Viruses modulate biochemical cellular pathways to permit infection. A recently described mechanism mediates selective protein interactions between acidic domain readers and unacetylated, lysine-rich ...regions, opposite of bromodomain function. Kaposiś sarcoma (KS)-associated herpesvirus (KSHV) is tightly linked with KS, primary effusion lymphoma, and multicentric Castleman’s disease. KSHV latently infects cells, and its genome persists as a multicopy, extrachromosomal episome. During latency, KSHV expresses a small subset of genes, including the latency-associated nuclear antigen (LANA), which mediates viral episome persistence. Here we show that LANA contains two tandem, partially overlapping, acidic domain sequences homologous to the SET oncoprotein acidic domain reader. This domain selectively interacts with unacetylated p53, as evidenced by reduced LANA interaction after overexpression of CBP, which acetylates p53, or with an acetylation mimicking carboxyl-terminal domain p53 mutant. Conversely, the interaction of LANA with an acetylation-deficient p53 mutant is enhanced. Significantly, KSHV LANA mutants lacking the acidic domain reader sequence are deficient for establishment of latency and persistent infection. This deficiency was confirmed under physiological conditions, on infection of mice with a murine gammaherpesvirus 68 chimera expressing LANA, where the virus was highly deficient in establishing latent infection in germinal center B cells. Therefore, LANA’s acidic domain reader is critical for viral latency. These results implicate an acetylation-dependent mechanism mediating KSHV persistence and expand the role of acidic domain readers.
A micro-Pirani pressure sensor, which consists of a pressure-dependent thermoresistance gauge, is traditionally exploited using a steady-state resistance measurement. Any signal variation occurs over ...an offset voltage due to the imperfection of the device, which affects the sensor's sensitivity. This paper presents, for the first time, an experimental investigation of a micro-Pirani gauge based on its dynamic behavior when heated by a current step. Such processing magnifies the pressure dependence of the gauge's signal by eliminating the constant offset influences on the measurement. Furthermore, a first-order low-pass filter step response identification of the experimental transient signal strongly reduces the noise influence on the measurement. Furthermore, such identification enables a direct calculation of the time constant. This paper investigates the pressure measurement based on the time-constant evaluation, which provides a range of measurement and a maximal sensitivity significantly shifted toward the atmospheric pressure compared to that of a traditionally processed Pirani gauge. The heating step, the recording of the transient response signal, and its digital postprocessing can be easily achieved by a small-sized controller. The proposed system provides a substantial performance enhancement of the micro-Pirani pressure sensor.
CKD is associated with increased oxidative stress that correlates with occurrence of cardiovascular events. Modifications induced by increased oxidative stress particularly affect circulating ...lipoproteins such as HDL that exhibit antiatheromatous and antithrombotic properties
.
To explore the specific role of oxidative modifications of HDL in CKD and their effect on the platelet-targeting antiaggregant properties of HDL, we used a CKD (5/6 nephrectomy) rabbit model. For
assessment of the antiaggregant properties of HDL, we collected blood samples from 15 healthy volunteers, 25 patients on hemodialysis, and 20 on peritoneal dialysis. We analyzed malondialdehyde, 4-hydroxynonenal (HNE), and 4-hydroxy-2-hexenal protein adduct levels. Platelet aggregation and activation were assessed by aggregometry, thromboxane B2 assay, or FACS. We modified HDL from controls by incubating it overnight at 37°C with 100
M of HNE.
HDL from CKD rabbits and patients on hemodialysis had HNE adducts. The percentage of platelet aggregation or activation induced by collagen was significantly higher when platelets were incubated with HDL from CKD rabbit and hemodialysis groups than with HDL from the control group. In both rabbits and humans, platelet aggregation and activation were significantly higher in the presence of HNE-modified HDL than with HDL from their respective controls. Incubation of platelets with a blocking antibody directed against CD36 or with a pharmacologic inhibitor of SRC kinases restored the antiaggregative phenotype in the presence of HDL from CKD rabbits, patients on hemodialysis and peritoneal dialysis, and HNE-modified HDL.
HDL from CKD rabbits and patients on hemodialysis exhibited an impaired ability to inhibit platelet aggregation, suggesting that altered HDL properties may contribute to the increased cardiovascular risk in this population.
Heparin is used to prevent clotting during hemodialysis, but heparin-free hemodialysis is sometimes needed to decrease the risk of bleeding. The HepZero study is a randomized, multicenter ...international controlled open-label trial comparing no-heparin hemodialysis strategies designed to assess non-inferiority of a heparin grafted dialyzer (NCT01318486). A total of 251 maintenance hemodialysis patients at increased risk of hemorrhage were randomly allocated for up to three heparin-free hemodialysis sessions using a heparin-grafted dialyzer or the center standard-of-care consisting of regular saline flushes or pre-dilution. The first heparin-free hemodialysis session was considered successful when there was neither complete occlusion of air traps or dialyzer, nor additional saline flushes, changes of dialyzer or bloodlines, or premature termination. The current standard-of-care resulted in high failure rates (50%). The success rate in the heparin-grafted membrane arm was significantly higher than in the control group (68.5% versus 50.4%), which was consistent for both standard-of-care modalities. The absolute difference between the heparin-grafted membrane and the controls was 18.2%, with a lower bound of the 90% confidence interval equal to plus 7.9%. The hypothesis of the non-inferiority at the minus 15% level was accepted, although superiority at the plus 15% level was not reached. Thus, use of a heparin-grafted membrane is a safe, helpful, and easy-to-use method for heparin-free hemodialysis in patients at increased risk of hemorrhage.
Introduction. Despite the rising trend in breast cancer incidence and mortality across Sub-Saharan Africa, there remains a critical knowledge gap about the burden and patterns of breast disease and ...breast cancer screening practices at the population level. This study aimed to identify socioeconomic factors associated with knowledge and practice of breast self-examination (BSE) as well as assess the prevalence of breast disease symptoms among a mixed urban-rural population of women in the Southwest region of Cameroon. Methods. We conducted a household-level community-based study in Southwest Cameroon between January and March 2017, using a three-stage cluster sampling framework. We surveyed 1287 households and collected self-reported data on 4208 female subjects, 790 of whom were household representatives. Each household representative provided information on behalf of all female household members about any ongoing breast disease symptoms. Moreover, female household representatives were questioned about their own knowledge and practice of BSE. Results. Women demonstrated low frequency of knowledge of BSE, as 25% (n=201) of household representatives reported any knowledge of BSE; and among these only 15% (n=30) practiced BSE on a monthly basis. Age (aOR: 1.04), usage of Liquid Petroleum Gas fuel, a marker of higher socioeconomic status (aOR: 1.86), and speaking English as a primary language in the household (aOR: 1.59) were significant predictors of knowledge of BSE. Eleven women reported ongoing breast disease symptoms resulting in an overall prevalence of 2.3 cases of breast disease symptoms per 1000 women. Conclusions. Socioeconomic disparities in access to health education may be a determinant of knowledge of BSE. Community-based strategies are needed to improve dissemination of breast cancer screening methods, particularly for women who face barriers to accessing care.
Objectives
Disease‐modifying therapies (DMTs) targeting B cells are amongst the most effective for preventing multiple sclerosis (MS) progression. IgG3 antibodies and their uncharacterised B‐cell ...clones are predicted to play a pathogenic role in MS. Identifying subsets of IgG3+ B cells involved in MS progression could improve diagnosis, could inform timely disease intervention and may lead to new DMTs that target B cells more specifically.
Methods
We designed a 31‐parameter B‐cell‐focused mass cytometry panel to interrogate the role of peripheral blood IgG3+ B cells in MS progression of two different patient cohorts: one to investigate the B‐cell subsets involved in conversion from clinically isolated syndrome (CIS) to MS; and another to compare MS patients with inactive or active stages of disease. Each independent cohort included a group of non‐MS controls.
Results
Nine distinct CD20+IgD−IgG3+ B‐cell subsets were identified. Significant changes in the proportion of CD21+CD24+CD27−CD38− and CD27+CD38hiCD71hi memory B‐cell subsets correlated with changes in serum IgG3 levels and time to conversion from CIS to MS. The same CD38− double‐negative B‐cell subset was significantly elevated in MS patients with active forms of the disease. A third CD21+CD24+CD27+CD38− subset was elevated in patients with active MS, whilst narrowband UVB significantly reduced the proportion of this switched‐memory B‐cell subset.
Conclusion
We have identified previously uncharacterised subsets of IgG3+ B cells and shown them to correlate with autoimmune attacks on the central nervous system (CNS). These results highlight the potential for therapies that specifically target IgG3+ B cells to impact MS progression.
Mass cytometry has allowed us to identify nine unique IgG3+ B‐cell subsets. Using two independent cohorts of multiple sclerosis (MS) patients, we show that a number of these IgG3+ subsets are not only associated with MS progression but also affected by disease‐modifying therapies. These studies highlight the potential for therapies that specifically target IgG3+ B cells to impact MS progression.
Leaf Swallowing (LS) is an atypically slow consumption of often rough leaves, which are rolled and swallowed, one by one, without chewing. This method seems to promote the expulsion of intestinal ...parasites and/or increase intestinal transit. We report observations of this type of behaviour in a population of chimpanzees (Pan troglodytes) living in captivity at the African reserve of Sigean (RAS), in France. Nine chimpanzees were provided with smooth, non-rough leaves of a plane tree (Platanus hispanica) and with rough, hispid leaves of a black mulberry (Morus nigra). All these individuals were presumed naive to LS because this behaviour had never been observed in this population before the study. This observation of LS behavior in naive chimpanzees supports the theory of a predisposition to the realization of LS with rough leaves, probably by individual learning. We also note the important role of social learning (facilitation and imitation) in the LS behaviour spread within the group. Indeed, some chimpanzees which initially rejected or chewed black mulberry leaves, then fold and swallow them (LS) after observing a congener demonstrator. Observation of LS in this healthy chimpanzee population (parasite-free, no noticeable intestinal discomfort) supports the hypothesis that LS originates from an opportunistic feeding behavior of primates in nature and not from an innate knowledge of the therapeutic property of this form of consumption. LS may simply be a spontaneous reaction to an unfamiliar leaf roughness. In this study, LS occurred with M. Nigra leaves, while this kind of behaviour was not observed with the leaves of the same species in a previous study. This allows us to refute the hypothesis of the existence of a roughness threshold, common to all chimpanzees, which would systematically trigger LS behavior.
Objective
Systemic lupus erythematosus (SLE) is a prototype autoimmune disease that is assumed to occur via a complex interplay of environmental and genetic factors. Rare causes of monogenic SLE have ...been described, providing unique insights into fundamental mechanisms of immune tolerance. The aim of this study was to identify the cause of an autosomal‐recessive form of SLE.
Methods
We studied 3 siblings with juvenile‐onset SLE from 1 consanguineous kindred and used next‐generation sequencing to identify mutations in the disease‐associated gene. We performed extensive biochemical, immunologic, and functional assays to assess the impact of the identified mutations on B cell biology.
Results
We identified a homozygous missense mutation in PRKCD, encoding protein kinase δ (PKCδ), in all 3 affected siblings. Mutation of PRKCD resulted in reduced expression and activity of the encoded protein PKCδ (involved in the deletion of autoreactive B cells), leading to resistance to B cell receptor– and calcium‐dependent apoptosis and increased B cell proliferation. Thus, as for mice deficient in PKCδ, which exhibit an SLE phenotype and B cell expansion, we observed an increased number of immature B cells in the affected family members and a developmental shift toward naive B cells with an immature phenotype.
Conclusion
Our findings indicate that PKCδ is crucial in regulating B cell tolerance and preventing self‐reactivity in humans, and that PKCδ deficiency represents a novel genetic defect of apoptosis leading to SLE.
Abstract
Background and Aims
Fabry Disease (FD) is an X linked lysosomal storage disease due to pathogenic α-galactosidase A (GLA) variants. It leads to damage in kidney and other organs. Numerous ...prevalence studies have been conducted over the past twenty years in ESRD patients in different countries. However, many screening studies did not perform confirmatory GLA variant analyses, and included recently recognized ‘benign/likely-benign’ variants, thereby inflating prevalence estimates. Thus, the prevalence of Fabry disease in patients with end-stage renal disease remains controversial.
The FABRYDIAL study aimed to measure the prevalence of Fabry disease in patients aged 18 to 75 years and treated by chronic dialysis, either hemodialysis or peritoneal dialysis.
Method
The study was conducted in France in 5 geographic sectors (Aquitaine, Ile-de-France, Rhône-Alpes and Picardie regions, and the Gard department). One hundred and twenty-four dialysis centers participated in the study, which targeted patients undergoing chronic dialysis during the week of November 20, 2017. The exclusion criteria were the existence of a proven nephropathy unrelated to FD (polycystic kidney disease, type 1 diabetes or biopsy-proven IgA nephropathy, membranous glomerulonephritis or ANCA-associated vasculitis), the absence of health insurance coverage or guardianship or tutelage. α-galactosidase A in men, and both α-galactosidase A and lyso-GL3 in women, were measured on a drop of dried blood during the usual care of patients. GLA gene sequencing was performed in patients in whom one biological value was outside normal values. If a genetic variant was identified, a multidisciplinary Diagnosis Validation Committee (DVC) concluded, based on precise literature, clinical, biological and genetic data, as to the reality of Fabry disease.
Results
Among the 6,032 patients aged 18 to 75 years under chronic dialysis during the period considered, 714 were no longer treated in the participating centers when the research staff visited for eligibility assessment. 1,121 had non-inclusion criteria, which in 89% of cases were a confirmed diagnosis of kidney disease (by renal biopsy or other means) making the existence of Fabry disease very unlikely. 4,197 patients met the inclusion criteria, of which 3,088 were included (1,888 men and 1,200 women). Valid biological analyzes were available for 2815 patients (1721 men and 1094 women), and a genetic test was indicated for 91 patients (52 men and 39 women). Ninety-seven percent of the samples were analyzed with a unique assay technique in a unique laboratory. Five patients had a genetic variant (4 men and one woman). After discussion in the DVC, one male patient was considered to have a confirmed Fabry disease. He presented early signs of the disease (first-degree family history of cardiac or unexplained death, hypohidrosis, heat intolerance, tendency to chronic diarrhea, angiokeratoma, hypoacousia and tinnitus) which could have been identified earlier. The GLA variant was c.1185dupG / p.Phe396Glyfs, a clearly pathogenic frameshift variant. The prevalence of FD in included patients with biological data was 0.035% 0.006; 0.201 (0.058% 0.010; 0.33 in men, 0.000 % 0,000; 0.350 in women). If we consider that patients who were not included because of a specific renal diagnosis unrelated to FD did not have FD, the estimated prevalence decreased to 0.028% 0.006; 0.121.
Conclusion
The estimated prevalence of FD in a cohort of French dialysis patients is 0.035% 0.006; 0.201, and by sex 0.058% in men 0.010; 0.328 and 0,000% in women 0,000; 0.35. Although it appears extremely low, it remains justified to bring up this diagnosis in the event of an evocative sign, whether for the patient or his relatives as FD benefit of effective specific treatments.
Funding for this Investigator Sponsored Study was provided by Sanofi Genzyme
Background
Treating dermatomyositis (DM) with isolated skin involvement is difficult and inconsistently performed. Intravenous immunoglobulins (IVIg) are recommended for corticoresistant or ...corticodependant DM, but only a few cases of IVIg use in DM with isolated skin involvement have been reported.
Design
We performed a retrospective monocentric study of 27 patients who were treated with IVIg for severe DM skin lesions (no or minor muscle involvement) after failure of photoprotection and at least one line of treatment.
Results
Nineteen patients (70%) exhibited a major response, four patients exhibited a partial response and four patients exhibited no response, including two patients with grade 3 side effects (headaches). The mean number of IVIg courses was 4.8 (range 1–15). Ten patients (53%) relapsed, with a median time of 6.2 months after the last IVIg course. Six of these patients were successfully treated with a new IVIg course. Muscle disease developed in six patients.
Conclusion
IVIg may be an effective and safe treatment for DM with isolated skin involvement. Relapse occurred frequently, but treatment with a new course of IVIg was successful. Controlled studies are required to confirm these results.
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