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Soldini D.,University of Zurich | Gaspert A.,University of Zurich | Montani M.,University of Zurich | Montani M.,University Hospital and University of Berne | And 4 more authors.
Journal of Clinical Pathology | Year: 2014

Aims: To investigate whether drugs others than mycophenolic acid and ipilimumab might cause graft-versus-host-like apoptotic enteropathy, the clinicopathological findings in four patients were examined who had developed watery diarrhoea and apoptotic enteropathy (three cases from colon and one case from ileal pouch) after intake of antimetabolites (methotrexate and capecitabine) and/or tumour necrosis factor-α inhibitors (etanercept and infliximab). Methods: The clinical charts, endoscopy reports and intestinal biopsies from all endoscopies were reviewed for all patients. Biopsies were evaluated semiquantitatively for apoptosis of basal crypts, dilated damaged crypts, defined as cystically dilated crypts with flattened degenerated epithelium containing apoptotic debris and few neutrophils, and mucosal architecture. Further, the presence of intraepithelial lymphocytes, chronic inflammatory cells in the lamina propria and mucosal ulcerations was recorded and immunohistochemical analysis for human cytomegalovirus and herpes simplex virus was performed. Results: Endoscopic examination revealed normal mucosa in two patients, whereas the other two showed focal ulcerations. Histological changes included increased apoptosis of basal crypts, the presence of dilated damaged crypts and architecture distortion. In all cases, a temporal association between drug intake and/or dose increase, and onset of diarrhoea, was observed, and no convincing evidence of other potentially underlying causes of colitis/enteritis was found, including infections. Conclusions: Pathologists should be aware of the expanding spectrum of drugs that can cause apoptotic enteropathy, including antimetabolites and tumour necrosis factor-α inhibitors.

Mossdorf E.,St. Francis Designated District Hospital | Mossdorf E.,Ifakara Health Institute | Mossdorf E.,Swiss Tropical and Public Health Institute | Mossdorf E.,University of Basel | And 15 more authors.
BMC Infectious Diseases | Year: 2011

Background: Data on combination antiretroviral therapy (cART) in remote rural African regions is increasing.Methods: We assessed prospectively initial cART in HIV-infected adults treated from 2005 to 2008 at St. Francis Designated District Hospital, Ifakara, Tanzania. Adherence was assisted by personal adherence supporters. We estimated risk factors of death or loss to follow-up by Cox regression during the first 12 months of cART.Results: Overall, 1,463 individuals initiated cART, which was nevirapine-based in 84.6%. The median age was 40 years (IQR 34-47), 35.4% were males, 7.6% had proven tuberculosis. Median CD4 cell count was 131 cells/μl and 24.8% had WHO stage 4. Median CD4 cell count increased by 61 and 130 cells/μl after 6 and 12 months, respectively. 215 (14.7%) patients modified their treatment, mostly due to toxicity (56%), in particular polyneuropathy and anemia. Overall, 129 patients died (8.8%) and 189 (12.9%) were lost to follow-up. In a multivariate analysis, low CD4 cells at starting cART were associated with poorer survival and loss to follow-up (HR 1.77, 95% CI 1.15-2.75, p = 0.009; for CD4 <50 compared to >100 cells/μl). Higher weight was strongly associated with better survival (HR 0.63, 95% CI 0.51-0.76, p < 0.001 per 10 kg increase).Conclusions: cART initiation at higher CD4 cell counts and better general health condition reduces HIV related mortality in a rural African setting. Efforts must be made to promote earlier HIV diagnosis to start cART timely. More research is needed to evaluate effective strategies to follow cART at a peripheral level with limited technical possibilities. © 2011 Mossdorf et al; licensee BioMed Central Ltd.

Gutbrodt K.L.,ETH Zurich | Schliemann C.,University Hospital Muenster | Giovannoni L.,Philogen SpA | Frey K.,ETH Zurich | And 4 more authors.
Science Translational Medicine | Year: 2013

Acute myeloid leukemia (AML) is a rapidly progressing disease that is accompanied by a strong increase in microvessel density in the bone marrow. This observation prompted us to stain biopsies of AML and acute lymphoid leukemia (ALL) patients with the clinical-stage human monoclonal antibodies F8, L19, and F16 directed against markers of tumor angiogenesis. The analysis revealed that the F8 and F16 antibodies strongly stained 70% of AML and 75% of ALL bone marrow specimens, whereas chloroma biopsies were stained with all three antibodies. Therapy experiments performed in immunocompromised mice bearing human NB4 leukemia with the immunocytokine F8-IL2 [consisting of the F8 antibody fused to human interleukin-2 (IL-2)] mediated a strong inhibition of AML progression. This effect was potentiated by the addition of cytarabine, promoting complete responses in 40% of treated animals. Experiments performed in immunocompetent mice bearing C1498 murine leukemia revealed long-lasting complete tumor eradication in all treated mice. The therapeutic effect of F8-IL2 was mediated by both natural killer cells and CD8+ T cells, whereas CD4 + T cells appeared to be dispensable, as determined in immunodepletion experiments. The treatment of an AML patient with disseminated extramedullary AML manifestations with F16-IL2 (consisting of the F16 antibody fused to human IL-2, currently being tested in phase 2 clinical trials in patients with solid tumors) and low-dose cytarabine showed significant reduction of AML lesions and underlines the translational potential of vascular tumor-targeting antibody-cytokine fusions for the treatment of patients with leukemia. Copyright © 2013, American Association for the Advancement of Science.

Pathak A.,U.S. National Institutes of Health | Seipel K.,University Hospital and University of Berne | Pemov A.,U.S. National Institutes of Health | Dewan R.,U.S. National Institutes of Health | And 13 more authors.
Haematologica | Year: 2016

Familial acute myeloid leukemia is rare and linked to germline mutations in RUNX1, GATA2 or CCAAT/enhancer binding protein-a (CEBPA). We re-evaluated a large family with acute myeloid leukemia originally seen at NIH in 1969. We used whole exome sequencing to study this family, and conducted in silico bioinformatics analysis, protein structural modeling and laboratory experiments to assess the impact of the identified CEBPA Q311P mutation. Unlike most previously identified germline mutations in CEBPA, which were N-terminal frameshift mutations, we identified a novel Q311P variant that was located in the C-terminal bZip domain of C/EBPa. Protein structural modeling suggested that the Q311P mutation alters the ability of the CEBPA dimer to bind DNA. Electrophoretic mobility shift assays showed that the Q311P mu-tant had attenuated binding to DNA, as predicted by the protein modeling. Consistent with these findings, we found that the Q311P mutation has reduced transactivation, consistent with a loss-of-function mutation. From 45 years of follow up, we observed incomplete penetrance (46%) of CEBPA Q311P. This study of a large multi-generational pedigree reveals that a germline mutation in the C-terminal bZip domain can alter the ability of C/EBP-α to bind DNA and reduces transactivation, leading to acute myeloid leukemia. © 2016 Ferrata Storti Foundation.

Gurber S.,University of Basel | Gurber S.,University of Bern | Bielinski-Blattmann D.,University of Basel | Bielinski-Blattmann D.,University of Bern | And 6 more authors.
Journal of Psychosomatic Obstetrics and Gynecology | Year: 2012

Objective: Acute stress reactions (ASR) and postpartum depressive symptoms (PDS) are frequent after childbirth. The present study addresses the change and overlap of ASR and PDS from the 1- to 3-week postpartum and examines the interplay of caregiver support and subjective birth experience with regard to the development of ASR/PDS within a longitudinal path model. Method: A total of 219 mothers completed questionnaires about caregiver support and subjective birth experience (Salmon's Item List) at 48-6-h postpartum. ASR and PDS were measured for 1- and 3-week postpartum. The Impact of Event Scale (IES) was used to assess ASR, and the Edinburgh Postnatal Depression Scale (EPDS) was used to assess PDS. Results: ASR was frequent 1-week postpartum (44.7%) and declined till week 3 (24.8%, p <.001), while the prevalence of PDS was continuous (14.2% week 1; 12.6% week 3; p = .380). Favorable reports of caregiver support were related to better subjective childbirth experience, which was related to lower ASR and PDS (controlled for age, mode of delivery, parity, EDA and duration of childbirth). Conclusion: High quality of intrapartum care and positive birth experiences facilitate psychological adjustment in the first 3-week postpartum. © 2012 Informa UK, Ltd.

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