ABSTRACT
Capacitation involves tyrosine phosphorylation (TP) as a key marker. Lifestyle-related factors, such as obesity and smoking, are recognized for their adverse effects on semen quality and male fertility, yet the underlying mechanisms, including their potential impact on TP, remain unclear. Moreover, the effect of sperm cryopreservation on TP at the human sperm population level is unexplored. Flow cytometry analysis of global TP was performed on pre-capacitated, post-capacitated and 1- and 3-hours' incubated fresh and frozen-thawed samples from sperm donors (n = 40). Neither being overweight nor smoking (or both) significantly affected the percentage of sperm showing TP. However, elevated BMI and smoking intensity correlated with heightened basal TP levels (r = 0.226, p = 0.003) and heightened increase in TP after 3 h of incubation (r = 0.185, p = 0.017), respectively. Cryopreservation resulted in increased global TP levels after capacitation but not immediately after thawing. Nonetheless, most donors' thawed samples showed increased TP levels before and after capacitation as well as after incubation. Additionally, phosphorylation patterns in fresh and frozen-thawed samples were similar, indicating consistent sample response to capacitation stimuli despite differences in TP levels. Overall, this study sheds light on the potential impacts of lifestyle factors and cryopreservation on the dynamics of global TP levels during capacitation.
Subject(s)
Body Mass Index , Cryopreservation , Sperm Capacitation , Spermatozoa , Tyrosine , Humans , Cryopreservation/methods , Male , Phosphorylation , Tyrosine/metabolism , Spermatozoa/metabolism , Adult , Cigarette Smoking/adverse effects , Semen Preservation/methods , Semen AnalysisABSTRACT
Background: Children and adolescents with cleft lip and/or palate (CL/P) are at an increased risk of developing emotional disorders. This study aims to explore this question in greater depth by addressing three objectives: (1) the presence of neuroticism as an indicator of emotional symptomatology, (2) the use of adaptive and non-adaptive emotional regulation strategies, and (3) the relationship between these strategies and neuroticism. Methods: A case-control correlational methodology was employed, with 60 children and adolescents with CL/P (mean age = 12.80 years; 33 females) and 60 non-clinical equivalent children and adolescents. Results: The CL/P group has higher scores on neuroticism (t = -7.74; p ≤ 0.001, d Cohen = 1.43) and lower scores in almost all emotional regulation strategies. The presence of CL/P moderated the relationship between neuroticism and self-blame (Beta = -0.46, t = -2.81, p = 0.005), rumination (Beta = -0.49, t = -3.73, p < 0.001), catastrophizing (Beta = -0.61, t = -4.26, p < 0.001), and blaming others (Beta = -0.45, t = -2.84, p = 0.005). This model predicted a significant variance of neuroticism (all p < 0.005), which ranged from 39% to 41%. Conclusions: The CL/P group has worse mental health indicators. Particularly novel results about the CL/P group are the lower scores on regulation strategies (both adaptive and non-adaptive) and the fact that non-adaptive strategies contribute, contrary to their effect in the general population, to a decrease in neuroticism. It supports the need to incorporate mental health indicators in the diagnosis and treatment of children and adolescents with CL/P.
Subject(s)
Keratosis , Humans , Keratosis/diagnosis , Keratosis/pathology , Infant , Male , Female , Anus Diseases/diagnosisABSTRACT
Biallelic variants in PPA2 gene cause a rare but lethal mitochondrial disorder. We describe the first four cases reported in Spain of PPA2 disease in two unrelated families. We have conducted a revision of the clinical history, necropsies, and postmortem genetic testing from probands, and clinical evaluation, genetic testing and blood transcript analysis in family members. All the cases harbored biallelic PPA2 variants in compound heterozygous status. Two brothers from family 1 suffered sudden death after a small first intake of alcohol in 2013 and 2022. The sister remains alive but affected with cardiomyopathy, extensive scar on cardiac imaging, and high sensitivity to alcohol intake. The three siblings carried PPA2 c.290A > G (p.Glu97Gly) novel missense variant and PPA2 c.513C > T (p.Cys171 = ) altering splicing site variant, both probably leading to mRNA degradation based on in-silico and transcript analyses. A teenager from family 2 suffered sudden death after a small intake of alcohol in 2018 and carried PPA2 c.683C > T (p.Pro228Leu) missense and PPA2 c.980_983del (p.Gln327fs) novel frameshift variant, both probably leading to abnormal protein structure. All cases were asymptomatic until adolescence. Furthermore, the sister in family 1 has survived as an asymptomatic adult. PPA2 disease can manifest as cardiac arrest in the young, especially after alcohol exposure. Our results show that PPA2 deficiency can be related to different pathogenicity mechanisms such as abnormal protein structure but also mRNA decay caused by synonymous or missense variants. Strict avoidance of alcohol consumption and early defibrillator implantation might prevent lethal arrhythmias in patients at risk.
Subject(s)
Alcohol Drinking , Death, Sudden, Cardiac , Inorganic Pyrophosphatase , Mitochondrial Proteins , Adolescent , Adult , Female , Humans , Male , Alcohol Drinking/genetics , Alcohol Drinking/adverse effects , Death, Sudden, Cardiac/etiology , Mutation, Missense , Pedigree , Spain , Mitochondrial Proteins/genetics , Inorganic Pyrophosphatase/geneticsABSTRACT
Cardiac amyloidosis is increasingly recognized as a treatable form of heart failure. Highly effective specific therapies have recently become available for the 2 most frequent forms of cardiac amyloidosis: immunoglobulin light chain amyloidosis and transthyretin (ATTR) amyloidosis. Nevertheless, initiation of specific therapies requires recognition of cardiac amyloidosis and appropriate characterization of the amyloid type. Although noninvasive diagnosis is possible for ATTR cardiac amyloidosis, histological demonstration and typing of amyloid deposits is still required for a substantial number of patients with ATTR and in all patients with light chain amyloidosis and other rarer forms of cardiac amyloidosis. Amyloid histological typing can be performed using different techniques: mass spectrometry, immunohistochemistry, and immunoelectron microscopy. This review describes which patients require histological confirmation of cardiac amyloidosis along with when and how to type amyloid deposits in histologic specimens. Furthermore, it covers the characteristics and limitations of the different typing methods that are available in clinical practice.
Subject(s)
Amyloid Neuropathies, Familial , Amyloidosis , Cardiomyopathies , Heart Failure , Humans , Plaque, Amyloid , Amyloidosis/pathology , Amyloid , Heart Failure/diagnosis , Immunohistochemistry , Amyloidogenic Proteins , Prealbumin , Amyloid Neuropathies, Familial/diagnosis , Cardiomyopathies/diagnosis , Cardiomyopathies/therapyABSTRACT
Background: Tubal pathology is the etiological factor in 20% of couples with female infertility. Historically, diagnostic evaluation of the fallopian tubes has been performed by means of hysterosalpingography (HSG). Hysterosonosalpingography with EXEM® foam is a recent technique with supposedly comparable effectiveness to HSG, but with better tolerability for patients. Methods: Tubal patency was assessed in patients who were candidates for intrauterine insemination (IUI) between January 2020 and July 2021. (I) Hysterosonosalpingography with EXEM® foam. (II) If the patient had both tubes patent, IUI was proposed. In case of inconclusive or pathological results, HSG was performed. (III) If the HSG concludes tubal patency, IUI is proposed. On the other hand, if it results in tubal obstruction, in vitro fertilization (IVF) is proposed. Results: Assessment of tubal patency by HSG showed concordance with previous Hysterosonosalpingography with EXEM® foam results in 45.5% (n=15) of cases of unilateral obstruction and 66.7% (n=6) of cases of bilateral obstruction. When we compare the total cost of HSG (54,899.46) with the sum of patients who only required Hysterosonosalpingography with EXEM® foam together with those who underwent both tests (45,575.96), it shows that the latter represents a cost benefit strategy (cost difference 9,323.50). Conclusions: Our results suggest a benefit of 9,323.50 when performing the contingent sequential strategy, in case of pathological or inconclusive results, compared to performing a systematic HSG in all patients. Patients with an obstructive hysterosalpingogram with EXEM® and a patent hysterosalpingogram will be the subgroup that will benefit the most, as IUI can be proposed instead of IVF. In addition, there is a benefit in terms of optimizing the medical procedure, hospital visits and speeding up the time to start assisted reproductive technology (ART).
ABSTRACT
BACKGROUND: Conventional right ventricle (RV) pacemaker stimulation has been associated with worse clinical outcomes in patients with cardiac amyloidosis (CA). Left bundle branch area pacing (LABPP) has been suggested as a promising alternative. We sought to assess the safety, feasibility, and outcomes of LABPP in patients with CA. METHODS: We retrospectively analyzed echocardiography and pacing parameters and clinical outcomes in 23 consecutive patients with CA and LBBAP implanted from June 2020 to October 2022. RESULTS: LBBAP was successfully performed in 22 over 23 patients (19 male, 78.6 ± 11.7 years, 20 ATTR, mean LVEF 45.5 ± 16.2%). After the procedure, 9 patients showed Qr pattern and 11 a qR pattern in V1 on ECG. Average procedure time was 67 ± 28 min. After 7.7 ± 5.2 months follow-up, no procedure-related complications had occurred. Although, a significant reduction in QRS width (p = .001) was achieved, we did not observe significant changes in LVEF and Nt ProBNP at 6 months of follow-up. Pacing parameters were stable during follow-up: LBB capture threshold and R wave amplitude were 1.0 ± 0.5 V and 10.6 ± 6.0 mV versus 0.8 ± 0.1 V, p = .21 and 10.6 ± 5.1 mV (p = .985) at follow up. CONCLUSION: LBBAP is safe and feasible pacing technique for patients with CA. LBBAP is associated with significant narrowing of QRSd without worsening in LVEF and Nt-proBNP.
Subject(s)
Amyloidosis , Ventricular Septum , Humans , Male , Feasibility Studies , Retrospective Studies , Amyloidosis/therapy , Heart Ventricles , Electrocardiography , Cardiac Pacing, Artificial , Bundle of His , Treatment OutcomeSubject(s)
Humans , Male , Middle Aged , Amyloidosis/diagnosis , Medical History Taking , Hypertrophy, Left Ventricular/diagnosis , Tobacco Use Disorder , Hypertension , Diabetes Mellitus, Type 2 , Inpatients , Physical Examination , Cardiology , Radionuclide Imaging , Electromyography , Amyloidosis/complications , Amyloidosis/geneticsABSTRACT
The ultimate goal of a preimplantation genetic testing and human leukocyte antigen (PGT-HLA) matching programme is the birth of a healthy, HLA-compatible child for the treatment or cure of a sick sibling. Several authors have published successful cases of the births of children HLA-matched to siblings affected by different conditions and diseases. However, there are many reports of failed attempts. Couples seeking an HLA-matched sibling for their affected child look for positive outcomes in the shortest possible time. Nevertheless, there is no published consensus or guidelines with recommendations for these cases. Here, the authors aimed to analyse different approaches for these programmes, highlighting the most promising strategies for the families and fertility units. Furthermore, the authors mention a successful case of a PGT-HLA matching programme after a previous failed attempt following the strategies proposed. Which is the most cost-effective and time-efficient approach in a PGT-HLA matching programme?
Subject(s)
Preimplantation Diagnosis , Siblings , Pregnancy , Female , Child , Humans , Fertilization in Vitro , Genetic Testing , HLA Antigens/genetics , Aneuploidy , BlastocystABSTRACT
OBJECTIVE: Data on cellular and humoral immunogenicity after the third dose of anti-SARS-CoV-2 vaccines in patients with immune-mediated rheumatic diseases (IMRDs) are scarce. Herein, we evaluated the adaptive immune response in IMRD patients treated with different immunosuppressive therapies (conventional synthetic disease-modifying antirheumatic drugs [csDMARDs], biological disease-modifying antirheumatic drugs [bDMARDs], and targeted synthetic disease-modifying antirheumatic drugs [tsDMARDs]) after the booster of the anti-SARS-CoV-2 vaccine to determine whether any drug reduced the vaccine's response. METHODS: A single-center prospective study was conducted, including patients presenting with IMRD and healthy controls (HC). Specific anti-SARS-CoV-2 interferon-gamma (IFN-γ) production was evaluated between 8-12 weeks after the third dose of the SARS-CoV-2 vaccine. In addition, anti-Spike IgG antibody titers were also measured. RESULTS: Samples were obtained from 79 IMRD patients (51 women, 28 men; mean age 57 ± 11.3 years old): 43 rheumatoid arthritis, 10 psoriatic arthritis, 14 ankylosing spondylitis, 10 undifferentiated spondyloarthritis, and 2 inflammatory bowel disease-associated spondyloarthritis (IBD-SpA). In total, 31 HC (mean age 50.9 ± 13.1 years old, 67.7% women) were included in the study. Post-vaccine results displayed positive T-cell immune responses in 68 out of 79 (86.1%) IMRD patients (82.3% of those without prior COVID-19). All HC and IMRDs patients had an antibody response against the SARS-CoV-2 receptor-binding domain; however, the HC response was significantly higher (median of 18,048 AU/mL) than in IMRDs patients (median of 6590.3 AU/mL, p < 0.001). MTX and leflunomide were associated with lower titers of IgG and IFN-γ responses. Among bDMARDs, adalimumab, etanercept, and guselkumab are associated with reduced cellular responses. CONCLUSION: Our preliminary data show that the majority of our IMRD patients develop cellular and humoral responses after the SARS-CoV-2 booster vaccination, emphasizing the relevance of vaccination in this group. However, the magnitude of specific responses was dependent on the immunosuppressive therapy administered. Specific vaccination protocols and personalized decisions about boosters are essential for these patients.
ABSTRACT
Las enfermedades mentales tienen especial relevancia tanto por su elevada prevalencia en el momento actual como por sus consecuencias en diferentes ámbitos de la vida. En este artículo se presenta un caso clínico de un trabajador diagnosticado de trastorno conversivo que es evaluado por parte del servicio de prevención con el fin de establecer la aptitud laboral. El conocimiento de la clínica, diagnóstico y abordaje de estos trastornos conjunta y coordinadamente por el servicio de prevención de riesgos labores, mandos directos y otros especialistas es el pilar fundamental para conseguir una adecuada adaptación del puesto de trabajo, así como una integración laboral siempre que se cumplan las restricciones especificadas en el informe de aptitud. (AU)
Mental illnesses are particularly relevant both because of their high prevalence at the present time and because of their consequences in different areas of life. This article presents a clinical case of a worker diagnosed with conversion disorder who is evaluated by the prevention service in order to establish work aptitude. Knowledge of the clinic, diagnosis and approach to these joint and coordinated disorders by the occupational risk prevention service, direct managers and other specialists is the fundamental pillar to achieve an adequate adaptation of the job, as well as labor integration whenever the restrictions specified in the suitability report are met. (AU)
Subject(s)
Humans , Male , Adult , Conversion Disorder/diagnosis , Rehabilitation, Vocational , Conversion Disorder/drug therapy , Work Capacity EvaluationABSTRACT
BACKGROUND: Mesenchymal stromal cells (MSCs) have been shown to exert their therapeutic effects through the secretion of broad spectrum of paracrine factors, including extracellular vesicles (EVs). Accordingly, EVs are being pursued as a promising alternative to cell-based therapies. Menstrual blood-derived stromal cells (MenSCs) are a type of MSC that, due to their immunomodulatory and regenerative properties, have emerged as an innovative source. Additionally, new strategies of cell priming may potentially alter the concentration and cargo of released EVs, leading to modification of their biological properties. In this study, we aimed to characterize the EVs released by MenSCs and compare their therapeutic potential under three different preconditioning conditions (proinflammatory stimuli, physioxia, and acute hypoxia). METHODS: MenSCs were isolated from five healthy women. Following culturing to 80% confluence, MenSCs were exposed to different priming conditions: basal (21% O2), proinflammatory stimuli (IFNγ and TNFα, 21% O2), physioxia (1-2% O2), and acute hypoxia (< 1% O2) for 48-72 h. Conditioned media from MenSCs was collected after 48 h and EVs were isolated by a combination of ultra-filtration and differential centrifugation. An extensive characterization ranging from nano-flow cytometry (nFC) to quantitative high-throughput shotgun proteomics was performed. Bioinformatics analyses were used to derive hypotheses on their biological properties. RESULTS: No differences in the morphology, size, or number of EVs released were detected between priming conditions. The proteome analysis associated with basal MenSC-EVs prominently revealed their immunomodulatory and regenerative capabilities. Furthermore, quantitative proteomic analysis of differentially produced MenSC-EVs provided sufficient evidence for the utility of the differential preconditioning in purpose-tailoring EVs for their therapeutic application: proinflammatory priming enhanced the anti-inflammatory, regenerative and immunomodulatory capacity in the innate response of EVs, physioxia priming also improves tissue regeneration, angiogenesis and their immunomodulatory capacity targeting on the adaptive response, while acute hypoxia priming, increased hemostasis and apoptotic processes regulation in MenSC-EVs, also by stimulating immunomodulation mainly through the adaptive response. CONCLUSIONS: Priming of MenSCs under proinflammatory and hypoxic conditions affected the cargo proteome of EVs released, resulting in different therapeutic potential, and thus warrants experimental exploration with the aim to generate better-defined MSC-derived bioproducts.
Subject(s)
Extracellular Vesicles , Mesenchymal Stem Cells , Humans , Female , Proteomics , Proteome , Hypoxia/therapyABSTRACT
OBJECTIVE: We sought to investigate prevalence, incidence and prognostic implications of permanent pacemaker (PPM) implantation in patients with cardiac amyloidosis (CA), thereby identifying the predictors of time to PPM implantation. METHODS: Seven hundred eighty-seven patients with CA (602 men, median age 74 years, 571 transthyretin amyloidosis (ATTR), 216 light-chain amyloidosis (AL)) evaluated at two European referral centres were retrospectively included. Clinical, laboratory and instrumental data were analysed. The associations between PPM implantation and mortality, heart failure (HF) or a composite endpoint of mortality, cardiac transplantation and HF were analysed. RESULTS: 81 (10.3%) patients had a PPM before initial evaluation. Over a median follow-up time of 21.7 months (IQR 9.6-45.2), 81 (10.3%) additional patients (18 with AL (22.2%) and 63 with ATTR (77.8%)) underwent PPM implantation with a median time to implantation of 15.6 months (IQR 4.2-40), complete atrioventricular block was the most common indication (49.4%). Independent predictors of PPM implantation were QRS duration (HR 1.03, 95% CI 1.02 to 1.03, p<0.001) and interventricular septum (IVS) thickness (HR 1.1, 95% CI 1.03 to 1.17, p=0.003). The model to estimate the probability of PPM at 12 months and containing both factors showed a C-statistic of 0.71 and a calibration of slope of 0.98. CONCLUSIONS: Conduction system disease requiring PPM is a common complication in CA that affects up to 20.6% of patients. QRS duration and IVS thickness are independently associated with PPM implantation. A PPM implantation at 12 months model was devised and validated to identify patients with CA at higher risk of requiring a PPM and who require closer follow-up.