Differential toxic effect of dissolved triamcinolone and its crystalline deposits on cultured human retinal pigment epithelium (ARPE19) cells

The aim of the study was to evaluate the antiproliferative and cytotoxic properties of triamcinolone acetonide (TA) on human retinal pigment epithelium cells (ARPE19) and the role of epicellular crystalline deposits. Monolayer cultures of ARPE19 cells were used. Purified or unpurified crystalline TA suspension (0.01-1.0 mg/ml) or the vehicle alone (benzyl alcohol, 0.025%-0.00025%), diluted in culture medium, were added to the cells that were either grown on cell culture dishes covered by a protecting membrane filter insert or without a filter. After 1, 3, 5 and 7 days mitochondrial activity was measured using the MTT assay and the morphology assessed microscopically. Cellular proliferative activity was monitored by BrdU-incorporation into cellular DNA. For cytotoxicity assays ARPE19 cells were grown to confluence and then cultured in a serum-deficient medium to ensure a static milieu. Annexin V-FITC and propidium iodide co-staining was performed and analyzed by flow cytometry. Exposure to TA without direct cellular contact showed a moderate antiproliferative activity resulting in a dose-dependent suppression of DNA synthesis (maximum 42.7%), but not a cytotoxic effect. In contrast, adherent deposits of crystalline TA particles on top of the cell layer caused a rapid-progressive and dose-dependent cell death preceded by an early phosphatidylserine externalization to the outer leaflet of the plasma membrane. Within a healthy, confluent cell layer the number of viable cells decreased by 14.2, 20.8 and 68.8%, respectively, after one day of direct exposure. Exposure to the vehicle alone caused only a slight growth inhibitory effect in a proliferating cell layer, but early signs of cell death were detected even at the lowest concentration tested. In conclusion, the effect of the vehicle is less pronounced than formerly assumed, but not negligible, thus indicating a beneficial effect of purification. While non-adherent TA, if purified, appears to be safe in clinically used concentrations, direct physical contact with crystalline particles might cause a local, rapid-progressive cytotoxicity that involves the induction of the apoptotic cascade. Therefore, epiretinal deposits after intravitreal TA administration might be critical in terms of long-term biocompatibility.     

Long-term survival in refractory acute myeloid leukemia after sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation

A sequential regimen of chemotherapy, reduced-intensity conditioning (RIC) for allogeneic stem cell transplantation (SCT), and prophylactic donor lymphocyte transfusion (pDLT) was studied in 103 patients with refractory acute myeloid leukemia (AML). According to published criteria, refractoriness was defined by primary induction failure (PIF; n = 37), early (n = 53), refractory (n = 8), or second (n = 5) relapse. Chemotherapy consisted of fludarabine (4 x 30 mg/m(2)), cytarabine (4 x 2 g/m(2)), and amsacrine (4 x 100 mg/m(2)), followed 4 days later by RIC, comprising 4 Gy total body irradiation (TBI), cyclophosphamide, and antithymocyte globulin. Patients without graft-versus-host disease (GvHD) at day +120 received pDLT in escalating doses. Patients' median age was 51.8 years. Before conditioning, 99 patients had active disease, 3 were aplastic, 1 was in second complete remission (CR2). Forty-one patients had family donors, 62 had unrelated donors. With a 25-month median follow-up, overall survival (OS) at 1, 2, and 4 years was 54%, 40%, and 32%; the respective leukemia-free survival (LFS) was 47%, 37%, and 30%. Patients with PIF showed a 2-year OS of 62.5%. OS was 87% in 17 patients receiving pDLT. One-year cumulative incidence of leukemic death and non-relapse-mortality was 28.7% and 17.2%. In a multivariate analysis, more than 2 courses of prior chemotherapy were the strongest predictor for poor outcome (P = .007; HR = 3.01 [OS]; P = .002; HR = 3.25 [LFS]). These results indicate a high activity of the regimen in refractory AML.     

Spezielle medizinische Probleme am Lebensende

Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz - Krisen am Lebensende sind für Patienten, Angehörige und Behandler eine besondere Herausforderung. Es gilt, einem...     

Correlation of postoperative axial length growth and intraocular pressure in congenital glaucoma – a retrospective study in trabeculotomy and goniotomy

BACKGROUND: This paper investigates the correlation of postoperative intraocular pressure (IOP) with axial length growth in children who underwent either trabeculotomy (TO) or goniotomy (GO) as primary surgery for congenital glaucoma. METHODS: Thirty-seven eyes of 21 children with congenital glaucoma who underwent one or two TOs from 1992 to 1997 and 26 eyes of 16 children with congenital glaucoma who underwent one or more GOs from 1974 to 1993 were retrospectively analyzed. None of the eyes had undergone other surgery previously. Thirteen of the TOs were combined with a small trabeculectomy. IOP was measured by handheld applanation tonometry (Perkins). Axial length was measured by ultrasound. The data were analyzed for correlation of postoperative IOP reduction with postoperative axial length growth. RESULTS: Mean duration of follow-up was 27.3 months in the TO eyes and 37.1 months in the GO eyes. Mean pretreatment IOP before surgery was 28.4+/-6.9 mmHg in the TO eyes and 30.8+/-8.5 mmHg in the GO eyes. Mean IOP at the end of follow-up was 17.5+/-5.8 mmHg in the TO eyes and 17.4+/-10.2 mmHg in the GO eyes. Axial length growth was normalized (proportional or slowed down compared with the nomogram of axial length growth) in 31 of the 37 TO eyes and in 20 of the 26 GO eyes, and was increased in 6 of the TO eyes and 6 of the GO eyes at the end of follow-up. Regarding axial length growth, 6 of 37 TO eyes had increased axial length growth at the end of follow-up. Three of these eyes also did not fulfill the IOP success criterion; 2 of the 3 eyes with normalized IOP had only borderline increased axial length growth. Six of 26 GO eyes had increased axial length growth at the end of follow-up. Five of these eyes did not fulfill the IOP success criterion; 1 eye with normalized IOP had only borderline increased axial length growth. CONCLUSION: The data show remarkably good correlation of postoperative IOP with postoperative axial length growth. Axial length measurements can therefore help to ascertain halting or progression of congenital glaucoma and thus are considered an important parameter for congenital glaucoma follow-up.     

Association of the spatial layout of the home and ADL abilities among older adults with dementia

We investigated the relationship between architectural space syntax measures describing the spatial layout of a home and activities of daily living (ADL) among people with dementia. We visited the homes of 82 participants in a dementia care comparative effectiveness clinical trial and measured the space syntax variables intelligibility and convexity along with several clinical variables, including ADLs. In regression models, we estimated the cross-sectional association between space syntax measures and ADLs. Higher convexity was associated with worse performance of basic but not instrumental ADLs (adjusted β =19.2, P = .02). Intelligibility was not associated with ADLs. These results imply that enclosed rooms with a clearly legible meaning and function might be better memorized and associated with the spatial layout of the home resulting in better basic ADL performance. These results warrant further research on space syntax measures in the home environment of people with dementia, including longitudinal study, which we are pursuing.     

Configurational analysis of tetracyclic dimeric pyrrole-imidazole alkaloids using a floating chirality approach

The structure elucidation of the palau'amine congener tetrabromostyloguanidine (1), which used interproton distances from ROESY spectra as restraints in a computational approach, the so-called fc-rDG/DDD method, led to a revision of the relative configuration of palau'amine (2) and its congeners in 2007. The recent total synthesis of (±)-palau'amine (2) subsequently confirmed the computed structural revision of the relative configuration. In order to test a broader application range of the fc-rDG/DDD method, the present study investigated two additional dimeric pyrrole-imidazole alkaloids, axinellamine A (3) and 3,7-epi-massadine chloride (4). These calculations allowed the simultaneous assignment of the relative configuration for all eight stereogenic centers of compounds 3 and 4 without using any information from the reported configurations. In contrast to the palau'amine congeners, the fc-rDG/DDD method confirmed the relative configuration originally described for axinellamine A (3) and 3,7-epi-massadine chloride (4).