Inhibitor Deficiency Research Articles

Preliminary results of a non-interventional single-center study evaluating the efficacy of long-term use of lanadelumab in routine clinical practice in the Russian Federation

BACKGROUND: Hereditary angioedema with C1 inhibitor deficiency is a rare disease caused by a deficiency and/or a decrease in the functional activity of the C1 inhibitor. The primary symptom of this condition is recurrent angioedema of various localizations. According to the modern concept of treatment, the therapy aims to stop emerging angioedema and prevent death as well as achieve complete control of the disease and a high quality of life. Lanadelumab is a modern medicine developed and used to prevent attacks in patients with hereditary angioedema aged 12 years.
 AIM: A retrospective study (IISR-2021-200085) was conducted to evaluate the efficiency and safety of lanadelumab in real-life practice in Russia.
 MATERIALS AND METHODS: In all, 16 patients with hereditary angioedema and C1 inhibitor deficiency were enrolled at the initiation of lanadelumab treatment. The patients were predominantly female (81%; 13/16). The average age of patients was 29.9 years; 19% (3/16) of the patients were adolescents. The effectiveness was evaluated by comparing the patient-reported attack rates. The following PROs for the adults only were assessed initially and during the treatment: angioedema activity score, angioedema control test (AECT), angioedema quality of life questionnaire (AE-QoL), and hereditary angioedema activity score. The incidences of adverse events were evaluated.
 RESULTS: Before lanadelumab, 69% (11/16) of the patients received alternative long-term prophylaxis, which was canceled after the start of lanadelumab treatment. The average number of attacks per month and treated attacks per month prelanadelumab were 10 and 4.7 per patient, respectively. After 6 months of treatment, these values were 0.26 and 0.09, respectively (10 patients were symptom free at 6 months after the initiation of the treatment). After 3 months of treatment, the mean AECT values improved from 5.6 to 14.2 (p 0.001), and all patients showed adequate disease control. After 6 months of treatment, AE-QoL decreased from 58 to 19 (p 0.001). No serious adverse events related to lanadelumab were observed.
 CONCLUSION: Our study demonstrated that the composite effect of lanadelumab minimizes the attack rate and improves the quality of life in patients with hereditary angioedema. A good safety profile of lanadelumab is shown.

Effects of a PDE10A inhibitor and PDE10A2 deficiency on voluntary alcohol intake in mice

Effects of a PDE10A inhibitor and PDE10A2 deficiency on voluntary alcohol intake in mice

Mechanisms involved in hereditary angioedema with normal C1-inhibitor activity.

Patients with the inherited disorder hereditary angioedema (HAE) suffer from episodes of soft tissue swelling due to excessive bradykinin production. In most cases, dysregulation of the plasma kallikrein-kinin system due to deficiency of plasma C1 inhibitor is the underlying cause. However, at least 10% of HAE patients have normal plasma C1 inhibitor activity levels, indicating their syndrome is the result of other causes. Two mutations in plasma protease zymogens that appear causative for HAE with normal C1 inhibitor activity have been identified in multiple families. Both appear to alter protease activity in a gain-of-function manner. Lysine or arginine substitutions for threonine 309 in factor XII introduces a new protease cleavage site that results in formation of a truncated factor XII protein (Δ-factor XII) that accelerates kallikrein-kinin system activity. A glutamic acid substitution for lysine 311 in the fibrinolytic protein plasminogen creates a consensus binding site for lysine/arginine side chains. The plasmin form of the variant plasminogen cleaves plasma kininogens to release bradykinin directly, bypassing the kallikrein-kinin system. Here we review work on the mechanisms of action of the FXII-Lys/Arg309 and Plasminogen-Glu311 variants, and discuss the clinical implications of these mechanisms.

Multicentric Observational Study on Safety and Tolerability of COVID-19 Vaccines in Patients with Angioedema with C1 Inhibitor Deficiency: Data from Italian Network on Hereditary and Acquired Angioedema (ITACA).

Angioedema due to C1 inhibitor deficiency (AE-C1-INH) is a rare disease characterized by recurrent and unpredictable attacks of angioedema. Multiple trigger factors, including trauma, emotional stress, infectious diseases, and drugs, could elicit angioedema attacks. The aim of this study was to collect data on the safety and tolerability of COVID-19 vaccines in a population of patients affected by AE-C1-INH. Adult patients with AE-C1-INH, followed by Reference Centers belonging to the Italian Network for Hereditary and Acquired Angioedema (ITACA), were enrolled in this study. Patients received nucleoside-modified mRNA vaccines and vaccines with adenovirus vectors. Data on acute attacks developed in the 72 h following COVID-19 vaccinations were collected. The frequency of attacks in the 6 months after the COVID-19 vaccination was compared with the rate of attacks registered in the 6 months before the first vaccination. Between December 2020 and June 2022, 208 patients (118 females) with AE-C1-INH received COVID-19 vaccines. A total of 529 doses of the COVID-19 vaccine were administered, and the majority of patients received mRNA vaccines. Forty-eight attacks of angioedema (9%) occurred within 72 h following COVID-19 vaccinations. About half of the attacks were abdominal. Attacks were successfully treated with on-demand therapy. No hospitalizations were registered. There was no increase in the monthly attack rate following the vaccination. The most common adverse reactions were pain at the site of injection and fever. Our results show that adult patients with angioedema due to C1 inhibitor deficiency can be safely vaccinated against SARS-CoV-2 in a controlled medical setting and should always have available on-demand therapies.

Acquired Angioedema in Selected Neoplastic Diseases.

Background and Objectives. Acquired angioedema is a relatively common revelation accompanying some diseases such as autoimmune or cancer. The study aimed to assess the incidence of one subtype of angioedema-C1-INH-AAE (acquired angioedema with C1 inhibitor deficiency). Material and methods. The study was retrospective and based on 1 312 patients with a final diagnosis of breast cancer, colorectal cancer, or lung cancer: 723 women and 589 men with a mean age of 58.2 ± 13.5 years. The cancer diagnosis according to the ICD (International Classification of Diseases)-10 code, medical history including TNM (Tumour, Node, Metastasis) staging, histopathology, and assessment of the occurrence of C1-INH-AAE angioedema were analysed. Results. C1-INH-AAE occurred more often in patients with cancer than in the control group, as follows: 327 (29%) vs. 53 (6%) for p < 0.05. C1-INH-AAEs were observed most often in the group of patients diagnosed with breast cancer compared to colorectal and lung groups: 197 (37%) vs. 108 (26%) vs. 22 (16%) (p < 0.05). A higher incidence of C1-INH-AAE was observed in the early stages of breast cancer. However, there was no relationship between the occurrence of C1-INH-AAE and the BRCA1 (Breast Cancer gene 1)/BRCA2 (Breast Cancer gene 2) mutation or histopathological types of breast cancer. Conclusion. Angioedema type C1-INH-AAE occurs more often in patients with selected neoplastic diseases, especially in the early stages of breast cancer.

Genetic deficiency of protein inhibitor of activated STAT3 suppresses experimental abdominal aortic aneurysms.

Signal transducer and activator of transcription (STAT) signaling is critical for the pathogenesis of abdominal aortic aneurysms (AAAs). Though protein inhibitor of activated STAT3 (PIAS3) negatively modulates STAT3 activity, but its role in AAA disease remains undefined. AAAs were induced in PIAS3 deficient (PIAS3-/-) and wild type (PIAS3+/+) male mice via transient intra-aortic elastase infusion. AAAs were assessed by in situ measurements of infrarenal aortic external diameters prior to (day 0) and 14 days after elastase infusion. Characteristic aneurysmal pathologies were evaluated by histopathology. Fourteen days following elastase infusion, aneurysmal aortic diameter was reduced by an approximately 50% in PIAS3-/- as compared to PIAS3+/+ mice. On histological analyses, PIAS3-/- mice showed less medial elastin degradation (media score: 2.5) and smooth muscle cell loss (media score: 3.0) than those in PIAS3+/+ mice (media score: 4 for both elastin and SMC destruction). Aortic wall leukocyte accumulation including macrophages, CD4+ T cells, CD8+ T cells and B cells as well as mural neovessel formation were significantly reduced in PIAS3-/- as compared to PIAS3+/+ mice. Additionally, PIAS3 deficiency also downregulated the expression levels of matrix metalloproteinases 2 and 9 by 61% and 70%, respectively, in aneurysmal lesion. PIAS3 deficiency ameliorated experimental AAAs in conjunction with reduced medial elastin degradation and smooth muscle cell depletion, mural leukocyte accumulation and angiogenesis.

Prevention of Recurrent Attacks of Hereditary Angioedema (HAE): Berotralstat and Its Oral Bioavailability.

Hereditary angioedema (HAE) is a condition characterized by episodes of cutaneous and submucosal edema. Angioedema of the extremities and abdominal attacks are the most common manifestations of the disease. It can also affect the upper airways with the potential of becoming life-threatening. The two most common causes of HAE are a deficiency of C1 inhibitor (classified as type 1 HAE) or a dysfunction of C1 inhibitor (type 2 HAE). A malfunction or deficiency of C1 inhibitor leads to an overactivated plasma kallikrein (an inflammatory vasoactive peptide), that increases bradykinin, mediating the angioedema episodes in patients with HAE. To minimize the difficulties of this pathology and to improve patients' quality of life, prevention of this condition is essential. Berotralstat is a unique option for oral administration for routine prophylaxis. This drug acts by binding to kallikrein and reducing its plasma activity, lowering bradykinin levels. Open-label studies have demonstrated the effectiveness of a single daily dose of berotralstat 150 mg in preventing HAE attacks. This review aims to examine studies performed to elucidate the efficacy, safety, and tolerability of berotralstat.

Burden of illness seen in hereditary angioedema in Japanese patients: Results from a patient reported outcome survey.

Hereditary angioedema (HAE) is a potentially life-threatening rare disease, which is mainly caused by the deficiency or dysfunction of C1-esterase inhibitor, and characterized by spontaneous, recurrent episodes of edema in various parts of the body including internal organs and the laryngeal area. Delayed diagnosis and treatment increase the burdens and risks of this condition. The current study aimed to understand the burden of illness for HAE patients in Japan before and after diagnosis through a patient reported outcome survey. A survey instrument was distributed to 121 adult patients with HAE by a patient organization via HAE treating physicians between July and November in 2016. Seventy patients (57.9%) returned the questionnaire. Patients reported high levels of medical resource utilization, including emergency procedures and services. Episodes of receiving laparotomy were somewhat less after diagnosis with HAE than before, but no apparent difference in episodes of tracheotomy between before and after the diagnosis. The economic burden, including direct and indirect medical costs, was highest before diagnosis, but still perceived as substantial after diagnosis. Patients reported disruption of work and school life, with 40% reporting that they miss 10 or more days from work or education per year. Sixty percent of patients reported that HAE affected their daily activities. We concluded that HAE is associated with considerable physical, social, economic and psycho-social burdens even after diagnosis, and that higher attack frequency is associated with a heavy disease burden for patients in Japan.

Fibrinolysis-Related Bleeding Troubles

An intricate enzymatic process called fibrinolysis is used to eliminate blood clots and stop vascular clogging. Numerous cofactors that make up the fibrinolytic system regulate fibrin breakdown and uphold the hemostatic balance. Different disease events that promote prothrombotic or hemorrhagic states based on the form of aberration are linked to the dysregulation of fibrinolysis. This review is centered on fibrinolysis ailments that can be either heritable or acquired and affect both adults and children. A shortage of one of the fibrinolysis inhibitors deficiencies, such as Plasminogen Activator Inhibitor Type 1 (PAI-1) or 2-plasmin inhibitor, or an overabundance of one of the activators, such as tissue-type plasminogen activator or urokinase-type plasminogen activator, can lead in hyperfibrinolytic bleeding. Delayed bleeding following trauma, surgery and dental interventions is a hallmark of fibrinolytic illnesses with a bleeding phenotype. Bleeding in states like menorrhagia and epistaxis, which has significant fibrinolytic activity, is also frequent. The most extreme bleeding episodes are experienced by patients with 2-plasmin inhibitor deficiency. Interestingly, it was found that, particularly in patients with PAI-1 deficiency, hyperfibrinolytic diseases are linked to a high prevalence of obstetric problems such as miscarriage and preterm delivery. Due to ignorance and a lack of reliable diagnostic tools, hyperfibrinolytic diseases are likely to be underdiagnosed. The vast majority of individuals whose bleeding was deemed to be “of unknown origin” may have a hyperfibrinolytic disease. Because these conditions may typically be successfully treated with antifibrinolytic drugs, early detection is crucial.

Analysis of the Association of Allergic Disease in Pediatric Patients with Hereditary Angioedema

Hereditary angioedema (HAE) is a rare autosomal dominant disease that is derived from the deficiency or dysfunction of C1 esterase inhibitor (C1-INH). In studies about the diseases that can accompany hereditary angioedema, allergic diseases occur more frequently compared to the healthy population but no studies on this issue have been carried out. This study was conducted in order to determine the frequency of the comorbidity of atopic sensitivity and allergic diseases in patients with hereditary angioedema. 32 patients who were diagnosed with hereditary angioedema in the Paediatric Allergy Polyclinic of Mersin City Hospital between 2019 and 2021 were included in the study. In these patients, the information about the existence of atopic diseases was obtained from their files and recorded. While asthma was observed in 6 (18.8%), allergic rhinitis in 18 (46.9%), and urticaria in 2 (6.2%) patients, dermatitis was not observed in any of the patients. While Fx5 test was positive in 5 (15.6%) patients, inhalant allergen mix sps IgE was positive in 7 (25.9%) patients. The IgE value was above 100 in 12 (52.2%) patients, and the eosinophil level was above 4% in 16 (50%) patients. In conclusion, we speculate in this study that the association of atopic disease and atopic sensitivity is observed more frequently in patients with angioedema than in the healthy population. However, a study with a larger sample is necessary to confirm this finding.

Validation of a suspicion index to identify patients at risk for hereditary angioedema.

Hereditary angioedema (HAE) is a genetic condition characterized by dysregulation of the contact (kallikrein-bradykinin) pathway, leading to recurrent episodes of angioedema. This project sought to determine whether a suspicion index screening tool using electronic health record (EHR) data can identify patients with an increased likelihood of a diagnosis of HAE. A suspicion index screening tool for HAE was created and validated by using known patients with HAE from the medical literature as well as positive and negative controls from HAE-focused centers. Through the use of key features of medical and family history, a series of logistic regression models for 5 known genetic causes of HAE were created. Top variables populated the digital suspicion scoring system and were run against deidentified EHR data. Patients at 2 diverse sites were categorized as being at increased, possible, or no increased risk of HAE. Prediction scoring using the strongest 13 variables on the "real-world" EHR-positive control data identified all but 1 patient with C1 inhibitor deficiency and patient with non-C1 inhibitor deficiency without false-positive results. The 2 missed patients had no documented family history of HAE in their EHR. When the prediction scoring variables were expanded to 25, the screening algorithm approached 100% sensitivity and specificity. The 25-variable algorithm run on general population EHR data identified 26 patients at the medical centers as being at increased risk for HAE. These results suggest that development, validation, and implementation of suspicion index screening tools can be useful to aid providers in identifying patients with rare genetic conditions.

Flow cytometry-based immunoassays for determining functional levels of plasma protease C1 inhibitor for the diagnosis of hereditary angioedema (HAE)

HAE types I and II are caused by a deficiency of functional C1 inhibitor (fC1-INH), leading to overproduction of bradykinin. Specific and sensitive methods to quantitate fC1-INH are required for accurate and timely diagnosis of HAE. Two commercially available assays either measure residual C1-esterase (C1s) activity or a complex ELISA measuring activated C1s. More physiologically relevant alternative methods measuring functional binding of Factor XIIa or kallikrein have been reported but they are not commercially available.

New medications to mitigate attacks of hereditary angioedema: does one size fit all?

Hereditary angioedema has received renewed attention in the past two decades, with the elucidation of the biochemical pathways resulting in bradykinin overproduction in patients with congenital C1esterase inhibitor (C1INH) deficiency, leading to recurrent attacks of tissue swelling due to uncontrolled vascular permeability. 1 Busse PJ Christiansen SC Hereditary angioedema. N Engl J Med. 2020; 382: 1136-1148 Crossref PubMed Scopus (132) Google Scholar Oedema attacks affecting the lingual or laryngeal area can become lethal as a result of asphyxiation. 2 Minafra FG Gonçalves TR Alves TM Pinto JA The mortality from hereditary angioedema worldwide: a review of the real-world data literature. Clin Rev Allergy Immunol. 2022; 62: 232-239 Crossref PubMed Scopus (4) Google Scholar Several new treatments have emerged, 143 years after Quincke's first description of hereditary angioedema and 15 years after the introduction of the first specific bradykinin B2 receptor inhibitor (icatibant). These drugs specifically target crucial steps in the kallikrein–kinin (contact) cascade downstream of bradykinin production. 3 Fijen LM Bork K Cohn DM Current and prospective targets of pharmacologic treatment of hereditary angioedema types 1 and 2. Clin Rev Allergy Immunol. 2021; 61: 66-76 Crossref PubMed Scopus (0) Google Scholar Many of these agents have shown their efficacy and safety in acute (on-demand) treatment and prophylaxis of hereditary angioedema attacks, saving lives and revolutionising patients’ quality of life. 4 Lumry WR Settipane RA Hereditary angioedema: epidemiology and burden of disease. Allergy Asthma Proc. 2020; 41: S08-S Crossref Google Scholar These modalities fit well into the modern paradigm in hereditary angioedema treatment, supporting patients’ autonomy, recommending self-administration, and reducing reliance on hospital emergency rooms, health-care providers, and medical points of care. 5 Maurer M Magerl M Betschel S et al. The international WAO/EAACI guideline for the management of hereditary angioedema—the 2021 revision and update. Allergy. 2022; 77: 1961-1990 Crossref PubMed Scopus (32) Google Scholar An investigational oral plasma kallikrein inhibitor for on-demand treatment of hereditary angioedema: a two-part, randomised, double-blind, placebo-controlled, crossover phase 2 trialOral administration of sebetralstat was well tolerated and led to rapid suppression of plasma kallikrein activity, resulting in increased time to use of conventional attack treatment and faster symptom relief versus placebo. Based on these results, a phase 3 trial to evaluate the efficacy and safety of two dose levels of sebetralstat in adolescent and adult participants with hereditary angioedema has been initiated ( NCT05259917 ). Full-Text PDF

C1 inhibitor deficiency enhances contact pathway–mediated activation of coagulation and venous thrombosis

AbstractC1 inhibitor (C1INH) is a multifunctional serine protease inhibitor that functions as a major negative regulator of several biological pathways, including the contact pathway of blood coagulation. In humans, congenital C1INH deficiency results in a rare episodic bradykinin-mediated swelling disorder called hereditary angioedema (HAE). Patients with C1INH deficiency–associated HAE (C1INH-HAE) have increased circulating markers of activation of coagulation. Furthermore, we recently reported that patients with C1INH-HAE had a moderate but significant increased risk of venous thromboembolism. To further investigate the impact of C1INH deficiency on activation of coagulation and thrombosis, we conducted studies using patient samples and mouse models. Plasmas from patients with C1INH-HAE had significantly increased contact pathway–mediated thrombin generation. C1INH-deficient mice, which have been used as a model of C1INH-HAE, had significantly increased baseline circulating levels of prothrombin fragment 1+2 and thrombin-antithrombin complexes. In addition, whole blood from C1INH-deficient mice supported significantly increased contact pathway–mediated thrombin generation. Importantly, C1INH-deficient mice exhibited significantly enhanced venous, but not arterial, thrombus formation. Furthermore, purified human C1INH normalized contact pathway–mediated thrombin generation and venous thrombosis in C1INH-deficient mice. These findings highlight a key role for endogenous C1INH as a negative regulator of contact pathway–mediated coagulation in humans and mice. Further, this work identifies endogenous C1INH as an important negative regulator of venous thrombus formation in mice, complementing the phenotype associated with C1INH-HAE.

Homeostatic, Non-Canonical Role of Macrophage Elastase in Vascular Integrity.

Matrix metalloproteinase (MMP)-12 is highly expressed in abdominal aortic aneurysms and its elastolytic function has been implicated in the pathogenesis. This concept is challenged, however, by conflicting data. Here, we sought to revisit the role of MMP-12 in abdominal aortic aneurysm. Apoe-/- and Mmp12-/-/Apoe-/- mice were infused with Ang II (angiotensin). Expression of neutrophil extracellular traps (NETs) markers and complement component 3 (C3) levels were evaluated by immunostaining in aortas of surviving animals. Plasma complement components were analyzed by immunoassay. The effects of a complement inhibitor, IgG-FH1-5 (factor H-immunoglobulin G), and macrophage-specific MMP-12 deficiency on adverse aortic remodeling and death from rupture in Ang II-infused mice were determined. Unexpectedly, death from aortic rupture was significantly higher in Mmp12-/-/Apoe-/- mice. This associated with more neutrophils, citrullinated histone H3 and neutrophil elastase, markers of NETs, and C3 levels in Mmp12-/- aortas. These findings were recapitulated in additional models of abdominal aortic aneurysm. MMP-12 deficiency also led to more pronounced elastic laminae degradation and reduced collagen integrity. Higher plasma C5a in Mmp12-/- mice pointed to complement overactivation. Treatment with IgG-FH1-5 decreased aortic wall NETosis and reduced adverse aortic remodeling and death from rupture in Ang II-infused Mmp12-/- mice. Finally, macrophage-specific MMP-12 deficiency recapitulated the effects of global MMP-12 deficiency on complement deposition and NETosis, as well as adverse aortic remodeling and death from rupture in Ang II-infused mice. An MMP-12 deficiency/complement activation/NETosis pathway compromises aortic integrity, which predisposes to adverse vascular remodeling and abdominal aortic aneurysm rupture. Considering these new findings, the role of macrophage MMP-12 in vascular homeostasis demands re-evaluation of MMP-12 function in diverse settings.

Mutant plasminogen in hereditary angioedema is bypassing FXII/kallikrein to generate bradykinin.

Hereditary angioedema (HAE) is characterized by recurrent localized edema in various organs, which can be potentially fatal. There are different types of hereditary angioedema, which include genetic deficiency of C1 inhibitor (C1-INH) and hereditary angioedema with normal C1-INH (HAEnCI). In HAEnCI patients mutations have been identified in the F12, PLG, KNG1, ANGPT1, MYOF, and HS3ST6 genes. The release of bradykinin from kininogen via the kallikrein-kinin system (KKS) has been shown to be the main mediator in HAE-FXII, but for HAE-PLG there are only first indications how the PLG mutations can result in bradykinin release. Here we identified in a multi-generation HAE-PLG family an additional F12 mutation, resulting in the loss of one F12 allele. There were no differences in the clinical presentation between HAE-PLG patients with and without the additional F12 mutation, thus we concluded that the kallikrein-kinin system is bypassed in HAE-PLG. Structural modeling and in vitro assays using purified proteins confirmed the PLG mutation c.988A>G; p.K330E to be a gain of function mutation resulting in an increased bradykinin release by direct cleavage of high molecular weight kininogen (HMWK). Thus, we can provide clinical and experimental evidence that mutant plasminogen in HAE-PLG is bypassing FXII/kallikrein to generate bradykinin.

Wnt signaling regulates MFSD2A-dependent drug delivery through endothelial transcytosis in glioma.

Systemic delivery of anti-tumor therapeutic agents to brain tumors is thwarted by the blood-brain barrier (BBB), an organotypic specialization of brain endothelial cells (ECs). A failure of pharmacological compounds to cross BBB is one culprit for the dismal prognosis of glioblastoma (GBM) patients. Identification of novel vascular targets to overcome the challenges posed by the BBB in tumors for GBM treatment is urgently needed. Temozolomide (TMZ) delivery was investigated in CT2A and PDGFB-driven RCAS/tv-a orthotopic glioma models. Transcriptome analysis was performed on ECs from murine gliomas. Mfsd2a deficient, Cav1 deficient, and Mfsd2a EC-specific inducible mice were developed to study the underlying molecular mechanisms. We demonstrated that inhibiting Wnt signaling by LGK974 could increase TMZ delivery and sensitize glioma to chemotherapy in both murine glioma models. Transcriptome analysis of ECs from murine gliomas revealed that Wnt signaling inhibition enhanced vascular transcytosis as indicated by the upregulation of PLVAP and downregulation of MFSD2A. Mfsd2a deficiency in mice enhances TMZ delivery in tumors, whereas constitutive expression of Mfsd2a in ECs suppresses the enhanced TMZ delivery induced by Wnt pathway inhibition in murine glioma. In addition, Wnt signaling inhibition enhanced caveolin-1 (Cav1)-positive caveolae-mediated transcytosis in tumor ECs. Moreover, Wnt signaling inhibitor or Mfsd2a deficiency fails to enhance TMZ penetration in tumors from Cav1-deficient mice. These results demonstrated that Wnt signaling regulates MFSD2A-dependent TMZ delivery through a caveolae-mediated EC transcytosis pathway. Our findings identify Wnt signaling as a promising therapeutic target to improve drug delivery for GBM treatment.

Slučaj angioedema hereditarnog porekla u seoskoj ambulanti nadomak Subotice

Introduction: Hereditary angioedema (HAE) is inherited in an autosomal dominant manner. It manifests with bradykinin-mediated swelling due to a deficiency of C1 inhibitor. Managing these patients is challenging during acute edema and the onset of asphyxiation. Transportation to the hospital takes 25 minutes. Objective: To present a patient with HAE for whom specific therapy has only recently become available. Case Presentation: A female patient presented with difficulty breathing, swelling of the lips, and periorbital edema. Status: visibly distressed, talkative, facial and lip swelling, visible mucosa without edema, uvula and pharynx calm. Respiratory movements symmetric, without the use of accessory muscles. Auscultation revealed normal breath sounds, tachycardic heart action, clear tones without murmurs, and no urticaria. Blood pressure 120/70 mmHg, heart rate 100/min., respiratory rate 30/min., SpO2 98%, capillary refill time (CRT) 2 sec. Treatment: infusion, Methylprednisolone 40 mg IV. She was transported with monitoring. During transport, the condition worsened: blood pressure 105/60 mmHg, heart rate 130/min., respiratory rate 40/min., SpO2 94%, CRT 2 sec. Oxygen at 15 L/min. was initiated, an additional IV line was opened, and capnography showed ETCO2 of 36 mmHg. Methylprednisolone was increased to 80 mg. Preparation for difficult intubation was initiated. Parameters did not worsen, and the patient was transferred to the emergency department of the General Hospital Subotica. Conclusion: Since specific therapies, such as human C1 inhibitor concentrate or bradykinin receptor antagonists, have been approved for self-administration at home during acute attacks, the treatment of these patients has been facilitated, minimizing the potential fatal outcomes and morbidity.

Hereditary angioedema with C1 inhibitor deficiency: traps in the diagnosis, treatment, and understanding

Hereditary angioedema with C1 inhibitor deficiency: traps in the diagnosis, treatment, and understanding

The validity and reliability of a Thai version of the Angioedema Control Test: Which recall period is preferable?

The Angioedema Control Test (AECT) is a questionnaire that monitors disease control in patients with angioedema, with a recall period of 4 weeks (AECT-4wk) or 3 months (AECT-3mo). This study investigated the psychometric properties of a Thai version of the AECT. Of 54 patients, 46, 5, 2, and 1 had recurrent angioedema with chronic spontaneous urticaria, hereditary angioedema, idiopathic histaminergic angioedema, and acquired angioedema due to C1 esterase inhibitor deficiency, respectively. The AECT, Angioedema Activity Score (AAS), Dermatology Life Quality Index (DLQI), Angioedema Quality of Life Questionnaire (AE-QoL), and anchors for disease control (numeric rating scale [NRS] and patient global assessment-Likert scale [PatGA-LS]) were used. The patients rated the efficacy of their treatment. Fifty-four and 47 patients completed the AECT-4wk and AECT-3mo, respectively. Both AECT versions showed significant correlations with disease activity (AAS, r = 0.6-0.8), disease control (NRS and PatGA-LS, r = 0.7-0.9), and quality of life impairment (DLQI and AE-QoL, r = 0.6-0.8). Higher correlations were found for the AECT-4wk than for the AECT-3mo. Excellent internal consistency (alpha = 0.98 and 0.97, respectively) and intraclass correlation (0.96 and 0.94, respectively) were found. A cutoff ≥ 10 was confirmed to identify patients with well-controlled disease for both AECT versions (AUCs = 0.89 and 0.97). The Thai version of the AECT is a valid and reliable tool for clinical practice. Due to the shorter recall period, the AECT-4wk may be more accurate than, and preferable to, the AECT-3mo. A cutoff ≥ 10 should be used to identify patients with well-controlled disease.