Sulfate groups position determines the ionic selectivity and syneresis properties of carrageenan systems.

The salt sensitivity and selectivity feature of α-carrageenan (α-Car) were investigated and compared with κ-carrageenan (κ-Car) and iota-carrageenan (ι-Car). These carrageenans are identified by one sulfate group on the 3,6-anhydro-D-galactose (DA) for α-Car, D-galactose (G) for κ-Car and on both carrabiose moieties (G and DA) for ι-Car. The viscosity and temperature, where order-disorder transition have been observed, were greater in presence of CaCl2 for α-Car and ι-Car compared with KCl and NaCl. Conversely, the reactivity of κ-Car systems were greater in presence of KCl than CaCl2. Unlike κ-Car systems, the gelation of α-Car in presence of KCl was observed without syneresis. Thus, the position of sulfate group on the carrabiose determines the importance of counterion valency too. The α-Car could be a good alternative to κ-Car to reduce the syneresis effects.

Determinants of work-family balance satisfaction during the pandemic: Insights from Québec.

The first wave of the COVID pandemic was the most challenging for employed parents, and more specifically for women. In Québec, research has shown a deterioration in the psychological health of parents in the early weeks of the pandemic. In this research, we investigate how Québec parents who remained employed during the lockdown in 2020 perceived their work-family balance in the stressful context of new earning and caregiving constraints, drawing on survey data collected in May 2020. Our approach integrates insights from psychological, managerial and sociological literatures. We find that most parents who remained employed found their work-family balance "easy" in the first months of the pandemic, but women felt less satisfied with their work-family balance than men as well as those whose employers were less understanding and supportive, and those whose workloads increased. The implications of these results are discussed in the light of previous studies on work-family intersections, to show that gender continues to matter when family members are faced with extraordinary circumstances such as the closing of childcare and schools, even in the egalitarian context of Québec, where fathers are perceived as legitimate caregivers.

La première vague de la pandémie de COVID a été la plus difficile pour les employés avec des enfants, et plus particulièrement pour les femmes. Au Québec, la recherche a révélé une détérioration de la santé psychologique des parents au Québec dans les premières semaines de la pandémie. Dans cette recherche, nous examinons la manière dont les parents québécois demeurés en emploi pendant le confinement en 2020 ont perçu leur conciliation emploi-famille dans le contexte stressant de nouvelles contraintes en matière de revenus et de prestation de soins, en nous appuyant sur les données d'enquête recueillies en mai 2020. Notre approche intègre des notions issues de la littérature en gestion, en psychologie et en sociologie. Nos résultats montrent que la plupart des parents qui ont conservé leur emploi ont perçu leur conciliation emploi-famille comme étant « facile ¼ au cours des premiers mois de la pandémie, mais que les femmes se sont senties moins satisfaites de leur conciliation emploi-famille que les hommes, ainsi que ceux dont les employeurs ont été moins compréhensifs et moins coopératifs, et ceux dont la charge de travail a augmenté. Les implications de ces résultats sont discutées à la lumière d'études antérieures sur les intersections emploi-famille, pour montrer que le genre continue d'avoir de l'importance lorsque les membres de la famille sont confrontés à des circonstances extraordinaires telles que la fermeture des services de garde et des écoles, même dans le contexte égalitaire du Québec, où les pères sont perçus comme des dispensateurs de soins légitimes.

The impact of a qualified medical documentation assistant on trauma room management.

PURPOSE: To improve quality of trauma room management, intra- and inter-hospital benchmarking are important tools. However, primary data quality is crucial for benchmarking reliability. In this study, we analyzed the effect of a medical documentation assistant on documentation completeness in trauma room management in comparison to documentation by physicians involved in direct patient treatment. METHODS: We included all patients treated in the trauma room from 2016/01/01 to 2016/12/31 that were documented with the trauma module of the German Emergency Department Medical Record V2015.1. We divided the data into documentation by medical documentation assistant (DA, 07:00 to 17:00), physician in daytime (PD, 07:00 to 17:00), and physician at night (PN, 17:00 to 07:00). Data were analyzed for completeness (primary outcome parameter) as well as diagnostic intervals. RESULTS: There was a significant increase in complete recorded data for DA (74.5%; IQR 14.5%) compared to PD (26.9%; IQR 18.7%; p < 0.001) and PN (30.8%; IQR 18.9; p < 0.001). The time to whole-body computed tomography (WBCT) significantly decreased for DA (19 min; IQR 8.3) compared to PD (24 min; IQR 12.8; p = 0.007) or PN (24.5 min; IQR 10.0; p = 0.001). CONCLUSION: In presence of a qualified medical documentation assistant, data completeness and time to WBCT improved significantly. Therefore, utilizing a professional DA in the trauma room appears beneficial for data quality and time management.

Implication of folate deficiency in CYP2U1 loss of function.

Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders. Understanding of their pathogenic mechanisms remains sparse, and therapeutic options are lacking. We characterized a mouse model lacking the Cyp2u1 gene, loss of which is known to be involved in a complex form of these diseases in humans. We showed that this model partially recapitulated the clinical and biochemical phenotypes of patients. Using electron microscopy, lipidomic, and proteomic studies, we identified vitamin B2 as a substrate of the CYP2U1 enzyme, as well as coenzyme Q, neopterin, and IFN-α levels as putative biomarkers in mice and fluids obtained from the largest series of CYP2U1-mutated patients reported so far. We also confirmed brain calcifications as a potential biomarker in patients. Our results suggest that CYP2U1 deficiency disrupts mitochondrial function and impacts proper neurodevelopment, which could be prevented by folate supplementation in our mouse model, followed by a neurodegenerative process altering multiple neuronal and extraneuronal tissues.

Pregnancy-induced increased heart rate is independent of thyroid hormones.

BACKGROUND: The heart rate increases by 10-20 beats per minute (bpm) throughout pregnancy in women, reaching maximum heart rate in the third trimester. During pregnancy, important changes in thyroid hormones also occur, with increases of up to 50% in the levels of triiodothyronine (T3), the biological active thyroid hormone. In addition, T3 has been shown to regulate cardiac electrophysiology. OBJECTIVE: Thus, in the present study the potential contribution of T3 in pregnancy-induced increased heart rate was explored. METHODS: We compared the heart rate between nonpregnant and pregnant mice under control conditions and after altering thyroid hormone levels with T3 and propylthiouracil (PTU, an antithyroid drug) treatments. RESULTS: Consistent with the clinical data, we found a 58% rise in T3 levels during pregnancy in mice. Although pregnant mice had a higher baseline heart rate (607 ± 8 bpm, P = .004) and higher T3 levels (1.9 ± 0.4 nM, P = .0005) than nonpregnant mice (heart rate: 546 ± 16 bpm; T3 levels: 1.2 ± 0.1 nM), their heart rate responded similarly to T3 treatment as nonpregnant mice (nonpregnant: Δ130 ± 22 bpm; pregnant: Δ126 ± 17 bpm, P = .858). Additionally, the heart rate remained significantly elevated (607 ± 11 bpm, P = .038) and comparable to untreated pregnant mice, after the use of the antithyroid drug PTU, although T3 levels (1.3 ± 0.2 nM, P = .559) returned to nonpregnant values. CONCLUSION: Based on these results, it is unlikely that T3 contributes significantly to the pregnancy-induced increased heart rate.

CSNK2B: A broad spectrum of neurodevelopmental disability and epilepsy severity.

CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures.

Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders.

BACKGROUND: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations. METHODS: We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk. RESULTS: We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs. CONCLUSIONS: Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.

Reconceptualizing Parental Leave Benefits in COVID-19 Canada: From Employment Policy to Care and Social Protection Policy.

Although the coronavirus disease 2019 (COVID-19) pandemic has spurred critical and much-needed attention to re-thinking policy approaches to child care and long-term elder care, little focus has been given to its implications for parental leave policies and parental benefits for the care of infants and young children. This article is about reconceptualizing and reconfiguring employment-based parental leave policies in Canada both during and after COVID-19. Informed by theoretical insights from the fields of care economies, feminist political economy, and care and social reproduction and by national and international parental leave research, we argue that it is time to reconceptualize parental leave benefits not only as employment policy but also as a care and social protection policy. To make this shift, we explore three topic areas: a mixed system of parental benefits that combine employment-based and citizenship-based entitlements, connections between policy design and gender equality, and the need for robust intersectional data to track which Canadian families are receiving parental benefits.

Bien que la pandémie causée par le coronavirus 2019 (COVID­19) ait largement attiré l'attention, comme le réclamaient impérieusement les circonstances, sur la réévaluation des approches politiques à l'égard des soins aux enfants et des soins de longue durée aux aînés, les répercussions de la pandémie sur les politiques de congé parental et les prestations parentales relatives aux soins aux nourrissons et aux jeunes enfants ont suscité peu d'intérêt. Les auteures se penchent sur la révision de la conception et de la configuration des politiques de congé parental basées sur l'emploi au Canada, tant pendant qu'après la COVID­19. En s'appuyant sur les connaissances théoriques relatives aux économies de soins, à l'économie politique féministe et à l'économie solidaire et la reproduction sociale, ainsi que sur les travaux de recherche sur les congés parentaux à l'échelle nationale et internationale, elles affirment que le moment est venu de repenser les prestations de congé parental à titre non seulement de politique en matière d'emploi, mais de politique de soins et de protection sociale. Elles proposent, pour opérer ce virage, trois sujets d'étude qu'elles explorent : un système mixte de prestations parentales conjuguant des droits fondés sur l'emploi et sur la citoyenneté, l'établissement de liens entre la conception des politiques et l'égalité des sexes, et la nécessité de données intersectionnelles solides pour déterminer quelles familles canadiennes reçoivent des prestations parentales.

La transformation de l'offre de services de garde au Québec: Une brèche dans la collectivisation du travail de reproduction sociale?

In 1997, the government of Québec instituted a low-cost and universal childcare services program most commonly available through the "centres de la petite enfance (CPE)" (early chilldhood centers). Since 2003, this model is being slowly dismantled on account of an explosion in the number of commercial daycare centers and, since 2015, an adjustment of rates according to family revenues. This research article gathers scattered information about the childcare services offer changes in Québec to demonstrate that tearing down a section of the Québécois family policy lowers the collectivization of social reproductive work.

En 1997, le gouvernement du Québec élabore un réseau de services de garde (SDG) à la petite enfance-au tarif faible et universel-dont l'offre se fait principalement dans les centres de la petite enfance (CPE). Depuis 2003, ce modèle fait l'objet d'un démantèlement avec l'explosion du nombre de garderies commerciales et, depuis 2015, de la modulation des tarifs selon le revenu familial. Cette article de recherche synthétise des connaissances éparses sur la transformation de l'offre de SDG au Québec pour démontrer que la déconstruction d'un pan de la politique familiale québécoise entraine une diminution de la collectivisation du travail de reproduction sociale.

Discovery of novel carbohydrate-active enzymes through the rational exploration of the protein sequences space.

Over the last two decades, the number of gene/protein sequences gleaned from sequencing projects of individual genomes and environmental DNA has grown exponentially. Only a tiny fraction of these predicted proteins has been experimentally characterized, and the function of most proteins remains hypothetical or only predicted based on sequence similarity. Despite the development of postgenomic methods, such as transcriptomics, proteomics, and metabolomics, the assignment of function to protein sequences remains one of the main challenges in modern biology. As in all classes of proteins, the growing number of predicted carbohydrate-active enzymes (CAZymes) has not been accompanied by a systematic and accurate attribution of function. Taking advantage of the CAZy database, which groups CAZymes into families and subfamilies based on amino acid similarities, we recombinantly produced 564 proteins selected from subfamilies without any biochemically characterized representatives, from distant relatives of characterized enzymes and from nonclassified proteins that show little similarity with known CAZymes. Screening these proteins for activity on a wide collection of carbohydrate substrates led to the discovery of 13 CAZyme families (two of which were also discovered by others during the course of our work), revealed three previously unknown substrate specificities, and assigned a function to 25 subfamilies.

Ancient acquisition of "alginate utilization loci" by human gut microbiota.

In bacteria from the phylum Bacteroidetes, the genes coding for enzymes involved in polysaccharide degradation are often colocalized and coregulated in so-called "polysaccharide utilization loci" (PULs). PULs dedicated to the degradation of marine polysaccharides (e.g. laminaran, ulvan, alginate and porphyran) have been characterized in marine bacteria. Interestingly, the gut microbiome of Japanese individuals acquired, by lateral transfer from marine bacteria, the genes involved in the breakdown of porphyran, the cell wall polysaccharide of the red seaweed used in maki. Sequence similarity analyses predict that the human gut microbiome also encodes enzymes for the degradation of alginate, the main cell wall polysaccharide of brown algae. We undertook the functional characterization of diverse polysaccharide lyases from family PL17, frequently found in marine bacteria as well as those of human gut bacteria. We demonstrate here that this family is polyspecific. Our phylogenetic analysis of family PL17 reveals that all alginate lyases, which have all the same specificity and mode of action, cluster together in a very distinct subfamily. The alginate lyases found in human gut bacteria group together in a single clade which is rooted deeply in the PL17 tree. These enzymes were found in PULs containing PL6 enzymes, which also clustered together in the phylogenetic tree of PL6. Together, biochemical and bioinformatics analyses suggest that acquisition of this system appears ancient and, because only traces of two successful transfers were detected upon inspection of PL6 and PL17 families, the pace of acquisition of marine polysaccharide degradation system is probably very slow.

Angiotensin II Overstimulation Leads to an Increased Susceptibility to Dilated Cardiomyopathy and Higher Mortality in Female Mice.

Heart failure (HF) is associated with high mortality and affects men and women differently. The underlying mechanisms for these sex-related differences remain largely unexplored. Accordingly, using mice with cardiac-specific overexpression of the angiotensin II (ANGII) type 1 receptor (AT1R), we explored male-female differences in the manifestations of hypertrophy and HF. AT1R mice of both sexes feature electrical and Ca2+ handling alterations, systolic dysfunction, hypertrophy and develop HF. However, females had much higher mortality (21.0%) rate than males (5.5%). In females, AT1R stimulation leads to more pronounced eccentric hypertrophy (larger increase in LV mass/body weight ratio [+31%], in cell length [+27%], in LV internal end-diastolic [LVIDd, +34%] and systolic [LVIDs, +67%] diameter) and dilation (larger decrease in LV posterior wall thickness, +17%) than males. In addition, in female AT1R mice the cytosolic Ca2+ extrusion mechanisms were more severely compromised and were associated with a specific increased in Ca2+ sparks (by 187%) and evidence of SR Ca2+ leak. Altogether, these results suggest that female AT1R mice have more severe eccentric hypertrophy, dysfunction and compromised Ca2+ dynamics. These findings indicate that females are more susceptible to the adverse effects of AT1R stimulation than males favouring the development of HF and increased mortality.

DMTMM-mediated amidation of alginate oligosaccharides aimed at modulating their interaction with proteins.

Alginate oligosaccharides (AOS) with a weight average molecular weight of 5 kDa were efficiently amidated with amino acids and carbohydrates in aqueous media in the presence of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM). Here, alanine, leucine, serine, as well as mannose and rhamnose, were amidated at high yields with a good control of the degree of substitution (DS). Amino acid- and carbohydrate-grafted AOS showed improved stability against degradation by alginate lyases having different specificities. This enzyme resistance was correlated with the DS: hydrolysis was reduced by 60-70% for low DS (0.1), whereas AOS with DS ranging from 0.4 to 0.6 remained unhydrolyzed. Competitive inhibition assays demonstrated multivalent binding of mannose-amidated AOS to concanavalin A lectin. A 178-fold affinity enhancement was observed for AOSMan-0.38 (DS 0.38) over α-methyl-mannoside with an IC50 of 5.6 µM, lending further evidence for the promising potential of AOS as multivalent scaffolds.

A risk-based, product-level approach for assuring aquatic environmental safety of cleaning products in the context of sustainability: The Environmental Safety Check (ESC) scheme of the A.I.S.E. Charter for Sustainable Cleaning.

Cleaning products have long been a focus of efforts to improve sustainability and assure safety for the aquatic environment when disposed of after use. The latter is addressed at ingredient level through environmental risk assessment, including in formal frameworks such as REACH. Nevertheless, in the context of programs to improve overall sustainability, stakeholders demand both environmental safety assurance and progress at product level. Current product-level approaches for aquatic toxicity (e.g., USEtox™, Critical Dilution Volume) can be seen as predominantly hazard-based. The more logical approach would be risk-based, because ecotoxicity is generally threshold-dependent and hazard-based assessment produces conflicts with risk-based learnings. The development of a risk-based approach to assess formulated products is described: the International Association for Soaps, Detergents and Maintenance Products (A.I.S.E.) Charter Environmental Safety Check (ESC), which is consistent with the scientific principles underlying REACH. This is implemented through a simple spreadsheet tool and internal database of ingredient parameters including predicted no-effect concentration (PNEC) and removal rate. A novel feature is applying market volume information for both product types and ingredients to permit a risk-based calculation. To pass the ESC check, the projected environmental safety ratio (PESR) for each ingredient as formulated and dosed (unless cleared by a published risk assessment or exempted as inherently low risk) must be less than 1. The advantages of a risk-based approach are discussed. The strengths and limitations of various possible approaches to standard-setting, product-ranking and driving continuous improvement in respect of potential ecotoxic impacts on the aquatic environment are considered. It is proposed that as ecotoxicity is generally accepted to be threshold-dependent, with no effect below the threshold, the most constructive approach to continuous improvement of sustainability with regard to ecotoxicity is to focus efforts on instances where the safety margins for ingredients as used in specific products are narrow. This necessitates a risk-based approach. Integr Environ Assess Manag 2017;13:127-138. © 2016 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of SETAC.

From Peptide Aptamers to Inhibitors of FUR, Bacterial Transcriptional Regulator of Iron Homeostasis and Virulence.

FUR (Ferric Uptake Regulator) protein is a global transcriptional regulator that senses iron status and controls the expression of genes involved in iron homeostasis, virulence, and oxidative stress. Ubiquitous in Gram-negative bacteria and absent in eukaryotes, FUR is an attractive antivirulence target since the inactivation of the fur gene in various pathogens attenuates their virulence. The characterization of 13-aa-long anti-FUR linear peptides derived from the variable part of the anti-FUR peptide aptamers, that were previously shown to decrease pathogenic E. coli strain virulence in a fly infection model, is described herein. Modeling, docking, and experimental approaches in vitro (activity and interaction assays, mutations) and in cells (yeast two-hybrid assays) were combined to characterize the interactions of the peptides with FUR, and to understand their mechanism of inhibition. As a result, reliable structure models of two peptide-FUR complexes are given. Inhibition sites are mapped in the groove between the two FUR subunits where DNA should also bind. Another peptide behaves differently and interferes with the dimerization itself. These results define these novel small peptide inhibitors as lead compounds for inhibition of the FUR transcription factor.

Functional Exploration of the Polysaccharide Lyase Family PL6.

Alginate, the main cell-wall polysaccharide of brown algae, is composed of two residues: mannuronic acid (M-residues) and, its C5-epimer, guluronic acid (G-residues). Alginate lyases define a class of enzymes that cleave the glycosidic bond of alginate by ß-elimination. They are classified according to their ability to recognize the distribution of M- and G-residues and are named M-, G- or MG-lyases. In the CAZy database, alginate lyases have been grouped by sequence similarity into seven distinct polysaccharide lyase families. The polysaccharide lyase family PL6 is subdivided into three subfamilies. Subfamily PL6_1 includes three biochemically characterized enzymes (two alginate lyases and one dermatan sulfatase lyase). No characterized enzymes have been described in the two other subfamilies (PL6_2 and PL6_3). To improve the prediction of polysaccharide-lyase activity in the PL6 family, we re-examined the classification of the PL6 family and biochemically characterized a set of enzymes reflecting the diversity of the protein sequences. Our results show that subfamily PL6_1 includes two dermatan sulfates lyases and several alginate lyases that have various substrate specificities and modes of action. In contrast, subfamilies PL6_2 and PL6_3 were found to contain only endo-poly-MG-lyases.

Reduction in Na(+) current by angiotensin II is mediated by PKCα in mouse and human-induced pluripotent stem cell-derived cardiomyocytes.

BACKGROUND: Ventricular arrhythmias and sudden cardiac deaths are among the leading causes of mortality in patients with heart failure, and the underlying mechanisms remain incompletely understood. Chronic elevation of angiotensin II (ANGII) is known to be one of the main contributors to heart failure. OBJECTIVE: We tested whether ANGII can alter ventricular conduction and Na(+) current using transgenic mice with cardiomyocyte-restricted overexpression of ANGII type 1 receptor (AT1R). METHODS: We used surface electrocardiograms along with current- and voltage-clamp techniques to characterize the electrophysiological properties of AT1R mice while the underlying regulatory mechanisms were explored using reverse transcription/quantitative polymerase chain reaction, Western blots, and immunofluorescence techniques. RESULTS: Electrophysiological data indicated that chronic AT1R activation in ventricular myocytes caused a 60% reduction in Na(+) current density that slowed the maximal velocity of the action potential upstroke, leading to a prolongation of the QRS complex. These changes occur independently of cardiac hypertrophy, suggesting a direct role for ANGII/AT1R in slowing ventricular conduction. Western blots demonstrated a selective increase in sarcolemmal protein kinase Cα (PKCα) in AT1R mice, indicating PKCα activation. Furthermore, immunofluorescence analysis showed reorganization of PKCα expression to sarcolemma and colocalization with NaV1.5 in AT1R myocytes. The involvement of PKCα in regulating Na(+) current was subsequently demonstrated in human-induced pluripotent stem cell-derived cardiomyocytes where ANGII treatment reduced Na(+) current density. Concomitant treatment with αV5-3, a PKCα translocation inhibitor peptide, blocked the ANGII effect. CONCLUSION: Overall, this study suggests that in mouse and human cardiomyocytes, PKCα is an important mediator of the ANGII-induced reduction in Na(+) current and may contribute to ventricular arrhythmias.

Challenges of the management of severe hemophilia A with inhibitors: two case reports emphasizing the potential interest of a high-purity human Factor VIII/von Willebrand factor concentrate and individually tailored prophylaxis guided by thrombin-generation test.

Severe hemophilia A is an X-linked bleeding disorder. Immune tolerance induction (ITI) is the best strategy of treatment when patients develop inhibitors. The objective is to illustrate the benefit of a high-purity human factor VIII/von Willebrand factor (VWF) concentrate (Octanate) in the management of ITI. We also wanted to raise the potential interest of laboratory assays such as thrombin-generation test (TGT) and epitope mapping. Two patients were treated during ITI, first with a recombinant FVIII and then with plasma-derived factor VIII without success, and, finally, with Octanate. Bypassing agents were used based on the results of TGT. Epitope mapping was performed during ITI therapy. These observations suggest the potential contribution of Octanate in the management of ITI in difficult cases. The use of bypassing agents can be necessary in prophylaxis or to treat bleedings, and may be guided by TGT results. Epitope mapping is used to describe the inhibitor. This article shows a decrease of the inhibitor directed against the C2 domain after initiation of Octanate. A high-purity human factor VIII/von Willebrand factor concentrate (Octanate) may be a valuable therapeutical option for ITI therapy. TGT and epitope mapping could be of help in the management of ITI.

Estrogen regulation of the transient outward K(+) current involves estrogen receptor α in mouse heart.

BACKGROUND AND OBJECTIVE: We have previously shown that androgens upregulate cardiac K(+) channels and shorten repolarization. However, the effects that estrogens (E2) and estrogen receptors (ER) might have on the various repolarizing K(+) currents and underlying ion channels remain incompletely understood. Accordingly, our objective was to verify whether and how E2 and its ERs subtypes influence these K(+) currents. METHODS AND RESULTS: In order to examine the influence of E2 and ERs on K(+) currents we drastically lowered the E2 level through ovariectomy (OVX; 74% reduction vs CTL) and in parallel, we used female mice lacking either ERα (ERαKO) or ERß (ERßKO). In OVX mice, results showed a specific increase of 35% in the density of the Ca(2+)-independent transient outward K(+) current (Ito) compared to CTL. Western blots showed increase in Kv4.2 and Kv4.3 sarcolemmal protein expression while qPCR revealed higher mRNA expression of only Kv4.3 in OVX mice. This upregulation of Ito was correlated with a shorter ventricular action potential duration and QTc interval. In ERαKO but not ERßKO mice, the mRNA of Kv4.3 was selectively increased. Furthermore, when ventricular myocytes obtained from ERαKO and ERßKO were cultured in the presence of E2, results showed that E2 reduced Ito density only in ERßKO myocytes confirming the repressive role of E2-ERα in regulating Ito. CONCLUSION: Altogether, these results suggest that E2 negatively regulates the density of Ito through ERα, this highlights a potential role for this female hormone and its α-subtype receptor in modulating cardiac electrical activity.

Managing the Risk of Occupational Allergy in the Enzyme Detergent Industry.

Enzyme proteins have potential to cause occupational allergy/asthma. Consequently, as users of enzymes in formulated products, detergents manufacturers have implemented a number of control measures to ensure that the hazard does not translate into health effects in the workforce. To that end, trade associations have developed best practice guidelines which emphasize occupational hygiene and medical monitoring as part of an effective risk management strategy. The need for businesses to recognize the utility of this guidance is reinforced by reports where factories which have failed to follow good industrial hygiene practices have given rise to incidences of occupational allergy. In this article, an overview is provided of how the industry guidelines are actually implemented in practice and what experience is to be derived therefrom. Both medical surveillance and air monitoring practices associated with the implementation of industry guidelines at approximately 100 manufacturing facilities are examined. The data show that by using the approaches described for the limitation of exposure, for the provision of good occupational hygiene and for the active monitoring of health, the respiratory allergenic risk associated with enzyme proteins can be successfully managed. This therefore represents an approach that could be recommended to other industries contemplating working with enzymes.