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Women's Health (London, England) 2022Nipple pain is a common reason for premature cessation of breastfeeding. Despite the benefits of breastfeeding for both infant and mother, clinical support for problems... (Review)
Review
Nipple pain is a common reason for premature cessation of breastfeeding. Despite the benefits of breastfeeding for both infant and mother, clinical support for problems such as maternal nipple pain remains a research frontier. Maternal pharmaceutical treatments, and infant surgery and bodywork interventions are commonly recommended for lactation-related nipple pain without evidence of benefit. The pain is frequently attributed to mammary dysbiosis, candidiasis, or infant anatomic anomaly (including to diagnoses of posterior or upper lip-tie, high palate, retrognathia, or subtle cranial nerve abnormalities). Although clinical protocols universally state that improved fit and hold is the mainstay of treatment of nipple pain and wounds, the biomechanical parameters of pain-free fit and hold remain an omitted variable bias in almost all clinical breastfeeding research. This article reviews the research literature concerning aetiology, classification, prevention, and management of lactation-related nipple-areolar complex (NAC) pain and damage. Evolutionary and complex systems perspectives are applied to develop a narrative synthesis of the heterogeneous and interdisciplinary evidence elucidating nipple pain in breastfeeding women. Lactation-related nipple pain is most commonly a symptom of inflammation due to repetitive application of excessive mechanical stretching and deformational forces to nipple epidermis, dermis and stroma during milk removal. Keratinocytes lock together when mechanical forces exceed desmosome yield points, but if mechanical loads continue to increase, desmosomes may rupture, resulting in inflammation and epithelial fracture. Mechanical stretching and deformation forces may cause stromal micro-haemorrhage and inflammation. Although the environment of the skin of the nipple-areolar complex is uniquely conducive to wound healing, it is also uniquely exposed to environmental risks. The two key factors that both prevent and treat nipple pain and inflammation are, first, elimination of conflicting vectors of force during suckling or mechanical milk removal, and second, elimination of overhydration of the epithelium which risks moisture-associated skin damage. There is urgent need for evaluation of evidence-based interventions for the elimination of conflicting intra-oral vectors of force during suckling.
Topics: Breast Feeding; Female; Humans; Infant; Lactation; Mothers; Nipples; Pain
PubMed: 35343816
DOI: 10.1177/17455057221087865 -
Gastroenterology Jan 2018Eosinophilic esophagitis is an emerging disease that is distinguished from gastroesophageal reflux disease by the expression of a unique esophageal transcriptome and... (Review)
Review
Eosinophilic esophagitis is an emerging disease that is distinguished from gastroesophageal reflux disease by the expression of a unique esophageal transcriptome and the interplay of early life environmental factors with distinct genetic susceptibility elements at 5q22 (TSLP) and 2p23 (CAPN14). Rare genetic syndromes have uncovered the contribution of barrier disruption, mediated in part by defective desmosomes and dysregulated transforming growth factor beta production and signaling, to eosinophilic esophagitis pathophysiology. Experimental modeling has defined a cooperative role of activated eosinophils, mast cells, and the cytokines IL-5 and IL-13, mediated by allergic sensitization to multiple foods. Understanding these processes is opening the way to better treatment based on disrupting allergic inflammatory and type 2 cytokine-mediated responses, including anti-cytokine therapeutics and dietary therapy.
Topics: Adult; Age Factors; Allergens; Biopsy; Child; Cytokines; Ehlers-Danlos Syndrome; Eosinophilic Esophagitis; Eosinophils; Epigenesis, Genetic; Esophageal Stenosis; Esophagus; Female; Fibrosis; Food Hypersensitivity; Gastroesophageal Reflux; Gastrointestinal Microbiome; Genetic Predisposition to Disease; Glucocorticoids; Humans; Loeys-Dietz Syndrome; Male; Mast Cells; Prevalence; Proton Pump Inhibitors; Sex Factors; Transcriptome
PubMed: 28757265
DOI: 10.1053/j.gastro.2017.06.065 -
Anais Brasileiros de Dermatologia Jul 2019Pemphigus vulgaris is a chronic autoimmune bullous dermatosis that results from the production of autoantibodies against desmogleins 1 and 3. It is the most frequent and...
Pemphigus vulgaris is a chronic autoimmune bullous dermatosis that results from the production of autoantibodies against desmogleins 1 and 3. It is the most frequent and most severe form of pemphigus, occurring universally, usually between 40 and 60 years of age. It usually begins with blisters and erosions on the oral mucosa, followed by lesions on other mucous membranes and flaccid blisters on the skin, which can be disseminated. There is a clinical variant, pemphigus vegetans, which is characterized by the presence of vegetating lesions in the large folds of the skin. Clinical suspicion can be confirmed by cytological examination, histopathological examination, and direct and indirect immunofluorescence tests. The treatment is performed with systemic corticosteroids, and immunosuppressive drugs may be associated, among them azathioprine and mycophenolate mofetil. More severe cases may benefit from corticosteroids in the form of intravenous pulse therapy, and recent studies have shown a beneficial effect of rituximab, an anti-CD20 immunobiological drug. It is a chronic disease with mortality around 10%, and septicemia is the main cause of death. Patients need long-term and multidisciplinary follow-up.
Topics: Adult; Autoantibodies; Desmosomes; Diagnosis, Differential; Female; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Immunotherapy; Male; Middle Aged; Pemphigus; Skin; Surveys and Questionnaires
PubMed: 31365654
DOI: 10.1590/abd1806-4841.20199011 -
Cold Spring Harbor Perspectives in... Apr 2018Cell-cell junctions link cells to each other in tissues, and regulate tissue homeostasis in critical cell processes that include tissue barrier function, cell... (Review)
Review
Cell-cell junctions link cells to each other in tissues, and regulate tissue homeostasis in critical cell processes that include tissue barrier function, cell proliferation, and migration. Defects in cell-cell junctions give rise to a wide range of tissue abnormalities that disrupt homeostasis and are common in genetic abnormalities and cancers. Here, we discuss the organization and function of cell-cell junctions primarily involved in adhesion (tight junction, adherens junction, and desmosomes) in two different epithelial tissues: a simple epithelium (intestine) and a stratified epithelium (epidermis). Studies in these tissues reveal similarities and differences in the organization and functions of different cell-cell junctions that meet the requirements for the specialized functions of each tissue. We discuss cell-cell junction responses to genetic and environmental perturbations that provide further insights into their roles in maintaining tissue homeostasis.
Topics: Adherens Junctions; Animals; Cell Movement; Cell Proliferation; Desmosomes; Epithelial Cells; Epithelium; Homeostasis; Humans; Intercellular Junctions; Intestinal Mucosa; Signal Transduction; Tight Junctions; Wound Healing
PubMed: 28600395
DOI: 10.1101/cshperspect.a029181 -
Circulation Jun 2020Mutations in desmoplakin (), the primary force transducer between cardiac desmosomes and intermediate filaments, cause an arrhythmogenic form of cardiomyopathy that has...
BACKGROUND
Mutations in desmoplakin (), the primary force transducer between cardiac desmosomes and intermediate filaments, cause an arrhythmogenic form of cardiomyopathy that has been variably associated with arrhythmogenic right ventricular cardiomyopathy. Clinical correlates of cardiomyopathy have been limited to small case series.
METHODS
Clinical and genetic data were collected on 107 patients with pathogenic mutations and 81 patients with pathogenic plakophilin 2 () mutations as a comparison cohort. A composite outcome of severe ventricular arrhythmia was assessed.
RESULTS
and cohorts included similar proportions of probands (41% versus 42%) and patients with truncating mutations (98% versus 100%). Left ventricular (LV) predominant cardiomyopathy was exclusively present among patients with (55% versus 0% for , <0.001), whereas right ventricular cardiomyopathy was present in only 14% of patients with versus 40% for (<0.001). Arrhythmogenic right ventricular cardiomyopathy diagnostic criteria had poor sensitivity for cardiomyopathy. LV late gadolinium enhancement was present in a primarily subepicardial distribution in 40% of patients with (23/57 with magnetic resonance images). LV late gadolinium enhancement occurred with normal LV systolic function in 35% (8/23) of patients with . Episodes of acute myocardial injury (chest pain with troponin elevation and normal coronary angiography) occurred in 15% of patients with and were strongly associated with LV late gadolinium enhancement (90%), even in cases of acute myocardial injury with normal ventricular function (4/5, 80% with late gadolinium enhancement). In 4 cases with 18F-fluorodeoxyglucose positron emission tomography scans, acute LV myocardial injury was associated with myocardial inflammation misdiagnosed initially as cardiac sarcoidosis or myocarditis. Left ventricle ejection fraction <55% was strongly associated with severe ventricular arrhythmias for cases (<0.001, sensitivity 85%, specificity 53%). Right ventricular ejection fraction <45% was associated with severe arrhythmias for cases (<0.001) but was poorly associated for cases (=0.8). Frequent premature ventricular contractions were common among patients with severe arrhythmias for both (80%) and (91%) groups (=non-significant).
CONCLUSIONS
cardiomyopathy is a distinct form of arrhythmogenic cardiomyopathy characterized by episodic myocardial injury, left ventricular fibrosis that precedes systolic dysfunction, and a high incidence of ventricular arrhythmias. A genotype-specific approach for diagnosis and risk stratification should be used.
Topics: Adult; Arrhythmogenic Right Ventricular Dysplasia; Cardiomyopathies; Cardiomyopathy, Dilated; Desmoplakins; Female; Fibrosis; Humans; Inflammation; Male; Middle Aged; Mutation; Retrospective Studies; Young Adult
PubMed: 32372669
DOI: 10.1161/CIRCULATIONAHA.119.044934 -
Nature Cell Biology Jun 2023The endoplasmic reticulum (ER) forms a dynamic network that contacts other cellular membranes to regulate stress responses, calcium signalling and lipid transfer. Here,...
The endoplasmic reticulum (ER) forms a dynamic network that contacts other cellular membranes to regulate stress responses, calcium signalling and lipid transfer. Here, using high-resolution volume electron microscopy, we find that the ER forms a previously unknown association with keratin intermediate filaments and desmosomal cell-cell junctions. Peripheral ER assembles into mirror image-like arrangements at desmosomes and exhibits nanometre proximity to keratin filaments and the desmosome cytoplasmic plaque. ER tubules exhibit stable associations with desmosomes, and perturbation of desmosomes or keratin filaments alters ER organization, mobility and expression of ER stress transcripts. These findings indicate that desmosomes and the keratin cytoskeleton regulate the distribution, function and dynamics of the ER network. Overall, this study reveals a previously unknown subcellular architecture defined by the structural integration of ER tubules with an epithelial intercellular junction.
Topics: Desmosomes; Cytoskeleton; Keratins; Intermediate Filaments; Endoplasmic Reticulum
PubMed: 37291267
DOI: 10.1038/s41556-023-01154-4 -
Journal of the American College of... Sep 2019Genotype-phenotype correlations in dilated cardiomyopathy (DCM) and, in particular, the effects of gene variants on clinical outcomes remain poorly understood.
BACKGROUND
Genotype-phenotype correlations in dilated cardiomyopathy (DCM) and, in particular, the effects of gene variants on clinical outcomes remain poorly understood.
OBJECTIVES
The purpose of this study was to investigate the prognostic role of genetic variant carrier status in a large cohort of DCM patients.
METHODS
A total of 487 DCM patients were analyzed by next-generation sequencing and categorized the disease genes into functional gene groups. The following composite outcome measures were assessed: 1) all-cause mortality; 2) heart failure-related death, heart transplantation, or destination left ventricular assist device implantation (DHF/HTx/VAD); and 3) sudden cardiac death/sustained ventricular tachycardia/ventricular fibrillation (SCD/VT/VF).
RESULTS
A total of 183 pathogenic/likely pathogenic variants were found in 178 patients (37%): 54 (11%) Titin; 19 (4%) Lamin A/C (LMNA); 24 (5%) structural cytoskeleton-Z disk genes; 16 (3.5%) desmosomal genes; 46 (9.5%) sarcomeric genes; 8 (1.6%) ion channel genes; and 11 (2.5%) other genes. All-cause mortality was no different between variant carriers and noncarriers (p = 0.99). A trend toward worse SCD/VT/VF (p = 0.062) and DHF/HTx/VAD (p = 0.061) was found in carriers. Carriers of desmosomal and LMNA variants experienced the highest rate of SCD/VT/VF, which was independent of the left ventricular ejection fraction.
CONCLUSIONS
Desmosomal and LMNA gene variants identify the subset of DCM patients who are at greatest risk for SCD and life-threatening ventricular arrhythmias, regardless of the left ventricular ejection fraction.
Topics: Adult; Arrhythmias, Cardiac; Cardiomyopathy, Dilated; Cross-Sectional Studies; Female; Genetic Variation; Humans; Male; Middle Aged; Phenotype; Prognosis; Risk Assessment; Risk Factors
PubMed: 31514951
DOI: 10.1016/j.jacc.2019.06.072 -
European Cells & Materials Aug 2019Epithelium attachment to the tooth or abutment surface is necessary to form a biological seal preventing pathogens and irritants from penetrating the body and reaching... (Review)
Review
Epithelium attachment to the tooth or abutment surface is necessary to form a biological seal preventing pathogens and irritants from penetrating the body and reaching the underlying soft tissues and bone, which in turn can lead to inflammation and subsequent bone resorption. The present review investigated oral wound closure and the role of micro-environment, saliva, crevicular fluid and microbiota in wound healing. The importance of the junctional epithelium (peri-implant epithelium) attachment to the abutment surface was investigated. Current research focuses on macro-design, surface-topography, surface-chemistry, materials, coatings and wettability to enhance attachment, since these optimised surface properties are expected to promote keratinocyte attachment and spreading through hemi-desmosome formation. Detailed studies describing the extent of junctional epithelium attachment - e.g. barrier function, hemi-desmosomes, epithelium quality, composition of the external basement membrane or ability of the epithelium to resist microbial penetration and colonisation - are not yet reported in animals due to ethical considerations, scalability, expense, technical challenges and limited availability of antibodies. In vitro studies generally include relatively simple 2D culture models, which lack the complexity required to draw relevant conclusions. Additionally, human organotypic 3D mucosa models are being developed. The present review concluded that more research using these organotypic mucosa models may identify relevant parameters involved in soft-tissue-abutment interactions, which could be used to study different macro-shapes and surface modifications. Such studies would bridge the gap between clinical, animal and traditional in vitro cell culture studies supporting development of abutments aiming at improved clinical performance.
Topics: Animals; Cell Adhesion; Dental Abutments; Epithelial Cells; Gingiva; Humans; Wound Healing
PubMed: 31410840
DOI: 10.22203/eCM.v038a06 -
Orphanet Journal of Rare Diseases Apr 2016Arrhythmogenic cardiomyopathy (AC) is a heart muscle disease clinically characterized by life-threatening ventricular arrhythmias and pathologically by an acquired and... (Review)
Review
Arrhythmogenic cardiomyopathy (AC) is a heart muscle disease clinically characterized by life-threatening ventricular arrhythmias and pathologically by an acquired and progressive dystrophy of the ventricular myocardium with fibro-fatty replacement. Due to an estimated prevalence of 1:2000-1:5000, AC is listed among rare diseases. A familial background consistent with an autosomal-dominant trait of inheritance is present in most of AC patients; recessive variants have also been reported, either or not associated with palmoplantar keratoderma and woolly hair. AC-causing genes mostly encode major components of the cardiac desmosome and up to 50% of AC probands harbor mutations in one of them. Mutations in non-desmosomal genes have been also described in a minority of AC patients, predisposing to the same or an overlapping disease phenotype. Compound/digenic heterozygosity was identified in up to 25% of AC-causing desmosomal gene mutation carriers, in part explaining the phenotypic variability. Abnormal trafficking of intercellular proteins to the intercalated discs of cardiomyocytes and Wnt/beta catenin and Hippo signaling pathways have been implicated in disease pathogenesis.AC is a major cause of sudden death in the young and in athletes. The clinical picture may include a sub-clinical phase; an overt electrical disorder; and right ventricular or biventricular pump failure. Ventricular fibrillation can occur at any stage. Genotype-phenotype correlation studies led to identify biventricular and dominant left ventricular variants, thus supporting the use of the broader term AC.Since there is no "gold standard" to reach the diagnosis of AC, multiple categories of diagnostic information have been combined and the criteria recently updated, to improve diagnostic sensitivity while maintaining specificity. Among diagnostic tools, contrast enhanced cardiac magnetic resonance is playing a major role in detecting left dominant forms of AC, even preceding morpho-functional abnormalities. The main differential diagnoses are idiopathic right ventricular outflow tract tachycardia, myocarditis, sarcoidosis, dilated cardiomyopathy, right ventricular infarction, congenital heart diseases with right ventricular overload and athlete heart. A positive genetic test in the affected AC proband allows early identification of asymptomatic carriers by cascade genetic screening of family members. Risk stratification remains a major clinical challenge and antiarrhythmic drugs, catheter ablation and implantable cardioverter defibrillator are the currently available therapeutic tools. Sport disqualification is life-saving, since effort is a major trigger not only of electrical instability but also of disease onset and progression. We review the current knowledge of this rare cardiomyopathy, suggesting a flowchart for primary care clinicians and geneticists.
Topics: Arrhythmias, Cardiac; Cardiomyopathies; Female; Heterozygote; Humans; Male; Mutation; beta Catenin
PubMed: 27038780
DOI: 10.1186/s13023-016-0407-1 -
Cell and Tissue Research Jun 2015Desmosomes are cell-cell junctions that mediate adhesion and couple the intermediate filament cytoskeleton to sites of cell-cell contact. This architectural arrangement... (Review)
Review
Desmosomes are cell-cell junctions that mediate adhesion and couple the intermediate filament cytoskeleton to sites of cell-cell contact. This architectural arrangement integrates adhesion and cytoskeletal elements of adjacent cells. The importance of this robust adhesion system is evident in numerous human diseases, both inherited and acquired, which occur when desmosome function is compromised. This review focuses on autoimmune and infectious diseases that impair desmosome function. In addition, we discuss emerging evidence that desmosomal genes are often misregulated in cancer. The emphasis of our discussion is placed on the way in which human diseases can inform our understanding of basic desmosome biology and in turn, the means by which fundamental advances in the cell biology of desmosomes might lead to new treatments for acquired diseases of the desmosome.
Topics: Animals; Desmosomes; Humans; Models, Biological; Skin Diseases
PubMed: 25795143
DOI: 10.1007/s00441-015-2155-2