-
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 -
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 -
Cancers Jan 2022Despite recent improvements in diagnostic ability and treatment strategies, advanced gastric cancer (GC) has a high frequency of recurrence and metastasis, with poor... (Review)
Review
Despite recent improvements in diagnostic ability and treatment strategies, advanced gastric cancer (GC) has a high frequency of recurrence and metastasis, with poor prognosis. To improve the treatment results of GC, the search for new treatment targets from proteins related to epithelial-mesenchymal transition (EMT) and cell-cell adhesion is currently being conducted. EMT plays an important role in cancer metastasis and is initiated by the loss of cell-cell adhesion, such as tight junctions (TJs), adherens junctions, desmosomes, and gap junctions. Among these, claudins (CLDNs) are highly expressed in some cancers, including GC. Abnormal expression of CLDN1, CLDN2, CLDN3, CLDN4, CLDN6, CLDN7, CLDN10, CLDN11, CLDN14, CLDN17, CLDN18, and CLDN23 have been reported. Among these, CLDN18 is of particular interest. In The Cancer Genome Atlas, GC was classified into four new molecular subtypes, and - fusion was observed in the genomically stable type. An anti-CLDN18.2 antibody drug was recently developed as a therapeutic drug for GC, and the results of clinical trials are highly predictable. Thus, CLDNs are highly expressed in GC as TJs and are expected targets for new antibody drugs. Herein, we review the literature on CLDNs, focusing on CLDN18 in GC.
PubMed: 35053454
DOI: 10.3390/cancers14020290 -
Circulation Jul 2021Each of the cardiomyopathies, classically categorized as hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy,...
BACKGROUND
Each of the cardiomyopathies, classically categorized as hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy, has a signature genetic theme. Hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning >10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted.
METHODS
An international panel with clinical and scientific expertise in DCM genetics evaluated evidence supporting monogenic relationships of genes with idiopathic DCM. The panel used the Clinical Genome Resource semiquantitative gene-disease clinical validity classification framework with modifications for DCM genetics to classify genes into categories on the basis of the strength of currently available evidence. Representation of DCM genes on clinically available genetic testing panels was evaluated.
RESULTS
Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from 8 gene ontologies were classified as having definitive (, , , , , , , , , , ) or strong () evidence. Seven genes (14%; , , , , , , ) including 2 additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of these 19 genes, 6 were similarly classified for hypertrophic cardiomyopathy and 3 for arrhythmogenic right ventricular cardiomyopathy. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of the 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence.
CONCLUSIONS
In the curation of 51 genes, 19 had high evidence (12 definitive/strong, 7 moderate). It is notable that these 19 genes explain only a minority of cases, leaving the remainder of DCM genetic architecture incompletely addressed. Clinical genetic testing panels include most high-evidence genes; however, genes lacking robust evidence are also commonly included. We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes.
Topics: Cardiomyopathy, Dilated; Evidence-Based Medicine; Expert Testimony; Genetic Predisposition to Disease; Genetic Testing; Humans
PubMed: 33947203
DOI: 10.1161/CIRCULATIONAHA.120.053033 -
JACC. Heart Failure Oct 2022The risk of adverse cardiovascular events in patients with acute myocarditis (AM) and desmosomal gene variants (DGV) remains unknown.
BACKGROUND
The risk of adverse cardiovascular events in patients with acute myocarditis (AM) and desmosomal gene variants (DGV) remains unknown.
OBJECTIVES
The purpose of this study was to ascertain the risk of death, ventricular arrhythmias, recurrent myocarditis, and heart failure (main endpoint) in patients with AM and pathogenic or likely pathogenetic DGV.
METHODS
In a retrospective international study from 23 hospitals, 97 patients were included: 36 with AM and DGV (DGV[+]), 25 with AM and negative gene testing (DGV[-]), and 36 with AM without genetics testing. All patients had troponin elevation plus findings consistent with AM on histology or at cardiac magnetic resonance (CMR). In 86 patients, CMR changes in function and structure were re-assessed at follow-up.
RESULTS
In the DGV(+) AM group (88.9% DSP variants), median age was 24 years, 91.7% presented with chest pain, and median left ventricular ejection fraction (LVEF) was 56% on CMR (P = NS vs the other 2 groups). Kaplan-Meier curves demonstrated a higher risk of the main endpoint in DGV(+) AM compared with DGV(-) and without genetics testing patients (62.3% vs 17.5% vs 5.3% at 5 years, respectively; P < 0.0001), driven by myocarditis recurrence and ventricular arrhythmias. At follow-up CMR, a higher number of late gadolinium enhanced segments was found in DGV(+) AM.
CONCLUSIONS
Patients with AM and evidence of DGV have a higher incidence of adverse cardiovascular events compared with patients with AM without DGV. Further prospective studies are needed to ascertain if genetic testing might improve risk stratification of patients with AM who are considered at low risk.
Topics: Gadolinium; Heart Failure; Humans; Myocarditis; Retrospective Studies; Stroke Volume; Troponin; Ventricular Function, Left; Young Adult
PubMed: 36175056
DOI: 10.1016/j.jchf.2022.06.013 -
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 -
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 -
Hepatology (Baltimore, Md.) Jun 2021Fructose intake is known to induce obesity, insulin resistance, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD). We aimed to evaluate the effects of...
Fructose intake is known to induce obesity, insulin resistance, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD). We aimed to evaluate the effects of fructose drinking on gut leakiness, endotoxemia, and NAFLD and study the underlying mechanisms in rats, mice, and T84 colon cells. Levels of ileum junctional proteins, oxidative stress markers, and apoptosis-related proteins in rodents, T84 colonic cells, and human ileums were determined by immunoblotting, immunoprecipitation, and immunofluorescence analyses. Fructose drinking caused microbiome change, leaky gut, and hepatic inflammation/fibrosis with increased levels of nitroxidative stress marker proteins cytochrome P450-2E1 (CYP2E1), inducible nitric oxide synthase, and nitrated proteins in small intestine and liver of rodents. Fructose drinking significantly elevated plasma bacterial endotoxin levels, likely resulting from decreased levels of intestinal tight junction (TJ) proteins (zonula occludens 1, occludin, claudin-1, and claudin-4), adherent junction (AJ) proteins (β-catenin and E-cadherin), and desmosome plakoglobin, along with α-tubulin, in wild-type rodents, but not in fructose-exposed Cyp2e1-null mice. Consistently, decreased intestinal TJ/AJ proteins and increased hepatic inflammation with fibrosis were observed in autopsied obese people compared to lean individuals. Furthermore, histological and biochemical analyses showed markedly elevated hepatic fibrosis marker proteins in fructose-exposed rats compared to controls. Immunoprecipitation followed by immunoblot analyses revealed that intestinal TJ proteins were nitrated and ubiquitinated, leading to their decreased levels in fructose-exposed rats. Conclusion: These results showed that fructose intake causes protein nitration of intestinal TJ and AJ proteins, resulting in increased gut leakiness, endotoxemia, and steatohepatitis with liver fibrosis, at least partly, through a CYP2E1-dependent manner.
Topics: Adult; Animals; Cytochrome P-450 CYP2E1; Endotoxemia; Endotoxins; Ethanol; Female; Fluorescent Antibody Technique; Fructose; Humans; Liver; Liver Cirrhosis; Male; Mice; Middle Aged; Nitric Oxide Synthase Type II; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Rats; Sugar-Sweetened Beverages; Tight Junctions
PubMed: 30959577
DOI: 10.1002/hep.30652 -
Developmental Cell Dec 2022Sorting transmembrane cargo is essential for tissue development and homeostasis. However, mechanisms of intracellular trafficking in stratified epidermis are poorly...
Sorting transmembrane cargo is essential for tissue development and homeostasis. However, mechanisms of intracellular trafficking in stratified epidermis are poorly understood. Here, we identify an interaction between the retromer endosomal trafficking component, VPS35, and the desmosomal cadherin, desmoglein-1 (Dsg1). Dsg1 is specifically expressed in stratified epidermis and, when properly localized on the plasma membrane of basal keratinocytes, promotes stratification. We show that the retromer drives Dsg1 recycling from the endo-lysosomal system to the plasma membrane to support human keratinocyte stratification. The retromer-enhancing chaperone, R55, promotes the membrane localization of Dsg1 and a trafficking-deficient mutant associated with a severe inflammatory skin disorder, enhancing its ability to promote stratification. In the absence of Dsg1, retromer association with and expression of the glucose transporter GLUT1 increases, exposing a potential link between Dsg1 deficiency and epidermal metabolism. Our work provides evidence for retromer function in epidermal regeneration, identifying it as a potential therapeutic target.
Topics: Humans; Cadherins; Desmoglein 1; Endosomes; Epidermal Cells; Epidermis; Keratinocytes
PubMed: 36495876
DOI: 10.1016/j.devcel.2022.11.010