ABSTRACT
The cacao swollen shoot disease (CSSD) caused by a complex of badnavirus species presents a major challenge for cacao production in West Africa, especially Ghana and Côte d'Ivoire. In this study, CSSD species detection efficiency, diversity, and geographic distribution patterns in cacao plantations in Ghana and Côte d'Ivoire were investigated through field surveillance, PCR detection assays, sequencing of positive amplicons, and phylogeographic clustering. Cumulatively, the detection efficiency of the tested CSSD primer sets that were targeting the movement protein domain of the virus ranged from 0.15% (CSSD-3 primer) to 66.91% (CSSD-1 primer) on all the symptomatic cacao leaf samples assessed. The identified CSSD species differed phylogenetically and overlapped in distribution, with the cacao swollen shoot Togo B virus (CSSTBV) (n = 588 sequences) being the most prevalent and widely distributed compared to the other CSSD species that were encountered in both countries. Geographically, the cacao swollen shoot CE virus (CSSCEV) species (n = 124 sequences) that was identified was largely restricted to the bordering regions of Ghana and Côte d'Ivoire. These results provide updated knowledge of the geographic distribution of the key CSSD species and their diagnostic efficiency and, thus, provide guidance in identifying locations for structured testing of cacao germplasm and optimal diagnostics for the predominant CSSD species in Ghana and Côte d'Ivoire.
Subject(s)
Badnavirus , Cacao , Phylogeny , Plant Diseases , Cacao/virology , Cote d'Ivoire/epidemiology , Ghana/epidemiology , Badnavirus/genetics , Badnavirus/isolation & purification , Badnavirus/classification , Plant Diseases/virology , Prevalence , PhylogeographyABSTRACT
Objective: The present study aimed to develop and optimize esomeprazole loaded proniosomes (EZL-PNs) to improve bioavailability and therapeutic efficacy. Method: EZL-PNs formulation was developed by slurry method and optimized by 33 box-Bhekhen statistical design software. Span 60 (surfactant), cholesterol, EZL concentration were taken as independent variables and their effects were evaluated on vesicle size (nm), entrapment efficiency (%, EE) and drug release (%, DR). Furthermore, optimized EZL-PNs (EZL-PNs-opt) formulation was evaluated for ex vivo permeation, pharmacokinetic and ulcer protection activity. Result: The EZL-PNs-opt formulation showed 616 ± 13.21 nm of vesicle size, and 81.21 ± 2.35% of EE. EZL-PNs-opt exhibited negative zeta potential and spherical confirmed scanning electron microscopy. EZL-PNs-opt showed sustained release of EZL (95.07 ± 2.10% in 12 h) than pure EZL dispersion. The ex-vivo gut permeation result exhibited a significantly (p < 0.05) enhanced flux than pure EZL. The in vivo results revealed 4.02-fold enhancement in bioavailability and 61.65% protection in ulcer than pure EZL dispersion (43.82%). Conclusion: Our findings revealed that EZL-PNs formulation could be an alternative delivery system of EZL to enhance oral bioavailability and antiulcer activity.
Subject(s)
Esomeprazole , Ulcer , Administration, Cutaneous , Biological Availability , Drug Carriers , Drug Liberation , Esomeprazole/pharmacology , Humans , Particle SizeABSTRACT
Generalized bullous fixed drug eruptions (GBFDEs) are rare in the paediatric population. We present the case of a 7-year-old girl with GBFDE believed to be secondary to oral ibuprofen, who experienced rapid resolution of lesions and cessation of blistering with a 3-week course of oral cyclosporine. To the best of our knowledge, this is the first report of a paediatric case of GBFDE treated with cyclosporine. In our report, we review published cases of GBFDE in children, and all adult cases managed with cyclosporine.
ABSTRACT
CD8+ T cell immunosurveillance dynamics influence the outcome of intracellular infections and cancer. Here we used two-photon intravital microscopy to visualize the responses of CD8+ resident memory T cells (TRM cells) within the reproductive tracts of live female mice. We found that mucosal TRM cells were highly motile, but paused and underwent in situ division after local antigen challenge. TRM cell reactivation triggered the recruitment of recirculating memory T cells that underwent antigen-independent TRM cell differentiation in situ. However, the proliferation of pre-existing TRM cells dominated the local mucosal recall response and contributed most substantially to the boosted secondary TRM cell population. We observed similar results in skin. Thus, TRM cells can autonomously regulate the expansion of local immunosurveillance independently of central memory or proliferation in lymphoid tissue.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Immunity, Mucosal/immunology , Immunologic Memory/immunology , Immunologic Surveillance/immunology , Mucous Membrane/immunology , Animals , Female , Intravital Microscopy , Mice , Mucous Membrane/cytology , Skin/immunologyABSTRACT
A case of left-main stem STEMI presenting "out of hours" is discussed, wherein an excellent result was achieved with acute thrombolysis.
Subject(s)
Fibrinolytic Agents/therapeutic use , Percutaneous Coronary Intervention , Postoperative Care/methods , ST Elevation Myocardial Infarction/drug therapy , Thrombolytic Therapy/methods , Coronary Angiography , Coronary Vessels/diagnostic imaging , Electrocardiography , Humans , Male , Middle Aged , ST Elevation Myocardial Infarction/diagnosis , ST Elevation Myocardial Infarction/surgery , Time FactorsABSTRACT
Pediatric skin diseases are a common presenting complaint to emergency medicine physicians but often pose a significant diagnostic challenge. Skin eruptions that are unusually severe for the diagnosis in question, lasting beyond the typical time of resolution, or not responding to conventional therapy should raise concern of a misdiagnosis. We present the case of a severe rash not responding to conventional atopic dermatitis therapy that led to a diagnosis of transient neonatal zinc deficiency. Clinicians caring for children should be aware of zinc deficiency and its corresponding clinical presentation, because it is readily treatable and may lead to the avoidance of unnecessary treatments and prevention of serious complications.
Subject(s)
Anti-Inflammatory Agents/administration & dosage , Breast Feeding/adverse effects , Exanthema/etiology , Gluconates/administration & dosage , Growth Disorders/diagnosis , Milk, Human/chemistry , Zinc/deficiency , Administration, Oral , Growth Disorders/blood , Humans , Infant , Male , Zinc/bloodABSTRACT
BACKGROUND: Neurofibromatosis type 1 (NF-1) predisposes individuals to the development of benign and malignant tumors. The association of NF-1, juvenile xanthogranuloma (JXG), and juvenile myelomonocytic leukemia has been described in the literature. It is unclear whether JXG alone constitute a risk factor for leukemia or other malignancies in children with NF-1. OBJECTIVE: To determine if there is an association between NF-1, JXG, and malignancy. METHODS: We conducted a retrospective case-control study comparing children with NF-1 and malignancy (cases) with sex- and age-matched children with NF-1 without malignancy (controls). RESULTS: We identified 739 patients with NF-1 over a 20-year period, 14 of whom also had a diagnosis of malignancy. These cases include 9 (64%) boys and 5 (36%) girls. JXG were found in 4/14 (28.5%) cases and 6/29 (21%) controls (odds ratio 1.5, 95% confidence interval 0.35-6.6, P = .56). LIMITATIONS: Retrospective design, small number of cases, and inconsistent documentation of clinical findings, including age at disappearance of JXG. CONCLUSIONS: Juvenile xanthogranulomas do not appear to confer an increased risk for malignancy in children with NF-1.
Subject(s)
Neoplasms/etiology , Neurofibromatosis 1/complications , Xanthogranuloma, Juvenile/complications , Case-Control Studies , Child , Child, Preschool , Female , Humans , Male , Neoplasms/epidemiology , Retrospective Studies , Risk AssessmentABSTRACT
Tufted angioma is an uncommon benign vascular tumor that typically is noted during infancy or childhood, with variable clinical presentation. We report the case of an infant with a tufted angioma initially presenting as a port-wine stain-like patch of the left cheek.
Subject(s)
Facial Dermatoses/diagnosis , Facial Neoplasms/diagnosis , Hemangioma/diagnosis , Port-Wine Stain/diagnosis , Skin Neoplasms/diagnosis , Diagnosis, Differential , Humans , Infant, Newborn , MaleABSTRACT
Cells of the immune system that reside in barrier epithelia provide a first line of defense against pathogens. Langerhans cells (LCs) and CD8(+) tissue-resident memory T cells (TRM cells) require active transforming growth factor-ß1 (TGF-ß) for epidermal residence. Here we found that integrins αvß6 and αvß8 were expressed in non-overlapping patterns by keratinocytes (KCs) and maintained the epidermal residence of LCs and TRM cells by activating latent TGF-ß. Similarly, the residence of dendritic cells and TRM cells in the small intestine epithelium also required αvß6. Treatment of the skin with ultraviolet irradiation decreased integrin expression on KCs and reduced the availability of active TGF-ß, which resulted in LC migration. Our data demonstrated that regulated activation of TGF-ß by stromal cells was able to directly control epithelial residence of cells of the immune system through a novel mechanism of intercellular communication.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Epidermis/immunology , Intestinal Mucosa/immunology , Keratinocytes/immunology , Langerhans Cells/immunology , Transforming Growth Factor beta/immunology , Animals , Antigens, Neoplasm/immunology , CD8-Positive T-Lymphocytes/cytology , Cell Movement , Epidermal Cells , Flow Cytometry , Fluorescent Antibody Technique , Humans , Immunity, Mucosal , Integrins/immunology , Intestinal Mucosa/cytology , Intestine, Small/cytology , Intestine, Small/immunology , Langerhans Cells/cytology , Mice , Mice, Knockout , Mink , Polymerase Chain Reaction , Stromal Cells , T-Lymphocyte Subsets/cytology , T-Lymphocyte Subsets/immunology , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Transforming Growth Factor beta1/immunologyABSTRACT
BACKGROUND: Recent studies have revealed that hypertension remains underdiagnosed in a significant number of children despite their recorded office blood pressure (OBP) exceeding the recommended fourth report OBP thresholds. Simplified OBP thresholds have been proposed to reduce this underdiagnosis of hypertension in children. In clinical practice, OBP screened as elevated according to the fourth report OBP thresholds are referred for ambulatory blood pressure (ABP) monitoring to rule out 'white coat' hypertension. OBJECTIVES: The present study tested the usefulness of simplified OBP thresholds to screen abnormal OBP for ABP monitoring referral. METHODS: A total of 155 subjects were retrospectively analyzed with paired OBP and ABP recordings obtained from an outpatient referral clinic. OBP recordings were classified as abnormal according to the simplified and fourth report OBP thresholds. ABP measurements were classified as abnormal according to the ABP reference tables. RESULTS: Simplified blood pressure (BP) tables correctly identified all OBP classified as abnormal according to fourth report BP thresholds (kappa [κ] 0.72 [95% CI 0.61 to 0.83]) for systolic OBP; κ 0.92 [95% CI 0.86 to 0.99] for diastolic OBP). OBP classified as abnormal by the simplified BP thresholds and by the fourth report BP thresholds performed similarly for correctly identifying abnormal ABP measurements as per ABP references (overlapping 95% CIs of the sensitivity, specificity and predictive values and likelihood ratios). CONCLUSIONS: Simplified BP tables, proposed to reduce the underdiagnosis of hypertension in children, can serve as a useful screening tool to decide a referral for ABP monitoring. Future prospective studies are needed to establish these findings.
HISTORIQUE: De récentes études ont démontré que l'hypertension demeure sous-diagnostiquée chez de nombreux enfants, même si leur tension artérielle prise en cabinet (TAC) dépassait les seuils recommandés pour la quatrième TAC enregistrée. Certains ont proposé des seuils simplifiés de TAC pour réduire ce sous-diagnostic. En pratique clinique, les TAC considérées comme élevées selon les seuils pour la quatrième TAC enregistrée sont dirigées vers une surveillance de la tension artérielle en milieu ambulatoire (TAA), pour écarter le « syndrome de la blouse blanche ¼. OBJECTIFS: La présente étude portait sur l'utilité des seuils simplifiés de TAC pour dépister les TAC anormales en vue de les aiguiller vers la surveillance de la TAA. MÉTHODOLOGIE: Au total, 155 sujets ont fait l'objet d'une analyse rétrospective par rapport à des enregistrements appariés de TAC et de TAA obtenues dans une clinique de consultation ambulatoire. Les enregistrements de TAC étaient classés comme anormaux d'après le seuil simplifié et le seuil de la quatrième TAC enregistrée. Les mesures de TAA étaient classées comme anormales en fonction des tableaux de référence de la TAA. RÉSULTATS: Les tableaux simplifiés de la tension artérielle (TA) ont permis de dépister toutes les TAC classées comme anormales selon les seuils de quatrième TA enregistrée (kappa [κ] 0,72 [95 % IC 0,61 à 0,83] pour la TAC systolique; κ 0,92 [95 % IC 0,86 à 0,99] pour la TAC diastolique). La TAC classée comme anormale selon les seuils simplifiés de la TA et les seuils de la quatrième TAC enregistrée ont permis de déterminer les mesures anormales de TAA conformément aux références de TAA (chevauchement 95 % IC de la sensibilité, de la spécificité et des valeurs prédictives ainsi que des ratios de probabilité). CONCLUSIONS: Les tableaux simplifiés de la TA proposés pour réduire le sous-diagnostic d'hypertension chez les enfants peuvent être utiles pour orienter ou non les patients vers une surveillance de la TAA. D'autres études prospectives s'imposent pour confirmer ces observations.
ABSTRACT
Candida albicans is a dimorphic fungus responsible for chronic mucocutaneous and systemic infections. Mucocutaneous immunity to C. albicans requires T helper 17 (Th17) cell differentiation that is thought to depend on recognition of filamentous C. albicans. Systemic immunity is considered T cell independent. Using a murine skin infection model, we compared T helper cell responses to yeast and filamentous C. albicans. We found that only yeast induced Th17 cell responses through a mechanism that required Dectin-1-mediated expression of interleukin-6 (IL-6) by Langerhans cells. Filamentous forms induced Th1 without Th17 cell responses due to the absence of Dectin-1 ligation. Notably, Th17 cell responses provided protection against cutaneous infection while Th1 cell responses provided protection against systemic infection. Thus, C. albicans morphology drives distinct T helper cell responses that provide tissue-specific protection. These findings provide insight into compartmentalization of Th cell responses and C. albicans pathogenesis and have critical implications for vaccine strategies.
Subject(s)
Candidiasis, Chronic Mucocutaneous/immunology , Cell Differentiation/immunology , Dendritic Cells/immunology , Th17 Cells/cytology , Th17 Cells/immunology , Animals , Basic-Leucine Zipper Transcription Factors/genetics , Candida albicans/immunology , Candidiasis, Chronic Mucocutaneous/microbiology , Interleukin-6/biosynthesis , Interleukin-6/genetics , Interleukin-6/immunology , Langerhans Cells/immunology , Lectins, C-Type/genetics , Lectins, C-Type/immunology , Lymphocyte Activation/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Repressor Proteins/genetics , Skin/immunology , Skin/microbiology , Th1 Cells/cytology , Th1 Cells/immunologyABSTRACT
PURPOSE: Biofilms are now recognized as potential factors in the pathogenesis of chronic inflammatory and infective diseases. The aim of this study was to examine the presence of biofilms and quantify their biomass on silastic nasolacrimal duct stents inserted after dacryocystorhinostomy (DCR). METHODS: A prospective study was performed on a series of patients undergoing DCR with O'Donoghue stent insertion. After removal, the stents were subjected to biofilm analysis using standard protocols of confocal laser scanning microscopy (CLSM) and scanning electron microscopy. These stents were compared against negative controls and positive in vitro ones established using Staphylococcus aureus strain ATCC 25923. Biofilm quantification was performed using the COMSTAT2 software and the total biofilm biomass was calculated. RESULTS: A total of nine consecutive patient samples were included in this prospective study. None of the patients had any evidence of postoperative infection. All the stents demonstrated evidence of biofilm formation using both imaging modalities. The presence of various different sized organisms within a common exopolysaccharide matrix on CLSM suggested the existence of polymicrobial communities. The mean biomass of patient samples was 0.9385 µm³/µm² (range: 0.3901-1.9511 µm³/µm²). CONCLUSIONS: This is the first study to report the quantification of biomass on lacrimal stents. The presence of biofilms on lacrimal stents after DCR is a common finding but this need not necessarily translate to postoperative clinical infection.
Subject(s)
Bacterial Physiological Phenomena , Biofilms , Dacryocystorhinostomy , Dimethylpolysiloxanes , Nasolacrimal Duct/surgery , Stents/microbiology , Biomass , Humans , Lacrimal Duct Obstruction/therapy , Microscopy, Confocal , Microscopy, Electron, Scanning , Prospective Studies , Staphylococcus aureus/physiologyABSTRACT
OBJECTIVE: To evaluate habitual physical activity in a cohort of adolescents with type 1 diabetes in relation to similarly aged control subjects. METHODS: A cross-sectional case control study of 54 healthy adolescents and 66 patients with type 1 diabetes, 14 to 18 years of age, was conducted. Subjects were surveyed using the Habitual Activity Estimation Scale, a validated self-report instrument to assess activity levels in teens. Subjects' time was classified into categories ranging from inactive (lying down, resting) to very active (increased heart rate and diaphoresis). Active time, described in relative (%) and absolute hours per day was determined for each individual. Age, sex, weight, height and body mass index were recorded for all participants, and the charts of subjects with type 1 diabetes were reviewed for most recent levels of glycated hemoglobin, low-density lipoproteins, high-density lipoproteins, total cholesterol, triglycerides and blood pressure. A regression analysis was performed to determine factors associated with hours spent being active. RESULTS: Subjects with type 1 diabetes spent similar hours being very active (3.4 hours vs. 3.5 hours, p=0.49) but reported more time being inactive than controls (2.0 hours vs. 1.3 hours, p=0.002). In both groups, female gender was associated with more hours spent being active. Metabolic control as assessed by glycated hemoglobin worsened with activity. In the group with type 1 diabetes, more hours spent being active were associated with lower systolic blood pressure, lower serum triglyceride levels, lower total cholesterol and higher high-density lipoproteins, whereas inactivity correlated with higher low-density lipoproteins and total cholesterol. CONCLUSIONS: Adolescents with type 1 diabetes reported significantly more time being inactive than did healthy controls. In patients with type 1 diabetes, activity was associated with improved cardiovascular risk profile.
Subject(s)
Diabetes Mellitus, Type 1/physiopathology , Motor Activity/physiology , Adolescent , Age Factors , Body Mass Index , Case-Control Studies , Cross-Sectional Studies , Female , Humans , Lipids/blood , Male , Self Report , Sex Factors , Time FactorsABSTRACT
IMPORTANCE: Infantile hemangiomas (IHs) are common benign tumors of infancy that have the potential to interfere with vital organ function and cause permanent disfigurement. Currently, few objective and validated measures exist to assess IHs. OBJECTIVE: To determine the utility of infrared thermography in assessing and monitoring the growth of IHs. DESIGN, SETTING, AND PARTICIPANTS: In a prospective cohort study conducted at an outpatient dermatology clinic of a tertiary care hospital between February 2011 and December 2012, a convenience sample of 42 infants aged 0 to 6 months with an IH were enrolled. The mean age of the study group was 3.7 months, with the majority of IHs being mixed type (57%) affecting the head and neck (81%). Of the infants, 36 (86%) were receiving active treatment during the study period, and patients were followed for a minimum of 3 clinical visits, at least 1 month apart. MAIN OUTCOMES AND MEASURES: Ability of infrared thermography to assess the proliferation and involution of IHs compared with a visual analog scale. Secondary outcomes were reliability, ease of use, and parental acceptance of the instrument. RESULTS: The mean temperature difference at baseline was 1.9°F (95% CI, 1.2°F to 2.7°F), which peaked at 3 months to 2.5°F (95% CI, 0.8°F to 4.2°F), and decreased progressively to 0.2°F (95% CI, -1.1°F to 1.4°F) at 18.5 months (P < .001). This change in temperature was inversely correlated with mean visual analog scale (r = -0.25). Mean temperature differences recorded at baseline and 30 minutes later were not significant (least squares mean baseline temperature, 87.9°F [95% CI, 87.4°F to 88.3°F], vs least squares mean temperature after 30 minutes, 88.1°F [95% CI, 87.7°F to 88.6°F] [P = .14]). Multivariate analysis demonstrated facial location (F(1,365) = 47.63, P < .001), IH type (F(2,365) = 3.26, P = .04), age (F(2,365) = 7.03, P = .001), and surface area at baseline (F(2,365) = 8.18, P < .001) as factors significantly affecting temperature difference over time. Only IH type (Wald χ(22) = 6.79, P = .03) and treatment (Wald χ(21) = 4.29, P = .04) significantly affected time to reach a zero-temperature difference. All caregivers (100%) reported IRT to be easy to implement, quick to perform, and comfortable for their child. CONCLUSIONS AND RELEVANCE: Infrared thermography is a reliable and valid measure of IH growth that is noninvasive, convenient, and well tolerated by infants, making it well suited to daily clinical practice. It has the potential to provide real-time objective results that can be used for routine monitoring and evaluating treatment efficacy.
Subject(s)
Hemangioma/pathology , Infrared Rays , Skin Neoplasms/pathology , Thermography , Cell Proliferation , Cohort Studies , Female , Humans , Infant , Infant, Newborn , Male , Prospective Studies , Reproducibility of Results , Thermography/methodsABSTRACT
We report a case of choroidal melanoma with features suggestive of orbital cellulitis. A 24-year-old Asian Indian male presented with a 20-day history of sudden loss of vision in the right eye. Edematous eyelids with complete mechanical ptosis, complete ophthalmoplegia, gross proptosis accompanied by massive chemosis, and prolapse of the inferior forniceal conjunctiva were noted. He denied perception of light in the right eye. The left eye was unremarkable. B-scan ultrasonography of the right eye showed a large dome-shaped mass filling the posterior segment suggestive of choroidal melanoma. Computed tomography confirmed those findings and showed no extraocular tumor extension. The patient was conservatively treated with systemic steroids following which the inflammation subsided. He underwent enucleation of the right eye and a diagnosis of spindle A cell choroidal melanoma was confirmed by histopathological examination. Although rare, orbital cellulitis is one of the presenting features of choroidal melanoma. Uveal melanoma-associated orbital cellulitis can be well controlled with systemic steroids, does not always indicate extraocular tumor extension, and can occur in spindle A cell melanomas.
Subject(s)
Choroid Neoplasms/complications , Melanoma/complications , Orbital Cellulitis/etiology , Choroid Neoplasms/pathology , Diagnosis, Differential , Humans , Male , Melanoma/pathology , Orbital Cellulitis/diagnosis , Young AdultABSTRACT
Transforming growth factor beta 1 (TGFß1) is a pleiotropic cytokine in the skin that can function both as a tumor promoter and suppressor in chemically induced skin carcinogenesis, but the function in ultraviolet B (UVB) carcinogenesis is not well understood. Treatment of SKH1 hairless mice with the activin-like kinase 5 (ALK5) inhibitor SB431542 to block UVB-induced activation of cutaneous TGFß1 signaling suppressed skin tumor formation but did not alter tumor size or tumor cell proliferation. Tumors that arose in SB-treated mice after 30 weeks had significantly reduced percentage of IFNγ(+) tumor-infiltrating lymphocytes compared with control mice. SB431542 blocked acute and chronic UVB-induced skin inflammation and T-cell activation in the skin-draining lymph node (SDLN) and skin but did not alter UVB-induced epidermal proliferation. We tested the effect of SB431542 on migration of skin dendritic cell (DC) populations because DCs are critical mediators of T-cell activation and cutaneous inflammation. SB431542 blocked (i) UVB-induced Smad2 phosphorylation in dermal DC (dDC) and (ii) SDLN and ear explant migration of CD103(+) CD207(+) and CD207(-) skin DC subsets but did not affect basal or UV-induced migration of Langerhans cells. Mice expressing a dominant-negative TGFß type II receptor in CD11c(+) cells had reduced basal and UVB-induced SDLN migration of CD103(+) CD207(+) and CD207(-) DC subsets and a reduced percentage of CD86(high) dDC following UVB irradiation. Together, these suggest that TGFß1 signaling has a tumor-promoting role in UVB-induced skin carcinogenesis and this is mediated in part through its role in UVB-induced migration of dDC and cutaneous inflammation.
Subject(s)
Dendritic Cells/cytology , Dermatitis/complications , Lymph Nodes/pathology , Neoplasms, Radiation-Induced/etiology , Signal Transduction , Skin Neoplasms/etiology , Transforming Growth Factor beta1/metabolism , Ultraviolet Rays , Animals , Flow Cytometry , Male , Mice , Mice, Hairless , Mice, Transgenic , Neoplasms, Radiation-Induced/metabolism , Neoplasms, Radiation-Induced/pathology , Phosphorylation , Protein Serine-Threonine Kinases/antagonists & inhibitors , Receptor, Transforming Growth Factor-beta Type I , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Smad Proteins/metabolismABSTRACT
BACKGROUND: Nighttime blood pressure (BP) and systolic BP variability on ambulatory blood pressure monitoring (ABPM) have been strongly associated with target-organ damage in hypertensive adults. The clinical relevance of these variables in children with hypertension remains under-studied. METHODS: The study group included children aged 5-18 years old referred to the outpatient nephrology clinic for an elevated casual BP who underwent an ABPM and echocardiography (ECHO) study and did not have secondary hypertension. The interpretation of ABPM parameters and left ventricular mass index (LVMI) was based on normative references. RESULTS: Seventy-two children fulfilled the inclusion criteria. The association of various potential predictors including age, BMI z-score, casual BP z-score and ABPM parameters (BP z-score, BP load, nocturnal dipping and BP variability- within-subject standard deviation (SD) of BP) with LVMI was analyzed. On adjusted regression analysis, nighttime systolic BP load [standardized regression coefficient (ß) 0.23; p < 0.05] and daytime systolic BP variability (ß 0.37; p < 0.05) had significant association with LVMI. CONCLUSIONS: In children with primary hypertension, nighttime systolic BP load and daytime systolic BP variability had a stronger association with LVMI than casual BP and other ABPM parameters. Future longitudinal studies are needed to establish the causality among these variables.
Subject(s)
Blood Pressure , Circadian Rhythm , Hypertension/complications , Hypertrophy, Left Ventricular/etiology , Systole , Adolescent , Blood Pressure Monitoring, Ambulatory , Chi-Square Distribution , Child , Child, Preschool , Cross-Sectional Studies , Female , Humans , Hypertension/diagnosis , Hypertension/physiopathology , Hypertrophy, Left Ventricular/diagnostic imaging , Hypertrophy, Left Ventricular/physiopathology , Linear Models , Logistic Models , Male , Multivariate Analysis , Predictive Value of Tests , Risk Factors , Time Factors , UltrasonographyABSTRACT
The RAS signaling pathway is constitutively activated in psoriatic keratinocytes. We expressed activated H-RAS(V12G) in suprabasal keratinocytes of adult mice and observed rapid development of a psoriasis-like skin phenotype characterized by basal keratinocyte hyperproliferation, acanthosis, hyperkeratosis, intraepidermal neutrophil microabscesses, and increased T helper type 1 (Th1)/Th17 and T cell type 1 (Tc1)/Tc17 skin infiltration. The majority of skin-infiltrating CD8(+) T cells coexpressed IFN-γ and IL-17A. When RAS was expressed on a Rag1-/- background, microabscess formation, inducible nitric oxide synthase expression, and keratinocyte hyperproliferation were suppressed. Depletion of CD8(+), but not CD4(+), T cells reduced cutaneous and systemic inflammation, the RAS-induced increase in cutaneous Th17 and IL-17(+) γδ T cells, and epidermal hyperproliferation to levels similar to a Rag1-/- background. Reconstitution of Rag1-/- inducible RAS mice with purified CD8(+) T cells restored microabscess formation and epidermal hyperproliferation. Neutralization of IFN-γ, but not of IL-17A, in CD8(+) T-cell-reconstituted Rag1-/- mice expressing RAS blocked CD8-mediated skin inflammation, inducible nitric oxide synthase expression, and keratinocyte hyperproliferation. These results show that CD8(+) T cells can orchestrate skin inflammation with psoriasis-like pathology in response to constitutive RAS activation in keratinocytes, and this is primarily mediated through IFN-γ.
Subject(s)
CD8-Positive T-Lymphocytes/pathology , Interferon-gamma/immunology , Proto-Oncogene Proteins p21(ras)/immunology , Psoriasis/immunology , Psoriasis/pathology , Signal Transduction/immunology , Abscess/immunology , Abscess/pathology , Animals , CD8-Positive T-Lymphocytes/immunology , Cell Proliferation , Dermatitis/genetics , Dermatitis/immunology , Dermatitis/pathology , Epidermis/immunology , Epidermis/metabolism , Epidermis/pathology , Female , Interferon-gamma/metabolism , Interleukin-17/genetics , Interleukin-17/immunology , Interleukin-17/metabolism , Keratinocytes/immunology , Keratinocytes/metabolism , Keratinocytes/pathology , Male , Mice , Mice, Transgenic , Neutrophils/immunology , Neutrophils/pathology , Phenotype , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Psoriasis/genetics , Th1 Cells/immunology , Th1 Cells/pathology , Th17 Cells/immunology , Th17 Cells/pathologyABSTRACT
Overexpression of transforming growth factor beta-1 (TGFß1) in mouse epidermis causes cutaneous inflammation and keratinocyte hyperproliferation. Here we examined acute effects of TGFß1 overproduction by keratinocytes on skin dendritic cells (DCs). TGFß1 induction for 2 and 4 days increased the numbers and CD86 expression of B220(+) plasmacytoid DCs (pDCs) and CD207(+)CD103(+), CD207(-)CD103(-)CD11b(+), and CD207(-)CD103(-)CD11b(-) dermal DCs (dDCs) in skin-draining lymph nodes (SDLNs). The dermis of TGFß1-overexpressing mice had significantly more pDCs, CD207(+)CD103(+) dDCs, and CD207(-)CD11b(+) dDCs in the absence of increased dermal proliferation. Application of dye, tetramethyl rhodamine iso-thiocyanate (TRITC), in dibutylpthalate (DBP) solution after TGFß1 induction increased the numbers of TRITC(+)CD207(-) dDCs in SDLNs, and augmented TRITC/DBP-induced Langerhans cell (LC) migration 72 hours post TRITC treatment. Consistent with this, LC migration was increased in vitro by TGFß1 overexpression in skin explants and by exogenous TGFß1 in culture media. Transient TGFß1 induction during DNFB sensitization increased contact hypersensitivity responses by 1.5-fold. Thus, elevated epidermal TGFß1 alone is sufficient to alter homeostasis of multiple cutaneous DC subsets, and enhance DC migration and immune responses to contact sensitizers. These results highlight a role for keratinocyte-derived TGFß1 in DC trafficking and in the initiation of skin inflammation.
