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1.
Environ Pollut ; 361: 124879, 2024 Sep 01.
Article de Anglais | MEDLINE | ID: mdl-39226983

RÉSUMÉ

Cities, contributing over 70% of global emissions, are key areas for climate change mitigation. Heterogeneity within cities determines the need for spatialized urban emissions reduction policies. However, few studies have attempted to characterize the spatial distribution of carbon emissions at the urban scale. To address this issue, a novel mapping method was proposed, using Xi'an as an example to explore the spatial distribution of carbon emissions at the city scale. Firstly, multiple geospatial open-source data, such as point of interest (POI), road networks, and land use, were utilized to identify the locations of emission sources. High-resolution carbon emission distributions were then mapped by allocating emissions based on the Intergovernmental Panel on Climate Change (IPCC) methodology. The study employed Global Moran's I to analyze the changes in spatial heterogeneity at different resolutions. Additionally, the Local Indicators of Spatial Association index (LISA) and Standard Deviation Ellipses (SDE) were adopted to examine the spatiotemporal characteristics of carbon emissions in Xi'an. The results show that carbon emissions at Xi'an City rises from 45.112 million tons to 72.701 million tons between 2010 and 2021. The construction of multi-scale carbon emissions spatial distributions, with a resolution of up to 30 m, allowed for a more detailed characterization of carbon emissions, especially in urban fringe areas. In addition, the results indicate that urban carbon emissions exhibit the strongest spatial autocorrelation at a resolution of 350 m. The study can provide a reference for the development of regional carbon emission reduction policies and spatial planning. In addition, the proposed spatialized method of city carbon emissions depends on open-source data, which allows it to have the potential for application in other cities.

2.
Expert Opin Investig Drugs ; : 1-8, 2024 Aug 22.
Article de Anglais | MEDLINE | ID: mdl-39166425

RÉSUMÉ

BACKGROUND: Inhibiting the coagulation factor XI (FXI) is a novel strategy for prevention and treatment of thromboembolism without affecting extrinsic coagulation pathways. SHR-2004 is a humanized monoclonal antibody that selectively binds to FXI and factor XIa (FXIa). RESEARCH DESIGN & METHODS: This randomized, double-blind, dose-escalation, placebo-controlled study evaluated SHR-2004 administered either intravenously (i.v.; Part A) or subcutaneously (s.c.; Part B). In Part A, 24 subjects received a single i.v. dose of SHR-2004 (0.1, 0.3, or 1.0 mg/kg) or placebo. In Part B, 40 subjects received a single s.c. dose of SHR-2004 (0.5, 1.0, 3.0, or 4.5 mg/kg) or placebo. RESULTS: SHR-2004 was well tolerated. Plasma exposure to SHR-2004 increased in a dose-dependent manner. The geometric mean half-time ranged from 11.6 to 13.0 days. FXI activity decreased, and the activated partial thromboplastin time (APTT) was prolonged after i.v. and s.c. administration in a dose- and time-dependent manner. FXI activity was nearly completely abolished immediately after administering the highest i.v. dose, with the average APTT prolonged to nearly three times of baseline. CONCLUSION: SHR-2004 is a promising candidate for further development as an anticoagulant drug that exerts effective anticoagulation with minimal risk of bleeding. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT05369767.

3.
Clin Appl Thromb Hemost ; 30: 10760296241266607, 2024.
Article de Anglais | MEDLINE | ID: mdl-39129349

RÉSUMÉ

The model for end-stage liver disease (MELD) and the model for end-stage liver disease excluding international normalized ratio (INR) (MELD-XI) scores, which reflect dysfunction of liver and kidneys, have been reported to be related to the prognosis of patients with right-sided "backward" failure. However, the relationship between the MELD/MELD-XI score and the in-hospital adverse events in pulmonary embolism (PE) patients was unknown. Normotensive PE patients were retrospectively enrolled at China-Japan friendship hospital from January 2017 to February 2020. The primary outcome was defined as death and clinical deterioration during hospitalization. Multivariate logistic analysis was used to explore the association between the MELD and MELD-XI scores for in-hospital adverse events. We also compared the accuracy of the MELD, MELD-XI, and the pulmonary embolism severity index (PESI) score using the time-dependent receiver operating characteristic curve and corresponding areas under the curve (AUC). A total of 222 PE patients were analyzed. Logistic regression analysis showed that the MELD score was independently associated with in-hospital adverse events (odds ratio = 1.115, 95% confidential interval = 1.022-1.217, P = .014). The MELD score has an AUC of 0.731 and was better than PESI (AUC of 0.629) in predicting in-hospital adverse events. Among PE patients with normal blood pressure on admission, the MELD score was associated with increased in-hospital adverse events.


Sujet(s)
Embolie pulmonaire , Humains , Embolie pulmonaire/diagnostic , Embolie pulmonaire/mortalité , Femelle , Mâle , Adulte d'âge moyen , Études rétrospectives , Sujet âgé , Maladie du foie en phase terminale/complications , Indice de gravité de la maladie , Valeur prédictive des tests , Pronostic , Maladie aigüe
4.
Cardiol Ther ; 2024 Aug 17.
Article de Anglais | MEDLINE | ID: mdl-39152241

RÉSUMÉ

Direct oral anticoagulants have a dose-dependent increased bleeding risk which limits use in certain populations. Studies in both animals and humans with inherited variations in factor XI levels provide a theoretical basis for a drug target capable of addressing current unmet needs. Milvexian is an oral factor XIa inhibitor that has the potential to provide robust anticoagulant effect without increased bleeding compared with current standard of care. Several key studies in the preclinical, phase I, and phase II stages have reported promising safety data in venous thromboembolism and stroke prevention without compromising hemostasis. The planned phase III trials will examine the efficacy of milvexian for prevention of thrombotic events in patients with acute stroke, acute coronary syndrome, and atrial fibrillation.

5.
Semin Dial ; 2024 Aug 18.
Article de Anglais | MEDLINE | ID: mdl-39155083

RÉSUMÉ

Coagulation Factor XI (FXI) and Factor XII (FXII) deficiencies are rare. FXI deficiency is associated with a bleeding disorder, while FXII deficiency is not, but both can cause chronic prolongation of activated partial thromboplastin time and impair thrombus formation, posing great challenges for hemodialysis anticoagulation. Traditionally, heparin or low-molecular-weight heparins (LMWHs) are not considered a safe anticoagulation option for patients with increased bleeding risk. In this context, FXI and FXII have received substantial attention as targets for new anticoagulants. We present the case of a 68-year-old woman with combined FXI and FXII deficiencies who successfully underwent hemodialysis with anticoagulation using a low dose of LMWHs. This case highlights that FXI and FXII deficiencies are associated with anticoagulant effects, which can reduce the dosage of anticoagulant during hemodialysis. With careful monitoring, an appropriate dosage of LMWHs is still an acceptable option for patients with a bleeding risk.

6.
J Neurol Sci ; 464: 123157, 2024 Sep 15.
Article de Anglais | MEDLINE | ID: mdl-39094433

RÉSUMÉ

The "holy grail" of preventing and treating thrombosis and thromboembolism would be a drug that was highly effective (preventing clots) and at the same time had a low risk of bleeding. From a hemostasiological perspective, the inhibition of factor XI represents a promising target because a reduced level of factor XI protects against thrombosis without significantly increasing the risk of spontaneous bleeding. Currently, three different classes of drugs of factor XI-inhibition are tested. These are (1) monoclonal antibodies (mAbs), (2) so-called synthetic, small molecules and (3) antisense oligonucleotides (ASOs). This article provides a narrative overview of the current status of studies on all three classes of drugs. Tests with mAbs have been conducted primarily in DVT prevention after knee replacement surgery. One large phase 3 study is testing the mAbs Abelacimab in patients with atrial fibrillation. The synthetic, small molecules Asundexian and Milvexian are tested in several phase 3 trials, mainly in patients with non-cardioembolic ischemic stroke. Results can be expected in the coming years. Clinical testing of ASOs to inhibit factor XI are still in their infancies.


Sujet(s)
Facteur XI , Humains , Facteur XI/antagonistes et inhibiteurs , Oligonucléotides antisens/usage thérapeutique , Anticorps monoclonaux/usage thérapeutique , Fibrinolytiques/usage thérapeutique , Thrombose/prévention et contrôle , Animaux
7.
Zhongguo Zhen Jiu ; 44(8): 871-5, 2024 Aug 12.
Article de Chinois | MEDLINE | ID: mdl-39111783

RÉSUMÉ

Based on the function of xi-cleft points and shu-streams points and in association with the anatomic structure where the acupoints are located, Cixi (stimulating meridian qi at xi-cleft points) is used for regulating the physical appearance, while Tongshu (promoting the qi circulation of shu-stream points) is for regulating the spirit. The depth and direction of needle insertion are controlled and deqi is determined by muscle twitching so as to relax the muscles. Rehabilitation training is combined to restore the foot proprioceptive sensibility. The above comprehensive method co-works on correcting post-stroke foot inversion and recovering walking ability in the patients.


Sujet(s)
Thérapie par acupuncture , Accident vasculaire cérébral , Humains , Accident vasculaire cérébral/complications , Accident vasculaire cérébral/thérapie , Accident vasculaire cérébral/physiopathologie , Mâle , Femelle , Adulte d'âge moyen , Sujet âgé , Réadaptation après un accident vasculaire cérébral/méthodes , Points d'acupuncture , Pied/physiopathologie , Adulte , Association thérapeutique
8.
J Clin Med ; 13(14)2024 Jul 19.
Article de Anglais | MEDLINE | ID: mdl-39064250

RÉSUMÉ

This case report details the surgical treatment of a rare enlarged cervical leiomyoma with uterine prolapse in a 48-year-old woman. She presented to Konyang University Hospital with a palpable vaginal mass, lower abdominal pain, and urinary incontinence. Despite being nulliparous, she had severe chronic constipation due to schizophrenia medication and lived in a health care facility separated from her family. Pelvic examination revealed stage 3 uterine prolapse with a large necrotic cervical leiomyoma. A robot-assisted vaginal hysterectomy followed by sacrocolpopexy was performed using the Da Vinci Xi Surgical System. Histopathology confirmed cervical leiomyoma with squamous metaplasia. At a three-month follow-up, there were no complications, pelvic anatomy was restored, and urinary incontinence improved. Although the patient had a systemic infection due to the necrotic cervical leiomyoma, raising concerns about the increased risk of infection associated with mesh use, she was high-risk for pelvic organ prolapse (POP) recurrence due to her medical history and living situation. Therefore, she underwent concurrent surgeries with pre- and postoperative antibiotic treatment, and recovered without complications. Given that the risk of developing POP increases after a hysterectomy, in high-risk patients, as demonstrated in this case, the concurrent surgical correction of POP may be an effective strategy.

9.
Article de Anglais | MEDLINE | ID: mdl-39078536

RÉSUMÉ

When selecting an anticoagulant, clinicians consider individual patient characteristic, the treatment indication, drug pharmacology, and safety and efficacy as demonstrated in randomized trials. An ideal anticoagulant prevents thrombosis with little or no increase in bleeding. Direct oral anticoagulants represent a major advance over traditional anticoagulants (e.g., unfractionated heparin, warfarin) but still cause bleeding, particularly from the gastrointestinal tract which can limit their use. Epidemiological studies indicate that patients with congenital factor XI (FXI) deficiency have a lower risk of venous thromboembolism (VTE) and ischemic stroke (IS) than non-deficient individuals, and do not have an increased risk of spontaneous bleeding, even with severe deficiency. These observations provide the rationale for targeting FXI as a new class of anticoagulant. Multiple FXI inhibitors have been introduced and several are being evaluated in Phase III trials. In this review, we explain why drugs that target FXI may be associated with a lower risk of bleeding than currently available anticoagulants and summarize the completed and ongoing trials.

10.
J Thromb Haemost ; 2024 Jul 17.
Article de Anglais | MEDLINE | ID: mdl-39029742

RÉSUMÉ

The currently approved direct oral anticoagulants (DOACs) are increasingly used in clinical practice. Although serious bleeding risks are lower with DOACs than with vitamin K antagonists, bleeding remains the most frequent side effect. Andexanet alfa and idarucizumab are the currently approved specific reversal agents for oral factor (F)Xa inhibitors and dabigatran, respectively. Our prior guidance document was published in 2016, but with more information available on the utility and increased use of these reversal agents and other bleeding management strategies, we have updated this International Society on Thrombosis and Haemostasis guidance document on DOAC reversal. In this narrative review, we compare the mechanism of action of specific and nonspecific reversal agents, review the clinical data supporting their use, and provide guidance on when reversal is indicated. In addition, we briefly discuss the reversal of oral FXIa inhibitors, a new class of DOACs currently under clinical development.

11.
Curr Cardiol Rep ; 26(9): 911-917, 2024 Sep.
Article de Anglais | MEDLINE | ID: mdl-39042343

RÉSUMÉ

PURPOSE OF REVIEW: This review provides an overview of the factor XI (FXI) inhibitor hypothesis for the development of novel anticoagulants which may be safer to those currently used in clinical practice and describes preliminary clinical data from phase 2 dose-ranging studies of patients with atrial fibrillation. RECENT FINDINGS: Recent data from phase 2 dose ranging studies demonstrate substantial reductions in bleeding with FXI pathway inhibition compared with currently approved anticoagulants. However, larger studies are necessary to demonstrate efficacy of FXI inhibition for stroke prevention in atrial fibrillation. FXI pathway inhibition holds great promise for revolutionizing the landscape of anticoagulation for atrial fibrillation, primarily by reducing bleeding risk; however, further data are necessary to demonstrate efficacy.


Sujet(s)
Anticoagulants , Fibrillation auriculaire , Facteur XI , Hémorragie , Accident vasculaire cérébral , Humains , Fibrillation auriculaire/complications , Fibrillation auriculaire/traitement médicamenteux , Accident vasculaire cérébral/prévention et contrôle , Accident vasculaire cérébral/étiologie , Anticoagulants/usage thérapeutique , Facteur XI/antagonistes et inhibiteurs , Hémorragie/induit chimiquement
12.
Haemophilia ; 2024 Jul 01.
Article de Anglais | MEDLINE | ID: mdl-38951042

RÉSUMÉ

INTRODUCTION: The management of Factor XI deficiency is challenged by a variable association between FXI level and bleeding phenotype. Additionally, there is scarce data describing management strategies and their outcomes, specifically bleeding, thrombosis, and other complications. AIMS: To evaluate bleeding, thrombosis, and other complications in individuals with severe FXI deficiency seen in our comprehensive haemophilia treatment centre (HTC). Peri-procedural management strategies and the resulting impact on bleeding and other clinically relevant outcomes were reported. METHODS: Retrospective review of the electronic medical record of adult patients with severe FXI deficiency (< 20% activity) seen at a New York City comprehensive HTC between 2017 and 2022. Procedures, haemostatic management, and outcomes were collected and analysed. RESULTS: We identified 38 individuals (64%) females with severe FXI deficiency. The mean age was 56 ± 21 years (SD). The median FXI activity level was 3% (IQR: 1-8%). The mean BAT score was 3.1 ± 2.4; (52%) individuals did not have a history of bleeding. A total of 256 surgeries and procedures were performed. There was reduced bleeding with preventative or reactive treatment during procedures. Arterial but not venous thrombotic complications were observed. Plasma was mostly used for procedures associated with higher risk of bleeding and antifibrinolytics for procedures at sites of high fibrinolysis. CONCLUSIONS: Current management strategies pose a burden of care for these patients and manifested as nonbleeding adverse events and changes in clinical management. These findings highlight the need for novel investigation in predicting and managing bleeding for individuals with severe FXI deficiency.

13.
Res Pract Thromb Haemost ; 8(4): 102462, 2024 May.
Article de Anglais | MEDLINE | ID: mdl-39006229

RÉSUMÉ

Background: Factor (F)XI deficiency is a rare bleeding disorder with a poor correlation between bleeding tendency and FXI level. Management of pregnant women with FXI deficiency is not clearly established, especially regarding neuraxial analgesia (NA). Objectives: A retrospective multicenter observational study was conducted in French hemostasis centers on pregnant women with FXI of <60 IU/dL. Methods: Data to report were (i) FXI levels before pregnancy and at time of delivery, (ii) type of NA and delivery management modalities, and (iii) possible complications related to NA and bleeding complications. Results: Three hundred fourteen pregnancies in patients with FXI deficiency of <60 IU/dL were reported (from 20 centers); among them, 199 NA procedures have been completed (137 epidurals and 61 spinals, 1 had both). The period of childbirth was mostly from 2014 to 2020 (281/314; 89.5%). Congenital FXI deficiency was established with certainty by investigators in 32.8% patients (n = 103). Previous bleedings were described in 20.4% of the patients (64/314; 45.3% cutaneous, 31.3% gynecologic, and 15.6% postsurgical). Thirteen deliveries had an NA procedure with FXI of <30 IU/dL, 42 with FXI of 30-40 IU/dL, and 118 with FXI of 40-60 IU/dL. Median FXI levels at delivery in the epidural and spinal groups were not significantly different but were significantly lower in the group without NA by medical staff contraindications. There were no complications related to NA. A 17.5% postpartum hemorrhage or excessive postpartum bleeding incidence was reported, which is consistent with previous data. Conclusion: Our data support the use of a 30 IU/dL FXI threshold for NA, as suggested by the French proposals published in August 2023.

14.
Cureus ; 16(6): e62328, 2024 Jun.
Article de Anglais | MEDLINE | ID: mdl-39006713

RÉSUMÉ

Sheehan's syndrome (SS) is a condition characterized by panhypopituitarism that generally occurs after an episode of postpartum bleeding. There are certain hypotheses regarding the development of SS in the postpartum period. Coagulation factor abnormalities have been reported to be associated with SS. Associated hypothyroidism and hypocortisolism have been found to cause coagulation abnormalities. After the correction of the hypothyroidism and hypocortisolism, there is a gradual correction of the coagulation abnormality. In our case, a middle-aged woman presented with recurrent episodes of hospital admission because of generalized weakness and fever. She was found to have a biochemistry profile suggestive of hypopituitarism with preserved gonadal function. Her hemogram was normal, but the coagulogram showed a prolongation of activated partial thromboplastin time with a near-normal prothrombin time. She was evaluated and found to have factor XI deficiency. In the background of excessive vaginal bleeding and hypopituitarism, a diagnosis of SS was made. The presence of factor XI deficiency may have led to excessive bleeding and the development of SS. To the best of our knowledge, there is no reported association of factor XI deficiency with SS in the literature, and this is the first reported case.

15.
Haemophilia ; 2024 Jul 22.
Article de Anglais | MEDLINE | ID: mdl-39039722

RÉSUMÉ

INTRODUCTION: Factor (F) XI deficiency is an inherited bleeding disorder with increased prevalence in Ashkenazi Jews where it is mainly caused by two variants, p.Glu135* (type II, leading to a null allele) and p.Phe301Leu (type III, missense variant). Inhibitor development is rare, and only seen in severe FXI deficiency (<20 IU/dL) upon exposure to plasma-based products. We report our experience of a large cohort of patients with severe FXI deficiency, including seven patients who developed FXI alloinhibitors, their presentation, natural history and subsequent perioperative management. METHODS: A single-centre retrospective database review of patients with FXI deficiency, including those who have subsequently developed inhibitors, and extraction of clinical, laboratory and genotype data, including operative management records. RESULTS: A total of 682 patients were identified with FXI deficiency, of whom 113 had FXI < 20 IU/dL and 42 had FXI ≤ 1 IU/dL. Factor XI inhibitors were seen in seven patients, six of whom were homozygous for the type II variant (prevalence of inhibitor with this genotype of 30%, risk of inhibitor upon plasma exposure 50%). FXI inhibitors were not seen, despite similar exposures, in patients with other genotypes. No alteration in bleeding phenotype occurred after inhibitor development and subsequent surgery was managed on 13 occasions with recombinant factor VIIa (rFVIIa), including low doses (15-30 µg/kg), with good haemostasis. The inhibitor spontaneously disappeared in four of seven patients over 1-22 years. CONCLUSION: FXI inhibitors were only observed in severe FXI deficient patients homozygous for p.Glu135* (null allele) upon plasma or FXI concentrate exposure, with a 30% prevalence. The bleeding phenotype was not altered and inhibitors may disappear with time. Adequate haemostasis in the perioperative setting is achievable with low doses of rFVIIa.

16.
Thromb Res ; 241: 109086, 2024 Sep.
Article de Anglais | MEDLINE | ID: mdl-38968817

RÉSUMÉ

INTRODUCTION: Postthrombotic syndrome (PTS), a common complication of deep vein thrombosis (DVT), is largely inflammatory by nature with contribution of prothrombotic mechanisms. The role of factor (F)XI in PTS has not been explored yet. We investigated whether elevated FXI is associated with PTS occurrence. MATERIALS AND METHODS: We enrolled 180 consecutive patients (aged 43 ± 13 years) with first-ever DVT. After 3 months FXI levels were measured, along with inflammatory markers, thrombin generation, plasma clot permeability (Ks), clot lysis time (CLT), and fibrinolysis proteins. We assessed PTS using the Villalta score and recorded symptomatic venous thromboembolism (VTE) at a 1-year and venous ulcers at a median 53 months follow-up. RESULTS: Baseline median FXI was 102 % [IQR 92-113 %] and showed positive association with Villalta score (R = 0.474, P < 0.001). Patients with PTS (n = 48, 26.7 %) had 16.1 % higher FXI (P < 0.001) and FXI ≥120 % occurred more often in PTS patients (odds ratio [OR] 5.55, 95 % confidence interval [CI] 2.28-13.47). There were associations of baseline FXI with Ks and CLT along with thrombin activatable fibrinolysis inhibitor (TAFI) activity, C-reactive protein, and interleukin-6, but not with fibrinogen, or thrombin generation. After age adjustment higher FXI was independently associated with PTS occurrence (OR per 1 % 1.06, 95 % CI 1.02-1.09) and VTE recurrence (OR 1.03, 95 % CI 1.01-1.06). At long-term follow-up, patients with venous ulcers had 13.6 % higher baseline FXI (P = 0.002). CONCLUSIONS: Elevated FXI in association with inflammation and prothrombotic fibrin clot properties may contribute to the development of PTS following DVT.


Sujet(s)
Facteur XI , Syndrome post-thrombotique , Humains , Femelle , Mâle , Syndrome post-thrombotique/sang , Adulte , Facteur XI/métabolisme , Adulte d'âge moyen , Thrombose veineuse/sang
17.
Eur Heart J Open ; 4(3): oeae043, 2024 May.
Article de Anglais | MEDLINE | ID: mdl-38933427

RÉSUMÉ

Aims: Anticoagulants are routinely used by millions of patients worldwide to prevent blood clots. Yet, problems with anticoagulant therapy remain, including a persistent and cumulative bleeding risk in patients undergoing prolonged anticoagulation. New safer anticoagulant targets are needed. Methods and results: To prioritize anticoagulant targets with the strongest efficacy [venous thromboembolism (VTE) prevention] and safety (low bleeding risk) profiles, we performed two-sample Mendelian randomization and genetic colocalization. We leveraged three large-scale plasma protein data sets (deCODE as discovery data set and Fenland and Atherosclerosis Risk in Communities as replication data sets] and one liver gene expression data set (Institut Universitaire de Cardiologie et de Pneumologie de Québec bariatric biobank) to evaluate evidence for a causal effect of 26 coagulation cascade proteins on VTE from a new genome-wide association meta-analysis of 44 232 VTE cases and 847 152 controls, stroke subtypes, bleeding outcomes, and parental lifespan as an overall measure of efficacy/safety ratio. A 1 SD genetically predicted reduction in F2 blood levels was associated with lower risk of VTE [odds ratio (OR) = 0.44, 95% confidence interval (CI) = 0.38-0.51, P = 2.6e-28] and cardioembolic stroke risk (OR = 0.55, 95% CI = 0.39-0.76, P = 4.2e-04) but not with bleeding (OR = 1.13, 95% CI = 0.93-1.36, P = 2.2e-01). Genetically predicted F11 reduction was associated with lower risk of VTE (OR = 0.61, 95% CI = 0.58-0.64, P = 4.1e-85) and cardioembolic stroke (OR = 0.77, 95% CI = 0.69-0.86, P = 4.1e-06) but not with bleeding (OR = 1.01, 95% CI = 0.95-1.08, P = 7.5e-01). These Mendelian randomization associations were concordant across the three blood protein data sets and the hepatic gene expression data set as well as colocalization analyses. Conclusion: These results provide strong genetic evidence that F2 and F11 may represent safe and efficacious therapeutic targets to prevent VTE and cardioembolic strokes without substantially increasing bleeding risk.

18.
J Scleroderma Relat Disord ; 9(2): 81-85, 2024 Jun.
Article de Anglais | MEDLINE | ID: mdl-38910594

RÉSUMÉ

Systemic sclerosis is a rare disease with a high mortality rate. It is a multisystem connective tissue disease due to endothelial autoimmune activation along with tissue and vascular fibrosis, inducing vasculopathy, with an angiogenesis wasting. The endothelial damage provokes platelet activation and immune cell adhesion. The detachment of endothelial cells leads to the interaction of platelets and collagen present in the exposed subendothelial layer. This provokes the activation of several coagulative factors, inducing a pro-thrombotic condition by thrombin generation, which converts fibrinogen into fibrin. Moreover, thrombin has other functions, such as the induction of hyperplasia in smooth muscle cells and fibroblasts, thereby favouring fibrosis. An increased risk of venous thromboembolism has been found in systemic sclerosis, whereas pulmonary hypertension may be due to the obstruction of small pulmonary arteries. Pulmonary veno-occlusive disease may also occur. Warfarin showed inconsistent results, while the outcomes of a randomised, placebo-controlled clinical trial on apixaban versus placebo are still awaited. A new anticoagulation strategy based on anti-factor XI drugs is being developed, with the aim of achieving optimal anticoagulation along with a low risk of bleeding. The molecule types under investigation in this category include monoclonal antibodies, small molecules, natural inhibitors, antisense oligonucleotides, and aptamers. Patients with systemic sclerosis may be ideal candidates for clinical trials planned to analyse the efficacy and safety of these molecules.

19.
Anaesth Rep ; 12(1): e12308, 2024.
Article de Anglais | MEDLINE | ID: mdl-38919170

RÉSUMÉ

Factor XI deficiency is a rare disorder with an unpredictable bleeding tendency. Here, we report the successful use of the sonic estimation of elasticity via resonance sonorheometry for guiding the management of haemostasis in a patient with a severe factor XI deficiency in repeated revision hip surgeries. Regardless of an administration of fresh frozen plasma, a significant haemorrhage occurred at the first of three hip surgeries. The repeat application of fresh frozen plasma normalised the prolonged activated partial thromboplastin time and the resonance sonorheometry clot time values; the factor XI activity increased to a sufficient level. No significant bleeding occurred in the second and third hip surgery. Using a resonance sonorheometry guided approach in haemostasis management has the potential to improve safety for patients with factor XI deficiency undergoing surgery by ensuring sufficient clotting and preventing side effects.

20.
Proc Natl Acad Sci U S A ; 121(25): e2312415121, 2024 Jun 18.
Article de Anglais | MEDLINE | ID: mdl-38875149

RÉSUMÉ

Plants rely on immune receptor complexes at the cell surface to perceive microbial molecules and transduce these signals into the cell to regulate immunity. Various immune receptors and associated proteins are often dynamically distributed in specific nanodomains on the plasma membrane (PM). However, the exact molecular mechanism and functional relevance of this nanodomain targeting in plant immunity regulation remain largely unknown. By utilizing high spatiotemporal resolution imaging and single-particle tracking analysis, we show that myosin XIK interacts with remorin to recruit and stabilize PM-associated kinase BOTRYTIS-INDUCED KINASE 1 (BIK1) within immune receptor FLAGELLIN SENSING 2 (FLS2)-containing nanodomains. This recruitment facilitates FLS2/BIK1 complex formation, leading to the full activation of BIK1-dependent defense responses upon ligand perception. Collectively, our findings provide compelling evidence that myosin XI functions as a molecular scaffold to enable a spatially confined complex assembly within nanodomains. This ensures the presence of a sufficient quantity of preformed immune receptor complex for efficient signaling transduction from the cell surface.


Sujet(s)
Protéines d'Arabidopsis , Arabidopsis , Immunité innée , Myosines , Immunité des plantes , Protein-Serine-Threonine Kinases , Arabidopsis/immunologie , Arabidopsis/métabolisme , Arabidopsis/génétique , Protéines d'Arabidopsis/métabolisme , Protéines d'Arabidopsis/génétique , Membrane cellulaire/métabolisme , Myosines/métabolisme , Maladies des plantes/immunologie , Maladies des plantes/microbiologie , Protein kinases/métabolisme , Protein-Serine-Threonine Kinases/métabolisme , Transduction du signal
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