Medical Faculty Mannheim

Mannheim, Germany

Medical Faculty Mannheim

Mannheim, Germany
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Bogomolovas J.,Medical Faculty Mannheim | Bogomolovas J.,University of Liverpool | Fleming J.R.,University of Liverpool | Fleming J.R.,University of Konstanz | And 16 more authors.
Open Biology | Year: 2016

Missense single-nucleotide polymorphisms (mSNPs) in titin are emerging as a main causative factor of heart failure. However, distinguishing between benign and disease-causing mSNPs is a substantial challenge. Here, we research the question of whether a single mSNP in a generic domain of titin can affect heart function as a whole and, if so, how. For this, we studied the mSNP T2850I, seemingly linked to arrhythmogenic right ventricular cardiomyopathy (ARVC). We used structural biology, computational simulations and transgenic muscle in vivo methods to track the effect of the mutation from the molecular to the organismal level. The data show that the T2850I exchange is compatible with the domain three-dimensional fold, but that it strongly destabilizes it. Further, it induces a change in the conformational dynamics of the titin chain that alters its reactivity, causing the formation of aberrant interactions in the sarcomere. Echocardiography of knock-in mice indicated a mild diastolic dysfunction arising from increased myocardial stiffness. In conclusion, our data provide evidence that single mSNPs in titin's I-band can alter overall muscle behaviour. Our suggested mechanisms of disease are the development of non-native sarcomeric interactions and titin instability leading to a reduced I-band compliance. However, understanding the T2850I-induced ARVC pathology mechanistically remains a complex problem and will require a deeper understanding of the sarcomeric context of the titin region affected. © 2016 The Authors. Published by the Royal Society.


PubMed | Karolinska Institutet, Ministry of Health, Ministry of Labour, Ministry of Public Health and 153 more.
Type: Journal Article | Journal: Lancet (London, England) | Year: 2014

Remarkable financial and political efforts have been focused on the reduction of child mortality during the past few decades. Timely measurements of levels and trends in under-5 mortality are important to assess progress towards the Millennium Development Goal 4 (MDG 4) target of reduction of child mortality by two thirds from 1990 to 2015, and to identify models of success.We generated updated estimates of child mortality in early neonatal (age 0-6 days), late neonatal (7-28 days), postneonatal (29-364 days), childhood (1-4 years), and under-5 (0-4 years) age groups for 188 countries from 1970 to 2013, with more than 29,000 survey, census, vital registration, and sample registration datapoints. We used Gaussian process regression with adjustments for bias and non-sampling error to synthesise the data for under-5 mortality for each country, and a separate model to estimate mortality for more detailed age groups. We used explanatory mixed effects regression models to assess the association between under-5 mortality and income per person, maternal education, HIV child death rates, secular shifts, and other factors. To quantify the contribution of these different factors and birth numbers to the change in numbers of deaths in under-5 age groups from 1990 to 2013, we used Shapley decomposition. We used estimated rates of change between 2000 and 2013 to construct under-5 mortality rate scenarios out to 2030.We estimated that 63 million (95% UI 60-66) children under-5 died in 2013, a 64% reduction from 176 million (171-181) in 1970. In 2013, child mortality rates ranged from 1525 per 1000 livebirths (1306-1774) in Guinea-Bissau to 23 (18-29) per 1000 in Singapore. The annualised rates of change from 1990 to 2013 ranged from -68% to 01%. 99 of 188 countries, including 43 of 48 countries in sub-Saharan Africa, had faster decreases in child mortality during 2000-13 than during 1990-2000. In 2013, neonatal deaths accounted for 416% of under-5 deaths compared with 374% in 1990. Compared with 1990, in 2013, rising numbers of births, especially in sub-Saharan Africa, led to 14 million more child deaths, and rising income per person and maternal education led to 09 million and 22 million fewer deaths, respectively. Changes in secular trends led to 42 million fewer deaths. Unexplained factors accounted for only -1% of the change in child deaths. In 30 developing countries, decreases since 2000 have been faster than predicted attributable to income, education, and secular shift alone.Only 27 developing countries are expected to achieve MDG 4. Decreases since 2000 in under-5 mortality rates are accelerating in many developing countries, especially in sub-Saharan Africa. The Millennium Declaration and increased development assistance for health might have been a factor in faster decreases in some developing countries. Without further accelerated progress, many countries in west and central Africa will still have high levels of under-5 mortality in 2030.Bill & Melinda Gates Foundation, US Agency for International Development.


PubMed | University of Liverpool, University of Mannheim, Medical Faculty Mannheim, Structural and Computational Biology Unit and 5 more.
Type: Journal Article | Journal: Open biology | Year: 2016

Missense single-nucleotide polymorphisms (mSNPs) in titin are emerging as a main causative factor of heart failure. However, distinguishing between benign and disease-causing mSNPs is a substantial challenge. Here, we research the question of whether a single mSNP in a generic domain of titin can affect heart function as a whole and, if so, how. For this, we studied the mSNP T2850I, seemingly linked to arrhythmogenic right ventricular cardiomyopathy (ARVC). We used structural biology, computational simulations and transgenic muscle in vivo methods to track the effect of the mutation from the molecular to the organismal level. The data show that the T2850I exchange is compatible with the domain three-dimensional fold, but that it strongly destabilizes it. Further, it induces a change in the conformational dynamics of the titin chain that alters its reactivity, causing the formation of aberrant interactions in the sarcomere. Echocardiography of knock-in mice indicated a mild diastolic dysfunction arising from increased myocardial stiffness. In conclusion, our data provide evidence that single mSNPs in titins I-band can alter overall muscle behaviour. Our suggested mechanisms of disease are the development of non-native sarcomeric interactions and titin instability leading to a reduced I-band compliance. However, understanding the T2850I-induced ARVC pathology mechanistically remains a complex problem and will require a deeper understanding of the sarcomeric context of the titin region affected.


Schmid-Bindert G.,Medical Faculty Mannheim | Engel-Riedel W.,Kliniken der Stadt Cologne | Reck M.,Airway Research Center North | Schuette W.,Krankenhaus Martha Maria Halle Doelau | And 10 more authors.
Lung Cancer | Year: 2015

Objectives: We investigated the feasibility of cisplatin or carboplatin combined with pemetrexed as adjuvant treatment in patients with completely resected Stage IB/II Non-Small-Cell Lung Cancer (NSCLC). Materials and methods: Patients in this multicenter, open-label, parallel-group, non-comparative Phase 2 study were randomized (1:1) to pemetrexed (500mg/m2) with either cisplatin (75mg/m2) or carboplatin (AUC5) for 4 cycles of 21 days. The primary endpoint was treatment feasibility (defined as 4 cycles completed with no cycle delay >42 days and ≤2 dose reductions, with a median relative dose intensity (RDI) ≥95% [overall]; and no Grade ≥3 toxicities at the follow-up visit 30 days after last drug administration). Secondary objectives included overall survival (OS) and safety. Results: We randomized 122 patients and treated 118. 71.9% (46/64) of patients in pemetrexed + cisplatin and 88.9% (48/54) in pemetrexed + carboplatin completed 4 cycles (median RDI >97% for all compounds). Neither treatment met the pre-defined feasibility level >60% of patients: 59.4% (95% confidence interval [CI]: 46.4;71.5) pemetrexed + cisplatin; 50.0% (95%CI: 36.1;63.9) in pemetrexed + carboplatin. In a post-hoc analysis considering only safety, both regimens were feasible with 81.3% (95%CI: 69.5;89.9) in pemetrexed + cisplatin and 90.7% (95%CI: 79.7;96.9) in pemetrexed + carboplatin. OS rates for both groups were 82-83% after 3 years and 80-83% after 5 years. Treatment-related Grade ≥3 adverse events (mostly hematological) were experienced by approximately 30% of patients in each group. Conclusion: Although the study did not meet the primary objective, both treatment groups demonstrated good safety-related feasibility and tolerability as adjuvant treatment in patients with completely resected Stage IB/II NSCLC. © 2015 Elsevier Ireland Ltd.


PubMed | Tumorgenetik Bonn Kooperation fur Tumordiagnostik, Lilly Deutschland, Airway Research Center North, Lilly France and 10 more.
Type: Clinical Trial, Phase II | Journal: Lung cancer (Amsterdam, Netherlands) | Year: 2016

We investigated the feasibility of cisplatin or carboplatin combined with pemetrexed as adjuvant treatment in patients with completely resected Stage IB/II Non-Small-Cell Lung Cancer (NSCLC).Patients in this multicenter, open-label, parallel-group, non-comparative Phase 2 study were randomized (1:1) to pemetrexed (500 mg/m(2)) with either cisplatin (75 mg/m(2)) or carboplatin (AUC5) for 4 cycles of 21 days. The primary endpoint was treatment feasibility (defined as 4 cycles completed with no cycle delay >42 days and 2 dose reductions, with a median relative dose intensity (RDI) 95% [overall]; and no Grade 3 toxicities at the follow-up visit 30 days after last drug administration). Secondary objectives included overall survival (OS) and safety.We randomized 122 patients and treated 118. 71.9% (46/64) of patients in pemetrexed+cisplatin and 88.9% (48/54) in pemetrexed+carboplatin completed 4 cycles (median RDI >97% for all compounds). Neither treatment met the pre-defined feasibility level >60% of patients: 59.4% (95% confidence interval [CI]: 46.4;71.5) pemetrexed+cisplatin; 50.0% (95%CI: 36.1;63.9) in pemetrexed+carboplatin. In a post-hoc analysis considering only safety, both regimens were feasible with 81.3% (95%CI: 69.5;89.9) in pemetrexed+cisplatin and 90.7% (95%CI: 79.7;96.9) in pemetrexed+carboplatin. OS rates for both groups were 82-83% after 3 years and 80-83% after 5 years. Treatment-related Grade 3 adverse events (mostly hematological) were experienced by approximately 30% of patients in each group.Although the study did not meet the primary objective, both treatment groups demonstrated good safety-related feasibility and tolerability as adjuvant treatment in patients with completely resected Stage IB/II NSCLC.


Altamura S.,University of Heidelberg | Altamura S.,Molecular Medicine Partnership Unit | Kessler R.,University of Heidelberg | Kessler R.,Molecular Medicine Partnership Unit | And 7 more authors.
Cell Metabolism | Year: 2014

Summary The regulatory axis between the iron hormone hepcidin and its receptor, the iron exporter ferroportin (FPN), is central to iron homeostasis. Mutations preventing hepcidin-mediated degradation of FPN cause systemic iron overload. We have introduced a point mutation (C326S) into the murine Fpn locus, resembling human hereditary hemochromatosis type 4, including elevated plasma iron and ferritin levels, high transferrin saturation, hepatic iron overload, and iron depletion of duodenal enterocytes and reticuloendothelial macrophages. Unlike other mouse models of iron overload, homozygous C326S mice die between 7 and 14 months of age. Pancreatic acinar cells display marked iron accumulation, oxidative damage and degeneration, associated with failure of the exocrine pancreas and severe body weight loss. Rescue experiments reveal iron overload and exocrine pancreatic failure as leading causes of death. This work uncovers the critical importance of the hepcidin-ferroportin regulatory axis for life and unveils the sensitivity of the exocrine pancreas to iron overload. © 2014 Elsevier Inc.


Boll H.,University of Heidelberg | Bag S.,University of Heidelberg | Nolte I.S.,University of Heidelberg | Wilhelm T.,University of Heidelberg | And 4 more authors.
International Journal of Colorectal Disease | Year: 2011

Purpose Models of colon cancer in small rodents are of particular interest as they most closely simulate the development and growth of colonic cancer in humans. Microcomputed tomography has been used for detection of polyps in murine models of colon cancer. The study was performed to evaluate whether a novel high-speed continuous-rotation, single-breath-hold scanning protocol in combination with double-contrasting of the colon can be successfully applied for colonoscopy of live mice at acquisition times of 40 s. Methods C57BL/6JApcMin/+ mice were intubated and ventilated. After double-contrasting the colon with barium and air, mice underwent continuous rotation micro-CT (mean resolution 41×41×53 ?m) during a single-breathhold period of 40 s. Sensitivity to detect colon polyps by four blinded radiologists was analysed. Number and location of polyps were verified in the excised colon. Radiation dose was measured using a thermoluminescence dosimeter placed within the distal colon. Results In six of sevenmice, a total of 12 polypswere detected in the explanted colon (one mouse without polyps). One tumor (8.3%) was located in the proximal third, seven tumors (58.1%) and four tumors (33.2%) were located in the middle and in the distal third of the colon, respectively. Mean tumor volume was 6.5±3.6 mm3. Sensitivity to detect colon polyps was 0.85±0.1. Mean radiation dose was 0.241±0.002 Gy. Conclusion Using a high-speed continuous rotationmicro-CT protocol, double-contrast single-breath-hold colonoscopy in mice is feasible and yields sufficient contrast to visualize the proximal colonic folds and to detect colonic polyps in vivo. © Springer-Verlag 2011.

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