The A1/A2 ß-casein genotype of cows, but not their horn status, influences peptide generation during simulated digestion of milk.

The effect of the horn status of cows on their milk composition and quality is a controversial research topic. In this study, 128 milk samples from 64 horned and 64 disbudded Brown Swiss and Original Braunvieh cows were collected from alpine farms where both horned and disbudded cows were grazing on mountain pastures. The samples were analyzed for their detailed composition and protein digestion in a simulated in vitro digestion (INFOGEST). To exclude probable influences on digestion, the ß-CN genotype with its variants A1 and A2 was also included in the study. The effects of horn status and ß-CN genotype were investigated in linear mixed models, which included additional influencing random factors such as Original Braunvieh blood proportion, stage of lactation, and farm. Horn status did not have any effect on milk composition or digestion. In contrast, milk from A1A1 cows showed a different protein digestion than milk of A1A2 and A2A2 cows in the gastric phase, including smaller amounts of ß-casomorphin(BCM)21-associated peptides and larger amounts of BCM11-associated peptides. Abundances of BCM7 did not differ between ß-CN genotypes. At the end of the intestinal phase, the digested milk of A1A1 and A2A2 ß-CN genotypes did not differ.

The Importance of Preventing and Managing Tear Dysfunction Syndrome in Allergic Conjunctivitis and How to Tackle This Problem.

Tear dysfunction syndrome, also known as dry eye disease (DED), is a multifactorial disease of the ocular surface characterized by the loss of tear film homeostasis. DED shows a significant clinical overlap with ocular allergy (OA), which alters tear film homeostasis, thus predisposing the patient to DED. Both conditions constitute the most common ocular surface disorders and have a potentially severe impact on patients' quality of life. Clinical practice guidelines recommend topical therapies as first-line treatment for OA. However, eye drop formulations may contain additional substances that can contribute to ocular surface damage and the development of DED. Therefore, physicians treating ocular allergy should be aware of problems affecting the tear film, the role of tear film disruption in OA, and topical treatment to prevent or minimize DED. The aim of this review is to present an updated overview of the topic.

Three major dimensions of human brain cortical ageing in relation to cognitive decline across the eighth decade of life.

Different brain regions can be grouped together, based on cross-sectional correlations among their cortical characteristics; this patterning has been used to make inferences about ageing processes. However, cross-sectional brain data conflate information on ageing with patterns that are present throughout life. We characterised brain cortical ageing across the eighth decade of life in a longitudinal ageing cohort, at ages ~73, ~76, and ~79 years, with a total of 1376 MRI scans. Volumetric changes among cortical regions of interest (ROIs) were more strongly correlated (average r = 0.805, SD = 0.252) than were cross-sectional volumes of the same ROIs (average r = 0.350, SD = 0.178). We identified a broad, cortex-wide, dimension of atrophy that explained 66% of the variance in longitudinal changes across the cortex. Our modelling also discovered more specific fronto-temporal and occipito-parietal dimensions that were orthogonal to the general factor and together explained an additional 20% of the variance. The general factor was associated with declines in general cognitive ability (r = 0.431, p < 0.001) and in the domains of visuospatial ability (r = 0.415, p = 0.002), processing speed (r = 0.383, p < 0.001) and memory (r = 0.372, p < 0.001). Individual differences in brain cortical atrophy with ageing are manifest across three broad dimensions of the cerebral cortex, the most general of which is linked with cognitive declines across domains. Longitudinal approaches are invaluable for distinguishing lifelong patterns of brain-behaviour associations from patterns that are specific to aging.

Severity and duration of allergic conjunctivitis: are they associated with severity and duration of allergic rhinitis and asthma?

Summary: Objective. The association of allergic conjunctivitis (AC) with rhinitis and/or asthma is poorly understood. The objective of this study was to apply the Consensus Document for Allergic Conjunctivitis (DECA) criteria for the classification of AC to a population of patients with AC to assess the association between the severity and duration of AC and rhinitis and/or asthma. Methods. Patients with ocular symptoms of AC who participated in the 'Alergológica 2015' study were included. The demographics, classification according to the DECA criteria, etiology, and comorbidities were evaluated by age groups (less or equal than 14 and greater than 14 years). Results. A total of 2,914 patients (age range, 1-90 years) were included in the "Alergológica 2015" study. Of these, 965 patients (33.1%) were diagnosed with AC (77.5% > 14 years). AC was classified as severe, moderate, or mild in 1.8%, 46.4%, and 51.8%, respectively; and as intermittent or persistent in 51.6% and 48.4% of the patients. AC alone occurred in 4% of patients. AC was mainly associated with rhinitis (88.4%), asthma (38.2%), food allergy (8.3%) and atopic dermatitis (3.5%). In allergic respiratory disease rhinitis preceded AC and asthma developed later. The severity and duration of AC was significantly associated with severity and duration of rhinitis (p less than 0.001 for both age groups) and asthma (p less than 0.001 only in adults). Conclusions. The application of the new DECA classification for AC reveals a direct relationship between AC, rhinitis and asthma respect to severity and duration. These relationships suggest that AC should be considered an integral part of the "one airway, one disease" hypothesis.

Molecular modeling and LC-MS-based metabolomics of a glutamine-valproic acid (Gln-VPA) derivative on HeLa cells.

Glutaminase plays an important role in carcinogenesis and cancer cell growth. This biological target is interesting against cancer cells. Therefore, in this work, in silico [docking and molecular dynamics (MD) simulations] and in vitro methods (antiproliferative and LC-MS metabolomics) were employed to assay a hybrid compound derived from glutamine and valproic acid (Gln-VPA), which was compared with 6-diazo-5-oxo-L-norleucine (DON, a glutaminase inhibitor) and VPA (contained in Gln-VPA structure). Docking results from some snapshots retrieved from MD simulations show that glutaminase recognized Gln-VPA and DON. Additionally, Gln-VPA showed antiproliferative effects in HeLa cells and inhibited glutaminase activity. Finally, the LC-MS-based metabolomics studies on HeLa cells treated with either Gln-VPA (IC60 = 8 mM) or DON (IC50 = 3.5 mM) show different metabolomics behaviors, suggesting that they modulate different biological targets of the cell death mechanism. In conclusion, Gln-VPA is capable of interfering with more than one pharmacological target of cancer, making it an interesting drug that can be used to avoid multitherapy of classic anticancer drugs.

Brain age predicts mortality.

Age-associated disease and disability are placing a growing burden on society. However, ageing does not affect people uniformly. Hence, markers of the underlying biological ageing process are needed to help identify people at increased risk of age-associated physical and cognitive impairments and ultimately, death. Here, we present such a biomarker, 'brain-predicted age', derived using structural neuroimaging. Brain-predicted age was calculated using machine-learning analysis, trained on neuroimaging data from a large healthy reference sample (N=2001), then tested in the Lothian Birth Cohort 1936 (N=669), to determine relationships with age-associated functional measures and mortality. Having a brain-predicted age indicative of an older-appearing brain was associated with: weaker grip strength, poorer lung function, slower walking speed, lower fluid intelligence, higher allostatic load and increased mortality risk. Furthermore, while combining brain-predicted age with grey matter and cerebrospinal fluid volumes (themselves strong predictors) not did improve mortality risk prediction, the combination of brain-predicted age and DNA-methylation-predicted age did. This indicates that neuroimaging and epigenetics measures of ageing can provide complementary data regarding health outcomes. Our study introduces a clinically-relevant neuroimaging ageing biomarker and demonstrates that combining distinct measurements of biological ageing further helps to determine risk of age-related deterioration and death.

Low percentages of regulatory T cells in common variable immunodeficiency (CVID) patients with autoimmune diseases and its association with increased numbers of CD4+CD45RO+ T and CD21low B cells.

BACKGROUND: Common variable immunodeficiency (CVID) is a heterogeneous group of primary antibody deficiencies defined by marked reductions in serum IgG, IgA and/or IgM levels and recurrent bacterial infections. Some patients are associated with defects in T cells and regulatory T cells (Tregs), resulting in recurrent viral infections and early-onset autoimmune disease. METHODS: We analyzed whether there is an association between Tregs cells (CD4+CD25+CD127low and CD4+CD25+FoxP3+); memory T cells (CD4+CD45RO+); memory B cells (CD19+CD27-IgD-); and CD21low B cells (CD19+CD38lowCD21low); as well as autoimmune manifestations in 36 patients with CVID (25 women and 11 men, mean age 24 years), all by flow cytometry. RESULTS: Fourteen patients presented with autoimmune diseases (AI) (39%), including 11 with autoimmune thrombocytopenia (ITP) (31%); two with vitiligo (6%); one with systemic lupus erythematosus (LES) (3%); and one with multiple sclerosis (MS) (3%). CVID patients with AI had a reduced proportion of Tregs (both CD4+CD25+CD127low and FoxP3+ cells) compared with healthy controls. CVID patients with AI had expanded CD21low B cell populations compared with patients who did not have AI. A correlation between increased CD4+CD45RO T cell populations and reduced Tregs was also observed. CONCLUSIONS: Our results showed that 39% of patients with CVID had AI and reduced Tregs populations. Research in this area might provide noteworthy data to better understand immune dysfunction and dysregulation related to CVID.

Position paper on nasal obstruction: evaluation and treatment.

Nasal obstruction (NO) is defined as the subjective perception of discomfort or difficulty in the passage of air through the nostrils. It is a common reason for consultation in primary and specialized care and may affect up to 30%-40% of the population. It affects quality of life (especially sleep) and lowers work efficiency. The aim of this document is to agree on how to treat NO, establish a methodology for evaluating and diagnosing it, and define an individualized approach to its treatment. NO can be unilateral or bilateral, intermittent or persistent and may be caused by local or systemic factors, which may be anatomical, inflammatory, neurological, hormonal, functional, environmental, or pharmacological in origin. Directed study of the medical history and physical examination are key for diagnosing the specific cause. NO may be evaluated using subjective assessment tools (visual analog scale, symptom score, standardized questionnaires) or by objective estimation (active anterior rhinomanometry, acoustic rhinometry, peak nasal inspiratory flow). Although there is little correlation between the results, they may be considered complementary and not exclusive. Assessing the impact on quality of life through questionnaires standardized according to the underlying disease is also advisable. NO is treated according to its cause. Treatment is fundamentally pharmacological (topical and/or systemic) when the etiology is inflammatory or functional. Surgery may be necessary when medical treatment fails to complement or improve medical treatment or when other therapeutic approaches are not possible. Combinations of surgical techniques and medical treatment may be necessary.

Consensus document on allergic conjunctivitis (DECA).

Allergic conjunctivitis (AC) is an inflammatory disease of the conjunctiva caused mainly by an IgE-mediated mechanism. It is the most common type of ocular allergy. Despite being the most benign form of conjunctivitis, AC has a considerable effect on patient quality of life, reduces work productivity, and increases health care costs. No consensus has been reached on its classification, diagnosis, or treatment. Consequently, the literature provides little information on its natural history, epidemiological data are scarce, and it is often difficult to ascertain its true morbidity. The main objective of the Consensus Document on Allergic Conjunctivitis (Documento dE Consenso sobre Conjuntivitis Alérgica [DECA]), which was drafted by an expert panel from the Spanish Society of Allergology and Spanish Society of Ophthalmology, was to reach agreement on basic criteria that could prove useful for both specialists and primary care physicians and facilitate the diagnosis, classification, and treatment of AC. This document is the first of its kind to describe and analyze aspects of AC that could make it possible to control symptoms.

Tibolone prevents oxidation and ameliorates cholinergic deficit induced by ozone exposure in the male rat hippocampus.

Oxidative stress is related to the development of central nervous system diseases involving memory processes. Cholinergic system and memory processes are disrupted by ozone exposure. In rats, ozone induces motor disturbances and memory deficits as well as biochemical changes in brain regions related to memory processes. In this work, we analyzed the effect of chronic tibolone (TIB) administration in central nervous system, specifically the content of choline acetyltransferase, acetylcholinesterase, acetylcholine and oxidative stress markers in the hippocampus of male rats exposed to ozone. Our results reveal a neuroprotective effect of TIB treatment on neuronal damage induced by chronic ozone exposure. Furthermore, we suggest that TIB can prevent memory deficits by providing a protective effect against oxidative stress and the cholinergic system disruption induced by ozone exposure. Together, these findings present a potential neuroprotective effect of TIB in processes linked to memory deficits induced by aging or neurodegenerative diseases.

A potential therapeutic strategy based on acute oxidative stress induction for wild-type NRF2/KEAP1 lung squamous cell carcinoma.

Extensive efforts have been conducted in the search for new targetable drivers of lung squamous cell carcinoma (LUSC); to date, however, candidates remain mostly unsuccessful. One of the oncogenic pathways frequently found to be active in LUSC is NFE2L2 (NRF2 transcription factor), the levels of which are regulated by KEAP1. Mutations in NFE2L2 or KEAP1 trigger NRF2 activation, an essential protector against reactive oxygen species (ROS). We hypothesized that the frequency of NRF2 activation in LUSC (∼35 %) may reflect a sensitivity of LUSC to ROS. Results from this study reveal that whereas tumors containing active forms of NRF2 were protected, ROS induction in wild-type NFE2L2/KEAP1 LUSC cells triggered ferroptosis. The mechanism of ROS action in normal-NRF2 LUSC cells involved transient NRF2 activation, miR-126-3p/miR-126-5p upregulation, and reduction of p85ß and SETD5 levels. SETD5 levels reduction triggered pentose pathway gene levels increase to toxic values. Simultaneous depletion of p85ßPI3K and SETD5 triggered LUSC cell death, while p85ßPI3K and SETD5 overexpression rescued survival of ROS-treated normal-NRF2 LUSC cells. This shows that the cascade involving NRF2 > miR-126-3p, miR-126-5p > p85ßPI3K and SETD5 is responsible for ROS-induced cell death in normal-NRF2 LUSC. Transient ROS-induced cell death is shown in 3D spheroids, patient-derived organoids, and in xenografts of wild-type NFE2L2/KEAP1 LUSC cells, supporting the potential of acute local ROS induction as a therapeutic strategy for LUSC patients with normal-NRF2.

Brain white matter tract integrity as a neural foundation for general intelligence.

General intelligence is a robust predictor of important life outcomes, including educational and occupational attainment, successfully managing everyday life situations, good health and longevity. Some neuronal correlates of intelligence have been discovered, mainly indicating that larger cortices in widespread parieto-frontal brain networks and efficient neuronal information processing support higher intelligence. However, there is a lack of established associations between general intelligence and any basic structural brain parameters that have a clear functional meaning. Here, we provide evidence that lower brain-wide white matter tract integrity exerts a substantial negative effect on general intelligence through reduced information-processing speed. Structural brain magnetic resonance imaging scans were acquired from 420 older adults in their early 70s. Using quantitative tractography, we measured fractional anisotropy and two white matter integrity biomarkers that are novel to the study of intelligence: longitudinal relaxation time (T1) and magnetisation transfer ratio. Substantial correlations among 12 major white matter tracts studied allowed the extraction of three general factors of biomarker-specific brain-wide white matter tract integrity. Each was independently associated with general intelligence, together explaining 10% of the variance, and their effect was completely mediated by information-processing speed. Unlike most previously established neurostructural correlates of intelligence, these findings suggest a functionally plausible model of intelligence, where structurally intact axonal fibres across the brain provide the neuroanatomical infrastructure for fast information processing within widespread brain networks, supporting general intelligence.

Mediterranean-Type Diet and Brain Structural Change from 73 to 79 Years in the Lothian Birth Cohort 1936.

OBJECTIVES: To test whether Mediterranean-type Diet (MeDi) at age 70 years is associated with longitudinal trajectories of total brain MRI volume over a six-year period from age 73 to 79. DESIGN: Cohort study which uses a correlational design. SETTING: Participants residing in the Lothian region of Scotland and living independently in the community. PARTICIPANTS: A relatively healthy Scottish sample drawn from the Lothian Birth Cohort 1936. MEASUREMENTS: Total brain volume measurements were available at ages 73, 76 and 79 (N ranged 332 to 563). Adherence to the MeDi was based on food frequency questionnaire data collected three years before the baseline imaging scans, and was used in growth curve models to predict the trajectory of total brain volume change. RESULTS: No association was found (p>.05) between adherence to the MeDi at age 70 and total brain volume change from 73 to 79 years in minimally-adjusted (sex) or fully adjusted models controlling for additional health confounders. CONCLUSIONS: Variation in adherence to the MeDi was not predictive of total brain atrophy over a six-year period. This suggests that previous findings of dietary associations with brain volume are not long lasting or become less important as ageing-related conditions account for greater variation in brain volume change. More frequent collection of dietary intake data is needed to clarify these findings.

Detection of markers of cardiovascular and renal risk in Cuba: Isle of Youth Study (ISYS).

UNLABELLED: Chronic vascular diseases constitute a growing global health problem. OBJECTIVES: To (a) determine marker positivity for renovascular damage in the total adult population of the Isle of Youth, Cuba; (b) describe marker association with common risk factors for renal and related chronic vascular conditions, and (c) identify best predictors of renovascular damage. METHODS: Previous informed consent was obtained, the population studied was 55,646, and subjects were aged ≥20 years. Blood pressure, weight and height were measured and a questionnaire applied. Urine markers for renovascular damage (hematuria, proteinuria and microalbuminuria) were also determined. RESULTS: Positive markers were detected in 21.3%: hematuria (12.6%), microalbuminuria (6.8%), proteinuria (0.9%), and proteinuria + hematuria (0.9%). Risk factors were highly prevalent: 15.1% were aged ≥60 years; 32.3% overweight, 13.9% obese, and 25.1% smokers. Prevalence of high blood pressure (30%), diabetes mellitus (5.4%) and cardiovascular disease (5%) was also high, while cerebrovascular disease registered 0.9%. Markers were more prevalent in older people and in those suffering from diabetes mellitus, high blood pressure, cardiovascular and cerebrovascular disease, overweight or obesity. Risk factor regression tree analysis identified hypertension as the best predictor of renovascular damage. CONCLUSIONS: Adult population-wide screening revealed hidden morbidity and permitted better risk stratification. Results serve to inform community-based multidisciplinary and intersectoral disease prevention and management.

12th Post-ECTRIMS Meeting: review of the novelties from the 2019 ECTRIMS Congress (II). / XII Reunión Post-ECTRIMS: revisión de las novedades presentadas en el Congreso ECTRIMS 2019 (II).

INTRODUCTION: Like every year, after the ECTRIMS Congress, renowned Spanish neurologists who are experts in multiple sclerosis presented the main novelties in research in this field at the Post-ECTRIMS Meeting. AIM: To summarise the content presented at the 12th edition of the Post-ECTRIMS Meeting, which took place in September 2019 in Sevilla and is presented in two parts. DEVELOPMENT: In this second part, the most recent evidence on the use of disease-modifying treatments during pregnancy is presented. Details are provided concerning the results of phase 3 clinical trials conducted to evaluate the efficacy and safety of two potential disease-modifying treatments for relapsing-remitting multiple sclerosis: ponesimod and ofatumumab. For the progressive forms, both available disease modifying treatments and others still in the research phase are reviewed. In the field of stem cell therapies, the article includes the results of the only clinical trial carried out to date comparing patients with relapsing-remitting multiple sclerosis treated with autologous haematopoietic stem cell transplantation and those treated with disease-modifying therapies. There are no important developments as regards symptomatic treatments, although the European Academy of Neurology has published a guide on palliative care. The various sources of information that collect pharmacovigilance data in the post-marketing setting are reviewed. CONCLUSIONS: Patients diagnosed in recent years tend to have less severe multiple sclerosis, probably due to the fact that it is diagnosed in its milder stages together with the steady increase in the number of treatments available.

TITLE: XII Reunión Post-ECTRIMS: revisión de las novedades presentadas en el Congreso ECTRIMS 2019 (II).Introducción. Como cada año, tras la celebración del Congreso del ECTRIMS, reconocidos neurólogos españoles expertos en esclerosis múltiple expusieron en la Reunión Post-ECTRIMS las principales novedades en investigación en este ámbito. Objetivo. Sintetizar el contenido presentado en la XII edición de la Reunión Post-ECTRIMS, que tuvo lugar en septiembre de 2019 en Sevilla y que se presenta en dos partes. Desarrollo. En esta segunda parte, se exponen las evidencias más recientes sobre el uso de tratamientos modificadores de la enfermedad durante el embarazo. Se detallan los resultados de ensayos clínicos en fase 3 en los que se ha evaluado la eficacia y la seguridad de dos potenciales tratamientos modificadores de la enfermedad para la esclerosis múltiple remitente recurrente: ponesimod y ofatumumab. Para las formas progresivas, se revisan los tratamientos modificadores de la enfermedad disponibles y en investigación. En el ámbito de las terapias con células madre, se incluyen los resultados del único ensayo clínico hasta la fecha que compara a pacientes con esclerosis múltiple remitente recurrente tratados con trasplante autólogo de células madre hematopoyéticas y a los tratados con tratamientos modificadores de la enfermedad. No hay grandes novedades sobre tratamientos sintomáticos, aunque la Academia Europea de Neurología ha publicado una guía sobre cuidados paliativos. Se revisan las distintas fuentes de información que recogen datos de farmacovigilancia en el entorno poscomercialización. Conclusiones. Los pacientes diagnosticados en los últimos años tienden a tener una menor gravedad de la esclerosis múltiple, probablemente debido al diagnóstico desde sus estadios más leves y al continuo aumento de tratamientos disponibles.

[12th Post-ECTRIMS Meeting: review of the novelties from the 2019 ECTRIMS Congress (I)]. / XII Reunión Post-ECTRIMS: revisión de las novedades presentadas en el Congreso ECTRIMS 2019 (I).

INTRODUCTION: Like every year, after the ECTRIMS Congress, renowned Spanish neurologists who are experts in multiple sclerosis presented the main novelties in research in this field at the Post-ECTRIMS Meeting. AIM: To summarise the content presented at the 12th edition of the Post-ECTRIMS Meeting, which took place in September 2019 in Sevilla and is presented in two parts. DEVELOPMENT: This first part addresses the latest studies on vitamin D deficiency and the discrepancies that currently exist regarding its treatment. The advances made in epigenetics allow us to present this approach as a possible biomarker of multiple sclerosis. An account is provided to explain the growing importance of imaging techniques to detect atrophy and other phenomena that occur during the disease, such as changes in iron concentration or remyelination processes, which allow us to further our understanding of the mechanisms of cortical pathology, and the dimensionality of neurodegeneration during its course. Findings related to immunological mechanisms and advances in potential antigen-specific therapies are discussed. The contribution presents the latest studies on the assessment of cognitive impairment and its rehabilitation, which are becoming increasingly important due to the high prevalence of these disorders and the absence of their systematic assessment in clinical practice. Finally, the unmet social and health needs of multiple sclerosis patients in our country are presented, with emphasis on the current deficits in the system of social protection.

TITLE: XII Reunión Post-ECTRIMS: revisión de las novedades presentadas en el Congreso ECTRIMS 2019 (I).Introducción. Como cada año, tras la celebración del Congreso ECTRIMS, reconocidos neurólogos españoles expertos en esclerosis múltiple expusieron en la Reunión Post-ECTRIMS las principales novedades en investigación en este ámbito. Objetivo. Sintetizar el contenido presentado en la XII edición de la Reunión Post-ECTRIMS, que tuvo lugar en septiembre de 2019 en Sevilla y que se presenta en dos partes. Desarrollo. Esta primera parte aborda los últimos estudios sobre el déficit de vitamina D y las discrepancias existentes acerca de su tratamiento. Los avances en epigenética realizados permiten presentar esta aproximación como un posible biomarcador de la esclerosis múltiple. Se explica el creciente protagonismo de las técnicas de imagen para detectar la atrofia y otros fenómenos que acontecen durante la enfermedad, como los cambios en la concentración de hierro o los procesos de remielinización, que nos permiten ganar comprensión sobre los mecanismos de la patología cortical, y sobre la dimensionalidad de la neurodegeneración durante su evolución. Se discuten los hallazgos relacionados con los mecanismos inmunológicos y los avances realizados en las potenciales terapias específicas del antígeno. Se presentan los últimos estudios sobre la evaluación del deterioro cognitivo y su rehabilitación, que cobran cada vez más importancia por la alta prevalencia de estas alteraciones y por la ausencia de su evaluación sistemática en la práctica clínica. Por último, se exponen las necesidades sociosanitarias no cubiertas de los pacientes de esclerosis múltiple en nuestro país, poniendo el acento en los déficits actuales del sistema de protección social.

Rare chromosomal complement of trisomy 21 in a boy conceived by IVF and cryopreservation.

This report describes a case of mosaic Down syndrome due to an unusual karyotype in a patient conceived by assisted reproductive techniques and cryopreservation. The chromosomal complement consists of two different cell lines, one predominantly trisomic with a derivative chromosome due to a Robertsonian translocation (21;21) and another carrying a ring chromosome 21. The present work analyses the different mechanisms that could have led to mosaicism.