| 1. |
- Akhmedov, Evgeny, et al.
(author)
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T violation in neutrino oscillations in matter
- 2001
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In: Nuclear Physics B. - : Elsevier Science B.V.. - 0550-3213 .- 1873-1562. ; 608:02-jan, s. 394-422
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Journal article (peer-reviewed)abstract
- We consider the interplay of fundamental and matter-induced T violation effects in neutrino oscillations in matter. After discussing the general features of these effects we derive a simple approximate analytic expression for the T-violating probability asymmetry DeltaP(ab)(T) for three-flavour neutrino oscillations in a matter with an arbitrary density profile in terms of the two-flavour neutrino amplitudes. Explicit examples are given for the cases of a two-layer medium and for the adiabatic Emit in the general case. We then discuss implications of the obtained results for long baseline experiments. We show, in particular, that asymmetric matter effects cannot hinder the determination of the fundamental CP- and T-violating phase delta (CP) in the long baseline experiments as far as the error in this determination is larger than 1% at 99% CL. Since there are no T-violating effects in the two-flavour case, and in the limits of vanishing theta (13) or Deltam(21)(2) the three-flavour neutrino oscillations effectively reduce to the two-flavour ones, studying the T-violating asymmetries ApT ab can in principle provide us with a complementary means of measuring theta (13) and Deltam(21)(2).
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| 2. |
- Bartsch, Yannic C, et al.
(author)
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IgG Fc sialylation is regulated during the germinal center reaction upon immunization with different adjuvants
- 2020
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In: The Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 1097-6825 .- 0091-6749. ; 146:3, s. 652-666
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Journal article (peer-reviewed)abstract
- BACKGROUND: Effector functions of IgG antibodies (Abs) are regulated by their Fc N-glycosylation pattern. IgG Fc glycans that lack galactose and terminal sialic acid residues correlate with the severity of inflammatory (auto)immune disorders and have also been linked to the protection against viral infection and discussed in the context of vaccine-induced protection. In contrast, sialylated IgG Abs have shown immunosuppressive effects.OBJECTIVE: We sought to investigate IgG glycosylation programming during the germinal center (GC) reaction upon immunization of mice with a foreign protein antigen and different adjuvants.METHODS: Mice were analyzed for GC T, B cell and plasma cell responses as well as antigen-specific serum IgG subclass titers and Fc glycosylation patterns.RESULTS: Different adjuvants induce distinct IgG+ GC B cell responses with specific transcriptomes and expression levels of the α2,6-sialyltransferase responsible for IgG sialylation that correspond to distinct serum IgG Fc glycosylation patterns. Low IgG Fc sialylation programming in GC B cells was overall highly dependent on the T follicular helper (TFH) cell-inducing cytokine IL-6, especially induced by water-in-oil adjuvants and Mycobacterium tuberculosis (Mtb). Furthermore, low IgG Fc sialylation programming was dependent on adjuvants that induced IL-27R-dependent IFNγ+ TFH1 cells, IL-6/IL-23-dependent IL-17A+ TFH17 cells and high TFH/T follicular regulatory (TFR) cell ratios. The two latter were here dependent on Mtb and its cord factor.CONCLUSION: These findings on adjuvant-dependent GC responses and IgG glycosylation programming may aid the development of novel vaccination strategies to induce IgG Abs with both high affinity and defined Fc glycosylation patterns.
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| 3. |
- Denk, Stephanie, et al.
(author)
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Complement C5a Functions as a Master Switch for the pH Balance in Neutrophils Exerting Fundamental Immunometabolic Effects
- 2017
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In: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 198:12, s. 4846-4854
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Journal article (peer-reviewed)abstract
- During sepsis, excessive activation of the complement system with generation of the anaphylatoxin C5a results in profound disturbances in crucial neutrophil functions. Moreover, because neutrophil activity is highly dependent on intracellular pH (pH(i)), we propose a direct mechanistic link between complement activation and neutrophil pHi. In this article, we demonstrate that in vitro exposure of human neutrophils to C5a significantly increased pHi by selective activation of the sodium/hydrogen exchanger. Upstream signaling of C5a-mediated intracellular alkalinization was dependent on C5aR1, intracellular calcium, protein kinase C, and calmodulin, and downstream signaling regulated the release of antibacterial myeloperoxidase and lactoferrin. Notably, the pH shift caused by C5a increased the glucose uptake and activated glycolytic flux in neutrophils, resulting in a significant release of lactate. Furthermore, C5a induced acidification of the extracellular micromilieu. In experimental murine sepsis, pHi of blood neutrophils was analogously alkalinized, which could be normalized by C5aR1 inhibition. In the clinical setting of sepsis, neutrophils from patients with septic shock likewise exhibited a significantly increased pHi. These data suggest a novel role for the anaphylatoxin C5a as a master switch of the delicate pHi balance in neutrophils resulting in profound inflammatory and metabolic changes that contribute to hyperlactatemia during sepsis.
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| 4. |
- Ekman, Björn, et al.
(author)
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Sustainable and equitable provision of wheelchairs in low- and middle-income countries : an economic assessment of the models for wheelchair provision in Tajikistan
- 2021
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In: Disability and Rehabilitation: Assistive Technology. - : Informa UK Limited. - 1748-3107 .- 1748-3115. ; 16:8, s. 865-870
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Journal article (peer-reviewed)abstract
- Introduction: Reaching universal coverage of assistive technologies remains a challenge in many low- and middle-income countries. Tajikistan has recently adopted several policies and national strategies to strengthen the rights of people with disabilities and improve the provision of assistive products. However, Tajikistan faces a number of challenges, including ensuring sustainable funding for the provision of wheelchairs in the medium and long term. Methods: This study presents the results of a recent analysis of the economic aspects of the provision of wheelchairs in Tajikistan to inform policy making in other low- and middle-income countries. The study draws on several sources of information, including local cost data, consultations with national and international experts and stakeholders, and reviews of the existing evidence. Results: Countries are advised to adopt an incremental approach to wheelchair provision. In the short term, countries may wish to import wheelchairs to move towards universal coverage. In the medium-to-long term, countries may wish to invest in national capacities for local production. Conclusion: Countries will need to continue implementing strategies to ensure universal access to wheelchairs without the risk of financial hardship for users, regardless of the approach to provision that has been chosen.Implication for Rehabilitation Reaching universal coverage of assistive technologies remains a challenge in many low- and middle-income countries. Countries are advised to adopt an incremental approach to wheelchair provision. The model of wheelchair importation may be a realistic model over the short- to medium-term for many LMICs countries to ensure effective and equitable provision of wheelchairs. In this article, we identify that sufficient funding needs to be allocated to the provision of wheelchairs regardless of the model of provision.
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| 6. |
- Mannes, Marco, et al.
(author)
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Complement and platelets : prothrombotic cell activation requires membrane attack complex-induced release of danger signals
- 2023
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In: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 7:20, s. 6367-6380
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Journal article (peer-reviewed)abstract
- Complement activation in the diseases paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) results in cytolysis and fatal thrombotic events, which are largely refractory to anticoagulation and/or antiplatelet therapy. Anticomplement therapy, however, efficiently prevents thrombotic events in PNH and aHUS, but the underlying mechanisms remain unresolved. We show that complement-mediated hemolysis in whole blood induces platelet activation similarly to activation by adenosine 5 '-diphosphate (ADP). Blockage of C3 or C5 abolished platelet activation. We found that human platelets failed to respond functionally to the anaphylatoxins C3a and C5a. Instead, complement activation did lead to prothrombotic cell activation in the whole blood when membrane attack complex (MAC)-mediated cytolysis occurred. Consequently, we demonstrate that ADP receptor antagonists efficiently inhibited platelet activation, although full complement activation, which causes hemolysis, occurred. By using an established model of mismatched erythrocyte transfusions in rats, we crossvalidated these findings in vivo using the complement inhibitor OmCI and cobra venom factor. Consumptive complement activation in this animal model only led to a thrombotic phenotype when MAC-mediated cytolysis occurred. In conclusion, complement activation only induces substantial prothrombotic cell activation if terminal pathway activation culminates in MAC-mediated release of intracellular ADP. These results explain why anticomplement therapy efficiently prevents thromboembolisms without interfering negatively with hemostasis.
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| 7. |
- Mishra, Satish, et al.
(author)
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National priority assistive product list development in low resource countries : lessons learned from Tajikistan
- 2021
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In: Disability and Rehabilitation: Assistive Technology. - : Informa UK Limited. - 1748-3107 .- 1748-3115. ; 16:8, s. 857-864
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Journal article (peer-reviewed)abstract
- Introduction: Developing a national assistive products list is an important part of an assistive technology policy and requires knowledge of total population need, and product costs and benefits; information is not always readily available in low-income countries. Our experience in Tajikistan of developing a national assistive products list provides guidance for others. Methods: Two hundred people with disabilities participated in a survey on self-reported need for assistive products, user experiences and barriers to access; 12 focus groups, of over 100 people with disabilities and older adults, conducted discussions on assistive technology. Major providers of assistive technology (government, nongovernmental organizations, local producers) were interviewed. Results: These results were presented at a meeting with government and other stakeholders, which led to a consensus on 30 assistive products for the national assistive products list. Conclusion: We identified the essential stakeholders responsible for developing the assistive products list, and discussed the data needed (total need, cost-effectiveness, unmet need, resources, barriers, system analysis) to make an informed decision on which products to include. This work can be used as a case study for developing an assistive products list quickly on a small budget without compromising on a user-centred approach or active participation of stakeholders.Implications for Rehabilitation Incorporating rehabilitation and assistive technology in universal health coverage. Establishing and strengthening networks and partnerships in rehabilitation and building on existing resources (stakeholders, knowledge, government policy documents) to strengthen rehabilitation and assistive technology particularly in low- and middle-income countries. Developing a national assistive products list is an important part of an assistive technology policy. Creating a national assistive products list requires knowledge of population need, and product costs and benefits; information that is not always readily available in low-income countries. In this article, we identify the essential stakeholders responsible for developing the assistive products list and the data needed for informed decisions. We demonstrate that developing an assistive products list can be carried out quickly and on a small budget.
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| 8. |
- Rolfs, Arndt, et al.
(author)
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Acute Cerebrovascular Disease in the Young The Stroke in Young Fabry Patients Study
- 2013
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In: Stroke: a journal of cerebral circulation. - 1524-4628. ; 44:2, s. 340-349
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Journal article (peer-reviewed)abstract
- Background and Purpose-Strokes have especially devastating implications if they occur early in life; however, only limited information exists on the characteristics of acute cerebrovascular disease in young adults. Although risk factors and manifestation of atherosclerosis are commonly associated with stroke in the elderly, recent data suggests different causes for stroke in the young. We initiated the prospective, multinational European study Stroke in Young Fabry Patients (sifap) to characterize a cohort of young stroke patients. Methods-Overall, 5023 patients aged 18 to 55 years with the diagnosis of ischemic stroke (3396), hemorrhagic stroke (271), transient ischemic attack (1071) were enrolled in 15 European countries and 47 centers between April 2007 and January 2010 undergoing a detailed, standardized, clinical, laboratory, and radiological protocol. Results-Median age in the overall cohort was 46 years. Definite Fabry disease was diagnosed in 0.5% (95% confidence interval, 0.4%-0.8%; n=27) of all patients; and probable Fabry disease in additional 18 patients. Males dominated the study population (2962/59%) whereas females outnumbered men (65.3%) among the youngest patients (18-24 years). About 80.5% of the patients had a first stroke. Silent infarcts on magnetic resonance imaging were seen in 20% of patients with a first-ever stroke, and in 11.4% of patients with transient ischemic attack and no history of a previous cerebrovascular event. The most common causes of ischemic stroke were large artery atherosclerosis (18.6%) and dissection (9.9%). Conclusions-Definite Fabry disease occurs in 0.5% and probable Fabry disease in further 0.4% of young stroke patients. Silent infarcts, white matter intensities, and classical risk factors were highly prevalent, emphasizing the need for new early preventive strategies.
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| 9. |
- Tanislav, Christian, et al.
(author)
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Clinically Relevant Depressive Symptoms in Young Stroke Patients - Results of the sifap1 Study
- 2015
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In: Neuroepidemiology. - : S. Karger AG. - 1423-0208 .- 0251-5350. ; 44:1, s. 30-38
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Journal article (peer-reviewed)abstract
- Background: Although post-stroke depression is widely recognized, less is known about depressive symptoms in the acute stage of stroke and especially in young stroke patients. We thus investigated depressive symptoms and their determinants in such a cohort. Methods:The Stroke in Young Fabry Patients study (sifap1) prospectively recruited a large multinational European cohort (n = 5,023) of patients with a cerebrovascular event aged 18-55. For assessing clinically relevant depressive symptoms (CRDS, defined by a BDI-score >= 18) the self-reporting Beck Depression Inventory (BDI) was obtained on inclusion in the study. Associations with baseline parameters, stroke severity (National Institutes of Health Stroke Scale, NIHSS), and brain MRI findings were analyzed. Results: From the 2007 patients with BDI documentation, 202 (10.1%) had CRDS. CRDS were observed more frequently in women (12.6 vs. 8.2% in men, p < 0.001). Patients with CRDS more often had arterial hypertension, diabetes mellitus, and hyperlipidemia than patients without CRDS (hypertension: 58.0 vs. 47.1%, p = 0.017; diabetes mellitus: 17.9 vs. 8.9%, p < 0.001; hyperlipidemia: 40.5 vs. 32.3%, p = 0.012). In the subgroup of patients with ischemic stroke or TIA (n = 1,832) no significant associations between CRDS and cerebral MRI findings such as the presence of acute infarcts (68.1 vs. 65.8%, p = 0.666), old infarctions (63.4 vs. 62.1%, p = 0.725) or white matter hyper-intensities (51.6 vs. 53.7%, p = 0.520) were found. Conclusion: Depressive symptoms were present in 10.1% of young stroke patients in the acute phase, and were related to riskfactors but not to imaging findings. (C) 2015 S. Karger AG, Basel
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| 10. |
- von Sarnowski, Bettina, et al.
(author)
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Lifestyle Risk Factors for Ischemic Stroke and Transient Ischemic Attack in Young Adults in the Stroke in Young Fabry Patients Study
- 2013
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In: Stroke: a journal of cerebral circulation. - 1524-4628. ; 44:1, s. 119-125
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Journal article (peer-reviewed)abstract
- Background and Purpose-Although many stroke patients are young or middle-aged, risk factor profiles in these age groups are poorly understood. Methods-The Stroke in Young Fabry Patients (sifap1) study prospectively recruited a large multinational European cohort of patients with cerebrovascular events aged 18 to 55 years to establish their prevalence of Fabry disease. In a secondary analysis of patients with ischemic stroke or transient ischemic attack, we studied age-and sex-specific prevalences of various risk factors. Results-Among 4467 patients (median age, 47 years; interquartile range, 40-51), the most frequent well-documented and modifiable risk factors were smoking (55.5%), physical inactivity (48.2%), arterial hypertension (46.6%), dyslipidemia (34.9%), and obesity (22.3%). Modifiable less well-documented or potentially modifiable risk factors like high-risk alcohol consumption (33.0%) and short sleep duration (20.6%) were more frequent in men, and migraine (26.5%) was more frequent in women. Women were more often physically inactive, most pronouncedly at ages <35 years (18-24: 38.2%; 25-34: 51.7%), and had high proportions of abdominal obesity at age 25 years or older (74%). Physical inactivity, arterial hypertension, dyslipidemia, obesity, and diabetes mellitus increased with age. Conclusions-In this large European cohort of young patients with acute ischemic cerebrovascular events, modifiable risk factors were highly prevalent, particularly in men and older patients. These data emphasize the need for vigorous primary and secondary prevention measures already in young populations targeting modifiable lifestyle vascular risk factors. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00414583. (Stroke. 2013; 44: 119-125.)
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