Phosphofurin acidic cluster sorting protein 2 (PACS2) plays a vital role in maintaining cellular homeostasis by regulating protein trafficking between cellular membranes. This function impacts crucial processes like apoptosis, mitochondria-endoplasmic reticulum interaction, and subsequently Ca2+ flux, lipid biosynthesis, and autophagy. Missense mutations, particularly E209K and E211K, are linked to developmental and epileptic encephalopathy-66 (DEE66), known as PACS2 syndrome. Individuals with this syndrome exhibit neurodevelopmental delay, seizures, facial dysmorphism, hypotonia, and delayed motor skills.Understanding the impact of these missense mutations on molecular processes is crucial. Studies suggest that E209K mutation decreases phosphorylation, increases the survival time of protein, and modifies protein-protein interaction, consequently leading to disruption of calcium flux and lower resistance to apoptosis induction. Unfortunately, to date, only a limited number of research groups have investigated the effects of mutations in the PACS2 gene. Current research on PACS2 syndrome is hampered by the lack of suitable models. While in vitro models using transfected cell lines offer insights, they cannot fully capture the disease's complexity.To address this, utilizing cells from individuals with PACS2 syndrome, specifically induced pluripotent stem cells (iPSCs), holds promise for understanding phenotypic diversity and developing personalized therapies. However, iPSC models may not fully capture tissue-specific effects of the E209K/E211K mutation. In vivo studies using animal models, particularly mice, could overcome these limitations.This review summarizes current knowledge about PACS2 structure and functions, explores the cellular consequences of E209K and E211K mutations, and highlights the potential of iPSC and mouse models in advancing our understanding of PACS2 syndrome.
- MeSH
- Induced Pluripotent Stem Cells metabolism MeSH
- Humans MeSH
- Mutation, Missense * MeSH
- Mutation MeSH
- Vesicular Transport Proteins * genetics metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Accumulation of environmental chitin in the lungs can lead to pulmonary fibrosis, characterized by inflammatory infiltration and fibrosis in acidic chitinase (Chia)-deficient mice. Transgenic expression of Chia in these mice ameliorated the symptoms, indicating the potential of enzyme supplementation as a promising therapeutic strategy for related lung diseases. This study focuses on utilizing hyperactivated human Chia, which exhibits low activity. We achieved significant activation of human Chia by incorporating nine amino acids derived from the crab-eating monkey (Macaca fascicularis) Chia, known for its robust chitin-degrading activity. The modified human Chia retained high activity across a broad pH spectrum and exhibited enhanced thermal stability. The amino acid substitutions associated with hyperactivation of human Chia activity occurred species specifically in monkey Chia. This discovery highlights the potential of hyperactivated Chia in treating pulmonary diseases resulting from chitin accumulation in human lungs.
- MeSH
- Enzyme Activation drug effects MeSH
- Chitin metabolism chemistry MeSH
- Chitinases * metabolism genetics chemistry MeSH
- Hydrogen-Ion Concentration MeSH
- Humans MeSH
- Macaca fascicularis MeSH
- Mice MeSH
- Lung metabolism pathology enzymology MeSH
- Enzyme Stability MeSH
- Amino Acid Substitution MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Global obesity rates have risen dramatically, now exceeding deaths from starvation. Metabolic and bariatric surgery (MBS), initially for severe obesity (BMI ≥35 kg/m2), is performed globally over 500 000 times annually, offering significant metabolic benefits beyond weight loss. However, varying eligibility criteria globally impact patient care and healthcare resources. Updated in 2022, ASMBS and IFSO guidelines aim to standardise MBS indications, reflecting current understanding and emphasising comprehensive preoperative assessments. Yet, clinical variability persists, necessitating consensus-based recommendations. This modified Delphi study engaged 45 global experts to establish consensus on perioperative management in MBS. Experts selected from bariatric societies possessed expertise in MBS and participated in a two-round Delphi protocol. Consensus was achieved on 90 of 169 statements (53.3%), encompassing multidisciplinary team composition, patient selection criteria, preoperative testing, and referral pathways. The agreement highlighted the critical role of comprehensive preoperative assessments and the integration of healthcare professionals in MBS. These findings offer essential insights to standardise perioperative practices and advocate for evidence-based guidelines in MBS globally. The study underscores the need for unified protocols to optimise outcomes and guide future research in MBS.
- MeSH
- Bariatric Surgery * standards methods MeSH
- Delphi Technique * MeSH
- Consensus * MeSH
- Humans MeSH
- Obesity, Morbid surgery MeSH
- Preoperative Care * standards methods MeSH
- Patient Selection MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Limited licensed medications are available for multiple sclerosis (MS) in pediatric patients. OBJECTIVE: To evaluate the efficacy, safety, and tolerability of alemtuzumab in pediatric patients with relapsing-remitting multiple sclerosis (RRMS) and disease activity on prior disease-modifying therapies (DMTs). METHODS: LemKids was a multicenter, multinational, single-arm, open-label, switch (from ongoing DMT to alemtuzumab treatment) study in pediatric RRMS patients (aged 10-<18 years), with disease activity on DMT. The primary endpoint was a comparison of the number of new/enlarging T2 lesions on the magnetic resonance imaging of the brain between the prior-DMT period and alemtuzumab treatment. RESULTS: This study was prematurely terminated due to low enrollment and an European Medicines Agency Article-20 pharmacovigilance review of alemtuzumab in adult RRMS. Of 46 screened patients, 16 were enrolled; 12 completed prior-DMT treatment period; 11 received alemtuzumab of whom 7 completed treatment. Patients on alemtuzumab developed fewer new/enlarging T2 lesions compared with prior-DMT (7 vs 178, relative risk (95% confidence interval): 0.04 (0.01-0.14)). No significant pharmacodynamic changes or safety concerns were noted in this limited dataset. CONCLUSION: Alemtuzumab treatment was associated with a low number of new/enlarging T2 lesions in pediatric patients with RRMS and was safe and well tolerated in seven patients during infusion and the initial 4 months.
- MeSH
- Alemtuzumab * adverse effects MeSH
- Child MeSH
- Immunologic Factors * adverse effects administration & dosage MeSH
- Humans MeSH
- Magnetic Resonance Imaging MeSH
- Adolescent MeSH
- Multiple Sclerosis, Relapsing-Remitting * drug therapy diagnostic imaging MeSH
- Treatment Outcome MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
PURPOSE: High-dose intravenous glucocorticoids are the standard first-line treatment in active, moderate to severe and severe thyroid eye disease (TED). We evaluate the usefulness of clinical activity score (CAS) and thyroid-stimulating immunoglobulin (TSI) as predictors and/or post-treatment markers of corticoresistance in patients with TED and the effect of rituximab in second-line treatment. METHODS: We enrolled 236 patients with an active TED into this retrospective single-tertiary-center cohort study. All patients were initially treated with high-dose systemic glucocorticoids. Rituximab was later administered to 29 of 42 corticoresistant patients. RESULTS: The CAS of the corticoresistant patients was significantly higher both before (p = 0.0001) and after (p = <0.0001) first-line treatment compared to the corticosensitive group. ROC analysis established the cut-point value as CAS ≥ 2.5 with a sensitivity of 96.3%, specificity of 57.5% and area under the curve of 82.8%. In 22 patients treated with rituximab, CAS gradually decreased to zero values without reactivation during extended follow-up. There was no difference in the TSI of corticosensitive and corticoresistant patients before or after first-line therapy. CONCLUSION: CAS ≥ 2, after first-line treatment, could be used as a corticoresistance marker. Corticoresistant patients should be subject to long-term follow-up for early detection of reactivation to reduce the delay to second-line treatment. Rituximab is a well-tolerated choice of second-line treatment and has a long-lasting effect on disease activity. Although TSI is a valuable biomarker of Graves' disease and TED activity, according to our results, TSI cannot be used as a marker of corticoresistance.
- MeSH
- Adult MeSH
- Glucocorticoids therapeutic use MeSH
- Graves Ophthalmopathy * drug therapy blood MeSH
- Immunoglobulins, Thyroid-Stimulating blood MeSH
- Immunologic Factors therapeutic use MeSH
- Drug Resistance * MeSH
- Middle Aged MeSH
- Humans MeSH
- Retrospective Studies MeSH
- Rituximab * therapeutic use MeSH
- Aged MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
OBJECTIVES: In axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) patients initiating secukinumab, we aimed to assess retention rates and proportions of patients achieving remission and low disease activity (LDA), according to disease activity measures and patient-reported outcomes at 24 and 48 months. PATIENTS AND METHODS: Data on patients with axSpA and PsA who initiated secukinumab treatment were pooled from 13 European registries. Analyses were performed overall and stratified according to the number of previous biologic/targeted synthetic Disease-Modifying Antirheumatic Drugs (b/tsDMARDs, 0/1/≥2). Kaplan-Meier plots and Cox regression analyses were performed to assess and compare secukinumab retention rates. Comparisons of remission and LDA rates were performed by logistic regression analyses. RESULTS: The overall 24-/48-month secukinumab retention rates were 61%/51% in 767 axSpA patients, and 64%/49% in 975 PsA patients, respectively. Compared to b/tsDMARD naïve patients, a higher risk of withdrawal from secukinumab was found for those with≥2 prior b/tsDMARDs in axSpA and PsA, and 1 prior b/tsDMARD in axSpA. Generally, remission and LDA rates were numerically higher in b/tsDMARD naïve patients. After adjustment for confounders, statistically significantly higher remission and LDA rates were found for b/tsDMARD naïve patients compared to patients with≥ 2 prior b/tsDMARDs at 24 months in axSpA and PsA. CONCLUSION: This large European real-world study demonstrates that 4-year secukinumab retention rates were approximately 50% in both axSpA and PsA. b/tsDMARD naïve patients had higher retention, remission and LDA rates than patients with prior b/tsDMARD exposure.
- MeSH
- Antirheumatic Agents * therapeutic use MeSH
- Axial Spondyloarthritis * drug therapy diagnosis MeSH
- Time Factors MeSH
- Adult MeSH
- Patient Reported Outcome Measures MeSH
- Antibodies, Monoclonal, Humanized * therapeutic use MeSH
- Remission Induction MeSH
- Middle Aged MeSH
- Humans MeSH
- Follow-Up Studies MeSH
- Arthritis, Psoriatic * drug therapy diagnosis MeSH
- Registries MeSH
- Severity of Illness Index MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Observational Study MeSH
- Geographicals
- Europe MeSH
Microbial transglutaminase (MTG) is an enzyme widely used in the food industry because it creates cross-links between proteins, enhancing the texture and stability of food products. Its unique properties make it a valuable tool for modifying the functional characteristics of proteins, significantly impacting the quality and innovation of food products. In this study, response surface methodology was employed to optimize the fermentation conditions for microbial transglutaminase production by the strain Streptoverticillium cinnamoneum KKP 1658. The effects of nitrogen dose, cultivation time, and initial pH on the activity of the produced transglutaminase were investigated. The significance of the examined factors was determined as follows: cultivation time > nitrogen dose > pH. The interaction between nitrogen dose and cultivation time was found to be crucial, having the second most significant impact on transglutaminase activity. Optimal conditions were identified as 48 h of cultivation with a 2% nitrogen source dose and an initial medium pH of approximately 6.0. Under these conditions, transglutaminase activity ranged from 4.5 to 5.5 U/mL. The results of this study demonstrated that response surface methodology is a promising approach for optimizing microbial transglutaminase production. Future applications of transglutaminase include the development of modern food products with improved texture and nutritional value, as well as its potential use in regenerative medicine for creating biomaterials and tissue scaffolds. This topic is particularly important and timely as it addresses the growing demand for innovative and sustainable solutions in the food and biomedical industries, contributing to an improved quality of life.
BACKGROUND: A third of endovascularly treated patients with stroke experience incomplete reperfusion (expanded Thrombolysis in Cerebral Infarction [eTICI] <3), and the natural evolution of this incomplete reperfusion remains unknown. We systematically reviewed the literature and performed a meta-analysis on the natural evolution of incomplete reperfusion after endovascular therapy. METHODS: A systematic review of MEDLINE, Embase, and PubMed up until March 1, 2024, using a predefined strategy. Only full-text English-written articles reporting rates of either favorable (ie, delayed reperfusion (DR) or no new infarct) or unfavorable progression (ie, persistent perfusion deficit or new infarct) of incompletely reperfused tissue were included. The primary outcome was the rate of DR and its association with functional independence (modified Rankin Scale score, 0-2) at 90 days postintervention. Pooled odds ratios with 95% CIs were calculated using a random-effects model. RESULTS: Six studies involving 950 patients (50.7% female; median age, 71 years; interquartile range, 60-79) were included. Four studies assessed the evolution of incomplete reperfusion on magnetic resonance imaging perfusion imaging, while 2 studies used diffusion-weighted imaging and noncontrast computed tomography imaging, where new infarct was used to denote unfavorable progression. Five studies defined incomplete reperfusion as eTICI 2b50 or 2c. DR occurred in 41% (interquartile range, 33%-51%) of cases 24 hours postintervention. Achieving DR was associated with a higher likelihood of functional independence at 90 days (odds ratio, 2.5 [95% CI, 1.9-3.4]). CONCLUSIONS: Nearly half of eTICI <3 patients achieve DR, leading to favorable clinical outcomes. This subgroup may derive limited or potentially harmful effects from pursuing additional reperfusion strategies (eg, intra-arterial lytics or secondary thrombectomy). Accurately predicting the evolution of incomplete reperfusion could optimize patient selection for adjunctive reperfusion strategies at the end of an intervention. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT05499832.
- MeSH
- Endovascular Procedures * methods MeSH
- Ischemic Stroke * surgery diagnostic imaging therapy MeSH
- Middle Aged MeSH
- Humans MeSH
- Reperfusion methods MeSH
- Aged MeSH
- Thrombolytic Therapy methods MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Meta-Analysis MeSH
- Systematic Review MeSH
INTRODUCTION: Alopecia areata is a common autoimmune disease which results in reversible hair loss. Janus kinase inhibitors are prescribed for severe alopecia areata with encouraging results. There are no studies comparing the efficacy and safety of Janus kinase inhibitors to traditional treatment options, such as topical immunomodulators and traditional immunosuppressants. AIMS: To retrospectively compare the efficacy and safety of baricitinib, an approved Janus kinase inhibitor, to other treatments for severe AA during a 6-month treatment period. MATERIALS/METHODS: We included patients with newly presenting, relapsing or treatment-resistant alopecia areata with Severity of Alopecia Tool (SALT) score ≥ 50, for the period between July 2021 and July 2023. Medical histories were reviewed and possible side effects were recorded. Primary endpoints were SALT ≤ 20 and SALT ≤ 10 after 6 months of treatment. RESULTS: Seventy-five patients (53 females) were divided into three groups: topical immunomodulators (51 patients); baricitinib (19 patients); and a group receiving pulsed intramuscular corticosteroids or traditional immunosuppressants (11 patients). Twenty-one patients received more than one treatment options within 2 years. After 6 months, the baricitinib group showed superior efficacy with 32% and 26% of patients achieving SALT ≤ 20 and SALT ≤ 10, compared to 12% and 9% in both other groups. Baricitinib demonstrated better secondary outcomes (50% and 90% reduction from initial SALT scores). All treatments exhibited mild-to-moderate and expected side effects. Weight gain, which had not been reported in clinical trials for alopecia areata, was observed in three baricitinib-treated patients. CONCLUSION: Baricitinib was superior to traditional treatments for severe alopecia areata after 6 months. Weight gain concerned 16% of patients receiving baricitinib.
- MeSH
- Alopecia Areata * drug therapy MeSH
- Azetidines * adverse effects therapeutic use administration & dosage MeSH
- Adult MeSH
- Adrenal Cortex Hormones therapeutic use administration & dosage adverse effects MeSH
- Immunologic Factors administration & dosage adverse effects therapeutic use MeSH
- Immunosuppressive Agents * adverse effects therapeutic use administration & dosage MeSH
- Janus Kinase Inhibitors * adverse effects administration & dosage therapeutic use MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Purines * adverse effects administration & dosage therapeutic use MeSH
- Pyrazoles * adverse effects administration & dosage therapeutic use MeSH
- Retrospective Studies MeSH
- Severity of Illness Index * MeSH
- Sulfonamides * adverse effects administration & dosage therapeutic use MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Comparative Study MeSH
The small airways, also referred to as the lung's silent zone, are closely associated with poor symptom control and more frequent asthma exacerbations. The oscillometry technique superimposes sound or airwaves onto normal tidal breathing and provides information on resistance and reactance, that is, obstacles to airflow occurring inside and outside of the bronchi. More recently, a management paradigm based on so-called "treatable traits" has been proposed to personalize and improve asthma care for individuals by proactively identifying and targeting modifiable pulmonary, extrapulmonary, and behavioral traits affecting asthma control. In this review article, we evaluate the literature on small airways dysfunction as a potential treatable trait in persistent asthma. In particular, we discuss whole- and intrabreath oscillometry and the impact of extrafine inhaled corticosteroids and systemic biologics on the peripheral airways.
- MeSH
- Asthma * physiopathology drug therapy diagnosis MeSH
- Adrenal Cortex Hormones therapeutic use MeSH
- Humans MeSH
- Oscillometry * methods MeSH
- Lung physiopathology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
