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PURPOSE: To evaluate the prevalence of dysphagia in survivors of head and neck cancer (sHNC) and to identify the predictors contributing to the development of dysphagia. METHODS: We enrolled 62 sHNC in a cross-sectional study to check the prevalence of dysphagia in sHNC and to evaluate which factors were influencing the presence of this side effect. Besides dysphagia, sociodemographic and clinical characteristics, oral symptoms, maximal mouth opening (MMO), sleep quality and physical condition were evaluated, and a linear regression analysis was performed to verify which of these outcomes impact dysphagia. RESULTS: Among all the sHNC, 85.5% presented dysphagia. The linear regression analysis confirmed that 44.9% of the variance in dysphagia was determined by coughing, MMO and sleep quality, being MMO the most powerful predictor, followed by coughing and sleep quality. CONCLUSION: Dysphagia affected the great majority of sHNC. Moreover, symptoms as coughing, reduced MMO and sleep disorders may act as predictors contributing to the development of dysphagia. Our results emphasize the importance of an early and proper identification of the symptoms as well as an adequate treatment strategy to address the cluster of symptoms that sHNC undergo.
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Trastornos de Deglución , Neoplasias de Cabeza y Cuello , Humanos , Trastornos de Deglución/epidemiología , Trastornos de Deglución/etiología , Estudios Transversales , Calidad de Vida , Neoplasias de Cabeza y Cuello/complicaciones , SobrevivientesRESUMEN
INTRODUCTION: The role of photobiomodulation (PBM) therapy for oral tissue damage induced by cancer treatment is currently unclear, and there is low-quality to moderate-quality evidence supporting the use of this approach for treating xerostomia and/or hyposalivation. Consequently, patients with head and neck cancer increasingly turn to basic oral hygiene to alleviate salivary gland dysfunction, and their adherence can be improved by mobile health (mHealth) education. The primary objective of this study will be to analyse the effects of different doses of PBM therapy (7.5 J/cm2 vs 3 J/cm2) plus mHealth education on quality of life (QoL), oral health, salivary secretion and salivary gland ultrasound assessment at postintervention and at the 6-month follow-up in patients with head and neck cancer after radiotherapy compared with those in control group. METHODS AND ANALYSIS: A prospective, three-arm, randomised, placebo-controlled, double-blinded study will be conducted among patients with head and neck cancer suffering from chronic xerostomia. A total of 20 patients per arm will be included and randomly assigned to receive 7.5 J/cm2 of PBM, 3 J/cm2 of PBM or placebo therapy. PBM therapy will be applied during 24 sessions at 22 points extra and intraorally two times per week for 3 months, combined with a mobile application (https://www.laxer.es). The assessments will be recorded at the beginning of the study, at postintervention and at the 6-month follow-up. The primary outcomes will be QoL, oral health, salivary secretion and salivary gland ultrasound. The pain pressure threshold, functional performance, mood and sleep quality will be secondary indicators. ETHICS AND DISSEMINATION: This study received ethics approval from the Andalusian Biomedical Research Ethics Portal (2402-N-21 CEIM/CEI Provincial de Granada) according to the Declaration of Helsinki for Biomedical Research. The results of this study will be presented at national and international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT05106608.
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Neoplasias de Cabeza y Cuello , Terapia por Luz de Baja Intensidad , Xerostomía , Humanos , Calidad de Vida , Estudios Prospectivos , Educación en Salud , Xerostomía/etiología , Xerostomía/terapia , Neoplasias de Cabeza y Cuello/radioterapia , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Severe hemophilia A (HA) negatively impacts health-related quality of life (HRQOL). OBJECTIVES: We aimed to analyze HRQOL in adult men with severe HA without inhibitors after valoctocogene roxaparvovec gene transfer in the phase 3 trial GENEr8-1. METHODS: Participant-reported outcomes were the hemophilia-specific quality of life questionnaire for adults (Haemo-QOL-A), the EQ-5D-5L instrument, the Hemophilia Activities List (HAL), and the Work Productivity and Activity Impairment Questionnaire: Hemophilia Specific (WPAI+CIQ:HS). Participants completed the questionnaires at baseline and through 104 weeks postinfusion with 6 × 1013 vg/kg of valoctocogene roxaparvovec. Scores were analyzed per participant characteristics and outcomes. RESULTS: For 132 HIV-negative participants, mean change from baseline in Haemo-QOL-A Total Score met the anchor-based clinically important difference (CID: 5.5) by week 12; the mean (SD) increase was 7.0 (12.6) at week 104. At week 104, improvement in Consequences of Bleeding, Treatment Concern, Worry, and Role Functioning domain scores exceeded the CID (6). EQ-5D-5L Utility Index scores improved above the CID at week 52, but not at week 104. EQ-5D-5L visual analog scale and HAL scores increased from baseline to week 104. Participants reported less activity and work impairment at week 104 than baseline. Participants with problem joints had lower mean baseline Haemo-QOL-A Total and domain scores than those without them, but improved over 104 weeks, except for 11 participants with ≥3 problem joints. Participants with 0 bleeds during the baseline prophylaxis period reported Haemo-QOL-A score improvements above the CID, including in the Consequences of Bleeding domain. CONCLUSION: Valoctocogene roxaparvovec provided clinically meaningful HRQOL improvement for men with severe HA.
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Hemofilia A , Adulto , Masculino , Humanos , Hemofilia A/diagnóstico , Hemofilia A/tratamiento farmacológico , Hemofilia A/genética , Calidad de Vida , Hemorragia , Encuestas y CuestionariosRESUMEN
OBJECTIVE: To assess the impact of prophylaxis with rIX-FP, a fusion protein linking recombinant factor IX (FIX) with human albumin, on joint outcomes. METHODS: Joint outcomes were assessed in pediatric (<12 years) and adult/adolescent (≥12 years) patients receiving rIX-FP prophylaxis every 7, 10, or 14 days; patients (>18 years) well-controlled on a 14-day regimen could switch to a 21-day regimen. Target joints were defined as ≥3 spontaneous bleeds into a single joint within a 6-month period. RESULTS: For adult/adolescent (n = 63) and pediatric (n = 27) patients, median (Q1, Q3) annualized joint bleeding rate was 0.39 (0.00, 2.31), 0.80 (0.00, 2.85), 0.20 (0.00, 2.58), and 0.00 (0.00, 1.78) when treated with 7-, 10-, 14-, or 21-day prophylaxis. 50.0%, 38.9%, 45.5%, and 63.6% of adult/adolescent patients had no joint bleeds when treated with 7-, 10-, 14-, or 21-day prophylaxis, respectively, and 40.7%, 37.5%, and 37.5% of pediatric patients had no joint bleeds when treated with 7-, 10-, or 14-day prophylaxis. Ten adult and two pediatric patients developed target joints; all resolved by the end of the study. CONCLUSION: Prophylaxis with rIX-FP produced low joint bleeding rates and provided excellent hemostatic efficacy in the treatment of joint bleeds. All target joints reported resolved with rIX-FP prophylaxis.
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Hemofilia A , Hemofilia B , Adulto , Adolescente , Humanos , Niño , Factor IX/uso terapéutico , Hemofilia B/complicaciones , Hemofilia B/tratamiento farmacológico , Proteínas Recombinantes de Fusión/uso terapéutico , Hemostasis , Hemartrosis/etiología , Hemartrosis/prevención & control , Hemofilia A/tratamiento farmacológicoRESUMEN
PURPOSE: The aim in this review was to evaluate recent advances in telerehabilitation for the management of patients with head and neck cancer (HNC) during and after their oncological treatment. METHODS: A systematic review was carried out in three databases (Medline, Web of Science and Scopus) in July 2022. The methodological quality of randomised clinical trials and quasi-experimental ones was assessed using the Cochrane tool (RoB 2.0) and the Critical Appraisal Checklists of the Joanna Briggs Institute, respectively. RESULTS: 14 out of 819 studies met the inclusion criteria: 6 studies were randomised clinical trials, 1 was a single-arm study with historical controls and 7 were feasibility studies. Most studies reported high participant satisfaction and efficacy of telerehabilitation used, in addition, no adverse effects were reported. None of the randomised clinical trials achieved a low overall risk of bias, whereas the methodological risk of bias of the quasi-experimental studies was low. CONCLUSIONS: This systematic review demonstrates that telerehabilitation offers feasible and effective interventions for the patients with HNC follow-up, during and after their oncological treatment. It was observed that telerehabilitation interventions should be personalised according to the patient's characteristics and the stage of the disease. Further research on telerehabilitation to support caregivers as well as to carry out studies with a long-term follow-up of these patients are imperative.
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Neoplasias de Cabeza y Cuello , Telerrehabilitación , Humanos , Estudios de Factibilidad , Calidad de Vida , Pacientes , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Type 3 von Willebrand disease (VWD) is the most severe form of this disease owing to the almost complete deficiency of von Willebrand factor (VWF). Replacement therapy with plasma-derived products containing VWF or recombinant VWF rarely cause the development of alloantibodies against VWF that may be accompanied by anaphylactic reactions. OBJECTIVE: The objective of this study was to assess the prevalence of anti-VWF alloantibodies in subjects with type 3 VWD enrolled in the 3WINTERS-IPS. METHODS: An indirect in-house enzyme-linked immunosorbent assay has been used to test all the alloantibodies against VWF. Neutralizing antibodies (inhibitors) have been tested with a Bethesda-based method by using a VWF collagen binding (VWF:CB) assay. Samples positive for anti-VWF antibodies were further tested with Bethesda-based methods by using the semiautomated gain-of-function glycoprotein-Ib binding (VWF:GPIbM) and a VWF antigen (VWF:Ag) enzyme-linked immunosorbent assay. RESULTS: In total, 18 of the 213 (8.4%) subjects tested positive for anti-VWF antibodies and 13 of 213 (6%) had VWF:CB inhibitors. These 13 were among the 18 with anti-VWF antibodies. Of the 5 without VWF:CB inhibitors, 3 had non-neutralizing antibodies, 1 only inhibitor against VWF:GPIbM, and one could not be tested further. Ten of the 13 subjects with VWF:CB inhibitors also had VWF:GPIbM inhibitors, 6 of whom also had VWF:Ag inhibitors. Subjects with inhibitors were homozygous for VWF null alleles (11/14), homozygous for a missense variant (1/14), or partially characterized (2/14). CONCLUSIONS: Anti-VWF antibodies were found in 8.4% of subjects with type 3 VWD, whereas neutralizing VWF inhibitors were found in 6%, mainly in subjects homozygous for VWF null alleles. Because inhibitors may be directed toward different VWF epitopes, their detection is dependent on the assay used.
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Enfermedad de von Willebrand Tipo 2 , Enfermedad de von Willebrand Tipo 3 , Enfermedades de von Willebrand , Humanos , Factor de von Willebrand/metabolismo , Enfermedades de von Willebrand/diagnóstico , Isoanticuerpos , Complejo GPIb-IX de Glicoproteína Plaquetaria/metabolismo , Enfermedad de von Willebrand Tipo 2/diagnósticoAsunto(s)
Humanos , Personal de Salud , Agresión , Salud Laboral , Agotamiento Profesional , Legislación Laboral , Atención Primaria de Salud , EspañaRESUMEN
Introduction: The state of alarm was declared in Spain due to the COVID-19 epidemic on March 14, 2020, and established population confinement measures. The objective is to describe the process of lifting these mitigation measures. Methods: The Plan for the Transition to a New Normality, approved on April 28, contained four sequential phases with progressive increase in socio-economic activities and population mobility. In parallel, a new strategy for early diagnosis, surveillance and control was implemented. A bilateral decision mechanism was established between the Spanish Government and the autonomous communities (AC), guided by a set of qualitative and quantitative indicators capturing the epidemiological situation and core capacities. The territorial units were established ad-hoc and could be from Basic Health Zones to entire AC. Results: The process run from May 4 to June 21, 2020. AC implemented plans for reinforcement of core capacities. Incidence decreased from a median (50% of territories) of 7.4 per 100,000 in 7 days at the beginning to 2.5 at the end. Median PCR testing increased from 53% to 89% of suspected cases and PCR total capacity from 4.5 to 9.8 per 1000 inhabitants weekly; positivity rate decreased from 3.5% to 1.8%. Median proportion of cases with traced contacts increased from 82% to 100%. Conclusion: Systematic data collection, analysis, and interterritorial dialogue allowed adequate process control. The epidemiological situation improved but, mostly, the process entailed a great reinforcement of core response capacities nation-wide, under common criteria. Maintaining and further reinforcing capacities remained crucial for responding to future waves.
Introducción: El 14 de marzo de 2020 España declaró el estado de alarma por la pandemia por COVID-19 incluyendo medidas de confinamiento. El objetivo es describir el proceso de desescalada de estas medidas. Métodos: Un plan de transición hacia una nueva normalidad, del 28 de abril, incluía 4 fases secuenciales incrementando progresivamente las actividades socioeconómicas y la movilidad. Concomitantemente, se implementó una nueva estrategia de diagnóstico precoz, vigilancia y control. Se estableció un mecanismo de decisión bilateral entre Gobierno central y comunidades autónomas (CCAA), guiado por un panel de indicadores cualitativos y cuantitativos de la situación epidemiológica y las capacidades básicas. Las unidades territoriales evaluadas comprendían desde zonas básicas de salud hasta CCAA. Resultados: El proceso se extendió del 4 de mayo al 21 de junio y se asoció a planes de refuerzo de las capacidades en las CCAA. La incidencia disminuyó de una mediana inicial de 7,4 por 100.000 en 7 días a 2,5 al final del proceso. La mediana de pruebas PCR aumentó del 53% al 89% de los casos sospechosos, y la capacidad total de 4,5 a 9,8 pruebas semanales por 1.000 habitantes; la positividad disminuyó del 3,5% al 1,8%. La mediana de casos con contactos trazados aumentó del 82% al 100%. Conclusión: La recogida y análisis sistemático de información y el diálogo interterritorial logaron un adecuado control del proceso. La situación epidemiológica mejoró, pero sobre todo, se aumentaron las capacidades, en todo el país y con criterios comunes, cuyo mantenimiento y refuerzo fue clave en olas sucesivas.
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INTRODUCTION: The state of alarm was declared in Spain due to the COVID-19 epidemic on March 14, 2020, and established population confinement measures. The objective is to describe the process of lifting these mitigation measures. METHODS: The Plan for the Transition to a New Normality, approved on April 28, contained four sequential phases with progressive increase in socio-economic activities and population mobility. In parallel, a new strategy for early diagnosis, surveillance and control was implemented. A bilateral decision mechanism was established between the Spanish Government and the autonomous communities (AC), guided by a set of qualitative and quantitative indicators capturing the epidemiological situation and core capacities. The territorial units were established ad-hoc and could be from Basic Health Zones to entire AC. RESULTS: The process run from May 4 to June 21, 2020. AC implemented plans for reinforcement of core capacities. Incidence decreased from a median (50% of territories) of 7.4 per 100,000 in 7 days at the beginning to 2.5 at the end. Median PCR testing increased from 53% to 89% of suspected cases and PCR total capacity from 4.5 to 9.8 per 1000 inhabitants weekly; positivity rate decreased from 3.5% to 1.8%. Median proportion of cases with traced contacts increased from 82% to 100%. CONCLUSION: Systematic data collection, analysis, and interterritorial dialogue allowed adequate process control. The epidemiological situation improved but, mostly, the process entailed a great reinforcement of core response capacities nation-wide, under common criteria. Maintaining and further reinforcing capacities remained crucial for responding to future waves.
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COVID-19 , Humanos , COVID-19/epidemiología , COVID-19/prevención & control , Prueba de COVID-19 , SARS-CoV-2 , España/epidemiologíaRESUMEN
Objective: To evaluate the current evidence of the effectiveness of dry needling in patients with chronic low back pain (LBP). Methods: PubMed, Medline, ScienceDirect, Web of Science, CINAHL and PEDro databases were searched until 2020. Study selection: Randomised controlled trials (RCTs) that used dry needling as the main treatment and which included participants diagnosed with chronic LBP. Data extraction: Two reviewers independently screened articles, scored methodologic quality, and extracted data. The primary outcomes were pain intensity and functional disability at post-intervention and follow-up. Results: A total of 8 RCTs involving 414 patients were included in the meta-analysis. All trials examined the efficacy of DN in patients with chronic LBP. Results suggested that compared with other treatments, dry needling combined was more effective in alleviating the pain intensity of LBP post-intervention (standardised mean difference [SMD], -0.42; 95% confidence interval [CI], -0.79 to -0.05; P = .03) and at short- term (SMD -0.99, 95% CI -1.61 to -0.37, P = .002). Conclusion: Current evidence showed that dry needling, especially if associated with other therapies, could be recommended to relieve the pain intensity of LBP at post-intervention and at short-term follow up. There is no evidence that dry needling alone or in combination improves disability at post-immediate or at short-term follow up. Registration: This review was registered on PROSPERO (PROSPERO CRD42020215781) and was aligned with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for reporting systematic reviews that evaluate healthcare interventions.
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Dolor Crónico , Punción Seca , Dolor de la Región Lumbar , Humanos , Dolor de la Región Lumbar/terapia , Ensayos Clínicos Controlados Aleatorios como Asunto , Dimensión del Dolor , Dolor Crónico/terapiaRESUMEN
The identification of inherited antithrombin deficiency (ATD) is critical to prevent potentially life-threatening thrombotic events. Causal variants in SERPINC1 are identified for up to 70% of cases, the majority being single-nucleotide variants and indels. The detection and characterization of structural variants (SVs) in ATD remain challenging due to the high number of repetitive elements in SERPINC1. Here, we performed long-read whole-genome sequencing on 10 familial and 9 singleton cases with type I ATD proven by functional and antigen assays, who were selected from a cohort of 340 patients with this rare disorder because genetic analyses were either negative, ambiguous, or not fully characterized. We developed an analysis workflow to identify disease-associated SVs. This approach resolved, independently of its size or type, all eight SVs detected by multiple ligation-dependent probe amplification, and identified for the first time a complex rearrangement previously misclassified as a deletion. Remarkably, we identified the mechanism explaining ATD in 2 out of 11 cases with previous unknown defect: the insertion of a novel 2.4 kb SINE-VNTR-Alu retroelement, which was characterized by de novo assembly and verified by specific polymerase chain reaction amplification and sequencing in the probands and affected relatives. The nucleotide-level resolution achieved for all SVs allowed breakpoint analysis, which revealed repetitive elements and microhomologies supporting a common replication-based mechanism for all the SVs. Our study underscores the utility of long-read sequencing technology as a complementary method to identify, characterize, and unveil the molecular mechanism of disease-causing SVs involved in ATD, and enlarges the catalogue of genetic disorders caused by retrotransposon insertions.
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Deficiencia de Antitrombina III , Retroelementos , Deficiencia de Antitrombina III/diagnóstico , Deficiencia de Antitrombina III/genética , Antitrombinas , Humanos , Nucleótidos , Retroelementos/genéticaRESUMEN
BACKGROUND: Type 3 von Willebrand disease (VWD) is a severe bleeding disorder caused by the virtually complete absence of von Willebrand factor (VWF). Pathophysiological mechanisms of VWD like defective synthesis, secretion, and clearance of VWF have previously been evaluated using ratios of VWF propeptide (VWFpp) over VWF antigen (VWF:Ag) and factor (F)VIII coagulant activity (FVIII:C) over VWF:Ag. OBJECTIVE: To investigate whether the VWFpp/VWF:Ag and FVIII:C/VWF:Ag ratios may also be applied to understand the pathophysiological mechanism underlying type 3 VWD and whether VWFpp is associated with bleeding severity. METHODS: European and Iranian type 3 patients were enrolled in the 3WINTERS-IPS study. Plasma samples and buffy coats were collected and a bleeding assessment tool was administered at enrolment. VWF:Ag, VWFpp, FVIII:C, and genetic analyses were performed centrally, to confirm patients' diagnoses. VWFpp/VWF:Ag and FVIII:C/VWF:Ag ratios were compared among different variant classes using the Mann-Whitney test. Median differences with 95% confidence intervals (CI) were estimated using the Hodges-Lehmann method. VWFpp association with bleeding symptoms was assessed using Spearman's rank correlation. RESULTS: Homozygosity/compound heterozygosity for missense variants showed higher VWFpp level and VWFpp/VWF:Ag ratio than homozygosity/compound heterozygosity for null variants ([VWFpp median difference, 1.4 IU/dl; 95% CI, 0.2-2.7; P = .016]; [VWFpp/VWF:Ag median difference, 1.4; 95% CI, 0-4.2; P = .054]). FVIII: C/VWF:Ag ratio was similarly increased in both. VWFpp level did not correlate with the bleeding symptoms (r = .024; P = .778). CONCLUSIONS: An increased VWFpp/VWF:Ag ratio is indicative of missense variants, whereas FVIII:C/VWF:Ag ratio does not discriminate missense from null alleles. The VWFpp level was not associated with the severity of bleeding phenotype.
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Enfermedad de von Willebrand Tipo 3 , Enfermedades de von Willebrand , Factor VIII/genética , Hemorragia/diagnóstico , Humanos , Irán , Enfermedad de von Willebrand Tipo 3/diagnóstico , Enfermedad de von Willebrand Tipo 3/genética , Enfermedades de von Willebrand/diagnóstico , Enfermedades de von Willebrand/genética , Factor de von Willebrand/químicaRESUMEN
Von Willebrand disease (VWD) is the most frequent inherited bleeding disorder caused by quantitative or qualitative defects of von Willebrand factor (VWF). This protein far from simplicity constitutes a very complex molecular model, remaining unravelled yet many aspects of it, even though the VWF gene (VWF) was cloned already in 1985 and the structure of VWF well defined. VWD diagnosis is difficult to achieve in a significant proportion of patients due to both disease heterogeneity and limitations in existing test processes. The cornerstone of diagnosis relies on interpretation of VWF test results, the presence of clinical manifestations of bleeding, especially mucocutaneous, and (in most cases) a positive family history. However, even with a significant bleeding history, a family history may not be positive due to factors of incomplete penetrance and variable expressivity that affect genetic changes. The laboratory diagnosis of VWD can be difficult, as the disease is heterogeneous and an array of assays is required to describe the phenotype. Basic classification of quantitative (type 1 and 3) and qualitative (type 2 variants) VWD requires determination of VWF antigenic (VWF:Ag) levels and assaying of VWF ristocetin cofactor (VWF:RCo) activity. The latter is required for identifying and subtyping VWD, but the assay is poorly standardized. For that reason, novel VWF activity assays have been developed awaiting more extensive comparison data between different methodologies and requiring validation on larger patient series. The qualitative type 2 VWF deficiency can be further divided into four different subtypes (A, B, M and N) using specific assays that measure other activities or the size distribution of VWF multimers. However, frequently, it may be difficult to correctly classify the VWD phenotype, and genetic analysis is through mutation identification may provide a tool to clarify the disorder.
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Hemofilia A , Enfermedades de von Willebrand , Pruebas de Coagulación Sanguínea , Técnicas de Laboratorio Clínico , Humanos , Enfermedades de von Willebrand/diagnóstico , Enfermedades de von Willebrand/genética , Factor de von Willebrand/genéticaRESUMEN
Antiglycation activities of herbs and spices, have been described in relation to their in vivo anti-diabetic or anti-aging activity at physiological temperature. Under the hypothesis that those natural antioxidants may inhibit the formation of Maillard intermediates, the behavior of several hydroalcoholic plant extracts was analyzed in sugar-protein systems. Allspice, thyme, green pepper and black pepper extracts were the most efficient inhibitors, decreasing furosine formation by 60, 45, 40 and 30%, respectively. 5-hydroxymethyl-2-furfural formation decreased in the presence of the extracts and protein glycation was inhibited by the thyme extract in advanced stages. Antiglycation activities were related to polyphenols content, to radical scavenging and to iron-reducing power. In the protein-sugar systems studied at the time in which 4000 ppm of furosine were formed, the antioxidant activity dropped between 30 and 40%. Polyphenols inhibit Maillard intermediates formation, revealing the incidence of oxidative pathways, but they are depleted as a function of time.
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Antioxidantes , Especias , Antioxidantes/análisis , Extractos Vegetales , Plantas Comestibles , AzúcaresRESUMEN
INTRODUCTION: Type 2N von Willebrand disease (VWD) is characterized by a decreased affinity of von Willebrand factor (VWF) for factor VIII (FVIII). Abnormal binding of FVIII to VWF (VWF:FVIIIB), results in low FVIII plasma levels, which can lead to a misdiagnosis of mild haemophilia A. Accurate diagnosis of type 2N VWD is essential for appropriate genetic counselling and therapy. This disease can be distinguished from haemophilia A by in vitro assays (measurement VWF:FVIIIB activity) and/or genetic analysis. AIM: To identify the current challenges in the diagnosis and treatment of this type of VWD and provide an in-depth description of the phenotypes and mutations identified. RESULTS: Twenty-eight patients had at least one type 2N mutation, and 13 of these had a type 2N mutation combined with other variations. Three type 2N mutations were detected: p.Arg816Trp, p.Arg854Gln, and p.Arg763Ser. Two of these are the most frequently described mutations worldwide. This mutational spectrum differs from the broad spectrum seen in neighbouring France, where at least eight distinct 2N mutations have been found. In the PCM-EVW-ES cohort, 11 asymptomatic type 2N carriers with borderline FVIII plasma levels would probably have been excluded if the evaluation had been based on clinical and laboratory data only. Likewise, three patients with a severe phenotype would have been classified as homozygous for a 2N mutation if only the phenotype study had been performed. CONCLUSION: The high detection yield and affordability of next-generation sequencing support the use of this technology as a first-line diagnostic tool in this setting.
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Hemofilia A , Enfermedad de von Willebrand Tipo 2 , Enfermedades de von Willebrand , Factor de von Willebrand/genética , Factor VIII/genética , Heterocigoto , Homocigoto , Humanos , Enfermedad de von Willebrand Tipo 2/diagnóstico , Enfermedad de von Willebrand Tipo 2/genéticaRESUMEN
ß1-Tubulin plays a major role in proplatelet formation and platelet shape maintenance, and pathogenic variants in TUBB1 lead to thrombocytopenia and platelet anisocytosis (TUBB1-RT). To date, the reported number of pedigrees with TUBB1-RT and of rare TUBB1 variants with experimental demonstration of pathogenicity is limited. Here, we report 9 unrelated families presenting with thrombocytopenia carrying 6 ß1-tubulin variants, p.Cys12LeufsTer12, p.Thr107Pro, p.Gln423*, p.Arg359Trp, p.Gly109Glu, and p.Gly269Asp, the last of which novel. Segregation studies showed incomplete penetrance of these variants for platelet traits. Indeed, most carriers showed macrothrombocytopenia, some only increased platelet size, and a minority had no abnormalities. Moreover, only homozygous carriers of the p.Gly109Glu variant displayed macrothrombocytopenia, highlighting the importance of allele burden in the phenotypic expression of TUBB1-RT. The p.Arg359Trp, p.Gly269Asp, and p.Gly109Glu variants deranged ß1-tubulin incorporation into the microtubular marginal ring in platelets but had a negligible effect on platelet activation, secretion, or spreading, suggesting that ß1-tubulin is dispensable for these processes. Transfection of TUBB1 missense variants in CHO cells altered ß1-tubulin incorporation into the microtubular network. In addition, TUBB1 variants markedly impaired proplatelet formation from peripheral blood CD34+ cell-derived megakaryocytes. Our study, using in vitro modeling, molecular characterization, and clinical investigations provides a deeper insight into the pathogenicity of rare TUBB1 variants. These novel data expand the genetic spectrum of TUBB1-RT and highlight a remarkable heterogeneity in its clinical presentation, indicating that allelic burden or combination with other genetic or environmental factors modulate the phenotypic impact of rare TUBB1 variants.
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Trombocitopenia , Tubulina (Proteína) , Plaquetas , Humanos , Megacariocitos , Trombocitopenia/genética , Tubulina (Proteína)/genéticaRESUMEN
Type 3 von Willebrand disease (VWD3) is a rare and severe bleeding disorder characterized by often undetectable von Willebrand factor (VWF) plasma levels, a recessive inheritance pattern, and heterogeneous genotype. The objective of this study was to identify the VWF defects in 265 European and Iranian patients with VWD3 enrolled in 3WINTERS-IPS (Type 3 Von Willebrand International Registries Inhibitor Prospective Study). All analyses were performed in centralized laboratories. The VWF genotype was studied in 231 patients with available DNA (121 [115 families] from Europe [EU], and 110 [91 families] from Iran [IR]). Among 206 unrelated patients, 134 were homozygous (EU/IR = 57/77) and 50 were compound heterozygous (EU/IR = 43/7) for VWF variants. In 22 patients, no or only one variant was found. A total of 154 different VWF variants (EU/IR = 101/58 [5 shared]) were identified among the 379 affected alleles (EU/IR = 210/169), of which 48 (EU/IR = 18/30) were novel. The variants p.Arg1659*, p.Arg1853*, p.Arg2535*, p.Cys275Ser, and delEx1_Ex5 were found in both European and Iranian VWD3 patients. Sixty variants were identified only in a single allele (EU/IR = 50/10), whereas 18 were recurrent (≥3 patients) within 144 affected alleles. Nine large deletions and one large insertion were found. Although most variants predicted null alleles, 21% of patients carried at least 1 missense variant. VWD3 genotype was more heterogeneous in the European population than in the Iranian population, with nearly twice as many different variants. A higher number of novel variants were found in the Iranian VWD3 patients.
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Enfermedad de von Willebrand Tipo 3 , Enfermedades de von Willebrand , Genotipo , Humanos , Irán/epidemiología , Estudios Prospectivos , Enfermedad de von Willebrand Tipo 3/diagnóstico , Enfermedad de von Willebrand Tipo 3/epidemiología , Enfermedad de von Willebrand Tipo 3/genéticaRESUMEN
Introduction: Current guidelines recommend prophylactic treatment of hemophilia B with the missing coagulation factor IX, either with standard half-life or extended half-life products. Extended half-life products have half-lives three to six times longer than the former, allowing a reduction in the number of weekly injections and therefore, potentially impacting on treatment adherence and quality of life. Albutrepenonacog alfa is an extended half-life fusion protein of coagulation factor IX with recombinant human albumin, indicated for both on-demand and prophylactic treatment for bleeding in patients with hemophilia B of all ages.Areas covered: The authors review the clinical and pharmacokinetic characteristics of albutrepenonacog alfa, as well as the available information regarding trough levels and real-world evidence. Given the availability of other factor IX products in the market, indirect comparisons of clinical and pharmacokinetic characteristics are presented.Expert opinion: The authors exhibit their expert opinion on which patient profiles are candidates for prophylactic treatment with albutrepenonacog alfa, and on the management of patients in terms of dosing, regimens of administration and protocols for switching the treatment.