The effect of pretreatment with FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride) or cyclosporin, or both, on neutrophil-mediated injury has been examined by use of a rat model of transient clamping of hepatic flow. Pretreatment with FTY720 alone or with cyclosporin induced a marked reduction of circulatory lymphocytes, whereas the use of these drugs in combination was very effective at suppressing the elevation of the number of peripheral polymorphonuclear neutrophils (PMN) after reperfusion. Pretreatment with cyclosporin, with or without FTY720, significantly reduced hepatic damage, whereas FTY720 alone tended to prolong hepatic damage. Pretreatment of cyclosporin alone, but not in combination with FTY720, significantly reduced the accumulation of PMN and led to lower myeloperoxidase levels in the damaged liver. In conclusion, pretreatment with cyclosporin, with or without FTY720, reduced hepatic damage after warm ischaemia-reperfusion, whereas pretreatment with FTY720 alone tended to prolong this damage.
In patients with ACTH-secreting pituitary tumor the peri-tumoral normal corticotrophs were supposed to be suppressed by cronic hypercortisolemia since frequently they develop transient secondary adrenal insufficiency after pituitary tumor resection and during early postoperative days. We evaluated the ACTH dynamics during transsphenoidal surgery in 16 patients with ACTH-secreting pituitary tumors (6 cured by surgery, 8 not cured Cushing's disease patients and 1 cured by surgery and 1 not cured Nelson's syndrome patients) and tested the hypothesis that in these patients, ACTH secretion from the peri-tumoral normal corticotrophs is inhibited and hence removal of the entire tumor should result in subtle postoperative reduction in plasma ACTH. Blood samples for ACTH determination were obtained from 14 Cushing's disease patients immediately before pituitary gland manipulation and 10, 30, 60, 90, 120, 150 and 300 min after pituitary tumor resection and on postoperative day one. In Nelson's syndrome patients the blood sample was obtained only after tumor removal. All patients received intravenous hydrocortisone during surgery and on the first postoperative day. Patients were considered cured by surgery if they presented adrenal insufficiency after hydrocortisone withdrawal. Mechanical pituitary manipulation induced increase in ACTH level. In all 14 Cushing's disease patients (cured and not cured), mean plasma ACTH levels were significantly greater 10 min after pituitary tumor resection (54.4+/-12.8 pmol/l) than in the premanipulation period (ACTH=26.3+/-5.3 pmol/l) (p=0.005). In Cushing's disease patients, the ACTH levels did not change significantly until 300 min after pituitary tumor resection either in those 6 patients cured by surgery (at 10 min after pituitary tumor resection ACTH was 54.4+/-12.8 pmol/l for all 14 Cushing's disease patients and at 300 min after tumor removal ACTH was 39.0+/-12.6 pmol/l for cured and 41.3+/-15.7 pmol/l for not cured Cushing's disease patients). The ACTH level also persisted high until 300 min after complete pituitary tumor resection in one cured patient with Nelson's syndrome. ACTH level does not change in the early recovery period after ACTH-secreting pituitary tumor, even in those cured patients, and probably peri-tumoral normal corticotrophs are not completely suppressed by cronic hypercortisolemia (and acute glucocorticoid administration) when these patients are under intense stress, like transsphenoidal surgery. Mechanical pituitary manipulation may induce ACTH release in patients with ACTH-secreting pituitary tumors but probably does not interfere in the maintenance of high ACTH-levels during the early postoperative period, since ACTH half-life is only 8-15 min. In patients with ACTH-secreting pituitary tumors, the behavior of the human hypothalamic-pituitary-adrenal system during transsphenoidal surgery does not conform to the specifications of a negative feedback mechanism.
Bullous pemphigoid (BP) has never before been reported to associate with silicosis, although there are numerous reports of silicosis accompanied by different autoimmune diseases, such as systemic sclerosis, systemic lupus erythematosus, dermatomyositis or rheumatoid arthritis. We report on a 63-year-old Japanese patient with silicosis who developed tensed bullae, erosions and macular pigmentation on the trunk and extremities. Indirect immunofluorescence revealed anti-basement-membrane-zone antibodies; immunoblotting analysis demonstrated that the patient’s serum reacted with the 230-kD BP antigen in the epidermal extracts, as well as a recombinant protein of the NC16a domain of 180-kD BP antigen. Clinical symptoms improved after treatment with systemic steroids. To the best of our knowledge, this is the first reported case of BP associated with silicosis.
Dosing-time-dependent differences in lipopolysaccharide (LPS)-induced liver injury were examined in rats housed under a 12 h light : dark (LD) cycle. LPS (5 mg/kg) was intravenously injected into different groups of rats at 2, 14, or 20 h after light on (HALO). Elevations in serum liver enzymes after 14 HALO were significantly greater than those after 2 HALO. These parameters were lower in rats given LPS at 20 HALO, compared to 14 HALO. The number of polymorphonuclear cells (PMN) in the liver and the amount of hepatic myeloperoxidase activity, which reflects the number of PMN in liver tissues, was significantly greater in the 14 than in the 2 HALO group. In addition, hepatic interleukin-6 (IL-6) production in the 14 HALO group was enhanced compared to that in the 2 HALO trial. These results suggest that LPS-induced liver injury is greater during the early active than during the early resting period. Dosing-time-dependent variation in the accumulation of PMN in the liver and, potentially, subsequent IL-6 production in liver tissues might be involved in this phenomenon.
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