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Sphingolipids are characterized by a broad range of bioactive properties. Particularly, the development of insulin resistance, a major pathophysiological hallmark of Type 2 Diabetes mellitus (T2D), has been linked to ceramide signaling. Since vitamin D supplementation may slow down T2D progression by improving glucose concentrations and insulin sensitivity, we investigated whether vitamin D supplementation impacts on plasma sphingolipid levels in T2D patients. Thus, plasma samples of 59 patients with non-insulin-requiring T2D from a placebo-controlled, randomized, and double-blind study were retrospectively analyzed. Once per week, patients received either 20 drops of Vigantol oil, corresponding to a daily dose of 1904 IU/d vitamin D (verum: n = 31), or a placebo oil consisting of medium chain triglycerides (placebo: n = 28). Blood samples were taken from all of the participants at three different time points: 1) at the beginning of the study (baseline), 2) after 6 months supplementation, and 3) after an additional 6 months of follow-up. Plasma sphingolipids were measured by high-performance liquid chromatography tandem mass spectrometry. At baseline and 6 months follow-up, no significant differences in plasma sphingolipid species were detected between the placebo and verum groups. After 6 months, vitamin D supplementation significantly enhanced plasma C18dihydroceramide (dhCer; N-stearoyl-sphinganine (d18:0/18:0)) and C18ceramide (Cer; N-stearoyl-sphingosine (d18:1/18:0)) levels were observed in the verum group compared to the placebo group. This was accompanied by significantly higher 25-hydroxyvitamin D3 (25(OH)D3) blood levels in patients receiving vitamin D compared to the placebo group. Taken together, vitamin D supplementation induced changes of the C18 chain-length-specific dhCer and Cer plasma levels in patients with T2D. The regulation of sphingolipid signaling by vitamin D may thus unravel a novel mechanism by which vitamin D can influence glucose utilization and insulin action. Whether this acts favorably or unfavorably for the progression of T2D needs to be clarified.
Background: Signal transduction pathways are important cellular processes to maintain the cell’s integrity. Their imbalance can cause severe pathologies. As signal transduction pathways feature complex regulations, they form intertwined networks. Mathematical models aim to capture their regulatory logic and allow an unbiased analysis of robustness and vulnerability of the signaling network. Pathway detection is yet a challenge for the analysis of signaling networks in the field of systems biology. A rigorous mathematical formalism is lacking to identify all possible signal flows in a network model.
Results: In this paper, we introduce the concept of Manatee invariants for the analysis of signal transduction networks. We present an algorithm for the characterization of the combinatorial diversity of signal flows, e.g., from signal reception to cellular response. We demonstrate the concept for a small model of the TNFR1-mediated NF- κB signaling pathway. Manatee invariants reveal all possible signal flows in the network. Further, we show the application of Manatee invariants for in silico knockout experiments. Here, we illustrate the biological relevance of the concept.
Conclusions: The proposed mathematical framework reveals the entire variety of signal flows in models of signaling systems, including cyclic regulations. Thereby, Manatee invariants allow for the analysis of robustness and vulnerability of signaling networks. The application to further analyses such as for in silico knockout was shown. The new framework of Manatee invariants contributes to an advanced examination of signaling systems.
Anticoagulation with warfarin and rivaroxaban ameliorates experimental autoimmune encephalomyelitis
(2017)
Background: In multiple sclerosis, coagulation factors have been shown to modulate inflammation. In this translational study, we investigated whether long-term anticoagulation with warfarin or rivaroxaban has beneficial effects on the course of autoimmune experimental encephalomyelitis (EAE).
Methods: Female SJL/J mice treated with anticoagulants namely warfarin or rivaroxaban were immunized with PLP139–151. Stable anticoagulation was maintained throughout the entire experiment. Mice without anticoagulation treated with the vehicle only were used as controls. The neurological deficit was recorded during the course of EAE, and histopathological analyses of inflammatory lesions were performed.
Results: In preventive settings, both treatment with warfarin and rivaroxaban reduced the maximum EAE score as compared to the control group and led to a reduction of inflammatory lesions in the spinal cord. In contrast, therapeutic treatment with warfarin had no beneficial effects on the clinical course of EAE. Signs of intraparenchymal hemorrhage at the site of the inflammatory lesions were not observed.
Conclusion: We developed long-term anticoagulation models that allowed exploring the course of EAE under warfarin and rivaroxaban treatment. We found a mild preventive effect of both warfarin and rivaroxaban on neurological deficits and local inflammation, indicating a modulation of the disease induction by anticoagulation.
Maintenance therapy after allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) is conceptually attractive to prevent relapse, but has been hampered by the limited number of suitable anti-leukemic agents. The deacetylase inhibitor (DACi) panobinostat demonstrated moderate anti-leukemic activity in a small subset of patients with advanced AML and high-risk MDS in phase I/II trials.1, 2 It also displays immunomodulatory activity3 that may enhance leukemia-specific cytotoxicity4 and mitigate graft versus host disease (GvHD), but conversely could impair T- and NK cell function.5, 6 We conducted this open-label, multi-center phase I/II trial (NCT01451268) to assess the feasibility and preliminary efficacy of prolonged prophylactic administration of panobinostat after HSCT for AML or MDS. The study protocol was approved by an independent ethics committee and conducted in compliance with the Declaration of Helsinki. All patients provided written informed consent. ...
BACKGROUND: Ketone bodies are known to substitute for glucose as brain fuel when glucose availability is low. Ketogenic diets have been described as neuroprotective. Similar data have been reported for triheptanoin, a fatty oil and anaplerotic compound. In this study, we monitored the changes of energy metabolites in liver, blood, and brain after transient brain ischemia to test for ketone body formation induced by experimental stroke.
METHODS AND RESULTS: Mice were fed a standard carbohydrate-rich diet or 2 fat-rich diets, 1 enriched in triheptanoin and 1 in soybean oil. Stroke was induced in mice by middle cerebral artery occlusion for 90 minutes, followed by reperfusion. Mice were sacrificed, and blood plasma and liver and brain homogenates were obtained. In 1 experiment, microdialysis was performed. Metabolites (eg glucose, β-hydroxybutyrate, citrate, succinate) were determined by gas chromatography-mass spectrometry. After 90 minutes of brain ischemia, β-hydroxybutyrate levels were dramatically increased in liver, blood, and brain microdialysate and brain homogenate, but only in mice fed fat-rich diets. Glucose levels were changed in the opposite manner in blood and brain. Reperfusion decreased β-hydroxybutyrate and increased glucose within 60 minutes. Stroke-induced ketogenesis was blocked by propranolol, a β-receptor antagonist. Citrate and succinate were moderately increased by fat-rich diets and unchanged after stroke.
CONCLUSIONS: We conclude that brain ischemia induces the formation of β-hydroxybutyrate (ketogenesis) in the liver and the consumption of β-hydroxybutyrate in the brain. This effect seems to be mediated by β-adrenergic receptors.
In the article by Chun et al, "The Impact of Cryoballoon Versus Radiofrequency Ablation for Paroxysmal Atrial Fibrillation on Healthcare Utilization and Costs: An Economic Analysis From the FIRE AND ICE Trial" which published online July 27, 2017, and appeared in the August 2017 issue of the journal (J Am Heart Assoc. 2017;6:e006043. DOI: 10.1161/JAHA.117.006043.), there were errors found in Figure 1. On page 5, Figure 1, "United Kingdom" and "United States" were misspelled.
Background: This study sought to assess payer costs following cryoballoon or radiofrequency current (RFC) catheter ablation of paroxysmal atrial fibrillation in the randomized FIRE AND ICE trial.
Methods and Results: A trial period analysis of healthcare costs evaluated the impact of ablation modality (cryoballoon versus RFC) on differences in resource use and associated payer costs. Analyses were based on repeat interventions, rehospitalizations, and cardioversions during the trial, with unit costs based on 3 national healthcare systems (Germany [€], the United Kingdom [£], and the United States [Embedded Image]). Total payer costs were calculated by applying standard unit costs to hospital stays, using International Classification of Diseases, 10th Revision diagnoses and procedure codes that were mapped to country‐specific diagnosis‐related groups. Patients (N=750) randomized 1:1 to cryoballoon (n=374) or RFC (n=376) ablation were followed for a mean of 1.5 years. Resource use was lower in the cryoballoon than the RFC group (205 hospitalizations and/or interventions in 122 patients versus 268 events in 154 patients). The cost differences per patient in mean total payer costs during follow‐up were €640, £364, and Embedded Image925 in favor of cryoballoon ablation (P=0.012, 0.013, and 0.016, respectively). This resulted in trial period total cost savings of €245 000, £140 000, and Embedded Image355 000.
Conclusions: When compared with RFC ablation, cryoballoon ablation was associated with a reduction in resource use and payer costs. In all 3 national healthcare systems analyzed, this reduction resulted in substantial trial period cost savings, primarily attributable to fewer repeat ablations and a reduction in cardiovascular rehospitalizations with cryoballoon ablation.
Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Identifier: NCT01490814.
Objective: Worldwide, the respiratory syncytial virus (RSV) represents the predominant viral agent causing bronchiolitis and pneumonia in children. To conduct research and tackle existing healthcare disparities, RSV-related research activities around the globe need to be described. Hence, we assessed the associated scientific output (represented by research articles) by geographical, chronological and socioeconomic criteria and analysed the authors publishing in the field by gender. Also, the 15 most cited articles and the most prolific journals were identified for RSV research.
Design: Retrospective, descriptive study.
Setting: The NewQIS (New Quality and Quantity Indices in Science) platform was employed to identify RSV-related articles published in the Web of Science until 2013. We performed a numerical analysis of all articles, and examined citation-based aspects (eg, citation rates); results were visualised by density equalising mapping tools.
Results: We identified 4600 RSV-related articles. The USA led the field; US-American authors published 2139 articles (46.5%% of all identified articles), which have been cited 83 000 times. When output was related to socioeconomic benchmarks such as gross domestic product or Research and Development expenditures, Guinea-Bissau, The Gambia and Chile were ranked in leading positions. A total of 614 articles on RSV (13.34% of all articles) were attributed to scientific collaborations. These were primarily established between high-income countries. The gender analysis indicated that male scientists dominated in all countries except Brazil.
Conclusions: The majority of RSV-related research articles originated from high-income countries whereas developing nations showed only minimal publication productivity and were barely part of any collaborative networks. Hence, research capacity in these nations should be increased in order to assist in addressing inequities in resource allocation and the clinical burden of RSV in these countries.
Background: Imbalances in female career promotion are a key factor of gender disparities at the workplace. They may lead to stress and stress-related diseases including burnout, depression or cardiovascular diseases. Since this problem cannot be generalized and varies between different fields, new approaches are needed to assess and describe the magnitude of the problem in single fields of work.
Methods: To construct a new index, operating figures of female and male medical students were collected for Germany in a period over 15 years and their progression throughout their studies towards specialization and academic chair positions. By the use of different female to male ratios (f:m), we constructed an index that describes the extend by which women can ascent in their academic career by using the field of academic medicine as an example.
Results: A medical student f:m ratio of 1.54 (52,366 female vs. 34,010 male) was found for Germany in 2013. In 1998, this f:m ratio was 0.999. In the same year (2013), the OB/GYN hospital specialists’ f:m ratio was 1.566 (3347 female vs. 2137 male physicians) and 0.577 (516 female vs 894 male physicians) for ENT hospital specialists, respectively. The f:m ratios concerning chairs of OB/GYN and ENT were 0.105 and 0.1, respectively. Then an index was generated that incorporated these operating figures with the student f:m ratio as denominator and the chair f:m ratio as numerator while the hospital specialist f:m ratio served as a corrector in the numerator in order to adjust to the attraction of a given field to female physicians. As a result, the index was 0.044 for OB/GYN and 0.113 for ENT instead of ideally ~1 in a completely gender harmonized situation.
Conclusion: In summary, a new index to describe female career advancement was established for academic medicine. By the use of this index, different academic and medical fields can now be compared to each other and future benchmarks could be proposed. Also, country differences may be examined using the proposed index and the success of specific funding programs.
Zika virus (ZIKV) infection, a public health emergency of international concern, has recently been confirmed in Indonesia. However, to date, there has been no study to assess how prepared healthcare workers in Indonesia are to confront this emerging infectious disease. The aim of this study was to assess the attitudes of medical doctors in Indonesia towards ZIKV infection and its associated explanatory variables. A cross-sectional self-administered online survey was conducted from 3 May to 3 June 2016 in Aceh province, Indonesia. A pre-tested questionnaire was used to collect data on doctors’ attitudes towards ZIKV infection and a range of explanatory variables (basic demographic data, professional characteristics, workplace characteristics and facilities, and medical experience related to ZIKV infection). Associations between attitude and explanatory variables were assessed using multiple-step logistic regression. We received 631 responses, 424 (67.19%) of which were included in the final analysis. Approximately 64% (271) of doctors had a poor attitude towards ZIKV infection. Experience considering ZIKV infection as a differential diagnosis and attendance at a national conference was associated with a good attitude, with odds ratios (OR) of 3.93 (95% confidence interval [CI]: 1.15–13.49) and 1.69 (95% CI: 1.03–2.76), respectively. Unexpectedly, doctors who had attended an international conference and those working at places that had molecular diagnostic (polymerase chain reaction based testing) facilities had lower odds of having a good attitude (OR: 0.35 [95% CI: 0.15–0.84] and 0.42 [95% CI: 0.19–0.95], respectively). In conclusion, the attitude towards ZIKV infection is relatively poor among doctors in Aceh. Therefore, strategies for enhancing their capacity to respond to ZIKV infection are needed. The survey concept and tools were well accepted by the participants of this study, suggesting that this rapid assessment could be rolled out across the Indonesian archipelago and elsewhere to identify and regionally differentiate unmet needs of disease and outbreak preparedness.