 7, 9, 11, and 13. Because multiple doses of 1 mg/m(2) caused delayed visilizumab accumulation and prolonged lymphopenia, the next 11 patients received a single dose of 3.0 mg/m(2) on day 1. GVHD improved in all patients; 15 were evaluable through day 42. Multiple dosing resulted in 1 of 6 complete responses (CRs) and 5 partial responses (PRs), but all 6 patients died at a median of 87 days after starting visilizumab therapy. Single dosing resulted in 6 of 9 CRs, 3 PRs, and 7 of 11 patients surviving after 260 to 490 days (median, 359 days; P =.03). There were no allergic reactions and 3 grade 1 acute infusional toxicities. Plasma Epstein-Barr virus (EBV) DNA titers more than 1000 copies/mL and posttransplant lymphoproliferative disease (PTLD) developed in 2 of the first 7 patients. Based on rising EBV DNA titers, 5 of the next 10 patients were given the B cell-specific monoclonal antibody, rituximab. EBV DNA became undetectable and no overt PTLD developed. Visilizumab is well tolerated and has activity in advanced GVHD. A phase 2 study incorporating preemptive therapy for PTLD is warranted to determine the efficacy of visilizumab in GVHD.
We have continued the preclinical evaluation of the efficacy and safety of the hexadentate phenolic aminocarboxylate iron chelator N, N'-bis(2-hydroxybenzyl) ethylenediamine-N, N'-diacetic acid monosodium salt (NaHBED) for the treatment of both chronic transfusional iron overload and acute iron poisoning. We examined the effect of route of administration by giving equimolar amounts of NaHBED and deferoxamine (DFO) to Cebus apella monkeys as either a subcutaneous (SC) bolus or a 20-minute intravenous (IV) infusion. By both routes, NaHBED was consistently about twice as efficient as DFO in producing iron excretion. For both chelators at a dose of 150 micromol/kg, SC was more efficient than IV administration. The biochemical and histopathologic effects of NaHBED administration were assessed. No systemic toxicity was found after either IV administration once daily for 14 days to iron-loaded dogs or after SC administration every other day for 14 days to dogs without iron overload. Evidence of local irritation was found at some SC injection sites. When the NaHBED concentration was reduced to 15% or less in a volume comparable to a clinically useful one, no local irritation was found with SC administration in rats. Because treatment of acute iron poisoning may require rapid chelator infusion, we compared the effects of IV bolus administration of the compounds to normotensive rats. Administration of DFO produced a prompt, prolonged drop in blood pressure and acceleration of heart rate; NaHBED had little effect. NaHBED may provide an alternative to DFO for the treatment of both chronic transfusional iron overload and of acute iron poisoning.