A novel cellular pathway of antigen presentation and CD4 T cell activation in vivo

Dendritic cell activation of CD4 T cells in the lymph node draining a site of infection or vaccination is widely considered the central event in initiating adaptive immunity. The accepted dogma is that this occurs by stimulating local activation and antigen acquisition by dendritic cells, with subsequent lymph node migration, however the generalizability of this mechanism is unclear. Here we show that in some circumstances antigen can bypass the injection site inflammatory response, draining freely and rapidly to the lymph nodes where it interacts with subcapsular sinus (SCS) macrophages resulting in their death. Debris from these dying SCS macrophages is internalized by monocytes recruited from the circulation. This coordinated response leads to antigen presentation by monocytes and interactions with naïve CD4 T cells that can drive the initiation of T cell and B cell responses. These studies demonstrate an entirely novel pathway leading to initiation of adaptive immune responses in vivo

Impact of geocoding methods on associations between long-term exposure to urban air pollution and lung function

Background: Errors in address geocodes may affect estimates of the effects of air pollution on health.Objective: We investigated the impact of four geocoding techniques on the association between urban air pollution estimated with a fine-scale (10 m × 10 m) dispersion model and lung function in adults.Methods: We measured forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC) in 354 adult residents of Grenoble, France, who were participants in two well-characterized studies, the Epidemiological Study on the Genetics and Environment on Asthma (EGEA) and the European Community Respiratory Health Survey (ECRHS). Home addresses were geocoded using individual building matching as the reference approach and three spatial interpolation approaches. We used a dispersion model to estimate mean PM10 and nitrogen dioxide concentrations at each participant's address during the 12 months preceding their lung function measurements. Associations between exposures and lung function parameters were adjusted for individual confounders and same-day exposure to air pollutants. The geocoding techniques were compared with regard to geographical distances between coordinates, exposure estimates, and associations between the estimated exposures and health effects.Results: Median distances between coordinates estimated using the building matching and the three interpolation techniques were 26.4, 27.9, and 35.6 m. Compared with exposure estimates based on building matching, PM10 concentrations based on the three interpolation techniques tended to be overestimated. When building matching was used to estimate exposures, a one-interquartile range increase in PM10 (3.0 μg/m3) was associated with a 3.72-point decrease in FVC% predicted (95% CI: -0.56, -6.88) and a 3.86-point decrease in FEV1% predicted (95% CI: -0.14, -3.24). The magnitude of associations decreased when other geocoding approaches were used [e.g., for FVC% predicted -2.81 (95% CI: -0.26, -5.35) using NavTEQ or 2.08 (95% CI -4.63, 0.47, p = 0.11) using Google Maps].Conclusions: Our findings suggest that the choice of geocoding technique may influence estimated health effects when air pollution exposures are estimated using a fine-scale exposure model.Citation: Jacquemin B, Lepeule J, Boudier A, Arnould C, Benmerad M, Chappaz C, Ferran J, Kauffmann F, Morelli X, Pin I, Pison C, Rios I, Temam S, Künzli N, Slama R, Siroux V. 2013. Impact of geocoding methods on associations between long-term exposure to urban air pollution and lung function. Environ Health Perspect 121:1054-1060; http://dx.doi.org/10.1289/ehp.1206016

Purine 5’-ribonucleotide-glutamate hybrids as potential tools to investigate the mechanism of umami taste reception

Umami taste is elicited predominantly by the presence of L-glutamate and purine 5’-ribonucleotides, in particular guanosine and inosine 5’-monophosphates. A significant peculiarity of umami compounds is their capacity to interact synergistically.[1] A possible explanation of such phenomenon at a molecular level is that both L-glutamate and ribonucleotides may interact simultaneously with the extracellular “Venus flytrap” (VFT) domain of the umami receptor (a heteromeric complex of two class C G protein-coupled receptors, T1R1 and T1R3), but at different sites.[2] Starting from this model, we reasoned that hybrid compounds, containing the two umami moieties covalently connected through flexible linkers of variable length, could be able to reach both umami receptor sites through a single molecule, thus giving a further insight into the mechanism of synergism. Molecular Dynamics simulations performed on the homology model of the VFT domain suggested that a chain of at least eight carbon atoms is requested to allow the interaction of both glutamate and 5’-ribonucleotide with their respective binding sites. We present here the synthesis of purine 5’-ribonucleotide-glutamate hybrids 3 and 4, characterized by long flexible linkers consisting of eight and ten carbon atoms, respectively, as well as of hybrids 1 and 2, characterized by shorter chains and used as negative controls. Key step in the synthetic route was the activation of the 2-position of the purine ring as a 2-bromo derivative, followed by substitution with the proper diamines. All umami hybrids were tested with the functionally expressed T1R1/T1R3 umami receptor in a cell-based assay.[3] References [1] W. Wang, X. Zhou, Y. Liu, Trends Anal. Chem. 2020, 127, 115876 [2] F. Zhang, B. Klebansky, R. M. Fine, H. Xu, A. Pronin, H. Liu, C. Tachdjian, X. Li, PNAS 2008, 105, 20930-20934 [3] B. Suess, A. Brockhoff, A. Degenhardt, S. Billmayer, W.Meyerhof, T. Hofmann, J. Agric. Food Chem. 2014, 62, 11429−11440Umami taste is elicited predominantly by the presence of l-glutamate and purine 5’-ribonucleotides, in particular guanosine and inosine 5’-monophosphates. A significant peculiarity of umami compounds is their capacity to interact synergistically.[1] A possible explanation of such phenomenon at a molecular level is that both l-glutamate and ribonucleotides may interact simultaneously with the extracellular “Venus flytrap” (VFT) domain of the umami receptor (a heteromeric complex of two class C G protein-coupled receptors, T1R1 and T1R3), but at different sites.[2] Starting from this model, we reasoned that hybrid compounds, containing the two umami moieties covalently connected through flexible linkers of variable length, could be able to reach both umami receptor sites through a single molecule, thus giving a further insight into the mechanism of synergism. Molecular Dynamics simulations performed on the homology model of the VFT domain suggested that a chain of at least eight carbon atoms is requested to allow the interaction of both glutamate and 5’-ribonucleotide with their respective binding sites. We present here the synthesis of purine 5’-ribonucleotide-glutamate hybrids 3 and 4, characterized by long flexible linkers consisting of eight and ten carbon atoms, respectively, as well as of hybrids 1 and 2, characterized by shorter chains and used as negative controls. Key step in the synthetic route was the activation of the 2-position of the purine ring as a 2-bromo derivative, followed by substitution with the proper diamines. All umami hybrids were tested with the functionally expressed T1R1/T1R3 umami receptor in a cell-based assay.[3] References [1] W. Wang, X. Zhou, Y. Liu, Trends Anal. Chem. 2020, 127, 115876 [2] F. Zhang, B. Klebansky, R. M. Fine, H. Xu, A. Pronin, H. Liu, C. Tachdjian, X. Li, PNAS 2008, 105, 20930-20934 [3] B. Suess, A. Brockhoff, A. Degenhardt, S. Billmayer, W.Meyerhof, T. Hofmann, J. Agric. Food Chem. 2014, 62, 11429−1144

Purine 5’‐Ribonucleotide‐L‐Glutamate Hybrids As Potential Tools To Investigate The Mechanism Of Umami Taste Reception

Umami taste is elicited predominantly by monosodium glutamate (MSG) and purine 5’-ribonucleotides, in particular guanosine and inosine 5’-monophosphates (GMP and IMP). A significant peculiarity of umami compounds is their capacity to interact synergistically. A possible explanation of such phenomenon is that both L-glutamate and ribonucleotides may interact simultaneously with the “Venus flytrap” domain of T1R1/T1R3 umami receptor, but at different sites. Starting from this model, we reasoned that hybrid compounds, containing the two umami moieties covalently connected through flexible linkers of variable length, could be able to reach both umami receptor sites through a single molecule, thus giving an insight into the mechanism of synergism. MD simulations suggested that a chain of at least eight carbon atoms is requested to allow the interaction of both L-glutamate and 5’-ribonucleotide with their respective binding sites. We report here the synthesis of such hybrids starting from 2’,3’-O-isopropylidene-5’-O-t-butyldimethylsilylguanosin

Arterial oxygenation and acid–base status before and during oxygen supplementation in captive European bison (Bison bonasus) immobilized with etorphine-acepromazine-xylazine

Chemical immobilization of captive European bison (Bison bonasus) is often required for veterinary care, transportation, or husbandry practices playing an important role in conservation breeding and reintroduction of the species. We evaluated the efficiency and physiological effects of an etorphine-acepromazine-xylazine combination with supplemental oxygen in 39 captive European bison. Animals were darted with a combination of 1.4 mg of etorphine, 4.5 mg of acepromazine, and 20 mg of xylazine per 100 kg based on estimated body mass. Arterial blood was sampled on average 20 min after recumbency and again 19 min later and analyzed immediately with a portable i-STAT analyzer. Simultaneously, heart rate, respiratory rate, and rectal temperature were recorded. Intranasal oxygen was started after the first sampling at a flow rate of 10 mL.kg−1.min−1 of estimated body mass until the end of the procedure. The initial mean partial pressure of oxygen (PaO2) was 49.7 mmHg with 32 out of 35 sampled bison presenting with hypoxemia. We observed decreased respiratory rates and pH and mild hypercapnia consistent with a mild respiratory acidosis. After oxygen supplementation hypoxemia was resolved in 21 out of 32 bison, but respiratory acidosis was accentuated. Bison immobilized with a lower initial drug dose required supplementary injections during the procedure. We observed that lower mean rectal temperatures during the immobilization event were significantly associated with longer recovery times. For three bison, minor regurgitation was documented. No mortality or morbidity related to the immobilizations were reported for at least 2 months following the procedure. Based on our findings, we recommend a dose of 0.015 mg.kg−1 etorphine, 0.049 mg.kg−1 acepromazine, and 0.22 mg.kg−1 xylazine. This dose reduced the need for supplemental injections to obtain a sufficient level of immobilization for routine management and husbandry procedures in captive European bison. Nevertheless, this drug combination is associated with development of marked hypoxemia, mild respiratory acidosis, and a small risk of regurgitation. Oxygen supplementation is strongly recommended when using this protocol.publishedVersio

Arterial oxygenation and acid-base status before and during oxygen supplementation in captive European bison (Bison bonasus) immobilized with etorphine-acepromazine-xylazine

Chemical immobilization of captive European bison (Bison bonasus) is often required for veterinary care, transportation, or husbandry practices playing an important role in conservation breeding and reintroduction of the species. We evaluated the efficiency and physiological effects of an etorphine-acepromazine-xylazine combination with supplemental oxygen in 39 captive European bison. Animals were darted with a combination of 1.4 mg of etorphine, 4.5 mg of acepromazine, and 20 mg of xylazine per 100 kg based on estimated body mass. Arterial blood was sampled on average 20 min after recumbency and again 19 min later and analyzed immediately with a portable i-STAT analyzer. Simultaneously, heart rate, respiratory rate, and rectal temperature were recorded. Intranasal oxygen was started after the first sampling at a flow rate of 10 mL.kg(-1).min(-1) of estimated body mass until the end of the procedure. The initial mean partial pressure of oxygen (PaO2) was 49.7 mmHg with 32 out of 35 sampled bison presenting with hypoxemia. We observed decreased respiratory rates and pH and mild hypercapnia consistent with a mild respiratory acidosis. After oxygen supplementation hypoxemia was resolved in 21 out of 32 bison, but respiratory acidosis was accentuated. Bison immobilized with a lower initial drug dose required supplementary injections during the procedure. We observed that lower mean rectal temperatures during the immobilization event were significantly associated with longer recovery times. For three bison, minor regurgitation was documented. No mortality or morbidity related to the immobilizations were reported for at least 2 months following the procedure. Based on our findings, we recommend a dose of 0.015 mg.kg(-1) etorphine, 0.049 mg.kg(-1) acepromazine, and 0.22 mg.kg(-1) xylazine. This dose reduced the need for supplemental injections to obtain a sufficient level of immobilization for routine management and husbandry procedures in captive European bison. Nevertheless, this drug combination is associated with development of marked hypoxemia, mild respiratory acidosis, and a small risk of regurgitation. Oxygen supplementation is strongly recommended when using this protocol

Improving effective contraception uptake through provision of bridging contraception within community pharmacies:findings from The Bridge-it Study process evaluation

OBJECTIVE: To present process evaluation results from the Bridge-it Study, a pragmatic cluster randomised cross-over trial to improve effective contraception uptake through provision of the progestogen only pill (POP) plus sexual and reproductive health (SRH) clinic rapid-access to women presenting to community pharmacies for emergency contraception (EC). RESEARCH DESIGN AND METHODS: A multimethod process evaluation was conducted to assess intervention implementation, mechanisms of change and contextual factors. Data were gathered from screening logs (n=599), observations of pharmacist training, analysis of data from 4-month follow-up questionnaires (n=406), monitoring of contemporaneous events and qualitative interviews with 22 pharmacists, 5 SRH clinical staff and 36 study participants in three participating UK sites in Lothian, Tayside and London. RESULTS: The intervention was largely delivered as intended and was acceptable. Pharmacists’, SRH clinical staff and participants’ accounts highlighted that providing a supply of POP with EC from the pharmacy as routine practice may have positive impacts on contraceptive practices in the short term, and potentially longer term. Key mechanisms of change included ease of access, increased awareness of contraception and services, and greater motivation and perceptions of self-efficacy. Few participants took up the offer to attend an SRH service (rapid-access component), and existing barriers within the SRH context were apparent (eg, lack of staff). Participant accounts highlight persistent barriers to accessing and using routine effective contraception remain. CONCLUSIONS: Implementation appeared to be acceptable and feasible, highlighting the potential for provision of POP within EC consultations as routine practice in community pharmacies. However, lack of engagement with the rapid access component of the intervention and existing barriers within the SRH context suggest that signposting to SRH services may be sufficient. Wider implementation should consider ways to address key implementation challenges to increase effectiveness and sustainability, and to overcome persistent barriers to accessing and using effective contraception. TRIAL REGISTRATION NUMBER: ISRCTN70616901

Klimadata til fugtsimuleringer:referenceår

​Denne rapport omhandler udarbejdelse af et referenceår til anvendelse ved varme- og fugtsimuleringer (hygrotermiske simuleringer). Referenceåret er udarbejdet på baggrund af historiske data for perioden 2001-2019 for Sjælsmark, suppleret med nedbørs data fra Holbæk flyveplads, Hillerød SØ, Store Hareskov og Gørløse for perioden 2001-2010

Role of selective V2-receptor-antagonism in septic shock: a randomized, controlled, experimental study

ABSTRACT : INTRODUCTION : V2-receptor (V2R) stimulation potentially aggravates sepsis-induced vasodilation, fluid accumulation and microvascular thrombosis. Therefore, the present study was performed to determine the effects of a first-line therapy with the selective V2R-antagonist (Propionyl1-D-Tyr(Et)2-Val4-Abu6-Arg8,9)-Vasopressin on cardiopulmonary hemodynamics and organ function vs. the mixed V1aR/V2R-agonist arginine vasopressin (AVP) or placebo in an established ovine model of septic shock. METHODS : After the onset of septic shock, chronically instrumented sheep were randomly assigned to receive first-line treatment with the selective V2R-antagonist (1 g/kg per hour), AVP (0.05 g/kg per hour), or normal saline (placebo, each n = 7). In all groups, open-label norepinephrine was additionally titrated up to 1 g/kg per minute to maintain mean arterial pressure at 70 ± 5 mmHg, if necessary. RESULTS : Compared to AVP- and placebo-treated animals, the selective V2R-antagonist stabilized cardiopulmonary hemodynamics (mean arterial and pulmonary artery pressure, cardiac index) as effectively and increased intravascular volume as suggested by higher cardiac filling pressures. Furthermore, left ventricular stroke work index was higher in the V2R-antagonist group than in the AVP group. Notably, metabolic (pH, base excess, lactate concentrations), liver (transaminases, bilirubin) and renal (creatinine and blood urea nitrogen plasma levels, urinary output, creatinine clearance) dysfunctions were attenuated by the V2R-antagonist when compared with AVP and placebo. The onset of septic shock was associated with an increase in AVP plasma levels as compared to baseline in all groups. Whereas AVP plasma levels remained constant in the placebo group, infusion of AVP increased AVP plasma levels up to 149 ± 21 pg/mL. Notably, treatment with the selective V2R-antagonist led to a significant decrease of AVP plasma levels as compared to shock time (P < 0.001) and to both other groups (P < 0.05 vs. placebo; P < 0.001 vs. AVP). Immunohistochemical analyses of lung tissue revealed higher hemeoxygenase-1 (vs. placebo) and lower 3-nitrotyrosine concentrations (vs. AVP) in the V2R-antagonist group. In addition, the selective V2R-antagonist slightly prolonged survival (14 ± 1 hour) when compared to AVP (11 ± 1 hour, P = 0.007) and placebo (11 ± 1 hour, P = 0.025). CONCLUSIONS : Selective V2R-antagonism may represent an innovative therapeutic approach to attenuate multiple organ dysfunction in early septic shock

Provision of the progestogen-only pill by community pharmacies as bridging contraception for women receiving emergency contraception:the Bridge-it RCT

Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 27. See the NIHR Journals Library website for further project information.Peer reviewedPublisher PD