Cerebral emboli and serum S100beta during cardiac operations

BACKGROUND: The glial protein S100beta has been used to estimate cerebral damage in a number of clinical settings. The purpose of this investigation was to determine the correlation between cerebral microemboli and S100beta levels during cardiac operations. METHODS: Transcranial Doppler ultrasonography was used to measure emboli in the right middle cerebral artery. Emboli counts (n = 111) were divided into five time periods: (1) incision to aortic cannulation; (2) aortic cannulation to cross-clamp onset; (3) cross-clamp onset to cross-clamp release; (4) cross-clamp release to decannulation; and (5) decannulation to chest closure. The level of S100beta (n = 156) was measured at baseline, at the end of cardiopulmonary bypass, then 150 and 270 minutes after cross-clamp release. RESULTS: The level of S100beta correlated with age, cardiopulmonary bypass time, cross-clamp time, and number of emboli at time period 2. Although cardiopulmonary bypass time was univariately associated with S100beta level, it became nonsignificant in a multivariable model that included age and cross-clamp time. CONCLUSIONS: The correlation of S100beta level with emboli measured during cannulation (time period 2) supports the hypothesis that cannulation is a high-risk time period for cerebral injury.     

Secondary prevention of ischemic heart disease after coronary revascularization

This study was aimed to assess the compliance with policies for secondary prevention of coronary heart disease (CHD) one year after coronary artery revascularization with special attention to the management of hyperlipidemia. One year after coronary revascularization during the year 1994, patients were contacted by letter to determine the modification of their risk factors, the treatment patterns for hypercholesterolemia and to have their plasma lipid level and blood pressure measured. Of the 245 consecutive patients contacted (110 after coronary artery bypass grafting, and 135 after percutaneous transluminal coronary angioplasty), 186 (76%) provided the information required for further analysis. Excluding the patients older than 65 years, only 29 out of 97 patients (30%) with a total cholesterol of more than 5.2 mmol/l, and only 20 out of 52 patients (38%) with a total cholesterol of more than 6.2 mmol/l were receiving lipid lowering therapy 1 year after coronary artery revascularization. In contrast, 97% (n = 180) of the entire population studied were taking antiplatelet drugs and/or coumadine. Participation in an in-house rehabilitation program yielded a positive influence on smoking, but not on treatment of hypercholesterolemia. In conclusion, only a small proportion of patients with documented CHD and hypercholesterolemia were being treated for their lipid disorder 1 year after coronary artery revascularization. In contrast, the great majority of patients received antiplatelet and/or coumadine therapy: These results indicate that the compliance with published treatment guidelines for hyperlipidemia in patients with CHD is still highly inadequate, irrespective of the participation in a rehabilitation program.     

Anagrelide in control of myeloproliferative thrombocythemia: long-term experiences in 6 patients

Symptomatic or asymptomatic chronic elevation of platelet count can be observed in all forms of myeloproliferative disorders (MPD). Benefits and limitations of the traditional platelet-reducing agents, such as radioactive phosphorus, alkylating agents, hydroxyurea and interferon alpha, are well known and have been largely described. Anagrelide (Agrelin) is an additional newer drug with a selective platelet-lowering effect. We describe our own long-term experience in 6 patients with MPD who were treated with anagrelide as part of a compassionate-use protocol between April 1991 and August 1997. The median duration of therapy was 54 months (range 17 to 75 months), with an overall response rate of 100% (complete and partial response for at least 4 weeks). The initial median platelet count of 1211 x 10(9)/l (range 847 to 2050 x 10(9)/l) was reduced rapidly and lastingly to 570 x 10(9)/l (range 216 to 667 x 10(9)/l) at the time of the last control. Under treatment with anagrelide 4 of the 6 patients showed a reduction of disease-associated symptoms or complications. Adverse reactions were generally mild and transitory, and no interruption or cessation of therapy was required. Development of drug resistance or late adverse events were not observed. Treatment with anagrelide is effective, safe and in our opinion easy to administer. It also appears to be suitable for long-term administration.     

Potential benefits of estrogens and progestogens on breast cancer

Comparatively few studies have examined the effects of methadone given during a clinical detoxification programme. Furthermore, their results are different especially because of changing drop-out rates. This study was carried out on a drug-detoxification ward and investigated the effects of methadone given to alleviate withdrawal symptoms. Comparisons were undertaken with patients withdrawn during a one-year period before methadone was available. No significant difference was found between drop-out rates of patients with methadone-supported detoxification (n = 113, drop-out rate: 41.6%) and patients who did not receive methadone during detoxification (n = 108, drop-out rate: 37.0%). Nevertheless the drop-out rate in the first three days of withdrawal was reduced from 15.7% to 8.0%. On average the critical drop-out moment shifted from 5.3 days to 10.1 days. Interpretations of these findings should take into account, that the number of patients who underwent a voluntary detoxification programme for the first time was nearly doubled after methadone was offered on the ward and, additionally, many more patients tried to withdraw from methadone taken within an outpatient methadone-maintenance programme.     

IFN-gamma-mediated prevention of graft-versus-host disease: pharmacodynamic studies and influence on proliferative capacity of chimeric spleen cells

Recently we demonstrated that prolonged administration of IFN-gamma prevented the development of GVHD in a MHC-mismatched murine BMT model. Treatment with IFN-gamma allowed the development of mature donor-derived allo-tolerant immunocompetent cells in complete chimeric recipients. Here we present data on the pharmacodynamics of this cytokine-mediated protection against GVHD. Treatment with 50000 U IFN-gamma twice weekly for a period of 5 weeks, starting at the day of BMT, was shown to be the optimal treatment protocol, resulting in complete prevention of GVHD-related mortality. Treatment during 1 week with a three-fold higher weekly dose of IFN-gamma (50000 U six times) did not result in significantly improved survival. The start of IFN-gamma administration was a critical factor since a delay of 3 days from the time of BMT resulted in substantial GVHD-induced mortality. Furthermore, it was shown that IFN-gamma treatment inhibited the spontaneous and Con-A-induced proliferation of T cells at 7-14 days after BMT, which is the critical period for the initiation of acute GVHD. However, long-term survivors after IFN-gamma treatment showed a recovery of immunity in contrast to long-term survivors of saline-injected animals, as tested by Con-A responsiveness. It seems that injection of high dose IFN-gamma suppresses the response of potentially alloreactive donor T cells during what normally is the initiation phase of the GVH reaction (GVHR), resulting in the abrogation of GVHD.     

Evidence implicating Gfi-1 and Pim-1 in pre-T-cell differentiation steps associated with beta-selection

After rearrangement of the T-cell receptor (TCR) beta-locus, early CD4(-)/CD8(-) double negative (DN) thymic T-cells undergo a process termed 'beta-selection' that allows the preferential expansion of cells with a functional TCR beta-chain. This process leads to the formation of a rapidly cycling subset of DN cells that subsequently develop into CD4(+)/CD8(+) double positive (DP) cells. Using transgenic mice that constitutively express the zinc finger protein Gfi-1 and the serine/threonine kinase Pim-1, we found that the levels of both proteins are important for the correct development of DP cells from DN precursors at the stage where 'beta-selection' occurs. Analysis of the CD25(+)/CD44(-,lo) DN subpopulation from these animals revealed that Gfi-1 inhibits and Pim-1 promotes the development of larger beta-selected cycling cells ('L subset') from smaller resting cells ('E subset') within this subpopulation. We conclude from our data that both proteins, Pim-1 and Gfi-1, participate in the regulation of beta-selection-associated pre-T-cell differentiation in opposite directions and that the ratio of both proteins is important for pre-T-cells to pass the 'E' to 'L' transition correctly during beta-selection.