Radiolocalisation and imaging of stably HPLAP-transfected MO4 tumours with monoclonal antibodies and fragments.

Immunotargeting of PLAP-expressing tumours was studied for two radioiodinated, highly specific anti-PLAP monoclonal antibodies, 7E8 and 17E3, differing 10-fold in affinity, as well as for 7E8 F(ab')2 fragments. An anti-CEA monoclonal antibody or anti-CD3 F(ab')2 fragments were used as controls. Specific and non-specific targeting was examined in nude mice simultaneously grafted with PLAP-positive tumours derived from MO4 1-4 cells, and CEA-positive tumours, derived from 5583-S cells. Results indicated that (1) MO4 1-4 tumours, with a stable expression of PLAP on the plasma membrane, represent a useful new in vivo model for immunodirected tumour targeting; (2) differences in antibody affinity for PLAP in vitro are not reflected in antibody avidity for tumour cells in vivo; and (3) excellent selective and specific localisation of the PLAP-positive tumours is achieved when 7E8 F(ab')2 fragments are used. The high tumour/blood ratios (10.7 +/- 3.9 at 46 h after injection) were due to a much faster blood clearance of 7E8 F(ab')2 fragments. At this time point, the mean tumour/non-tumour tissue ratio was as high as 34.5, and the mean specific localisation index was 29.0. As expected, the F(ab')2 fragments provided high tumour imaging efficiency on gamma camera recording. These data imply important potentials of the PLAP/anti-PLAP system for immunolocalisation and therapy in patients, but also emphasise that in vitro criteria alone are not reflected in in vivo tumour localisation capacities of antibodies

Ferulic acid-4-O-sulfate rather than ferulic acid relaxes arteries and lowers blood pressure in mice

Consumption of foods rich in ferulic acid (FA) such as wholegrain cereals, or FA precursors such as chlorogenic acids in coffee, is inversely correlated with risk of cardiovascular disease and type 2 diabetes. As a result of digestion and phase II metabolism in the gut and liver, FA is converted predominantly into ferulic acid-4-O-sulfate (FA-sul), an abundant plasma metabolite. Although FA-sul may be the main metabolite, very little has been reported regarding its bioactivities. We have therefore compared the ex vivo vasorelaxing effect of FA and FA-sul (10−7 - 3.10−5 M) on isolated mouse arteries mounted in tissue myographs. FA-sul, but not FA, elicited a concentration-dependent vasorelaxation of saphenous and femoral arteries and aortae. The FA-sul mediated vasorelaxation was blunted by 1H- [1, 2, 4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a soluble guanylate cyclase (sGC) inhibitor. The role of sGC was confirmed in femoral arteries isolated from sGCα1(−/−) knockout mice. Furthermore, 4-aminopyridine, a specific inhibitor of voltage-dependent potassium channels, significantly decreased FA-sul mediated effects. In anesthetized mice, intravenous injection of FA-sul decreased mean arterial pressure, whereas FA had no effect, confirming the results obtained ex vivo. FA-sul is probably one of the major metabolites accounting for the blood pressure-lowering effects associated with FA consumption

Clinical, Cellular, and Molecular Effects of Corticosteroids on the Response to Intradermal Lipopolysaccharide Administration in Healthy Volunteers

The intradermal lipopolysaccharide (LPS) challenge in healthy volunteers has proven to be a valuable tool to study local inflammation in vivo. In the current study the inhibitory effects of oral and topical corticosteroid treatment on intradermal LPS responses were evaluated to benchmark the challenge for future investigational drugs. Twenty-four healthy male volunteers received a two-and-a-half-day twice daily (b.i.d.) pretreatment with topical clobetasol propionate 0.05% and six healthy volunteers received a two-and-a-half-day b.i.d. pretreatment with oral prednisolone at 0.25 mg/kg body weight per administration. Participants received one injection regimen of either 0, 2, or 4 intradermal LPS injections (5 ng LPS in 50 µL 0.9% sodium chloride solution). The LPS response was evaluated by noninvasive (perfusion, skin temperature, and erythema) and invasive assessments (cellular and cytokine responses) in suction blister exudate. Both corticosteroids significantly suppressed the clinical inflammatory response (erythema P = 0.0001 for clobetasol and P = 0.0016 for prednisolone; heat P = 0.0245 for clobetasol, perfusion P < 0.0001 for clobetasol and P = 0.0036 for prednisolone). Clobetasol also significantly reduced the number of monocytes subsets, dendritic cells, natural killer cells, and T cells in blister exudate. A similar effect was observed for prednisolone. No relevant corticosteroid effects were observed on the cytokine response to LPS. We successfully demonstrated that the anti-inflammatory effects of corticosteroids can be detected using our intradermal LPS challenge model, validating it for evaluation of future investigational drugs, as an initial assessment of the anti-inflammatory effects of such compounds in a minimally invasive manner

The breadth of primary care: a systematic literature review of its core dimensions

Background: Even though there is general agreement that primary care is the linchpin of effective health care delivery, to date no efforts have been made to systematically review the scientific evidence supporting this supposition. The aim of this study was to examine the breadth of primary care by identifying its core dimensions and to assess the evidence for their interrelations and their relevance to outcomes at (primary) health system level. Methods: A systematic review of the primary care literature was carried out, restricted to English language journals reporting original research or systematic reviews. Studies published between 2003 and July 2008 were searched in MEDLINE, Embase, Cochrane Library, CINAHL, King's Fund Database, IDEAS Database, and EconLit. Results: Eighty-five studies were identified. This review was able to provide insight in the complexity of primary care as a multidimensional system, by identifying ten core dimensions that constitute a primary care system. The structure of a primary care system consists of three dimensions: 1. governance; 2. economic conditions; and 3. workforce development. The primary care process is determined by four dimensions: 4. access; 5. continuity of care; 6. coordination of care; and 7. comprehensiveness of care. The outcome of a primary care system includes three dimensions: 8. quality of care; 9. efficiency care; and 10. equity in health. There is a considerable evidence base showing that primary care contributes through its dimensions to overall health system performance and health. Conclusions: A primary care system can be defined and approached as a multidimensional system contributing to overall health system performance and health

Risk adjustment and risk selection on the sickness fund insurance market in five European countries

From the mid-1990s citizens in Belgium, Germany, Israel, the Netherlands and Switzerland have a guaranteed periodic choice among risk-bearing sickness funds, who are responsible for purchasing their care or providing them with medical care. The rationale of this arrangement is to stimulate the sickness funds to improve efficiency in health care production and to respond to consumers’ preferences. To achieve solidarity, all five countries have implemented a system of risk-adjusted premium subsidies (or risk equalization across risk groups), along with strict regulation of the consumers’ direct premium contribution to their sickness fund. In this article we present a conceptual framework for understanding risk adjustment and comparing the systems in the five countries. We conclude that in the case of imperfect risk adjustment—as is the case in all five countries in the year 2001—the sickness funds have financial incentives for risk selection, which may threaten solidarity, efficiency, quality of care and consumer satisfaction. We expect that without substantial improvements in the risk adjustment formulae, risk selection will increase in all five countries. The issue is particularly serious in Germany and Switzerland. We strongly recommend therefore that policy makers in the five countries give top priority to the improvement of the system of risk adjustment. That would enhance solidarity, cost-control, efficiency and client satisfaction in a system of competing, risk-bearing sickness funds

Risk adjustment and risk selection on the sickness fund insurance market in five European countries

From the mid-1990s citizens in Belgium, Germany, Israel, the Netherlands and Switzerland have a guaranteed periodic choice among risk-bearing sickness funds, who are responsible for purchasing their care or providing them with medical care. The rationale of this arrangement is to stimulate the sickness funds to improve efficiency in health care production and to respond to consumers' preferences. To achieve solidarity, all five countries have implemented a system of risk-adjusted premium subsidies (or risk equalization across risk groups), along with strict regulation of the consumers' direct premium contribution to their sickness fund. In this article we present a conceptual framework for understanding risk adjustment and comparing the systems in the five countries. We conclude that in the case of imperfect risk adjustment-as is the case in all five countries in the year 2001-the sickness funds have financial incentives for risk selection, which may threaten solidarity, efficiency, quality of care and consumer satisfaction. We expect that without substantial improvements in the risk adjustment formulae, risk selection will increase in all five countries. The issue is particularly serious in Germany and Switzerland. We strongly recommend therefore that policy makers in the five countries give top priority to the improvement of the system of risk adjustment. That would enhance solidarity, cost-control, efficiency and client satisfaction in a system of competing, risk-bearing sickness funds. [Authors]]]> Health Care Reform ; Insurance Selection Bias ; Managed Competition ; National Health Programs ; Risk Adjustment eng oai:serval.unil.ch:BIB_C1056E4EB1E1 2022-05-07T01:26:22Z openaire documents urnserval <oai_dc:dc xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:oai_dc="http://www.openarchives.org/OAI/2.0/oai_dc/" xsi:schemaLocation="http://www.openarchives.org/OAI/2.0/oai_dc/ http://www.openarchives.org/OAI/2.0/oai_dc.xsd"> https://serval.unil.ch/notice/serval:BIB_C1056E4EB1E1 Accurate Estimation of Running Temporal Parameters Using Foot-Worn Inertial Sensors info:doi:10.3389/fphys.2018.00610 info:eu-repo/semantics/altIdentifier/doi/10.3389/fphys.2018.00610 info:eu-repo/semantics/altIdentifier/pmid/29946263 Falbriard, M. Meyer, F. Mariani, B. Millet, G.P. Aminian, K. info:eu-repo/semantics/article article 2018 Frontiers in physiology, vol. 9, pp. NA info:eu-repo/semantics/altIdentifier/pissn/1664-042X urn:issn:1664-042X <![CDATA[The aim of this study was to assess the performance of different kinematic features measured by foot-worn inertial sensors for detecting running gait temporal events (e.g., initial contact, terminal contact) in order to estimate inner-stride phases duration (e.g., contact time, flight time, swing time, step time). Forty-one healthy adults ran multiple trials on an instrumented treadmill while wearing one inertial measurement unit on the dorsum of each foot. Different algorithms for the detection of initial contact and terminal contact were proposed, evaluated and compared with a reference-threshold on the vertical ground reaction force. The minimum of the pitch angular velocity within the first and second half of a mid-swing to mid-swing cycle were identified as the most precise features for initial and terminal contact detection with an inter-trial median ± IQR precision of 2 ± 1 ms and 4 ± 2 ms respectively. Using these initial and terminal contact features, this study showed that the ground contact time, flight time, step and swing time can be estimated with an inter-trial median ± IQR bias less than 12 ± 10 ms and the a precision less than 4 ± 3 ms. Finally, this study showed that the running speed can significantly affect the biases of the estimations, suggesting that a speed-dependent correction should be applied to improve the system's accuracy

Pediatric Life Support: 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations

This 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations (CoSTR) for pediatric life support is based on the most extensive evidence evaluation ever performed by the Pediatric Life Support Task Force. Three types of evidence evaluation were used in this review: systematic reviews, scoping reviews, and evidence updates. Per agreement with the evidence evaluation recommendations of the International Liaison Committee on Resuscitation, only systematic reviews could result in a new or revised treatment recommendation. Systematic reviews performed for this 2020 CoSTR for pediatric life support included the topics of sequencing of airway-breaths-compressions versus compressions-airway-breaths in the delivery of pediatric basic life support, the initial timing and dose intervals for epinephrine administration during resuscitation, and the targets for oxygen and carbon dioxide levels in pediatric patients after return of spontaneous circulation. The most controversial topics included the initial timing and dose intervals of epinephrine administration (new treatment recommendations were made) and the administration of fluid for infants and children with septic shock (this latter topic was evaluated by evidence update). All evidence reviews identified the paucity of pediatric data and the need for more research involving resuscitation of infants and children

Metal-organic framework templated electrodeposition of functional gold nanostructures

Utilizing a pair of quick, scalable electrochemical processes, the permanently porous MOF HKUST-1 was electrochemically grown on a copper electrode and this HKUST-1-coated electrode was used to template electrodeposition of a gold nanostructure within the pore network of the MOF. Transmission electron microscopy demonstrates that a proportion of the gold nanostructures exhibit structural features replicating the pore space of this ∼1.4 nm maximum pore diameter MOF, as well as regions that are larger in size. Scanning electron microscopy shows that the electrodeposited gold nanostructure, produced under certain conditions of synthesis and template removal, is sufficiently inter-grown and mechanically robust to retain the octahedral morphology of the HKUST-1 template crystals. The functionality of the gold nanostructure within the crystalline HKUST-1 was demonstrated through the surface enhanced Raman spectroscopic (SERS) detection of 4-fluorothiophenol at concentrations as low as 1 μM. The reported process is confirmed as a viable electrodeposition method for obtaining functional, accessible metal nanostructures encapsulated within MOF crystals