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Background and Objectives: The detection of treponemal antibodies, which are used to make a diagnosis of syphilis, is important both for diagnostic purposes and as a mandatory blood donor test in most countries. We evaluated the feasibility of using Kode Technology to make syphilis peptide red cell kodecytes for use in column agglutination serologic platforms. Materials and Methods: Candidate Kode Technology function‐spacer‐lipid (FSL) constructs were made for the Treponema pallidum lipoprotein (TmpA) of T. pallidum, using the peptide and FSL selection algorithms, and then used to make kodecytes. Developmental kodecytes were evaluated against a large range of syphilis antibody reactive and non‐reactive samples in column agglutination platforms and compared against established methodologies. Overall, 150 reactive and 2072 non‐reactive Syphicheck assay (a modified T. pallidum particle agglutination) blood donor samples were used to evaluate the agreement rate of the developed kodecyte assay. Results: From three FSL‐peptide candidate constructs, one was found to be the most suitable for diagnostics. Of 150 Syphicheck assay reactive samples, 146 were TmpA–kodecyte reactive (97.3% agreement), compared with 58.0% with the rapid plasmin reagin (RPR) assay for the same samples. Against the 2072 expected syphilis non‐reactive samples the agreement rate for TmpA–kodecytes was 98.8%. Conclusion: TmpA–kodecytes are viable for use as cost‐effective serologic reagent red cells for the detection of treponemal antibodies to diagnose syphilis with a high level of specificity in blood centres. This kodecyte methodology also potentially allows for introduction of the reverse‐algorithm testing into low‐volume laboratories, by utilizing existing transfusion laboratory infrastructure. [ABSTRACT FROM AUTHOR]

Hypertriglyceridemia is an independent risk factor for cardiovascular disease, and plasma triglycerides (TGs) correlate strongly with plasma apolipoprotein C-III (ApoC-III) levels. Antisense oligonucleotides (ASOs) for ApoC-III reduce plasma TGs in primates and mice, but the underlying mechanism of action remains controversial. We determined that a murine-specific ApoC-III-targeting ASO reduces fasting TG levels through a mechanism that is dependent on low-density lipoprotein receptors (LDLRs) and LDLR-related protein 1 (LRP1). ApoC-III ASO treatment lowered plasma TGs in mice lacking lipoprotein lipase (LPL), hepatic heparan sulfate proteoglycan (HSPG) receptors, LDLR, or LRP1 and in animals with combined deletion of the genes encoding HSPG receptors and LDLRs or LRP1. However, the ApoC-III ASO did not lower TG levels in mice lacking both LDLR and LRP1. LDLR and LRP1 were also required for ApoC-III ASO-induced reduction of plasma TGs in mice fed a high-fat diet, in postprandial clearance studies, and when ApoC-III-rich or ApoC-III-depleted lipoproteins were injected into mice. ASO reduction of ApoC-III had no effect on VLDL secretion, heparin-induced TG reduction, or uptake of lipids into heart and skeletal muscle. Our data indicate that ApoC-III inhibits turnover of TG-rich lipoproteins primarily through a hepatic clearance mechanism mediated by the LDLR/LRP1 axis.

Noise in the immunohematological investigations can be described as a false reactivity of red blood cells (RBCs) in serologic testing that is not related to the interaction of RBC antigens and antibodies that the test system is intended to detect. These false-positive reactions can cause confusion during the cross-matching and RBC antibody screening and may result in delays in patient transfusion. Although these antibodies are predominantly clinically insignificant, proper laboratory work-up is indicated to avoid misidentification of a clinically significant antibody as a noise. In this report, we describe the three rare cases where the reactivity was found against the ingredients of the column matrix (glass beads). It is imperative that such reactivity is recognized and resolved during the investigation of blood group discrepancies, positive RBC antibody screens and in cases of positive cross-matches. [ABSTRACT FROM AUTHOR]

Loss-of-function mutations in the transcription factor CREB3L3 (CREBH) associate with severe hypertriglyceridemia in humans. CREBH is believed to lower plasma triglycerides by augmenting the activity of lipoprotein lipase (LPL). However, by using a mouse model of type 1 diabetes mellitus (T1DM), we found that greater liver expression of active CREBH normalized both elevated plasma triglycerides and cholesterol. Residual triglyceride-rich lipoprotein (TRL) remnants were enriched in apolipoprotein E (APOE) and impoverished in APOC3, an apolipoprotein composition indicative of increased hepatic clearance. The underlying mechanism was independent of LPL, as CREBH reduced both triglycerides and cholesterol in LPL-deficient mice. Instead, APOE was critical for CREBH's ability to lower circulating remnant lipoproteins because it failed to reduce TRL cholesterol in [Apoe.sup.-/-] mice. Importantly, individuals with CREB3L3 loss- of-function mutations exhibited increased levels of remnant lipoproteins that were deprived of APOE. Recent evidence suggests that impaired clearance of TRL remnants promotes cardiovascular disease in patients with T1DM. Consistently, we found that hepatic expression of CREBH prevented the progression of diabetes-accelerated atherosclerosis. Our results support the proposal that CREBH acts through an APOE-dependent pathway to increase hepatic clearance of remnant lipoproteins. They also implicate elevated levels of remnants in the pathogenesis of atherosclerosis in T1DM., Introduction The basic leucine zipper transcription factor CREBH (gene name CREB3L3; cAMP responsive element-binding protein 3-like 3) was identified 20 years ago (1), and was found to be expressed primarily [...]

This essay argues that "The lamentacion of a Gentilwoman vpon the death of her late deceased frend William Gruffith Gent." in The Gorgeous Gallery of Gallant Inventions (1578), attributed to Isabella Whitney, is a witty reimagining of one of the most popular Renaissance literary genres: the epitaph. The poet's grief revolves around the personal consequences of her secret lover's death, handling stock phrases and situational irony to strangely moving effect. While the poem's first-person speaker invokes the epitaph only to repudiate it, the three quatrains framing the text (written in the third person and therefore generally attributed to the volume's editor Thomas Proctor), pins down the mourning presence with the epitaphic "here." This paper suggests single authorship of the doubled text by showing how the poem posits personal lament as the site of interment located by the spatial demonstrative "here," to fashion a poetics of closure in which the voice of the languishing female poet becomes, through linguistic and textual splitting, a living epitaph for the dead beloved. [ABSTRACT FROM AUTHOR]

Movement of circulating fatty acids (FAs) to parenchymal cells requires their transfer across the endothelial cell (EC) barrier. The multiligand receptor cluster of differentiation 36 (CD36) facilitates tissue FA uptake and is expressed in ECs and parenchymal cells such as myocytes and adipocytes. Whether tissue uptake of FAs is dependent on EC or parenchymal cell CD36, or both, is unknown. Using a cell-specific deletion approach, we show that EC, but not parenchymal cell, CD36 deletion increased fasting plasma FAs and postprandial triglycerides. EC-Cd36-KO mice had reduced uptake of radiolabeled long- chain FAs into heart, skeletal muscle, and brown adipose tissue; these uptake studies were replicated using [[sup.11]C]palmitate PET scans. High-fat diet-fed EC-CD36-deficient mice had improved glucose tolerance and insulin sensitivity. Both EC and cardiomyocyte (CM) deletion of CD36 reduced heart lipid droplet accumulation after fasting, but CM deletion did not affect heart glucose or FA uptake. Expression in the heart of several genes modulating glucose metabolism and insulin action increased with EC-CD36 deletion but decreased with CM deletion. In conclusion, EC CD36 acts as a gatekeeper for parenchymal cell FA uptake, with important downstream effects on glucose utilization and insulin action., Introduction Long-chain fatty acids (LCFAs) provide cellular energy and are precursors for membrane components and intracellular lipid stores. Their bioactive derivatives influence gene expression and signal transduction pathways. Distribution of [...]

Platelets play a critical role In atherogenesis and thrombosis-mediated myocardial Ischemia, processes that are accelerated In diabetes. Whether hyperglycemia promotes platelet production and whether enhanced platelet production contributes to enhanced atherothrombosis remains unknown. Here we found that in response to hyperglycemia, neutrophil-derived S100 calcium-binding proteins A8/A9 (S100A8/A9) interact with the receptor for advanced glycation end products (RAGE) on hepatic Kupffer cells, resulting in increased production of IL-6, a pleiotropic cytokine that is implicated in inflammatory thrombocytosis. IL-6 acts on hepatocytes to enhance the production of thrombopoietin, which in turn interacts with its cognate receptor c-MPL on megakaryocytes and bone marrow progenitor cells to promote their expansion and proliferation, resulting in reticulated thrombocytosis. Lowering blood glucose using a sodium -glucose cotransporter 2 inhibitor (dapagliflozin), depleting neutrophils or Kupffer cells, or inhibiting S100A8/A9 binding to RAGE (using paquinimod), all reduced diabetes-induced thrombocytosis. Inhibiting S100A8/A9 also decreased atherogenesis in diabetic mice. Finally, we found that patients with type 2 diabetes have reticulated thrombocytosis that correlates with glycated hemoglobin as well as increased plasma S100A8/A9 levels. These studies provide insights into the mechanisms that regulate platelet production and may aid in the development of strategies to improve on current antiplatelet therapies and to reduce cardiovascular disease risk in diabetes., Introduction Diabetes is a major risk factor for cardiovascular disease (CVD), which remains the leading cause of mortality worldwide (1-3). Atherosclerosis is the major underlying cause of CVD and is [...]

A 52-year-old male repeats voluntary blood donor donated at our blood center for the first time. Historical blood group was O, Rh (D) positive. Initial blood grouping was done on the fully automated immunohematology analyzer using column agglutination technique (CAT). Discrepant results (forward as group O and reverse as group B) were observed while performing the ABO blood grouping by CAT. Repeat testing by conventional tube technique showed the same discrepancy. Antibody detection test and direct antiglobulin test results were negative. After adsorption-elution, the eluate reacted only with group B red cells. Saliva testing for secretor status shows the presence of B and H substances. Finally, it was classified as a case of Bm (now called Bweak) phenotype. As a precautionary measure, the donor was recalled and a special blood group card was issued with a clear mention of his respective donor and recipient status. This case showed the importance of ABO subgroup determination that can help blood centers to establish defined transfusion protocol and prepare an elaborate rare blood donor registry. [ABSTRACT FROM AUTHOR]