Parathyromatosis: a cause for recurrent hyperparathyroidism.

OBJECTIVE: To report a case of parathyromatosis as a cause for recurrent hyperparathyroidism. METHODS: We present the case history, laboratory results, operative interventions, and pathologic findings in a 36-year-old woman. Relevant reports from the literature are reviewed. RESULTS: Our patient, who had been undergoing long-term hemodialysis because of renal failure, presented with secondary hyperparathyroidism and progressive bone pain. After an uneventful subtotal parathyroidectomy (removal of 3-1/2 glands), her symptoms resolved in conjunction with normalization of parathyroid hormone levels. Subsequently, however, recurrent hyperparathyroidism and severe bone pain necessitated second and third neck explorations, during which parathyromatosis was discovered. A total thyroidectomy was performed because of the bilateral nature of the disease. Postoperatively, the patient's bone pain resolved substantially, although her parathyroid hormone levels remained high. CONCLUSION: Parathyromatosis is a rare cause of recurrent hyperparathyroidism after parathyroidectomy. It consists of hyperfunctioning parathyroid tissues scattered throughout the neck, due either to intraoperative tissue spillage and subsequent implantation or to hyperplasia of parathyroid rests from embryologic development. This is one of the few case reports of parathyromatosis and the first case report of a mixed form of the disease, consisting of features of both subcapsular parathyroid rests and extracapsular implantation.

Elective surgical treatment of symptomatic chronic mesenteric occlusive disease: early results and late outcomes.

PURPOSE: The purpose of this study was to determine the safety and efficacy of the elective surgical treatment of symptomatic chronic mesenteric occlusive disease (SCMOD) and to identify the factors that influence the results of this procedure. METHODS: From 1977 to 1997, 85 patients (mean age, 62 years) underwent elective surgical treatment of SCMOD. The presenting symptoms were abdominal pain in 78 patients (92%) and weight loss in 74 patients (87%). The surgical procedures included retrograde bypass grafting in 34 patients (40%), antegrade bypass grafting in 24 patients (28%), transaortic endarterectomy in 19 patients (22%), local arterial endarterectomy with patch angioplasty in six patients (7%), thrombectomy alone in one patient (1%), and superior mesenteric artery reimplantation in one patient (1%). Thirty-five patients (41%) underwent concomitant aortic replacement. All the involved mesenteric vessels were revascularized in 21 patients (25%), whereas revascularization was incomplete for the remaining 64 patients (75%). Late information was available for all 85 patients at a mean interval of 4.8 years. RESULTS: There were seven early (<35 days) postoperative deaths (8%). The cumulative 5-year survival rate was 64% (95% confidence interval [CI], 53% to 75%), and the 3-year symptom-free survival rate was 81% (95% CI, 72% to 90%). Serious complications occurred in 28 patients (33%). The results of univariate analysis identified advancing age at operation (P <.001), cardiac disease (P =.03), hypertension (P =.03), and additional occlusive disease (P =.05) as variables associated with mortality. Concomitant aortic replacement (P =.037), renal disease (P =.011), advancing age ( P =.035), and complete revascularization ( P =.032) were associated with postoperative morbidity including mortality. Late recurrent mesenteric occlusive disease was seen in 21 patients (16 symptomatic and five asymptomatic). Nine patients (43%) died, and 8 patients (38%) required subsequent surgical or endovascular procedures to treat their recurrent lesions. The 3-year survival rate from recurrent mesenteric occlusive disease was 76% (95% CI, 66% to 86%). CONCLUSION: We conclude that the elective surgical treatment of SCMOD may be performed with reasonable early and late mortality rates and that most of the patients remain free from recurrent symptoms of mesenteric ischemia. Advancing age, cardiac disease, hypertension, and additional occlusive disease significantly influenced the overall mortality rates, and concomitant aortic replacement, renal disease, and complete revascularization were significantly associated with postoperative morbidity rates. Surveillance and appropriate correction of recurrent disease appear to be necessary for optimal long-term results.

NO is not sufficient to explain maximal cytotoxicity of tumoricidal macrophages against an NO-sensitive cell line.

Nitric oxide (NO) is a macrophage cytotoxic effector. Results presented here, however, demonstrate that NO does not fully explain macrophage cytotoxicity against NO-sensitive cells because (1) inhibition of NO production by activated macrophages reduces, not eliminates, cytotoxicity; (2) NO produced chemically in amounts equimolar to those released from macrophages fails to lyse P815 cells; and (3) macrophages isolated from wounds 10 days after injury generate NO just as tumoricidal activated macrophages but are not tumor cytotoxic. The noncytotoxic nature of these wound-derived macrophages is not explained by the release of inactive forms of NO, because they suppress lymphocyte proliferation in an NO-dependent manner, nor by the production of cytoprotective molecules, because their addition to activated macrophage-tumor cell cocultures does not quench cytotoxicity. Interestingly, cytotoxicity can be aroused in day 10 wound-derived macrophages by culture with lipopolysaccharide, and macrophages harvested earlier in the development of the wound are cytotoxic. By generating NO but not killing an NO-sensitive cell, day 10 wound-derived macrophages demonstrate that NO production is not sufficient to account for the killing of an NO-sensitive tumor by macrophages.

Impact of nitric oxide on macrophage glucose metabolism and glyceraldehyde-3-phosphate dehydrogenase activity.

Conflicting evidence has been presented regarding the role of nitric oxide (NO) in the regulation of cellular glucose metabolism. While it enhances glucose uptake and utilization through glycolysis and the hexose monophosphate shunt in macrophages and other cells, NO also inhibits glyceraldehyde-3-phosphate dehydrogenase, an enzyme catalyzing the metabolism of intermediates generated by both pathways. Indeed, it has been proposed that NO modulates glycolytic flux by suppressing glyceraldehyde-3-phosphate dehydrogenase activity. To establish the relative impact of these apparently incompatible actions, the effects of exogenous or endogenous NO on different aspects of glucose metabolism in macrophages were investigated. Cell activation increased NO production, maximal glyceraldehyde-3-phosphate dehydrogenase activity, and glucose metabolism through glycolysis and the hexose monophosphate shunt. NO generated endogenously or from S-nitroso-N-acetylpenicillamine (> 500 microM) reduced maximal glyceraldehyde-3-phosphate dehydrogenase activity in culture. The suppression of maximal glyceraldehyde-3-phosphate dehydrogenase coincided with decreased lactate accumulation only in concert with a marked loss of viable cells in the cultures. The maximal glyceraldehyde-3-phosphate dehydrogenase activity did not appear to be rate limiting for glucose metabolism when moderately inhibited by NO. A potential causal relationship between profound glyceraldehyde-3-phosphate dehydrogenase inhibition and cell death remains to be established.

Interleukin-6 activity in wounds.

Interleukin-6 (IL-6) is a multifunctional cytokine with local and systemic effects during immunological and inflammatory reactions. The IL-6 activity in wound fluids and serum from wounded animals, its release by wound cells in culture, and its role in the regulation of wound fibroblast proliferation were determined. IL-6 activity in wound fluid and serum peaked within 12 h after wounding. Wound-derived polymorphonuclear leukocytes, macrophages, and fibroblasts released IL-6 in culture. Wound macrophages harvested 5 days after injury produced more IL-6 than those taken at 3 or 10 days. An anti-IL-6 antibody partially reversed the suppression of wound fibroblast proliferation by wound fluid and wound macrophage culture supernatants. Finally, human wound fluids exhibited a temporal pattern of IL-6 activity similar to that found in rat wounds. The early wound, then, and more specifically the polymorphonuclear leukocytes of the immediate inflammatory response appear to be the source of circulating IL-6 after injury. In the later wound, IL-6 may provide signals to suppress fibroblast proliferation.

Activated murine macrophages induce apoptosis in tumor cells through nitric oxide-dependent or -independent mechanisms.

Work reported here investigated aspects of macrophage-mediated tumor cell death, in particular the role of apoptosis as a mechanism for nitric oxide (NO)-mediated macrophage tumor cytotoxicity. Nitric oxide induced apoptosis in P815 cells in macrophage P815 cocultures where fragmentation of tumor cell [3H]thymidine-labeled DNA preceded cell lysis (as measured by 51Cr release), paralleled nitrite accumulation, and was prevented by a specific inhibitor of NO synthase, N-MMA. DNA from P815 cells separated from macrophages in culture by a cell-impermeable membrane or exposed to authentic NO gas showed the pattern of internucleosomal cleavage that is characteristic of apoptosis. Additionally, culture of P815 cells with the NO donor sodium nitroprusside was followed by DNA fragmentation. Macrophages also induced apoptosis in L929 cells but, in this case, apoptosis was NO independent and partially inhibited in cocultures by an antitumor necrosis factor alpha monoclonal antibody. The anti-tumor necrosis factor alpha monoclonal antibody fully prevented apoptosis when macrophages and L929 were separated by a cell-impermeable membrane. Exposure of L929 cells to NO gas or sodium nitroprusside did not result in their apoptotic death. Like other immune cytotoxic cells, macrophages can determine tumor cell death through the induction of apoptosis and do so through more than one effector mechanism.

Nitric oxide-mediated apoptosis in murine peritoneal macrophages.

Nitric oxide (NO) synthase, the enzyme responsible for the generation of the cytotoxic compound NO from L-arginine, is induced in macrophages during activation. Previous work demonstrated that the cytotoxicity of NO extends to the macrophages that produce it, because the activity of NO synthase in these cells correlates inversely with their life span in culture. Data presented here demonstrate that the NO-dependent death of murine peritoneal macrophages activated in vitro with IFN-gamma and LPS is mediated through apoptosis. Evidence in this direction was provided by microscopic examination of the cells, which revealed the presence of nuclear and cytoplasmic alterations characteristic of apoptosis, and by the specific pattern of internucleosomal DNA fragmentation detected by electrophoresis. That these alterations resulted from the production of NO was confirmed by the preventive effects of cell activation in L-arginine-restricted medium or in medium containing an inhibitor of NO synthase, NG-monomethy L-arginine, and more directly by the induction of apoptosis by exposure of the cells to authentic NO gas. Additional results demonstrated that glucose starvation, the inhibition of the tricarboxylic acid cycle with fluorocitrate or of glycolysis with iodoacetate, but not the suppression of the electron transport chain with potassium cyanide, also induced macrophage apoptosis. The potential role of metabolic inhibition as a mechanism for NO-mediated apoptosis, as well as the relationship of these findings with events occurring in wounds and other sites of macrophage infiltration are discussed.