Biomedical subjects
Publications and source records attributed to A Stucki.
We describe the clinical course and treatment of a young woman diagnosed with tuberous sclerosis. Classical as well as atypical clinical findings are discussed with regards to the differential diagnosis. The most important components of the pathogenesis and the criteria necessary for diagnosis are highlighted. In addition the similarities and differences to lymphangioleiomyomatosis are discussed.
We report on a 36-year-old man with a history of mild head trauma. The initial clinical findings and the CT-scan of the brain revealed no pathological result, although the patient suffered from weakness of the right arm and bilateral blindness. Those findings were interpreted as psychogenic disorder. Nine days later he developed an instable gait, a child like attitude, amnesia and enuresis. The CT-scan revealed a subacute bilateral occipital stroke in the region of the arteriae cerebri posteriors. No cause for the stroke was found. In spite of the rareness of cortical blindness in young people as a cause of stroke, a detailed medical history and clinical examination should always be performed, and by unclearness additional investigations should be considered.
Ceftriaxone acted synergistically with levofloxacin in time-killing assays in vitro over 8 h against two penicillin-resistant pneumococcal strains (WB4 and KR4; MIC of penicillin: 4 mg/L). Synergy was confirmed with the chequerboard method, showing FIC indices of 0.25. In the experimental rabbit meningitis model, ceftriaxone (1x 125 mg/kg) was slightly less bactericidal (-0.30 Deltalog(10) cfu/mL(.)h) compared with levofloxacin (-0.45 Deltalog(10) cfu/mL(.)h) against the penicillin-resistant strain WB4. The combination therapy (levofloxacin and ceftriaxone) was significantly superior (-0.64 Deltalog(10) cfu/mL(.)h) to either monotherapy. In cycling experiments in vitro, the addition of ceftriaxone at a sub-MIC concentration (1/16 MIC) reduced levofloxacin-induced resistance in the two strains KR4 and WB4. After 12 cycles with levofloxacin monotherapy, the MIC increased 64-fold in both strains versus a 16-fold increase with the combination (levofloxacin + ceftriaxone 1/16 MIC). In both strains, levofloxacin-induced resistance was confirmed by mutations detected in the genes parC and gyrA, encoding for subunits of topoisomerase IV and gyrase, respectively. The addition of ceftriaxone suppressed mutations in parC but led to a new mutation in parE in both strains.
The aim of the present study was to investigate the potential synergy between meropenem and levofloxacin in vitro and in experimental meningitis and to determine the effect of meropenem on levofloxacin-induced resistance in vitro. Meropenem increased the efficacy of levofloxacin against the penicillin-resistant pneumococcal strain KR4 in time-killing assays in vitro and acted synergistically against a second penicillin-resistant strain WB4. In the checkerboard, only an additive effect (FIC indices: 1.0) was observed for both strains. In cycling experiments in vitro, levofloxacin alone led to a 64-fold increase in the MIC for both strains after 12 cycles. Addition of meropenem in sub-MIC concentrations (0.25 x MIC) completely inhibited the selection of levofloxacin-resistant mutants in WB4 after 12 cycles. In KR4, the addition of meropenem led to just a twofold increase in the MIC for levofloxacin after 12 cycles. Mutations detected in the genes encoding for topoisomerase IV (parC) and gyrase (gyrA) confirmed the levofloxacin-induced resistance in both strains. Addition of meropenem was able to completely suppress levofloxacin-induced mutations in WB4 and led to only one mutation in parE in KR4. In experimental meningitis, meropenem, given in two doses (2 x 125 mg/kg), produced a good bactericidal activity (-0.45 Deltalog10 cfu/ml.h) comparable to one dose (1 x 10 mg/kg) of levofloxacin (-0.44 Deltalog10 cfu/ml.h) against the penicillin-resistant strain WB4. Meropenem combined with levofloxacin acted synergistically (-0.93 Deltalog10 cfu/ml.h), sterilizing the CSF of all rabbits.
Leukostasis and tissue infiltration by leukemic cells are poorly understood life-threatening complications of acute leukemia. This study has tested the hypothesis that adhesion receptors and cytokines secreted by blast cells play central roles in these reactions. Immunophenotypic studies showed that acute myeloid leukemia (AML) cells (n = 78) of the M0 to M5 subtypes of the French-American-British Cooperative Group expressed various amounts of adhesion receptors, including CD11a, b, c/CD18, CD49d, e, f/CD29, CD54, sCD15, and L-selectin. The presence of functional adhesion receptors was evaluated using a nonstatic adhesion assay. The number of blast cells attached to unactivated endothelium increased by 7 to 31 times after a 6-hour exposure of endothelium to tumor necrosis factor (TNF)-alpha. Inhibition studies showed that multiple adhesion receptors--including L-selectin, E-selectin, VCAM-1, and CD11/CD18--were involved in blast cell adhesion to TNF-alpha-activated endothelium. Leukemic cells were then cocultured at 37 degrees C on unactivated endothelial cell monolayers for time periods up to 24 hours. A time-dependent increase in the number of blasts attached to the endothelium and a concomitant induction of ICAM-1, VCAM-1, and E-selectin were observed. Additional experiments revealed that endothelial cell activation by leukemic myeloblasts was caused by cytokine secretion by blast cells, in particular TNF-alpha and IL-1 beta, and direct contacts between adhesion receptors expressed by blast cells and endothelial cells. Thus, leukemic cells have the ability to generate conditions that promote their own adhesion to vascular endothelium, a property that may have important implications for the pathophysiology of leukostasis and tissue infiltration by leukemic blast cells. (Blood. 2001;97:2121-2129)
We report a patient with Ph-positive CML who developed a Ph-negative AML in donor cells 14 months after BMT from an HLA-identical male unrelated donor. The Ph translocation could not be detected by either conventional cytogenetics, FISH or RT-PCR analysis excluding relapse of CML in myeloid blast crisis. Chimerism studies were performed by variable number of tandem repeats (VNTR) analysis. These revealed donor-type hematopoiesis in both unseparated mononuclear cells and CD34+ selected blasts proving the leukemia to be of donor origin. The patient received three cycles of polychemotherapy with mitoxantrone, topotecan and ara-c resulting in CR after the first treatment cycle and reconstitution with donor hematopoiesis. A second transplant from a female alternative matched unrelated donor was performed after conditioning with fludarabine and 200 cGy TBI and was well tolerated. Nine months after the second transplant the patient is at home and in CR. T cell chimerism was studied by sex chromosome analysis and revealed complete female donor chimerism.
Intercellular adhesion molecule 3 (ICAM-3, CD50) is an immunoglobulin (Ig) domain-containing cell-cell adhesion receptor that binds to the lymphocyte function antigen 1 (LFA-1; CD11a/CD18) integrin. It is constitutively expressed on haematopoietic precursors and differentiated leucocytes, as well as on most leukaemic cells. ICAM-3/LFA-1 binding during a lymphocyte-mediated cellular immune response has been well established; however, its role in the marrow compartment is unclear. In this study, marrow cells from normal and acute leukaemic donors, as well as leukaemic cell lines, were cultured in the presence of various monoclonal antibodies (mAbs) to ICAM-3, and apoptosis was subsequently measured by annexin V binding. Anti-ICAM-3 mAb ICR 1.1 engagement triggered increased percentages of apoptosis among normal and leukaemic marrow myeloid cells. Fab fragments of ICR 1.1 mimicked the intact mAb, suggesting that the apoptotic signal was independent of Fc receptor interactions and did not require bivalent epitope engagement. In addition, the apoptotic signal was found to be independent of ICAM-1/LFA-1 binding interactions, as well as Fas/FasL and tumour necrosis factor alpha (TNF-alpha)/TNF receptor-activated pathways, as neutralizing antibodies to CD11a/CD18, Fas and TNF-alpha failed to abrogate the response.
In this overview general risk factors for postoperative complications are discussed with special reference to pulmonary complications, which frequently occur in patients with chronic obstructive pulmonary disease (COPD). In a second part the functional evaluation of lung resection candidates is presented. Pulmonary complications are the most frequent cause of postoperative morbidity and mortality. Risk factors include: underlying respiratory disease, especially COPD, current smoking, duration of anaesthesia, type of surgical procedure (upper abdominal or thoracic surgery), age and obesity. The preoperative evaluation of patients at risk is discussed. For non-thoracic surgery preoperative pulmonary function testing and a preoperative chest radiograph are indicated for high-risk patients only, whereas they are mandatory for all lung resection candidates. There are no cut-off values in pulmonary function testing which would preclude non-thoracic surgical procedures. In patients with COPD, laparascopic procedures are recommended; and regional or epidural anaesthesia have less adverse effects on pulmonary function than general anaesthesia. Prevention of postoperative pulmonary complications includes smoking cessation at least eight weeks before surgery, and, if indicated preoperative treatment with antibiotics, beta2-agonists, steroids (steroid-trial) and intensive perioperative chest physiotherapy (incentive spirometry). The functional reserves of lung resection candidates is assessed with an algorithm based on the forced expiratory volume in one second (FEV1), the transfer factor of the lung for carbon monoxide (DLCO), and the maximal oxygen uptake on exercise (VO2max). In critical patients additional split function studies are necessary to estimate the remaining pulmonary function depending on the extent of resection.
To analyze the value of real time RT-PCR for monitoring of bcr-abl expression in CML patients after allogeneic or autologous stem cell transplantation (SCT), we generated pairs of PCR-primers and TaqMan probes specific for either the b2a2- or the b3a2-variant of bcr-abl. Either variant could be detected specifically from cDNA from a single K562 (b3a2) and BV173 (b2a2) cell with the respective TaqMan probe. Bcr-abl expression was normalized by comparison with GAPDH expression, and samples were quantitated using standard cDNA dilutions from K562 or BV173 cells. In a retrospective analysis 13 patients with CML after allogeneic (n = 10) or autologous (n = 3) SCT including patients with relapsed or persistent CML were analyzed by both real-time and conventional nested RT-PCR. In addition chimerism was monitored by FISH analysis of sex chromosomes in three patients with relapsed disease. The bcr-abl/GAPDH ratio dropped at least 1000-fold in all seven patients evaluable prior to and after allogeneic SCT as estimated by real-time RT-PCR, and conventional RT-PCR became negative in 6/7 patients. In five patients with relapsed or persistent disease after allogeneic SCT the bcr-abl/GAPDH ratio eventually increased again, and real-time RT-PCR was as sensitive as conventional RT-PCR for detection of bcr-abl. Donor lymphocyte infusions (DLI) were given to all five patients, and the bcr-abl/GAPDH ratio dropped to undetectable levels in two patients both remaining in continuing molecular remission. In contrast, in three other patients the bcr-abl/GAPDH ratio decreased only or did not change significantly after DLI. In three patients undergoing autologous SCT the bcr-abl/GAPDH ratio dropped only 1.1 to 30-fold, and the patients were tested positive with real-time RT-PCR at all time points. These data demonstrate that real-time RT-PCR is valuable to quantitate bcr-abl expression in CML patients after transplantation.
We conducted a prospective study to see how accurately hospital doctors can predict length of patient stays on an acute medical ward. The study covered an 18-month period and included all internal medicine patients admitted to Clinic B of Basel University Hospital. 1989 patients (57% male and 43% female) were included. Average age was 62.5 years. Average stay was 15.3 days against an average predicted 14.6 days (S.D. 0.7, not significantly different at 5% C.I. Correlation coefficient 0.44-slight correlation). The discharge destination was accurately predicted in 90% of patients going home and in 80% of patients who later died. However, prediction of those patients who would require further rehabilitation or a nursing home place was poor (60% and 50% respectively). The results show that although the average predicted hospital stay was fairly accurate, for individuals it varied widely. Short hospital stays were generally overpredicted and longer stays underpredicted. The causes of prolonged stays were medical in 60% of cases, social in 20%, inefficient organization in 10% and other in 10%. Patients requiring only nursing care accounted for only 6% of all bed occupancies.
Between 1970 and 1996, 333 patients with severe aplastic anemia underwent HLA-matched related marrow transplant after conditioning with cyclophosphamide (CY). Thirty-five percent of patients transplanted between 1970 and 1976 (group 1), 12% of those transplanted between 1977 and 1981 (group 2), and 9% of patients transplanted between 1982 and 1997 (group 3) had graft rejection. Graft rejection occurred later among group 3 patients (median, 180 days) than among those in groups 1 and 2 (medians, 28 and 47 days, respectively; P < .001 group 3 v 2). In group 3, 92% of rejecting patients underwent a second transplant, compared with 78% and 77% in groups 1 and 2, respectively. Group 1 patients received various conditioning regimens before second transplant, whereas most patients of groups 2 and 3 received CY combined with antithymocyte globulin (ATG). Graft-versus-host disease (GVHD) prophylaxis after second transplant consisted of methotrexate (MTX) for all group 1 and 2 patients, whereas group 3 patients received MTX combined with cyclosporine (CSP). Over the three time periods studied, first graft rejection decreased from 35% to 9%, and the proportion of rejecting patients undergoing second transplants increased from 77% to 92%. The 10-year probability of survival after second transplants increased from 5% to 83%. Multivariate analysis showed MTX/CSP GVHD prophylaxis to be a significant factor accounting for the increase in patient survival after second transplant.
Explore the source record for details and available documents.
BACKGROUND: The clinical use of ex vivo expanded hematopoietic progenitor cells is currently explored. MATERIAL AND METHODS: In this study the culturing of G-CSF mobilized and purified CD34+ blood cells was investigated. The interleukins IL-1 beta, IL-3 and IL-6 (each at a dose of 300 U/ml) and stem cell factor (25 ng/ml) without or with erythropoietin (1 U/ml) were used. Cells of 10 healthy sibling donors and 10 patients with solid tumors were incubated under small-scale (n = 15, 2 ml) and large-scale (n = 7, 50 ml) culture conditions at 37 degrees C for 5 and 4 weeks, respectively. The cell density was adjusted to about 1 x 10(5) cells/ml. RESULTS: The nucleated cell counts increased approximately 7-fold and 10- to 70-fold after 1 and 2 weeks of incubation. Numbers of CD34+ cells doubled to triplicated within this time interval, without any significant changes in their clonogenicity (CFU-GM and BFU-E output). Thereafter a depletion of the CD34+ cell pool was noticed. However the numbers of CD34+/CD38(-)- or CD34+/ HLA-DR(-)- cells were reduced to a lesser extent. The expanded cells generated predominantly myeloid and almost no lymphoid cells. More glycophorin-A+ cells were produced when erythropoietin was added. Replacement of non-human additives with heat-inactivated autologous plasma had no influence on cell growth. Almost no proliferation was obtained with a 10-fold higher cell density (1.7 x 10(6)/ml in 100 ml), but the cells maintained their viability for 13 to 16 days. CONCLUSIONS: This study suggests, that the chosen culture conditions might be feasible for a large-scale ex vivo expansion of hematopoietic progenitor cells for clinical application. The impact of the ex vivo generated cells on hematopoietic regeneration after chemotherapy is currently under clinical investigation.
Explore the source record for details and available documents.
Involvement of the central nervous system has important therapeutic implications in acute leukaemia. Because the identification of blast cells in cerebrospinal fluid (CSF) is often difficult, there is a need for sensitive markers of leukaemic infiltration. Since the shed form of L-selectin (sL-selectin) is frequently increased in acute leukaemia (sL-selectin+ leukaemia), we examined whether assay of sL-selectin in CSF could improve our ability to detect such meningeal involvement. CSF sL-selectin was significantly (p < 0.001) higher in 15 patients with sL-selectin+ meningeal leukaemia (median 60 ng/mL, range 34-150) than in 20 patients with acute leukaemia without meningeal involvement (12 ng/mL, 1-39) or 88 control patients (14 ng/mL, 0-37). Serial measurements of sL-selectin in patients with sL-selectin+ leukaemic meningitis showed increased CSF concentrations of the cleaved receptor in 4 patients with therapy-resistant meningeal leukaemia and sustained normal concentrations in 9 patients in remission. Our results suggest that CSF sL-selectin may be a useful marker in the detection of meningeal involvement by blast cells in patients with sL-selectin+ leukaemia.
Sideropenic anemia is a common long-term complication of surgical bilio-pancreatic bypass for morbid obesity, and is frequently resistant to oral iron therapy. To study the pathogenesis of this phenomenon we investigated 7 such patients clinically and biologically, with special emphasis on iron absorption. Our results show that sideropenia, consistently present and frequently complicated by anemia, is due to deficient iron absorption and that this malabsorption is non-selective. Replacement therapy, when indicated, should therefore use the parenteral route.
Twin pregnancy entails an enhanced hazard especially for the newborn, with regard to both perinatal mortality and neonatal morbidity. The authors deal with the following points in the first part of the article: 1. The classical concepts concerning the distribution of twin pregnancy with regard to enzygotism and dizygotism, and the importance of the modus of placentation. 2. Pathophysiology of twin pregnancy, making three factors responsible for prematurity and hypotrophy of the twins: Lack of sufficient space in the uterus, insufficient uteroplacental exchange and inability of the cardiovascular system to become adapted to the situation. In the second part of the article, conclusions are drawn with regard to the course of pregnancy as well as the twin birth. The main problems listed here emphasise the importance of the following points: -systematic, early ultrasound examination and more frequent controls for keeping a better check on the course of pregnancy and birth, -complete and strict rest in bed around the 31st week of pregnancy to combat prematurity and hypotrophy, -induction of labour before the due date and more liberal application of the indications leading to Caesarian section to combat perinatal mortality and morbidity. Subsequent to the practical application of these conclusions within a prospective study conducted from 1977 to 1978, the authors achieved a mortality decrease from 5.6% to 3.2% (WHO definition).
Explore the source record for details and available documents.