Unravelling the immune signature of Plasmodium falciparum transmission-reducing immunity

Infection with Plasmodium can elicit antibodies that inhibit parasite survival in the mosquito, when they are ingested in an infectious blood meal. Here, we determine the transmission-reducing activity (TRA) of naturally acquired antibodies from 648 malaria-exposed individuals using lab-based mosquito-feeding assays. Transmission inhibition is significantly associated with antibody responses to Pfs48/45, Pfs230, and to 43 novel gametocyte proteins assessed by protein microarray. In field-based mosquito-feeding assays the likelihood and rate of mosquito infection are significantly lower for individuals reactive to Pfs48/45, Pfs230 or to combinations of the novel TRA-associated proteins. We also show that naturally acquired purified antibodies against key transmission-blocking epitopes of Pfs48/45 and Pfs230 are mechanistically involved in TRA, whereas sera depleted of these antibodies retain high-level, complement-independent TRA. Our analysis demonstrates that host antibody responses to gametocyte proteins are associated with reduced malaria transmission efficiency from humans to mosquitoes

Taping patients with clinical signs of subacromial impingement syndrome: the design of a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Shoulder problems are a common complaint of the musculoskeletal system. Physical therapists treat these patients with different modalities such as exercise, massage, and shoulder taping. Although different techniques have been described, the effectiveness of taping has not yet been established. The aim of this study is to assess the effectiveness and cost-effectiveness of usual physical therapy care in combination with a particular tape technique for subacromial impingement syndrome of the shoulder compared to usual physical therapy care without this tape technique in a primary healthcare setting.</p> <p>Methods and design</p> <p>An economic evaluation alongside a randomized controlled trial will be conducted. A sample of 140 patients between 18 and 65 years of age with a diagnosis of subacromial impingement syndrome (SAIS) as assessed by physical therapists will be recruited. Eligible patients will be randomized to either the intervention group (usual care in combination with the particular tape technique) or the control group (usual care without this tape technique). In both groups, usual care will consist of individualized physical therapy care. The primary outcomes will be shoulder-specific function (the Simple Shoulder Test) and pain severity (11-point numerical rating scale). The economic evaluation will be performed using a societal perspective. All relevant costs will be registered using cost diaries. Utilities (Quality Adjusted Life Years) will be measured using the EuroQol. The data will be collected at baseline, and 4, 12, and 26 weeks follow-up.</p> <p>Discussion</p> <p>This pragmatic study will provide information about the effectiveness and cost-effectiveness of taping in patients presenting with clinical signs of SAIS.</p> <p>Trial registration</p> <p>Trial registration number: <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2575">NTR2575</a></p

Broad spectrum late blight resistance in potato differential set plants MaR8 and MaR9 is conferred by multiple stacked R genes

Phytophthora infestans is the causal agent of late blight in potato. The Mexican species Solanum demissum is well known as a good resistance source. Among the 11 R gene differentials, which were introgressed from S. demissum, especially R8 and R9 differentials showed broad spectrum resistance both under laboratory and under field conditions. In order to gather more information about the resistance of the R8 and R9 differentials, F1 and BC1 populations were made by crossing Mastenbroek (Ma) R8 and R9 clones to susceptible plants. Parents and offspring plants were examined for their pathogen recognition specificities using agroinfiltration with known Avr genes, detached leaf assays (DLA) with selected isolates, and gene-specific markers. An important observation was the discrepancy between DLA and field trial results for Pi isolate IPO-C in all F1 and BC1 populations, so therefore also field trial results were included in our characterization. It was shown that in MaR8 and MaR9, respectively, at least four (R3a, R3b, R4, and R8) and seven (R1, Rpi-abpt1, R3a, R3b, R4, R8, R9) R genes were present. Analysis of MaR8 and MaR9 offspring plants, that contained different combinations of multiple resistance genes, showed that R gene stacking contributed to the Pi recognition spectrum. Also, using a Pi virulence monitoring system in the field, it was shown that stacking of multiple R genes strongly delayed the onset of late blight symptoms. The contribution of R8 to this delay was remarkable since a plant that contained only the R8 resistance gene still conferred a delay similar to plants with multiple resistance genes, like, e.g., cv Sarpo Mira. Using this “de-stacking” approach, many R gene combinations can be made and tested in order to select broad spectrum R gene stacks that potentially provide enhanced durability for future application in new late blight resistant varieties

Shared communication processes within healthcare teams for rare diseases and their influence on healthcare professionals' innovative behavior and patient satisfaction

<p>Abstract</p> <p>Background</p> <p>A rare disease is a pattern of symptoms that afflicts less than five in 10,000 patients. However, as about 6,000 different rare disease patterns exist, they still have significant epidemiological relevance. We focus on rare diseases that affect multiple organs and thus demand that multidisciplinary healthcare professionals (HCPs) work together. In this context, standardized healthcare processes and concepts are mainly lacking, and a deficit of knowledge induces uncertainty and ambiguity. As such, individualized solutions for each patient are needed. This necessitates an intensive level of innovative individual behavior and thus, adequate idea generation. The final implementation of new healthcare concepts requires the integration of the expertise of all healthcare team members, including that of the patients. Therefore, knowledge sharing between HCPs and shared decision making between HCPs and patients are important. The objective of this study is to assess the contribution of shared communication and decision-making processes in patient-centered healthcare teams to the generation of innovative concepts and consequently to improvements in patient satisfaction.</p> <p>Methods</p> <p>A theoretical framework covering interaction processes and explorative outcomes, and using patient satisfaction as a measure for operational performance, was developed based on healthcare management, innovation, and social science literature. This theoretical framework forms the basis for a three-phase, mixed-method study. Exploratory phase I will first involve collecting qualitative data to detect central interaction barriers within healthcare teams. The results are related back to theory, and testable hypotheses will be derived. Phase II then comprises the testing of hypotheses through a quantitative survey of patients and their HCPs in six different rare disease patterns. For each of the six diseases, the sample should comprise an average of 30 patients with six HCP per patient-centered healthcare team. Finally, in phase III, qualitative data will be generated via semi-structured telephone interviews with patients to gain a deeper understanding of the communication processes and initiatives that generate innovative solutions.</p> <p>Discussion</p> <p>The findings of this proposed study will help to elucidate the necessity of individualized innovative solutions for patients with rare diseases. Therefore, this study will pinpoint the primary interaction and communication processes in multidisciplinary teams, as well as the required interplay between exploratory outcomes and operational performance. Hence, this study will provide healthcare institutions and HCPs with results and information essential for elaborating and implementing individual care solutions through the establishment of appropriate interaction and communication structures and processes within patient-centered healthcare teams.</p

Tracing the effects of high-pressure metasomatic fluids and seawater alteration in blueschist-facies overprinted eclogites: Implications for subduction channel processes

Eclogites from the Tian Shan high-pressure/low-temperature (HP/LT) metamorphic belt show evidence for successively increasing metasomatic alteration with increasing retrograde, blueschist-facies overprint. To constrain the source(s) of the metasomatizing fluid and to evaluate elemental and isotopic changes during this overprint, two sequences of eclogite-blueschist transitions were investigated: A layered transition from eclogite to blueschist (FTS 9–1 sequence) and blueschist-facies overprinted pillow metabasalts (FTS 4 samples). Geochemical trends based on the relationships of K, Ba, Rb and Th are consistent with HP metasomatism, but distinct from typical seafloor alteration trends. In contrast, oxygen isotope ratios in garnet (δ18OV-SMOW = 7.3–8.7‰) and omphacite (δ18OV-SMOW = 8.2–9.7‰) are similar to δ18OV-SMOW in bulk low-temperature altered oceanic crust (AOC), suggesting O isotopic preservation of a seafloor alteration signature. Carbonate crystallization related to the metasomatic overprint demonstrate CO2 mobility during subduction and potential C storage in HP metamorphic rocks. Carbon isotope ratios in the two sequences differ markedly: Disseminated calcite in the layered FTS 9–1 sequence has δ13CV-PDB = − 9.14 ± 0.19‰, whereas vein-forming ankerite in the pillow metabasalts has δ13CV-PDB = − 2.08 ± 0.12‰. The ankerite reflects an inorganic marine/hydrothermal signature, as observed in ophiolites, whereas the low δ13CV-PDB values from the calcite point to a contribution of organic carbon. The time when the metasomatic overprint occurred is estimated to be ~ 320 ± 11 Ma based on a Rb-Sr isochron age of six blueschist samples from the pillow metabasalts, which is in agreement with active subduction in this region. Initial (T = 320 Ma) 87Sr/86Sr ratios for all HP/LT rocks range from 0.7059 – 0.7085, and εNd320Ma varies from − 0.4 to + 10.9. Both eclogite-blueschist sequences have initial Sr isotope compositions (87Sr/86Sr ~ 0.707) that are significantly higher than those of typical oceanic mantle-derived basalts. They are thought to derive from a fluid that preserved the Sr isotopic signature of seawater by fluid-rock interaction with seawater-altered oceanic lithosphere in a subduction channel. Mixing models between eclogite and various fluids suggest that the contribution of a sediment-derived fluid was likely less than 20%. A fluid predominantly derived from seawater-altered oceanic lithosphere is also supported by the calculated O isotope composition of the fluids (10.2 – 11.2‰). It is thus evident that subduction channel fluids carry complex, mixed elemental and isotopic signatures, which reflect the composition of their source rocks modified by interaction with various other lithologies. Highlights ► Eclogites from the Tian Shan show blueschist-facies metasomatic overprint ► Fluid-induced metasomatism occurred at 320 ± 11 Ma ► Fluid predominantly derived from seawater-altered oceanic lithosphere ► Carbonates reflect C sequestration of mixture of organic and inorganic component

Ovotoxic Effects of Galactose Involve Attenuation of Follicle-Stimulating Hormone Bioactivity and Up-Regulation of Granulosa Cell p53 Expression

Clinical evidence suggests an association between galactosaemia and premature ovarian insufficiency (POI); however, the mechanism still remains unresolved. Experimental galactose toxicity in rats produces an array of ovarian dysfunction including ovarian development with deficient follicular reserve and follicular resistance to gonadotrophins that characterize the basic tenets of human POI. The present investigation explores if galactose toxicity in rats attenuates the bioactivity of gonadotrophins or interferes with their receptor competency, and accelerates the rate of follicular atresia. Pregnant rats were fed isocaloric food-pellets supplemented with or without 35% D-galactose from day-3 of gestation and continuing through weaning of the litters. The 35-day old female litters were autopsied. Serum galactose-binding capacity, galactosyltransferase (GalTase) activity, and bioactivity of FSH and LH together with their receptor competency were assessed. Ovarian follicular atresia was evaluated in situ by TUNEL. The in vitro effects of galactose were studied in isolated whole follicles in respect of generation of reactive oxygen species (ROS) and expression of caspase 3, and in isolated granulosa cells in respect of mitochondrial membrane potential, expression of p53, and apoptosis. The rats prenatally exposed to galactose exhibited significantly decreased serum GalTase activity and greater degree of galactose-incorporation capacity of sera proteins. LH biopotency and LH-FSH receptor competency were comparable between the control and study population, but the latter group showed significantly attenuated FSH bioactivity and increased rate of follicular atresia. In culture, galactose increased follicular generation of ROS and expression of caspase 3. In isolated granulosa cells, galactose disrupted mitochondrial membrane potential, stimulated p53 expression, and induced apoptosis in vitro; however co-treatment with either FSH or estradiol significantly prevented galactose-induced granulosa cell p53 expression. We conclude that the ovotoxic effects of galactose involves attenuation of FSH bioactivity that renders the ovary resistant to gonadotrophins leading to increased granulosa cell expression of p53 and follicular atresia

Exercise therapy and cognitive behavioural therapy to improve fatigue, daily activity performance and quality of life in Postpoliomyelitis Syndrome: the protocol of the FACTS-2-PPS trial

Contains fulltext : 88661.pdf (publisher's version ) (Open Access)BACKGROUND: Postpoliomyelitis Syndrome (PPS) is a complex of late onset neuromuscular symptoms with new or increased muscle weakness and muscle fatigability as key symptoms. Main clinical complaints are severe fatigue, deterioration in functional abilities and health related quality of life. Rehabilitation management is the mainstay of treatment. Two different therapeutic interventions may be prescribed (1) exercise therapy or (2) cognitive behavioural therapy (CBT). However, the evidence on the effectiveness of both interventions is limited. The primary aim of the FACTS-2-PPS trial is to study the efficacy of exercise therapy and CBT for reducing fatigue and improving activities and quality of life in patients with PPS. Additionally, the working mechanisms, patients' and therapists' expectations of and experiences with both interventions and cost-effectiveness will be evaluated. METHODS/DESIGN: A multi-centre, single-blinded, randomized controlled trial will be conducted. A sample of 81 severely fatigued patients with PPS will be recruited from 3 different university hospitals and their affiliate rehabilitation centres. Patients will be randomized to one of three groups i.e. (1) exercise therapy + usual care, (2) CBT + usual care, (3) usual care. At baseline, immediately post-intervention and at 3- and 6-months follow-up, fatigue, activities, quality of life and secondary outcomes will be assessed. Costs will be based on a cost questionnaire, and statistical analyses on GEE (generalized estimated equations). Analysis will also consider mechanisms of change during therapy. A responsive evaluation will be conducted to monitor the implementation process and to investigate the perspectives of patients and therapists on both interventions. DISCUSSION: A major strength of the FACTS-2-PPS study is the use of a mixed methods design in which a responsive and economic evaluation runs parallel to the trial. The results of this study will generate new evidence for the rehabilitation treatment of persons with PPS. TRIAL REGISTRATION: Dutch Trial Register NTR1371

Prognostic value of right ventricular longitudinal strain in patients with pulmonary hypertension: a systematic review and meta-analysis.

Aims: Pulmonary hypertension (PH) is associated with high morbidity and mortality and the predictive capacity of traditional functional echocardiographic measures is poor. Recent studies assessed the predictive capacity of right ventricular longitudinal strain (RVLS). Diversity in methods between these studies resulted in conflicting outcomes. The purpose of this systematic review and meta-analysis was to determine the independent prognostic value of RVLS for PH-related events and all-cause mortality. Methods and results: A systematic search in Pubmed (MEDLINE), Embase, the Cochrane Library, and Web of Science was performed to identify studies that examined the prognostic value of RVLS in patients with PH. Studies reporting Cox regression based hazard ratios (HRs) for a combined endpoint of mortality and PH-related events or all-cause mortality for echocardiographic derived RVLS were included. A weighted mean of the multivariate HR was used to determine the independent predictive value of RVLS. Eleven studies met our criteria, including 1169 patients with PH (67% female, 0.6-3.8 years follow-up). PH patients with a relative reduction of RVLS of 19% had a significantly higher risk for the combined endpoint [HR 1.22, 95% confidence interval (CI) 1.07-1.40], while patients with a relative reduction of RVLS of 22% had a significantly higher risk for all-cause mortality (HR 2.96, 95% CI 2.00-4.38). Conclusion: This systematic review and meta-analysis showed that RVLS has independent prognostic value for a combined endpoint and all-cause mortality in patients with PH. Collectively, these findings emphasize that RVLS may have value for optimizing current predictive models for clinical events or mortality in patients with PH