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Kipfer S.,Kantonsspital Olten
Multiple Sclerosis Journal | Year: 2014

Predilection sites for infratentorial multiple sclerosis lesions are well known and frequently involve the fasciculus longitudinalis medialis leading to classical internuclear ophthalmoplegia. We report a very rare oculomotor disorder due to a demyelinating central nervous system (CNS) lesion in the medial part of the lower pontine tegmentum. A 36-year-old man presented with sudden onset of blurred vision. Clinically there was limited eye adduction and abduction to either side, which corresponds to bilateral horizontal gaze palsy. Brain magnetic resonance imaging (MRI) showed a demyelinating CNS lesion affecting the fasciculus longitudinalis medialis, abducens nuclei or abducens fibres in the medial part of the lower pontine tegmentum. Furthermore there were six further demyelinating white matter lesions fulfilling all Barkhof criteria for multiple sclerosis. Demyelinating CNS lesions causing isolated bilateral horizontal gaze palsy are exceptional and usually associated with further focal neurological deficits, which was not the case in the presenting patient. This is a unique video report of isolated bilateral horizontal gaze palsy as the initial manifestation of demyelinating CNS disease, which lead to definite diagnosis of relapsing remitting multiple sclerosis. © The Author(s) 2014.


Marcocci C.,University of Pisa | Kahaly G.J.,Gutenberg University Medical Center | Krassas G.E.,Panagia General Hospital | Bartalena L.,University of Insubria | And 7 more authors.
New England Journal of Medicine | Year: 2011

BACKGROUND: Oxygen free radicals and cytokines play a pathogenic role in Graves' orbitopathy. METHODS: We carried out a randomized, double-blind, placebo-controlled trial to determine the effect of selenium (an antioxidant agent) or pentoxifylline (an antiinflammatory agent) in 159 patients with mild Graves' orbitopathy. The patients were given selenium (100 μg twice daily), pentoxifylline (600 mg twice daily), or placebo (twice daily) orally for 6 months and were then followed for 6 months after treatment was withdrawn. Primary outcomes at 6 months were evaluated by means of an overall ophthalmic assessment, conducted by an ophthalmologist who was unaware of the treatment assignments, and a Graves' orbitopathy-specific quality-of-life questionnaire, completed by the patient. Secondary outcomes were evaluated with the use of a Clinical Activity Score and a diplopia score. RESULTS: At the 6-month evaluation, treatment with selenium, but not with pentoxifylline, was associated with an improved quality of life (P<0.001) and less eye involvement (P = 0.01) and slowed the progression of Graves' orbitopathy (P = 0.01), as compared with placebo. The Clinical Activity Score decreased in all groups, but the change was significantly greater in the selenium-treated patients. Exploratory evaluations at 12 months confirmed the results seen at 6 months. Two patients assigned to placebo and one assigned to pentoxifylline required immunosuppressive therapy for deterioration in their condition. No adverse events were evident with selenium, whereas pentoxifylline was associated with frequent gastrointestinal problems. CONCLUSIONS: Selenium administration significantly improved quality of life, reduced ocular involvement, and slowed progression of the disease in patients with mild Graves' orbitopathy. (Funded by the University of Pisa and the Italian Ministry for Education, University and Research; EUGOGO Netherlands Trial Register number, NTR524.) Copyright © 2011 Massachusetts Medical Society.


Renner C.,University of Zürich | Zinzani P.L.,University of Bologna | Gressin R.,Joseph Fourier University | Klingbiel D.,Coordinating Center | And 14 more authors.
Haematologica | Year: 2012

Background Mantle cell lymphoma accounts for 6% of all B-cell lymphomas and is generally incurable. It is characterized by the translocation t(11;14) leading to cyclin D1 over-expression. Cyclin D1 is downstream of the mammalian target of rapamycin threonine kinase and can be effectively blocked by mammalian target of rapamycin inhibitors. We set out to examine the single agent activity of the orally available mammalian target of rapamycin inhibitor everolimus in a prospective, multicenter trial in patients with relapsed or refractory mantle cell lymphoma (NCT00516412). Design and Methods Eligible patients who had received a maximum of three prior lines of chemotherapy were given everolimus 10 mg for 28 days (one cycle) for a total of six cycles or until disease progression. The primary endpoint was the best objective response. Adverse reactions, progression-free survival and molecular response were secondary endpoints. Results Thirty-six patients (35 evaluable) were enrolled and treatment was generally well tolerated with Common Terminology Criteria grade ≥3 adverse events (>5%) including anemia (11%), thrombocytopenia (11%) and neutropenia (8%). The overall response rate was 20% (95% CI: 8-37%) with two complete remissions and five partial responses; 49% of the patients had stable disease. At a median follow-up of 6 months, the median progression-free survival was 5.5 months (95% CI: 2.8-8.2) overall and 17.0 (6.4-23.3) months for 18 patients who received six or more cycles of treatment. Three patients achieved a lasting complete molecular response, as assessed by polymerase chain reaction analysis of peripheral blood. Conclusions Everolimus as a single agent is well tolerated and has anti-lymphoma activity in relapsed or refractory mantle cell lymphoma. Further studies of everolimus in combination with chemotherapy or as a single agent for maintenance treatment are warranted. (Clinicaltrials.gov identifier: NCT00516412). ©2012 Ferrata Storti Foundation.


Challa T.D.,ETH Zurich | Straub L.G.,ETH Zurich | Balaz M.,ETH Zurich | Kiehlmann E.,ETH Zurich | And 6 more authors.
Diabetes | Year: 2015

There are many known adipokines differentially secreted from the different adipose depots; however, their paracrine and autocrine effects on de novo adipocyte formation are not fully understood. By developing a coculture method of preadipocytes with primary subcutaneous and visceral adipocytes or tissue explants, we could show that the total secretome inhibited preadipocyte differentiation. Using a proteomics approach with fractionated secretome samples, we were able to identify a spectrum of factors that either positively or negatively affected adipocyte formation. Among the secreted factors, Slc27a1, Vim, Cp, and Ecm1 promoted adipocyte differentiation, whereas Got2, Cpq, interleukin-1 receptor-like 1/ST2-IL-33, Sparc, and Lgals3bp decreased adipocyte differentiation. In human subcutaneous adipocytes of lean subjects, obese subjects, and obese subjects with type 2 diabetes, Vim and Slc27a1 expression was negatively correlated with adipocyte size and BMI and positively correlated with insulin sensitivity, while Sparc and Got2 showed the opposite trend. Furthermore, we demonstrate that Slc27a1 was increased upon weight loss in morbidly obese patients, while Sparc expression was reduced. Taken together, our findings identify adipokines that regulate adipocyte differentiation through positive or negative paracrine and autocrine feedback loop mechanisms, which could potentially affect whole-body energy metabolism. © 2015 by the American Diabetes Association.


Background: The operative treatment of thumb carpometacarpal joint arthritis may include resection-suspension-interposition-arthroplasty. Although quite a technically demanding procedure, a suspension arthroplasty using a strip of the flexor carpi radialis tendon is quite a popular technique. Other techniques, which use the abductor pollicis longus (APL) tendon, is also widely accepted. Purpose: The aim of this randomized, prospective study was to compare the results of these 2 procedures 8 months postoperatively. Patients and Methods: From May 2005 to December 2006 a total of 55 operations in 53 patients with symptomatic Grade III or IV 1 st CMC joint arthritis were identified and recruited into the study. They were then randomized to one of the 2 groups (APL vs. FCR). Patients were assessed preoperatively, and then immediately and 8 months postoperatively. Both, subjective parameters (Visual Analog Scale and DASH-Score) and functional parameters (maximum radial abduction, opposition and pinch- and key grip strength) where recorded. Additionally, the trapezial space was assessed radiographically postoperatively. Results: After 8 months both groups had comparable subjective results (APL-group: VAS 2.3 points, DASH 24 points; FCR-group: VAS 1.9 points, DASH 20 points) as well as functional results (APL-group: radial abduction 55.3, key-grip strength 8.1kg, pinch-grip strength 5.5kg; FCR-group: radial abduction 55.8, key-grip strength 7.2kg, pinch-grip strength 4.7kg). Radiologically both groups showed an approximate 50% reduction in the height of the trapezial space. Conclusion: In resection-suspension-interposition-arthroplasty of the 1 st CMC joint, similar results can be obtained using the technically less demanding APL-procedure when compared with the FCR-technique 8 months postoperatively. © Georg Thieme Verlag KG Stuttgart New York.


Reichlin T.,University of Basel | Irfan A.,University of Basel | Twerenbold R.,University of Basel | Reiter M.,University of Basel | And 13 more authors.
Circulation | Year: 2011

BACKGROUND-: Current guidelines for the diagnosis of acute myocardial infarction (AMI), among other criteria, also require a rise and/or fall in cardiac troponin (cTn) levels. It is unknown whether absolute or relative changes in cTn have higher diagnostic accuracy and should therefore be preferred. METHODS AND RESULTS-: In a prospective, observational, multicenter study, we analyzed the diagnostic accuracy of absolute (Δ) and relative (Δ%) changes in cTn in 836 patients presenting to the emergency department with symptoms suggestive of AMI. Blood samples for the determination of high-sensitive cTn T and cTn I ultra were collected at presentation and after 1 and 2 hours in a blinded fashion. The final diagnosis was adjudicated by 2 independent cardiologists. The area under the receiver operating characteristic curve for diagnosing AMI was significantly higher for 2-hour absolute (Δ) versus 2-hour relative (Δ%) cTn changes (area under the receiver operating characteristic curve [95% confidence interval], high-sensitivity cTn T: 0.95 [0.92 to 0.98] versus 0.76 [0.70 to 0.83], P<0.001; cTn I ultra: 0.95 [0.91 to 0.99] versus 0.72 [0.66 to 0.79], P<0.001). The receiver operating characteristic curve-derived cutoff value for 2-hour absolute (Δ) change was 0.007 μg/L for high-sensitivity cTn T and 0.020 μg/L for cTn I ultra (both cutoff levels are half of the 99th percentile of the respective cTn assay). Absolute changes were superior to relative changes in patients with both low and elevated baseline cTn levels. CONCLUSIONS-: Absolute changes of cTn levels have a significantly higher diagnostic accuracy for AMI than relative changes, and seem therefore to be the preferred criteria to distinguish AMI from other causes of cTn elevations. © 2011 American Heart Association, Inc.


Potocki M.,University of Basel | Reichlin T.,University of Basel | Reichlin T.,Harvard University | Thalmann S.,University of Basel | And 14 more authors.
Heart | Year: 2012

Objective: The early diagnosis of acute myocardial infarction (AMI) can be particularly challenging in patients with known coronary artery disease (CAD) due to pre-existing ECG changes and chronic increases in cardiac troponin (cTn) levels. Design: Of 1170 consecutive patients presenting with symptoms suggestive of AMI, 433 (37%) with pre-existing CAD were analysed in a prospective multicentre study and the diagnostic and prognostic impact of copeptin in combination with either fourth generation cardiac troponin T (cTnT) or high-sensitivity cTnT (hs-cTnT) was evaluated. Results: AMI was the final diagnosis in 78 patients with pre-existing CAD (18%). Copeptin was significantly higher in patients with AMI than in those without (26 pmol/l (IQR 9-71) vs 7 pmol/l (IQR 4e16), p<0.001). The diagnostic accuracy for AMI as quantified by the area under the receiver operating characteristic curve (AUC) was significantly higher for the combination of copeptin and cTnT than for cTnT alone (0.94 vs 0.86, p<0.001). The combination of copeptin and hs-cTnT (0.94) was trending to superiority compared with hs-cTnT alone (0.92, p=0.11). The combination of copeptin and the cTn assays was able to improve the negative predictive value up to 99.5% to rule out AMI. Copeptin was a strong and independent predictor of 1-year mortality (HR 4.18-4.63). Irrespective of cTn levels, patients with low levels of copeptin had an excellent prognosis compared with patients with raised levels of both copeptin and cTn (360-day mortality 2.8-3.6% vs 23.1-33.8%, p<0.001). Conclusion: In patients with pre-existing CAD, copeptin significantly improves the diagnostic accuracy if used in addition to cTnT, but only trended to superiority compared with hs-cTnT alone. Copeptin provides independent prognostic information, largely by overcoming the challenging interpretation of mild increases in hs-cTnT. Clinical trial registration number: ClinicalTrials Gov number NCT00470587.


Schaub N.,University of Basel | Reichlin T.,University of Basel | Twerenbold R.,University of Basel | Reiter M.,University of Basel | And 9 more authors.
Clinical Chemistry | Year: 2012

BACKGROUND: Growth differentiation factor-15 (GDF- 15) is a stress-responsive marker that might aid in the early diagnosis and risk stratification of patients with suspected acute myocardial infarction (AMI). METHODS: In a prospective, international multicenter study, GDF-15, high-sensitivity cardiac troponin T (hs-cTnT), and B-type natriuretic peptide (BNP) were measured in 646 unselected patients presenting to the emergency department with acute chest pain. The final diagnosis was adjudicated by 2 independent cardiologists. The primary prognostic end point was all-cause mortality during a median follow-up of 26 months. RESULTS: AMI was the adjudicated final diagnosis in 115 patients (18%). GDF-15 concentrations at presentation were significantly higher in AMI patients compared to patients with other diagnoses. The diagnostic accuracy of GDF-15 at presentation for the diagnosis of AMI as quantified by the area under the ROC curve (AUC) was lower (AUC 0.69, 95% CI 0.64-0.74) compared to hs-cTnT (AUC 0.96, 95% CI 0.94-0.98, P <0.001) and BNP (AUC 0.74, 95% CI 0.69-0.80, P =0.02). A total of 55 deaths occurred during follow-up. GDF-15 predicted all-cause mortality independently of and more accurately than hs-cTnT [AUC 0.85 (95% CI 0.81- 0.90) vs 0.77 (95% CI 0.72- 0.83), P=0.002] and BNP (AUC 0.75, 95% CI 0.68-0.82, P = 0.007). Net reclassification improvement was 0.15 (P = 0.01), and the absolute integrated discrimination improvement was 0.07, yielding a relative integrated discrimination improvement of 0.36 (P = 0.07). CONCLUSIONS: GDF-15 predicts all-cause mortality in unselected patients with acute chest pain independently of and more accurately than hs-cTnT and BNP. However, GDF-15 does not seem to help in the early diagnosis of AMI. © 2011 American Association for Clinical Chemistry.


Simon D.,University of Bern | Straumann A.,Kantonsspital Olten | Dahinden C.,University of Bern | Simon H.-U.,University of Bern
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2013

Background Eosinophilic esophagitis (EoE) is often associated with atopic airway and skin diseases. More than 80% of EoE patients are sensitized to aero- and/or food allergens. Immunoglobulin (Ig)E-mediated immune responses to microbes have been reported to be deleterious in connection with atopic diseases. Aim The aim of this study was to obtain a comprehensive overview about the sensitization spectrum of adult EoE patients. Methods IgE in sera of 35 patients with active EoE were analyzed for reactivity to Candida albicans, as well as to a panel of recombinant and purified natural allergen components, using a microarray. Results IgE sensitization to Candida albicans was found in 43% of EoE patients. More than 80% of EoE patients were sensitized to aeroallergens and 22% to food-specific allergen components, whereas 69% of the patients exhibited specific IgE to cross-reactive allergens. Among the latter, profilins were identified as most frequent IgE cross-reactive allergen components. Interestingly, dysphagia, the main symptom of adult EoE patients following rice and/or bread ingestion, was associated with sensitization to cross-reactive allergens such as profilins, pathogenesis-related (PR) 10 and lipid transfer proteins (LTP). Intolerance toward meat rarely correlated with sensitization to animal food allergens. Conclusion Candida albicans and cross-reactive plant allergen components, in particular profilins, were identified as frequent sensitizers in adult EoE patients. Specific elimination therapies are suggested to reveal their actual roles in the pathogenesis of EoE. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


PubMed | Kantonsspital Olten, Viollier AG, Kantonsspital St. Gallen and University of Basel
Type: | Journal: BMC cancer | Year: 2016

Lymph node (LN) involvement represents the strongest prognostic factor in colon cancer patients. The objective of this prospective study was to assess the prognostic impact of isolated tumor cells (ITC, defined as cell deposits 0.2 mm) in loco-regional LN of stage I & II colon cancer patients.Seventy-four stage I & II colon cancer patients were prospectively enrolled in the present study. LN at high risk of harboring ITC were identified via an in vivo sentinel lymph node procedure and analyzed with multilevel sectioning, conventional H&E and immunohistochemical CK-19 staining. The impact of ITC on survival was assessed using Cox regression analyses.Median follow-up was 4.6 years. ITC were detected in locoregional lymph nodes of 23 patients (31.1%). The presence of ITC was associated with a significantly worse disease-free survival (hazard ratio = 4.73, p = 0.005). Similarly, ITC were associated with significantly worse overall survival (hazard ratio = 3.50, p = 0.043).This study provides compelling evidence that ITC in stage I & II colon cancer patients are associated with significantly worse disease-free and overall survival. Based on these data, the presence of ITC should be classified as a high risk factor in stage I & II colon cancer patients who might benefit from adjuvant chemotherapy.

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