Posttransplant T-cell lymphoproliferative disorders--an aggressive, late complication of solid-organ transplantation

T-cell non-Hodgkin's lymphomas are an uncommon occurrence after solid- organ transplantation. We describe a morphologically and immunophenotypically distinct group of T-cell lymphoproliferative disorders that occurred late in the course of six patients with solid- organ transplants. The patients ranged in age from 31 to 56 years (median, 43). Three were male; all were splenectomized. The interval from transplant to the diagnosis of lymphoma ranged from 4 to 26 years (median, 15). Symptoms at presentation were related to sites of involvement. Pulmonary, marrow, and CNS involvement were present in five, four, and one case, respectively. No patient had lymphadenopathy. Five patients had an elevated lactate dehydrogenase level (range, 226 to 4,880 IU/L; median, 1,220 IU/L). Five of six patients had a leukoerythroblastic reaction. All cases had large-cell histology and frequently contained cytoplasmic granules. Those cases tested expressed CD2, CD3, and CD8 and were negative for B-cell antigens. T-cell receptor beta- and gamma-chain genes were clonally rearranged in three of three and one of three cases, respectively. All T-cell posttransplant lymphoproliferative disorders (T-PTLDs) studied were negative for Epstein-Barr virus (EBV), human T-cell leukemia/lymphoma virus type 1 (HTLV-1), human T-cell leukemia/lymphoma virus type 2 (HTLV-2), and human herpes virus type 8 (HHV-8) genomes. Treatment with acyclovir (three patients) or chemotherapy (three patients) resulted in two responses. All patients had an aggressive course, with a median survival duration of 5 weeks. In conclusion, a clinically aggressive T- PTLD may be a late complication of solid-organ transplantation and does not appear to be related to EBV, HTLV-1, HTLV-2, or HHV-8 infection.     

Major vessel involvement in Behçet disease

PURPOSE OF REVIEW: Large vessel vasculitis occurs in a subgroup of patients with Beh?et disease at high risk for disease-related morbidity and mortality. Recognition of patients at risk, early detection of vasculitis, and the need for aggressive treatment are essential for optimal care of these patients. The authors review the clinical spectrum and management of large vessel problems in Beh?et disease, highlighting contributions over the past year. RECENT FINDINGS: Vasculo-Beh?et patients are at risk for multiple vessel-related complications including thromboses, stenoses, occlusions, and aneurysms. A number of factors may contribute to thrombosis in individual cases, but the primary reason for clot seems to reside in the inflammatory process in the arterial wall, still incompletely understood. An appreciation for the challenges in the perioperative period requires the joint efforts of physicians and surgeons, and fuels the study of alternate, less invasive procedures for Beh?et patients. SUMMARY: Because of earlier recognition, aggressive medical treatment, and novel surgical procedures, the morbidity and mortality of large vessel vasculitis in Beh?et disease are beginning to change. In the absence of controlled treatment studies, reports of clinical experience remain an important source of information for clinicians. Identification of patients at risk for vascular complications remains a priority.     

First-pass midazolam metabolism catalyzed by 1alpha,25-dihydroxy vitamin D3-modified Caco-2 cell monolayers

Cytochrome P-450 (CYP) 3A4 accounts for approximately 50% of all P-450s found in the small intestine (Paine et al., 1997) and contributes to the extensive and variable first-pass extraction of drugs such as cyclosporine and saquinavir. We recently demonstrated that CYP3A4 expression in a differentiated Caco-2 subclone is increased when cell monolayers are treated with 1alpha,25-dihydroxy-vitamin-D3 (Schmiedlin-Ren et al., 1997). This improved metabolic capacity permits the in vitro modeling of first-pass intestinal metabolic kinetics. Midazolam (MDZ) 1'-hydroxylation was used as a specific probe for CYP3A-mediated metabolism in modified Caco-2 monolayers. Caco-2 cells were grown to confluence on laminin-coated culture inserts, and then for two additional weeks in the presence of 1alpha,25-dihydroxy vitamin-D3. Cell monolayers were subsequently exposed to MDZ for varying lengths of time and concentrations. The amount of MDZ in the monolayer increased rapidly after apical drug administration, reaching a pseudo steady state within 6 min. The cellular uptake rate was considerably slower after a basolateral dose. By either route of administration, the rate of 1'-hydroxymidazolam formation was stable and linear for 2 h. Under basolateral sink conditions and low apical MDZ dosing concentration (1-8 microM), the first-pass extraction ratio was found to be approximately 15%. Higher dosing concentrations led to saturation of the hydroxylation reaction and reduction in the extraction ratio. The modified Caco-2 cell monolayer is an excellent model for studying drug absorption and first-pass intestinal metabolic kinetic processes. In this system, the selective CYP3A probe MDZ was rapidly absorbed, yet extensively metabolized, as is observed in vivo.     

Relation of psychological distress to the international normalized ratio in patients with venous thromboembolism with and without oral anticoagulant therapy

Summary. Background: Psychological distress might affect the international normalized ratio (INR), but effects might vary depending on oral anticoagulant (OAC) therapy. Objectives: To investigate the association of psychological distress with INR and clotting factors of the extrinsic pathway in patients with and without OAC therapy. Patients and methods: We studied 190 patients with a previous venous thromboembolism (VTE); 148 had discontinued OAC therapy and 42 had ongoing OAC therapy. To assess psychological distress, all patients completed validated questionnaires to measure symptoms of depression, anxiety, worrying, anger and hostility. INR, fibrinogen, factor (F)II:C, FV:C, FVII:C and FX:C were measured as part of outpatient thrombophilia work‐up. Results: In VTE patients without OAC therapy, the odds of a reduced INR (< 1.00) were significantly increased from 1.5 to 1.8 times for an increase of 1 standard deviation (SD) in symptoms of depression, anxiety, worrying and anger, respectively, after adjusting for gender, age, body mass index, socioeconomic status, hematocrit and C‐reactive protein. Worrying, anger and hostility also showed significant direct associations with FVII:C. In patients with OAC therapy, INR was unrelated to a negative affect; however, lower FVII:C related to anxiety and worrying as well as lower FX:C related to anger and hostility were observed in patients with OAC therapy compared with those without OAC therapy. Conclusions: Psychological distress was associated with a reduced INR in VTE patients without OAC therapy. The direction of the association between psychological distress and activity in some clotting factors of the extrinsic coagulation pathway might differ depending on whether VTE patients are under OAC therapy or not.     

Human megakaryocytes express clusterin and package it without apolipoprotein A-1 into alpha-granules

Clusterin, a 70-Kd disulfide-linked two-chain plasma glycoprotein circulates in blood as a high-density lipoprotein particle and is highly induced after tissue injury and tissue remodeling. In this study, peripheral blood leukocytes were assayed for clusterin expression. The protein was predominantly detectable in human platelets by immune cytochemistry. The content of clusterin was determined and amounts to 2.5 +/- 1.3 micrograms/10(9) platelets, thus representing about 2% of the blood pool. Clusterin purified from human platelets had the same molecular weight as plasma clusterin under nonreducing conditions and was composed of two disulfide-linked nonidentical subunits of the same size. Both preparations were sensitive to reduction yielding the two subunits of 35 Kd. In contrast to plasma clusterin, the platelet form was not complexed to apolipoprotein A-I. By immunogold labeling, alpha-granule localization of clusterin was observed. Complete release of platelet clusterin occurred at optimal doses of A23187, phorbol myristate acetate (PMA), and thrombin. Because clusterin mRNA was detected by hybridization in situ in bone marrow- derived megakaryocytes, platelet clusterin is most likely produced and packaged into alpha-granules during megakaryocyte development.     

Oral health education in schools: promoting health agents

Abstract: Purpose: The aim of this study was to verify the influence of preschool children participating in an oral health education programme on daily health practices of their families, through parent’s perception. Methods: A sample of 119 parents of 5‐ to 6‐year‐old preschool children were selected. Data were collected using a structured open–closed questionnaire, self‐administered. The questions focused on parents’ knowledge about activities of oral health education conducted in school, the importance given by them to these activities, learning from their offspring and the presence of habit change at home. Results: In total, 63 (52.9%) parents agreed to participate. Ninety‐eight per cent knew about educative and preventive activities developed at school and all of them affirmed that these activities were important, mainly because of knowledge, motivation and improvement in children’s health. Ninety and half per cent of parents reported that they learned something about oral health from their children and, among these, almost half (47.8%) cited toothbrushing as the indicator for better learning. Besides this, 87.3% of participants revealed the change in oral health habits of their family members. Conclusion: Preschool children were able to transmit knowledge acquired at school to their parents that included change in oral health routine of their family members.