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41.
Liana Ghazarian Julien Diana Lucie Beaudoin P?r G. Larsson Raj K. Puri Nico van Rooijen Malin Flodstr?m-Tullberg Agnès Lehuen 《Diabetes》2013,62(11):3785-3796
Invariant natural killer T (iNKT) cells belong to the innate immune system and exercise a dual role as potent regulators of autoimmunity and participate in responses against different pathogens. They have been shown to prevent type 1 diabetes development and to promote antiviral responses. Many studies in the implication of environmental factors on the etiology of type 1 diabetes have suggested a link between enteroviral infections and the development of this disease. This study of the pancreatropic enterovirus Coxsackievirus B4 (CVB4) shows that although infection accelerated type 1 diabetes development in a subset of proinsulin 2–deficient NOD mice, the activation of iNKT cells by a specific agonist, α-galactosylceramide, at the time of infection inhibited the disease. Diabetes development was associated with the infiltration of pancreatic islets by inflammatory macrophages, producing high levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α and activation of anti-islet T cells. On the contrary, macrophages infiltrating the islets after CVB4 infection and iNKT-cell stimulation expressed a number of suppressive enzymes, among which indoleamine 2,3-dioxygenase was sufficient to inhibit anti-islet T-cell response and to prevent diabetes. This study highlights the critical interaction between virus and the immune system in the acceleration or prevention of type 1 diabetes.Type 1 diabetes is characterized by the destruction of pancreatic islet β-cells by autoreactive CD4 and CD8 T cells, leading to low insulin production and incapacity to regulate blood glucose levels (1). Despite numerous studies, the etiology of type 1 diabetes remains elusive. Besides genetics (2–4), environmental factors such as viral infections have been suggested as triggers of type 1 diabetes (5–7). Most striking of these infections are the type B Coxsackieviruses belonging to the enterovirus genus whose genome and anti-Coxsackievirus antibodies were detected more frequently in the blood of recently diagnosed patients compared with healthy controls (8,9). Besides, enteroviral RNA or enteroviral particles were directly detected in the pancreas of type 1 diabetic patients, whereas they were undetectable in the pancreas of healthy donors (9,10). In a mouse model of type 1 diabetes, Serreze et al. (11) showed that diabetes can develop rapidly after Coxsackievirus B4 (CVB4) infection if mice had an advanced age and sufficient insulitis. Others have reported that inefficient islet β-cell response, viral dose, and replication rate as well as a lack of islet neogenesis could also promote accelerated diabetes development after CVB4 infection (12–14).Natural killer T (NKT) cells are CD1d-restricted, nonconventional T cells recognizing self and exogenous glycolipids. Most NKT cells express an invariant T-cell receptor α chain, Vα14-Jα18 (Vα14) in mice and Vα24-Jα18 in humans, and are named invariant NKT (iNKT) cells. They can promptly secrete copious amounts of interferon-γ (IFN-γ) and interleukin (IL)-4 and provide maturation signals to dendritic cells (DCs) and lymphocytes, thereby contributing to both innate and acquired immunity (15,16). iNKT cells are potent regulatory cells that can inhibit autoimmunity and promote immune responses against pathogens (1,17). Diabetes can be prevented in NOD mice by increasing iNKT cell numbers and by iNKT-cell stimulation with exogenous ligands such as α-galactosylceramide (αGalCer) (15,18,19). NOD mice protected from diabetes by iNKT cells have weak T helper 1 anti-islet β-cell responses (20). Indeed, iNKT cells can impair the differentiation of anti-islet CD4 and CD8 T cells, which become hyporesponsive or anergic (21). Contrary to their suppressive role in type 1 diabetes, iNKT cells can enhance immune responses to pathogens such as parasites, bacteria, and viruses (22,23).Our previous studies conducted in a murine model of type 1 diabetes with lymphocytic choriomeningitis virus infection revealed that iNKT cells could promote systemic antiviral CD8 T-cell responses while inhibiting deleterious anti-islet T-cell responses, thereby preventing type 1 diabetes (24,25). In the present study, we investigated the role of iNKT cells after CVB4 infection, revealing that diabetes development following CVB4 infection is associated with the infiltration of inflammatory macrophages into the pancreatic islets with subsequent activation of anti-islet T cells. However, the activation of iNKT cells during CVB4 infection results in the infiltration of suppressive macrophages into pancreatic islets. Indoleamine 2,3-dioxygenase (IDO) expressed by these macrophages was critical for the inhibition of diabetes development. 相似文献
42.
Castrillon EE Cairns BE Ernberg M Wang K Sessle BJ Arendt-Nielsen L Svensson P 《Journal of orofacial pain》2007,21(3):216-224
AIMS: To test the hypothesis that local injection of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine would significantly attenuate glutamate-evoked masseter mechanical sensitization and muscle pain in healthy young women either taking oral contraceptives (W+OC) or not taking oral contraceptives (W-OC). METHODS: Experimental pain was evoked in 47 healthy female subjects (W+OC, n=25; W-OC, n=22) by 2 injections of glutamate (0.2 mL, 1 mol/L) into the masseter muscle. A first injection of glutamate alone was followed by a second injection, 35 minutes later, of glutamate combined with ketamine (0, 1, or 10 mmol/L). Evoked pain intensity was scored on a 10-cm electronic visual analog scale (VAS). Distribution of perceived pain was drawn on a lateral view of the face (pain drawing). Masseter muscle pressure pain thresholds (PPT) and pressure-pain tolerances (PPTOL) were determined bilaterally before and at regular time intervals after injections. Analyses of variance (ANOVA) were used to test the data. RESULTS: There were no main effects of ketamine on any of the VAS pain parameters or on the pain drawing (ANOVAs: P > .055). Furthermore, there were no differences in PPT, PPTOL, VAS peak pain, duration, overall VAS pain, or pain drawing when W-OC were compared with W+OC (ANOVAs: P > .087). Repeated injection of glutamate alone significantly decreased PPT and PPTOL (ANOVAs: P < .001); however, this effect was not significantly attenuated by ketamine. CONCLUSIONS: Peripherally administered ketamine had no effect on glutamate-evoked masseter muscle pain and sensitization in healthy young women, which contrasts with recent observations in healthy young men. Further studies will be needed to reveal the mechanisms that underlie this apparent sex-related difference in ketamine-mediated analgesia. 相似文献
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47.
Gordon LJ Steffen W Jönsson BF Folke C Falkenmark M Johannessen A 《Proceedings of the National Academy of Sciences of the United States of America》2005,102(21):7612-7617
It is well documented that human modification of the hydrological cycle has profoundly affected the flow of liquid water across the Earth's land surface. Alteration of water vapor flows through land-use changes has received comparatively less attention, despite compelling evidence that such alteration can influence the functioning of the Earth System. We show that deforestation is as large a driving force as irrigation in terms of changes in the hydrological cycle. Deforestation has decreased global vapor flows from land by 4% (3,000 km(3)/yr), a decrease that is quantitatively as large as the increased vapor flow caused by irrigation (2,600 km(3)/yr). Although the net change in global vapor flows is close to zero, the spatial distributions of deforestation and irrigation are different, leading to major regional transformations of vapor-flow patterns. We analyze these changes in the light of future land-use-change projections that suggest widespread deforestation in sub-Saharan Africa and intensification of agricultural production in the Asian monsoon region. Furthermore, significant modification of vapor flows in the lands around the Indian Ocean basin will increase the risk for changes in the behavior of the Asian monsoon system. This analysis suggests that the need to increase food production in one region may affect the capability to increase food production in another. At the scale of the Earth as a whole, our results emphasize the need for climate models to take land-use change, in both land cover and irrigation, into account. 相似文献
48.
Maagaard A Holberg-Petersen M Løvgården G Holm M Pettersen FO Kvale D 《The Journal of infectious diseases》2008,198(10):1474-1481
49.
Bina Patel Shrimali Jessica Luginbuhl Christina Malin Rebecca Flournoy Anita Siegel 《Maternal and child health journal》2014,18(2):373-379
Too many children are born into poverty, often living in disinvested communities without adequate opportunities to be healthy and thrive. Two complementary frameworks—health equity and life course—propose new approaches to these challenges. Health equity strategies seek to improve community conditions that influence health. The life course perspective focuses on key developmental periods that can shift a person’s trajectory over the life course, and highlights the importance of ensuring that children have supports in place that set them up for long-term success and health. Applying these frameworks, the Alameda County Public Health Department launched the Building Blocks Collaborative (BBC), a countywide multi-sector initiative to engage community partners in improving neighborhood conditions in low-income communities, with a focus on young children. A broad cross-section of stakeholders, called to action by the state of racial and economic inequities in children’s health, came together to launch the BBC and develop a Bill of Rights that highlights the diverse factors that contribute to children’s health. BBC partners then began working together to improve community conditions by learning and sharing ideas and strategies, and incubating new collaborative projects. Supportive health department leadership; dedicated staff; shared vision and ownership; a flexible partnership structure; and broad collective goals that build on partners’ strengths and priorities have been critical to the growth of the BBC. Next steps include institutionalizing BBC projects into existing infrastructure, ongoing partner engagement, and continued project innovation—to achieve a common vision that all babies have the best start in life. 相似文献
50.
Elsa Brånvall Åsa Rangert Derolf Eva Johansson Malin Hultcrantz Karin Bergmark Magnus Björkholm 《Annals of hematology》2014,93(9):1491-1498
Acute myeloid leukemia (AML) survival rates in younger patients have improved considerably since the 1970s. In order to evaluate the impact of AML and its treatment on fertility and family situation in adult long-term survivors, we used the Swedish population-based registries to identify 161 adult patients diagnosed with AML within the Leukemia Group of Middle Sweden (LGMS) 1973–2003, who survived for more than 5 years and were alive in 2010. Ninety-eight patients (61 %) completed a questionnaire including items on reproductive concerns, family situation, and infertility-related distress. After excluding women >45 years and/or postmenopausal women and men >55 years, 22 women and 38 men were included in the final analysis. Nine of the women (41 %) tried to conceive after treatment, but only three succeeded. Five (83 %) of the unwillingly childless women reported “a moderate” or “a lot” of distress caused by this. Among men in the same age group, all six who wanted children after treatment succeeded. None of the men 46–55 years old cryopreserved their sperm or tried to father a child. Among patients who wanted children after AML treatment, 46 % of the women and 40 % of the younger men reported that they were not, or not fully, informed about fertility-related issues. In contrast, among men 46–55 years, none reported they would have wanted more information. Infertility among young female AML survivors thus remains an important clinical issue, and there is a need for improved clinical counseling and education in this area. 相似文献