Endotoxin preconditioning protects against the cytotoxic effects of TNFalpha after stroke: a novel role for TNFalpha in LPS-ischemic tolerance.

Lipopolysaccharide (LPS) preconditioning provides neuroprotection against subsequent cerebral ischemic injury. Tumor necrosis factor-alpha (TNFalpha) is protective in LPS-induced preconditioning yet exacerbates neuronal injury in ischemia. Here, we define dual roles of TNFalpha in LPS-induced ischemic tolerance in a murine model of stroke and in primary neuronal cultures in vitro, and show that the cytotoxic effects of TNFalpha are attenuated by LPS preconditioning. We show that LPS preconditioning significantly increases circulating levels of TNFalpha before middle cerebral artery occlusion in mice and show that TNFalpha is required to establish subsequent neuroprotection against ischemia, as mice lacking TNFalpha are not protected from ischemic injury by LPS preconditioning. After stroke, LPS preconditioned mice have a significant reduction in the levels of TNFalpha (approximately threefold) and the proximal TNFalpha signaling molecules, neuronal TNF-receptor 1 (TNFR1), and TNFR-associated death domain (TRADD). Soluble TNFR1 (s-TNFR1) levels were significantly increased after stroke in LPS-preconditioned mice (approximately 2.5-fold), which may neutralize the effect of TNFalpha and reduce TNFalpha-mediated injury in ischemia. Importantly, LPS-preconditioned mice show marked resistance to brain injury caused by intracerebral administration of exogenous TNFalpha after stroke. We establish an in vitro model of LPS preconditioning in primary cortical neuronal cultures and show that LPS preconditioning causes significant protection against injurious TNFalpha in the setting of ischemia. Our studies suggest that TNFalpha is a twin-edged sword in the setting of stroke: TNFalpha upregulation is needed to establish LPS-induced tolerance before ischemia, whereas suppression of TNFalpha signaling during ischemia confers neuroprotection after LPS preconditioning.     

Control of intraocular pressure after cataract extraction

We carried out a prospective randomized study in 172 patients undergoing cataract extraction and lens implantation to compare the effects of pilocarpine gel, 1% acetylcholine chloride and 0.01% carbachol on early postoperative intraocular pressure (IOP), to determine the effect of sodium hyaluronate on IOP and to compare the effects of 0.01% carbachol (full-strength) and 0.005% carbachol (half-strength) on IOP, pupil size and brow ache. IOP was measured 3, 6, 9 and 24 hours after surgery, and in the full- and half-strength carbachol groups pupil size and subjective complaints of brow ache were recorded. The mean IOP 3 and 6 hours after surgery was significantly lower in all the treatment groups than in the control groups. At 9 and 24 hours it was significantly lower only in the carbachol groups. The use of sodium hyaluronate was not found to affect the postoperative IOP. There was no difference in postoperative IOP or miosis between the full- and half-strength carbachol groups, but fewer patients in the half-strength group than in the full-strength group reported brow ache at 9 and 24 hours. The results suggest that carbachol is the most effective agent currently available for the management of IOP after cataract extraction.     

Prospective study of the occurrence of monoclonal gammapathies following bone marrow transplantation in young children

We have prospectively studied the occurrence of monoclonal serum immunoglobulins in 38 recipients of BMT. Patients were young children with primary immunodeficiencies (n = 31), other inherited diseases (n = 4), leukemia (n = 2), or aplastic anemia (n = 1). Twenty-nine received an HLA-nonidentical marrow and nine an HLA-identical marrow. Serum monoclonal immunoglobulins were detected by the immunofixation method. Monoclonal immunoglobulins were found in 26 patients. Monoclonal components were more frequently detected in patients with primary severe T cell deficiencies (21/25) rather than in the other patients (6/13). In 7 of 29 recipients of HLA-nonidentical transplants, versus 0 out of 9 recipients of HLA-identical transplants, serum monoclonal immunoglobulins were found associated with a B lymphocyte proliferation syndrome due to an Epstein-Barr virus infection. In this group, monoclonal immunoglobulins were detected early, prior to the onset of the clinical syndrome. The simultaneous occurrence of several monoclonal immunoglobulins was more frequent in these patients, while monoclonal immunoglobulin concentrations increased faster, especially those of IgM isotype. These characteristics may allow in patients at risk (recipients with primary T cell immunodeficiencies and receiving HLA-nonidentical transplantation) an earlier diagnosis of B lymphocyte proliferative syndrome that may eventually lead to early and more efficient therapy.     

Ergebnisse des seletiven venösen Etagenkatheters (SVK) beim okkulten C-Zell-Karzinom der Schilddrüse

Background: Medullary thyroid carcinoma (MTC) can — even in recurrent cases — only be treated surgically. Therefore, preoperative localization of the tumor is essential.Methods: From April 1986 through April 1997, 137 patients with MTC were operated on at our clinic. In 22 patients with recurrent tumor which had not been radiologically localized, 28 selective venous catheterizations (SVC) with determination of calcitonin levels were carried out.Results: In 23 examinations a suspected tumor could be identified (nine cervical unilateral, seven mediastinal, four cervical unilateral and mediastinal, one cervical bilateral and mediastinal, one liver, one cervical unilateral and liver). In 18 cases surgery was performed for recurrence (nine cervical revisions, one mediastinal dissection, six cervicomediastinal dissections, two laparotomies). In 15 of 18 cases, tumor tissue was found in the previously suspected area. In ten cases serum calcitonin levels dropped postoperatively by 6%–75%. A normalization of the hormone level was achieved only once by yet another operation. During further follow-up, five of the reoperated patients died from their disease. The other 17 patients are being followed up, whereby calcitonin levels are elevated but there is no clinical or radiological evidence of tumor.Conclusions: Although in the patient cohort presented a normalization of serum calcitonin could be achieved only once, the authors consider SVC useful because it is the only means of localization of tumor tissue in cases of negative radiologic studies and therefore allows a planned approach to the operation procedure in these cases.