IgM-Associated Cryoglobulinaemia

Cryoglobulinaemia is characterised by serum immunoglobulins that precipitate at temperatures below 37 ◦C and redissolve on warming. Monoclonal IgM immunoglobulin can be associated with type I and II cryoglobulinaemia with underlying Waldenström macroglobulinemia, monoclonal gammopathy of undetermined significance, or another non-Hodgkin lymphoma. In this research, we review the clinical characteristics of monoclonal IgM-associated cryoglobulinaemia and suggest a management approach for addressing them. Laboratory testing is critical as even a minimal amount of measurable cryoglobulin may result in symptoms. Accurate detection of cryoglobulins may be challenging, care must be taken with preanalytical variables, and repeated testing of monoclonal protein and cryoglobulins is indicated if clinical suspicion is high. Presentations range from asymptomatic to showing multisystem involvement, meaning that careful evaluation of the features and a thorough interrogation of organ systems and the underlying clone are critical. Immediate management is required for clinical red-flag features. Due to their rarity, data to inform treatment decisions are scant and collaborative research is imperative must be conducted to aid researchers in efforts to define optimal treatment strategies

Maternal high-fat feeding in pregnancy programmes atherosclerotic lesion size in the ApoE*3 Leiden mouse

Periods of rapid growth seen during the early stages of fetal development, including cell proliferation and differentiation, are greatly influenced by the maternal environment. We demonstrate here that over-nutrition, specifically exposure to a high fat diet in utero, programmed the extent of atherosclerosis in the offspring of ApoE*3 Leiden transgenic mice. Pregnant ApoE*3 Leiden mice were fed either a control chow diet (2.8% fat, n=12) or a high-fat, moderate-cholesterol diet (MHF, 19.4% fat, n=12). Dams were fed the chow diet during the suckling period. At 28d postnatal age wild type and ApoE*3 Leiden offspring from chow or MHF-fed mothers were fed either a control chow diet (n=37) or a diet rich in cocoa butter (15%) and cholesterol (0.25%), for 14 weeks to induce atherosclerosis (n=36). Offspring from MHF-fed mothers had 1.9-fold larger atherosclerotic lesions (p<0.001). There was no direct effect of prenatal diet on plasma triglycerides or cholesterol, however transgenic ApoE*3 Leiden offspring displayed raised cholesterol when on an atherogenic diet compared to wild-type controls (p=0.031). Lesion size was correlated with plasma lipid parameters after adjustment for genotype, maternal diet and postnatal diet (R2=0.563, p<0.001). ApoE*3 Leiden mothers fed a MHF diet developed hypercholesterolemia (plasma cholesterol 2-fold higher than in chow fed mothers, p=0.011). The data strongly suggest that maternal hypercholesterolaemia programmes later susceptibility to atherosclerosis. This is consistent with previous observations in humans and animal models

Quantifying distortions in two-photon remote focussing microscope images using a volumetric calibration specimen

This Document is Protected by copyright and was first published by Frontiers. All rights reserved. it is reproduced with permission.Remote focussing microscopy allows sharp, in-focus images to be acquired at high speed from outside of the focal plane of an objective lens without any agitation of the specimen. However, without careful optical alignment, the advantages of remote focussing microscopy could be compromised by the introduction of depth-dependent scaling artifacts. To achieve an ideal alignment in a point-scanning remote focussing microscope, the lateral (XY) scan mirror pair must be imaged onto the back focal plane of both the reference and imaging objectives, in a telecentric arrangement. However, for many commercial objective lenses, it can be difficult to accurately locate the position of the back focal plane. This paper investigates the impact of this limitation on the fidelity of three-dimensional data sets of living cardiac tissue, specifically the introduction of distortions. These distortions limit the accuracy of sarcomere measurements taken directly from raw volumetric data. The origin of the distortion is first identified through simulation of a remote focussing microscope. Using a novel three-dimensional calibration specimen it was then possible to quantify experimentally the size of the distortion as a function of objective misalignment. Finally, by first approximating and then compensating the distortion in imaging data from whole heart rodent studies, the variance of sarcomere length (SL) measurements was reduced by almost 50%.Medical Research Council (MRC)Engineering and Physical Sciences Research Council (EPSRC)Biotechnology and Biological Sciences Research Council (BBSRC)British Heart Foundation Centre of Research Excellence, Oxfor

Maternal high-fat feeding in pregnancy programmes atherosclerotic lesion size in the ApoE*3 Leiden mouse

Periods of rapid growth seen during the early stages of fetal development, including cell proliferation and differentiation, are greatly influenced by the maternal environment. We demonstrate here that over-nutrition, specifically exposure to a high fat diet in utero, programmed the extent of atherosclerosis in the offspring of ApoE*3 Leiden transgenic mice. Pregnant ApoE*3 Leiden mice were fed either a control chow diet (2.8% fat, n=12) or a high-fat, moderate-cholesterol diet (MHF, 19.4% fat, n=12). Dams were fed the chow diet during the suckling period. At 28d postnatal age wild type and ApoE*3 Leiden offspring from chow or MHF-fed mothers were fed either a control chow diet (n=37) or a diet rich in cocoa butter (15%) and cholesterol (0.25%), for 14 weeks to induce atherosclerosis (n=36). Offspring from MHF-fed mothers had 1.9-fold larger atherosclerotic lesions (p<0.001). There was no direct effect of prenatal diet on plasma triglycerides or cholesterol, however transgenic ApoE*3 Leiden offspring displayed raised cholesterol when on an atherogenic diet compared to wild-type controls (p=0.031). Lesion size was correlated with plasma lipid parameters after adjustment for genotype, maternal diet and postnatal diet (R2=0.563, p<0.001). ApoE*3 Leiden mothers fed a MHF diet developed hypercholesterolemia (plasma cholesterol 2-fold higher than in chow fed mothers, p=0.011). The data strongly suggest that maternal hypercholesterolaemia programmes later susceptibility to atherosclerosis. This is consistent with previous observations in humans and animal models

Influence of environmental and genetic factors on food protein quality: current knowledge and future directions

© 2021 Elsevier Ltd Dietary protein quality is commonly defined by the bioavailability of essential amino acids, a function of amino acid composition and protein digestibility. This review assesses the potential for manipulation of amino acid composition in organisms, for improving protein quality in nutrition. Animal protein is generally regarded as higher quality than plant protein, but it is also relatively resistant to change. Plant protein quality appears more susceptible to genetic and environmental influence with seed storage protein a potentially promising target, subject to GMO regulatory limitations. There is increasing interest in alternative dietary-protein sources including insects and fungi or other microorganisms. Each may be manipulated through environment or diet. Microorganisms also enable assessment of impacts on protein quality of biochemical-pathway manipulation or tailored growth regimes. We conclude that such approaches offer the greatest potential for manipulation. These means could help in producing protein of sufficient quantity and quality to meet future demand

Maternal high-fat feeding in pregnancy programmes atherosclerotic lesion size in the ApoE*3 Leiden mouse

Periods of rapid growth seen during the early stages of fetal development, including cell proliferation and differentiation, are greatly influenced by the maternal environment. We demonstrate here that over-nutrition, specifically exposure to a high fat diet in utero, programmed the extent of atherosclerosis in the offspring of ApoE*3 Leiden transgenic mice. Pregnant ApoE*3 Leiden mice were fed either a control chow diet (2.8% fat, n=12) or a high-fat, moderate-cholesterol diet (MHF, 19.4% fat, n=12). Dams were fed the chow diet during the suckling period. At 28d postnatal age wild type and ApoE*3 Leiden offspring from chow or MHF-fed mothers were fed either a control chow diet (n=37) or a diet rich in cocoa butter (15%) and cholesterol (0.25%), for 14 weeks to induce atherosclerosis (n=36). Offspring from MHF-fed mothers had 1.9-fold larger atherosclerotic lesions (

Pneumococcal within-host diversity during colonization, transmission and treatment

Characterizing the genetic diversity of pathogens within the host promises to greatly improve surveillance and reconstruction of transmission chains. For bacteria, it also informs our understanding of inter-strain competition and how this shapes the distribution of resistant and sensitive bacteria. Here we study the genetic diversity of Streptococcus pneumoniae within 468 infants and 145 of their mothers by deep sequencing whole pneumococcal populations from 3,761 longitudinal nasopharyngeal samples. We demonstrate that deep sequencing has unsurpassed sensitivity for detecting multiple colonization, doubling the rate at which highly invasive serotype 1 bacteria were detected in carriage compared with gold-standard methods. The greater resolution identified an elevated rate of transmission from mothers to their children in the first year of the child's life. Comprehensive treatment data demonstrated that infants were at an elevated risk of both the acquisition and persistent colonization of a multidrug-resistant bacterium following antimicrobial treatment. Some alleles were enriched after antimicrobial treatment, suggesting that they aided persistence, but generally purifying selection dominated within-host evolution. Rates of co-colonization imply that in the absence of treatment, susceptible lineages outcompeted resistant lineages within the host. These results demonstrate the many benefits of deep sequencing for the genomic surveillance of bacterial pathogens. Longitudinal population deep sequencing of Streptococcus pneumoniae sampled from infants and their mothers improves our understanding of the dynamics of colonization, transmission, inter-strain competition and the impact of antibiotic treatment.Peer reviewe

On-chip beam rotators, polarizers and adiabatic mode converters through low-loss waveguides with variable cross-sections

Photonics integrated circuitry would benefit considerably from the ability to arbitrarily control waveguide cross-sections with high precision and low loss, in order to provide more degrees of freedom in manipulating propagating light. Here, we report on a new optical-fibres-compatible glass waveguide by femtosecond laser writing, namely spherical phase induced multi-core waveguide (SPIM-WG), which addresses this challenging task with three dimensional on-chip light control. Precise deformation of cross-sections is achievable along the waveguide, with shapes and sizes finely controllable of high resolution in both horizontal and vertical transversal directions. We observed that these waveguides have high refractive index contrast of 0.017, low propagation loss of 0.14 dB/cm, and very low coupling loss of 0.19 dB coupled from a single mode fibre. SPIM-WG devices were easily fabricated that were able to perform on-chip beam rotation through varying angles, or manipulate polarization state of propagating light for target wavelengths. We also demonstrated SPIM-WG mode converters that provide arbitrary adiabatic mode conversion with high efficiency between symmetric and asymmetric non-uniform modes; examples include circular, elliptical modes and asymmetric modes from ppKTP waveguides which are generally applied in frequency conversion and quantum light sources. Created inside optical glass, these waveguides and devices have the capability to operate across ultra-broad bands from visible to infrared wavelengths. The compatibility with optical fibre also paves the way toward packaged photonic integrated circuitry, which usually needs input and output fibre connections

Potentiation of Synaptic GluN2B NMDAR Currents by Fyn Kinase Is Gated through BDNF-Mediated Disinhibition in Spinal Pain Processing

In chronic pain states, the neurotrophin brain-derived neurotrophic factor (BDNF) transforms the output of lamina I spinal neurons by decreasing synaptic inhibition. Pain hypersensitivity also depends on N-methyl-D-aspartate receptors (NMDARs) and Src-family kinases, but the locus of NMDAR dysregulation remains unknown. Here, we show that NMDAR-mediated currents at lamina I synapses are potentiated in a peripheral nerve injury model of neuropa

Comprehensive identification of single nucleotide polymorphisms associated with beta-lactam resistance within pneumococcal mosaic genes.

Traditional genetic association studies are very difficult in bacteria, as the generally limited recombination leads to large linked haplotype blocks, confounding the identification of causative variants. Beta-lactam antibiotic resistance in Streptococcus pneumoniae arises readily as the bacteria can quickly incorporate DNA fragments encompassing variants that make the transformed strains resistant. However, the causative mutations themselves are embedded within larger recombined blocks, and previous studies have only analysed a limited number of isolates, leading to the description of "mosaic genes" as being responsible for resistance. By comparing a large number of genomes of beta-lactam susceptible and non-susceptible strains, the high frequency of recombination should break up these haplotype blocks and allow the use of genetic association approaches to identify individual causative variants. Here, we performed a genome-wide association study to identify single nucleotide polymorphisms (SNPs) and indels that could confer beta-lactam non-susceptibility using 3,085 Thai and 616 USA pneumococcal isolates as independent datasets for the variant discovery. The large sample sizes allowed us to narrow the source of beta-lactam non-susceptibility from long recombinant fragments down to much smaller loci comprised of discrete or linked SNPs. While some loci appear to be universal resistance determinants, contributing equally to non-susceptibility for at least two classes of beta-lactam antibiotics, some play a larger role in resistance to particular antibiotics. All of the identified loci have a highly non-uniform distribution in the populations. They are enriched not only in vaccine-targeted, but also non-vaccine-targeted lineages, which may raise clinical concerns. Identification of single nucleotide polymorphisms underlying resistance will be essential for future use of genome sequencing to predict antibiotic sensitivity in clinical microbiology