Measurement and interpretation of Salmonella typhi Vi IgG antibodies for the assessment of adaptive immunity

Response to polysaccharide vaccination can be an invaluable tool for assessing functionality of the adaptive immune system. Measurement of antibodies raised in response to Pneumovax®23 is the current gold standard test, but there are significant challenges and constraints in both the measurement and interpretation of the response. An alternative polysaccharide vaccine approach (Salmonella typhi Vi capsule (ViCPS)) has been suggested. In the present article, we review current evidence for the measurement of ViCPS antibodies in the diagnosis of primary and secondary antibody deficiencies. In particular, we review emerging data suggesting their interpretation in combination with the response to Pneumovax®23 and comment upon the utility of these vaccines to assess humoral immune responses while receiving immunoglobulin replacement therapy (IGRT)

Cerebrospinal fluid immunoglobulin light chain ratios predict disease progression in multiple sclerosis

Objective To determine whether the ratio of cerebrospinal fluid (CSF) immunoglobulin kappa to lambda light chains at time of multiple sclerosis (MS) diagnosis predicts disease progression and whether this was intrinsic to CSF plasmablasts. Methods CSF and peripheral blood were obtained from patients undergoing elective diagnostic lumbar puncture and included clinically isolated syndrome (CIS) (n=43), relapsing remitting MS (RRMS; n=50), primary progressive MS (PPMS; n=20) and other neurological disease controls, both inflammatory (ONID; n=23) and non-inflammatory (OND; n=114). CSF samples were assayed for free and immunoglobulin-associated light chains and on B cells and plasmablasts. Clinical follow-up data were collected during a 5-year follow-up period where available. Results There was an increased median CSF κ:λ free light chain (FLC) in all MS groups (CIS: 18.2, 95% CI 6.8 to 30.3; RRMS: 4.4, 95% CI 2.7 to 11.4; PPMS: 12.0, 95% CI 3.6 to 37.1) but not controls (OND: 1.61, 95% CI 1.4 to 1.9; ONID: 1.7, 95% CI 1.3 to 2.2; p10) CSF κ:λ FLC (0.0, 95% CI 0 to 2.5 vs 2.5, 95% CI 0 to 4, high vs low; p=0.049). CSF κ:λ FLC correlated with CSF IgG1 κ:λ (r=0.776; p<0.0001) and was intrinsic to CSF plasmablasts (r=0.65; p=0.026). Conclusions These data demonstrate that CSF immunoglobulin κ:λ ratios, determined at the time of diagnostic lumbar puncture, predict MS disease progression and may therefore be useful prognostic markers for early therapeutic stratification

Quantification of human C1 esterase inhibitor protein using an automated turbidimetric immunoassay

BACKGROUND: Impaired levels or function of C1 inhibitor (C1-INH) results in angioedema due to increased bradykinin. It is important to distinguish between angioedema related to C1-INH deficiency and that caused by other mechanisms, as treatment options are different. In hereditary (HAE) and acquired (AAE) angioedema, C1-INH concentration is measured to aid patient diagnosis. Here, we describe an automated turbidimetric assay to measure C1-INH concentration on the Optilite® analyzer. METHODS: Linearity, precision, and interference were established over a range of C1-INH concentrations. The 95th percentile reference interval was generated from 120 healthy adult donors. To compare the Optilite C1-INH assay with a predicate assay used in a clinical laboratory, samples sent for C1-INH investigation were used. The predicate results were provided to allow comparison. RESULTS: The Optilite C1-INH assay was linear across the measuring range at the standard sample dilution. Intra and interassay variability was <6%. The 95th percentile adult reference interval for the assay was 0.21-0.38 g/L. There was a strong correlation between the Optilite concentrations and those generated with the predicate assay (R2 = 0.94, P < 0.0001, slope y = 0.83x). All patients with Type I HAE (n = 24) and AAE (n = 3) tested had concentrations below the measuring range in both assays, while all patients with unspecified angioedema (UAE), not diagnosed with HAE or AAE had values within the reference range. CONCLUSION: The Optilite assay allows the automated and precise quantification of C1-INH concentrations in patient samples. It could therefore be used as a tool to aid the investigation of patients with angioedema

Prediction of attrition in agitated particle beds

The majority of pharmaceutical powders produced through crystallisation are dried in agitated dryers. The rotation of the impeller causes shear deformation of the bed, which enhances the drying rate, but also leads to particle breakage. A method of predicting the extent of breakage occurring due to agitation is described and applied for Paracetamol in a small-scale dryer. The distributions of stresses and strains in the bed are estimated using the Distinct Element Method (DEM). The information obtained here is then coupled with the measured attrition of Paracetamol in an annular shear cell in order to predict the attrition in the agitated bed. The experiments are carried out on dry material so as to establish purely the effect of stresses and strains on attrition, whilst keeping moisture content and temperature constant.The shear cell provides uniform condition for stresses and strains so that the breakage taking place under relatively well-defined conditions is quantified. In contrast, the prevailing shear stresses and strains in the agitated bed have wide distributions, as little shearing takes place near the impeller shaft, whilst there are considerable shearing stresses near the impeller tip. Therefore, the bed is divided into a number of segments for which the extent of attrition can be evaluated for each segment, based on the shear cell data. A good quantitative agreement is found between the predictions and experimental results obtained for the attrition of Paracetamol in the small scale dryer. The resulting prediction also suggests that, for a given number of impeller rotations, the extent of breakage is independent of impeller speed in the range tested (20-78. rpm). This is expected as the prevailing strain rates are too low for the inertial effects to be dominating and the shear stresses are independent of shear rates within the range investigated. The attrition prediction suggest that over half of the attrition occurs in the bottom third of the bed, with increased attrition at greater radial distances. The attrition is also predicted to occur predominantly within the region extending from 30° in front of to 30° behind the impeller

Is bisexuality invisible? A review of sexualities scholarship 1970–2015

This article provides a review of sexualities scholarship within the social sciences between 1970 and 2015. It takes an innovative approach by focusing on the way in which bisexuality is addressed in this body of literature. The article reveals the marginalisation, under-representation and invisibility of bisexuality within and across the social sciences in relation to both bisexual experience and identity. Reasons for this varied across the different eras, including the heterosexist nature of the literature, the impact of gay and lesbian-focused identity politics, and queer deconstructionism. In addition, patterns of bisexual erasure and invisibility were uneven, with some scholarship taking inclusive approaches or criticising prejudice against bisexuality. The initial findings of the review were enriched by critical commentary from key relevant sociologists and political scientists. The article concludes that future sexualities scholarship could be enhanced by greater consideration of bisexuality

Prioritization of knowledge-needs to achieve best practices for bottom trawling in relation to seabed habitats

Management and technical approaches that achieve a sustainable level of fish production while at the same time minimizing or limiting the wider ecological effects caused through fishing gear contact with the seabed might be considered to be ‘best practice’. To identify future knowledge-needs that would help to support a transition towards the adoption of best practices for trawling, a prioritization exercise was undertaken with a group of 39 practitioners from the seafood industry and management, and 13 research scientists who have an active research interest in bottom-trawl and dredge fisheries. A list of 108 knowledge-needs related to trawl and dredge fisheries was developed in conjunction with an ‘expert task force’. The long list was further refined through a three stage process of voting and scoring, including discussions of each knowledge-need. The top 25 knowledge-needs are presented, as scored separately by practitioners and scientists. There was considerable consistency in the priorities identified by these two groups. The top priority knowledge-need to improve current understanding on the distribution and extent of different habitat types also reinforced the concomitant need for the provision and access to data on the spatial and temporal distribution of all forms of towed bottom-fishing activities. Many of the other top 25 knowledge-needs concerned the evaluation of different management approaches or implementation of different fishing practices, particularly those that explore trade-offs between effects of bottom trawling on biodiversity and ecosystem services and the benefits of fish production as food.Fil: Kaiser, Michel J.. Bangor University; Reino UnidoFil: Hilborn, Ray. University of Washington; Estados UnidosFil: Jennings, Simon. Fisheries and Aquaculture Science; Reino UnidoFil: Amaroso, Ricky. University of Washington; Estados UnidosFil: Andersen, Michael. Danish Fishermen; DinamarcaFil: Balliet, Kris. Sustainable Fisheries Partnership; Estados UnidosFil: Barratt, Eric. Sanford Limited; Nueva ZelandaFil: Bergstad, Odd A. Institute of Marine Research; NoruegaFil: Bishop, Stephen. Independent Fisheries Ltd; Nueva ZelandaFil: Bostrom, Jodi L. Marine Stewardship Council; Reino UnidoFil: Boyd, Catherine. Clearwater Seafoods; CanadáFil: Bruce, Eduardo A. Friosur S.A.; ChileFil: Burden, Merrick. Marine Conservation Alliance; Estados UnidosFil: Carey, Chris. Independent Fisheries Ltd.; Estados UnidosFil: Clermont, Jason. New England Aquarium; Estados UnidosFil: Collie, Jeremy S. University of Rhode Island,; Estados UnidosFil: Delahunty, Antony. National Federation of Fishermen; Reino UnidoFil: Dixon, Jacqui. Pacific Andes International Holdings Limited; ChinaFil: Eayrs, Steve. Gulf of Maine Research Institute; Estados UnidosFil: Edwards, Nigel. Seachill Ltd.; Reino UnidoFil: Fujita, Rod. Environmental Defense Fund; Reino UnidoFil: Gauvin, John. Alaska Seafood Cooperative; Estados UnidosFil: Gleason, Mary. The Nature Conservancy; Estados UnidosFil: Harris, Brad. Alaska Pacific University; Estados UnidosFil: He, Pingguo. University of Massachusetts Dartmouth; Estados UnidosFil: Hiddink, Jan G. Bangor University; Reino UnidoFil: Hughes, Kathryn M. Bangor University; Reino UnidoFil: Inostroza, Mario. EMDEPES; ChileFil: Kenny, Andrew. Fisheries and Aquaculture Science; Reino UnidoFil: Kritzer, Jake. Environmental Defense Fund; Estados UnidosFil: Kuntzsch, Volker. Sanford Limited; Estados UnidosFil: Lasta, Mario. Diag. Montegrande N° 7078. Mar del Plata; ArgentinaFil: Lopez, Ivan. Confederacion Española de Pesca; EspañaFil: Loveridge, Craig. South Pacific Regional Fisheries Management Organisation; Nueva ZelandaFil: Lynch, Don. Gorton; Estados UnidosFil: Masters, Jim. Marine Conservation Society; Reino UnidoFil: Mazor, Tessa. CSIRO Marine and Atmospheric Research; AustraliaFil: McConnaughey, Robert A. US National Marine Fisheries Service; Estados UnidosFil: Moenne, Marcel. Pacificblu; ChileFil: Francis. Marine Scotland Science; Reino UnidoFil: Nimick, Aileen M. Alaska Pacific University; Estados UnidosFil: Olsen, Alex. A. Espersen; DinamarcaFil: Parker, David. Young; Reino UnidoFil: Parma, Ana María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Nacional Patagónico; ArgentinaFil: Penney, Christine. Clearwater Seafoods; CanadáFil: Pierce, David. Massachusetts Division of Marine Fisheries; Estados UnidosFil: Pitcher, Roland. CSIRO Marine and Atmospheric Research; AustraliaFil: Pol, Michael. Massachusetts Division of Marine Fisheries; Estados UnidosFil: Richardson, Ed. Pollock Conservation Cooperative; Estados UnidosFil: Rijnsdorp, Adriaan D. Wageningen IMARES; Países BajosFil: Rilatt, Simon. A. Espersen; DinamarcaFil: Rodmell, Dale P. National Federation of Fishermen's Organisations; Reino UnidoFil: Rose, Craig. FishNext Research; Estados UnidosFil: Sethi, Suresh A. Alaska Pacific University; Estados UnidosFil: Short, Katherine. F.L.O.W. Collaborative; Nueva ZelandaFil: Suuronen, Petri. Fisheries and Aquaculture Department; ItaliaFil: Taylor, Erin. New England Aquarium; Estados UnidosFil: Wallace, Scott. The David Suzuki Foundation; CanadáFil: Webb, Lisa. Gorton's Inc.; Estados UnidosFil: Wickham, Eric. Unit four –1957 McNicoll Avenue; CanadáFil: Wilding, Sam R. Monterey Bay Aquarium; Estados UnidosFil: Wilson, Ashley. Department for Environment; Reino UnidoFil: Winger, Paul. Memorial University Of Newfoundland; CanadáFil: Sutherland, William J. University of Cambridge; Reino Unid

X-linked primary ciliary dyskinesia due to mutations in the cytoplasmic axonemal dynein assembly factor PIH1D3

By moving essential body fluids and molecules, motile cilia and flagella govern respiratory mucociliary clearance, laterality determination and the transport of gametes and cerebrospinal fluid. Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder frequently caused by non-assembly of dynein arm motors into cilia and flagella axonemes. Before their import into cilia and flagella, multi-subunit axonemal dynein arms are thought to be stabilized and pre-assembled in the cytoplasm through a DNAAF2–DNAAF4–HSP90 complex akin to the HSP90 co-chaperone R2TP complex. Here, we demonstrate that large genomic deletions as well as point mutations involving PIH1D3 are responsible for an X-linked form of PCD causing disruption of early axonemal dynein assembly. We propose that PIH1D3, a protein that emerges as a new player of the cytoplasmic pre-assembly pathway, is part of a complementary conserved R2TP-like HSP90 co-chaperone complex, the loss of which affects assembly of a subset of inner arm dyneins

Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis

Hypothalamic neurons expressing the anorectic peptide Pro-opiomelanocortin (Pomc) regulate food intake and body weight. Here, we show that Steroid Receptor Coactivator-1 (SRC-1) interacts with a target of leptin receptor activation, phosphorylated STAT3, to potentiate Pomc transcription. Deletion of SRC-1 in Pomc neurons in mice attenuates their depolarization by leptin, decreases Pomc expression and increases food intake leading to high-fat diet-induced obesity. In humans, fifteen rare heterozygous variants in SRC-1 found in severely obese individuals impair leptin-mediated Pomc reporter activity in cells, whilst four variants found in non-obese controls do not. In a knock-in mouse model of a loss of function human variant (SRC-1L1376P), leptin-induced depolarization of Pomc neurons and Pomc expression are significantly reduced, and food intake and body weight are increased. In summary, we demonstrate that SRC-1 modulates the function of hypothalamic Pomc neurons, and suggest that targeting SRC-1 may represent a useful therapeutic strategy for weight loss.Peer reviewe