FK506 in combination with methotrexate for the prevention of graft- versus-host disease after marrow transplantation from matched unrelated donors

The safety and potential efficacy of FK506 in combination with a short course of methotrexate (MTX) for the prevention of acute graft-versus- host disease (GVHD) after marrow transplantation from HLA-matched unrelated donors was evaluated in a single-arm Phase II study conducted at two centers. Forty-three patients, 15 to 54 (median 41) years of age, were transplanted for hematologic malignancies. Thirty-seven of 43 evaluable patients had evidence of sustained marrow engraftment. Five patients died before day 17 after transplantation. The median time to an absolute neutrophil count of > 0.5 x 10(5)/L was 21 (range, 14 to 30) days. Nephrotoxicity (serum creatinine concentration > 2 mg/dL or doubling of baseline) occurred in 32 patients (74% cumulative incidence during the first 100 days after transplant). Other adverse effects included hypertension (n = 27), hyperglycemia (n = 27), neurotoxicity (n = 9) and thrombotic thrombocytopenic purpura (n = 2). Severe veno- occlusive disease of the liver occurred in 9 (21%) of the 43 patients. Eighteen patients (42%) developed grades II to IV acute GVHD and five (12%) developed grades III to IV acute GVHD. Twelve of 25 evaluable patients developed extensive chronic GVHD within 1 year of marrow transplantation resulting in an estimate of the probability of developing this complication of 48%. The cumulative incidence of transplant-related mortality during the first 100 days was 37%. Kaplan- Meier estimates of disease-free survival at 2 years for good-risk, poor- risk, and all patients were 65%, 4%, and 32%, respectively. FK506 in combination with a short course of MTX appears active in preventing acute GVHD after marrow transplantation from unrelated donors. Further studies comparing the combination of FK506 and MTX with cyclosporine and MTX for the prevention of acute GVHD are warranted.     

Mobilization of early hematopoietic progenitor cells with BB-10010: a genetically engineered variant of human macrophage inflammatory protein- 1 alpha

BB-10010 is a genetically engineered variant of human macrophage inflammatory protein-1 alpha with improved solution properties. We show here that it mobilizes stem cells into the peripheral blood. We investigated the mobilizing effects of BB-10010 on the numbers of circulating 8-day spleen colony-forming units (CFU-S8), CFU-S12, and progenitors with marrow repopulating ability (MRA). A single subcutaneous dose of BB-10010 caused a twofold increase in circulating numbers of CFU-S8, CFU-S12, and MRA 30 minutes after dosing. We also investigated the effects of granulocyte colony-stimulating factor (G- CSF) and the combination of G-CSF with BB-10010 on progenitor mobilization. Two days of G-CSF treatment increased circulating CFU-S8, CFU-S12, and MRA progenitors by 25.7-, 19.8-, and 27.7-fold. A single administration of BB-10010 after 2 days of G-CSF treatment increased circulating CFU-S8, CFU-S12, and MRA even further to 38-, 33-, and 100- fold. Splenectomy resulted in increased circulating progenitor numbers but did not change the pattern of mobilization. Two days of treatment with G-CSF then increased circulating CFU-S8, CFU-S12, and MRA by 64-, 69-, and 32-fold. A single BB-10010 administration after G-CSF treatment further increased them to 85-, 117-, and 140-fold, respectively, compared with control. We conclude that BB-10010 causes a rapid increase in the number of circulating hematopoietic progenitors and further enhances the numbers induced by pretreatment with G-CSF. BB- 10010 preferentially mobilized the more primitive progenitors with marrow repopulating activity, releasing four times the number achieved with G-CSF alone. Translated into a clinical setting, this improvement in progenitor cell mobilization may enhance the efficiency of harvest and the quality of grafts for peripheral blood stem cell transplantation.     

Activated protein C decreases plasminogen activator-inhibitor activity in endothelial cell-conditioned medium

Confluent cultures of endothelial cells from human umbilical cord were used to study the effect of activated human protein C (APC) on the production of plasminogen activators, plasminogen activator-inhibitor, and factor VIII-related antigen. Addition of APC to the cells in a serum-free medium did not affect the production of tissue-type plasminogen activator (t-PA) or factor VIII-related antigen; under all measured conditions, no urokinase activity was found. However, less plasminogen activator-inhibitor activity accumulated in the conditioned medium in the presence of APC. This decrease was dose dependent and could be prevented by specific anti-protein C antibodies. No decrease was observed with the zymogen protein C or with diisopropylfluorophosphate-inactivated APC. APC also decreased the t-PA inhibitor activity in endothelial cell-conditioned medium in the absence of cells, which suggests that the effect of APC is at least partly due to a direct effect of APC on the plasminogen activator- inhibitor. High concentrations of thrombin-but not of factor Xa or IXa-- had a similar effect on the t-PA inhibitor activity. The effect of APC on the plasminogen activator-inhibitor provides a new mechanism by which APC may enhance fibrinolysis. The data suggest that activation of the coagulation system may lead to a secondary increase of the fibrinolytic activity by changing the balance between plasminogen activator(s) and its (their) fast-acting inhibitor.     

Infusing Diversity and Equity Into Clinical Teaching: Training the Trainers

Clinical instructors in health care disciplines are charged with engaging students in experiential learning wherein respect and cultural sensitivity is applied. This article reports on the results of 3 diversity workshops conducted for clinical preceptors and field instructors from various disciplines. The workshops were developed in response to students’ growing concerns that their academic learning experiences were negatively affected by dissatisfying management of differences between students, faculty, and preceptors with respect to ethno‐racial group membership, socioeconomic level, and degree of privilege and power. The workshops included a didactic session that presented basic principles of social and health equity followed by small‐group reflection about various ethical and moral dilemmas that were presented in clinical education scenarios. Examples of discrimination on a variety of levels were addressed in these workshops, including race, ethnicity, immigration status, sexual orientation, religion, body size and appearance, ability, age, socioeconomic class, religious faith, and gender. The group exercises and discussion from these sessions provided valuable insight and approaches to difficult but common areas of discomfiture encountered in the clinical teaching setting. This article presents the findings from participants of these diversity workshops in order to encourage the application of equity principles into clinical teaching in midwifery and other health care education contexts.     

Effects of long working hours and the night shift on severe sleepiness among workers with 12‐hour shift systems for 5 to 7 consecutive days in the automobile factories of Korea

We investigated the effects of 12‐hour shift work for five to seven consecutive days and overtime on the prevalence of severe sleepiness in the automobile industry in Korea. [Correction added after online publication 28 Nov: Opening sentence of the summary has been rephrased for better clarity.] A total of 288 randomly selected male workers from two automobile factories were selected and investigated using questionnaires and sleep‐wake diaries in South Korea. The prevalence of severe sleepiness at work [i.e. Karolinska Sleepiness Scale (KSS) score of 7 or higher] was modeled using marginal logistic regression and included theoretical risk factors related to working hours and potential confounding factors related to socio‐economic status, work demands, and health behaviors. Factors related to working hours increased the risk for severe sleepiness at the end of the shift in the following order: the night shift [odds ratio (OR): 4.7; 95% confidence interval (CI): 3.6–6.0)], daily overtime (OR: 2.2; 95% CI: 1.7–2.9), weekly overtime (OR: 1.6; 95% CI: 1.0–2.6), and night overtime (OR: 1.6; 95% CI: 0.8–3.0). Long working hours and shift work had a significant interactive effect for severe sleepiness at work. Night shift workers who worked for 12 h or more a day were exposed to a risk of severe sleepiness that was 7.5 times greater than day shift workers who worked less than 11 h. Night shifts and long working hours were the main risk factors for severe sleepiness among automobile factory workers in Korea. Night shifts and long working hours have a high degree of interactive effects resulting in severe sleepiness at work, which highlight the need for immediate measures to address these characteristics among South Korean labor force patterns.