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The Journal of Allergy and Clinical... Aug 2023Job syndrome is a disease of autosomal dominant hyper-IgE syndrome (AD-HIES). Patients harboring STAT3 mutation are particularly prone to airway remodeling and airway...
BACKGROUND
Job syndrome is a disease of autosomal dominant hyper-IgE syndrome (AD-HIES). Patients harboring STAT3 mutation are particularly prone to airway remodeling and airway infections.
OBJECTIVES
Airway epithelial cells play a central role as the first line of defense against pathogenic infection and express high levels of STAT3. This study thus interrogates how AD-HIES STAT3 mutations impact the physiological functions of airway epithelial cells.
METHODS
This study created human airway basal cells expressing 4 common AD-HIES STAT3 mutants (R382W, V463del, V637M, and Y657S). In addition, primary airway epithelial cells were isolated from a patient with Job syndrome who was harboring a STAT3-S560del mutation and from mice harboring a STAT3-V463del mutation. Cell proliferation, differentiation, barrier function, bacterial elimination, and innate immune responses to pathogenic infection were quantitatively analyzed.
RESULTS
STAT3 mutations reduce STAT3 protein phosphorylation, nuclear translocation, transcription activity, and protein stability in airway basal cells. As a consequence, STAT3-mutated airway basal cells give rise to airway epithelial cells with abnormal cellular composition and loss of coordinated mucociliary clearance. Notably, AD-HIES STAT3 airway epithelial cells are defective in bacterial killing and fail to initiate vigorous proinflammatory responses and neutrophil transepithelial migration in response to an experimental model of Pseudomonas aeruginosa infection.
CONCLUSIONS
AD-HIES STAT3 mutations confer numerous abnormalities to airway epithelial cells in cell differentiation and host innate immunity, emphasizing their involvement in the pathogenesis of lung complications in Job syndrome. Therefore, therapies must address the epithelial defects as well as the previously noted immune cell defects to alleviate chronic infections in patients with Job syndrome.
Topics: Humans; Mice; Animals; Job Syndrome; STAT3 Transcription Factor; Cell Differentiation; Epithelial Cells; Mutation
PubMed: 36638921
DOI: 10.1016/j.jaci.2022.12.821 -
Journal of Clinical Immunology Nov 2023Autosomal recessive dedicator of cytokinesis 8 (DOCK8) and autosomal dominant signal transducer and activator of transcription 3 (STAT3) deficiencies are inborn errors...
PURPOSE
Autosomal recessive dedicator of cytokinesis 8 (DOCK8) and autosomal dominant signal transducer and activator of transcription 3 (STAT3) deficiencies are inborn errors of immunity (IEI) disorders present with the classic features of eczema and create a dilemma during differentiation from atopic dermatitis (AD). Therefore, an appropriate approach is required for eczema to diagnose DOCK8 and STAT3 early. Here, we described a set of clinical and immunological variables, including atypical AD localizations and lymphocyte subsets, to differentiate DOCK8 or STAT3 from AD.
METHODS
This multicenter study involved 100 patients with DOCK8 and STAT3 and moderate/severe AD. We recruited disease manifestations, including detailed localizations of eczema, infections, and allergy. Principle component analysis (PCA) was used to discriminate DOCK8 or STAT3 from AD.
RESULTS
There were 43 patients with DOCK8, 23 with STAT3, and 34 with AD. Pneumonia, severe infections, mucocutaneous candidiasis, and skin abscesses were commonly observed in DOCK8 and STAT3 deficiencies. Atypical skin involvement with neonatal rash, retro auricular, axillary, sacral, and genital eczema discriminate DOCK8 and STAT3 from AD with high specificity ranges between 73.5 and 94.1% and positive predictive index ranges between 55 and 93.1%. Together with using absolute numbers of CD3, CD4, and CD8 T cells, the combined clinical and laboratory features showed perfect differentiation between DOCK8 or STAT3 and AD via PCA.
CONCLUSIONS
The described features can be easily implemented by physicians providing early diagnosis of DOCK8 and STAT3 deficiencies.
Topics: Infant, Newborn; Humans; Dermatitis, Atopic; CD8-Positive T-Lymphocytes; Job Syndrome; Pneumonia; Eczema; STAT3 Transcription Factor; Guanine Nucleotide Exchange Factors
PubMed: 37507632
DOI: 10.1007/s10875-023-01554-z -
Evaluation & the Health Professions Dec 2023Job demands and resources have been consistently associated with the burnout syndrome in physicians, however the literature points to a lack of robust measures to assess...
Job demands and resources have been consistently associated with the burnout syndrome in physicians, however the literature points to a lack of robust measures to assess these job characteristics across various medical specialties. This study aimed to develop a theoretically and empirically grounded physician-specific job demands and resources self-report measure - the . Relevant dimensions of physicians' job demands and resources were identified, corresponding measurement items were generated and pre-tested, and the factor structure of the resulting 44 items was tested with a sample of 9,176 Portuguese physicians. The results of EFAs and CFAs with two random split samples provided consistent evidence of a nine-factor structure with 38 of the 44 items. Importantly, the nine-factor structure is consistent with the dimensions identified in the literature. The paper discusses the theoretical and practical impacts of the scale.
Topics: Humans; Psychometrics; Burnout, Professional; Surveys and Questionnaires; Physicians; Self Report; Job Satisfaction; Workload
PubMed: 37587739
DOI: 10.1177/01632787231195077 -
Clinical and Experimental Medicine Dec 2023The hyper-immunoglobulin E syndrome (HIES) is a primary immunodeficiency disease originally described as Job syndrome. The fundamental causative variant of the HIES is...
The hyper-immunoglobulin E syndrome (HIES) is a primary immunodeficiency disease originally described as Job syndrome. The fundamental causative variant of the HIES is an autosomal dominant mutation in the signal transducer and activator of transcription 3 (STAT3) gene. It is characterized by recurrent staphylococcal cold skin abscess, sinopulmonary infection, eczema, head and face anomalies, frequent bone fractures, eosinophilia and extremely high serum IgE levels (IgE ≥ 2000 IU/mL). However, multiple other genetic defects are also known as HIES-like disorders. Apart from infectious manifestations, STAT3, DOCK8 and TYK2 gene mutations are associated with various malignancies. The most common malignancies reported in these patients are lymphomas, including Hodgkin's and non-Hodgkin's lymphomas (NHL) of B and T cells. This systematic review aimed to investigate the prevalence of malignancies in HIES and the factors associated with malignancy in these patients. In this survey, all articles published until April 1st, 2023, in Scopus, PubMed and Web of Science databases based on three groups of keywords related to HIES syndrome and malignancy were reviewed by three different researchers. Finally, 26 articles were evaluated from which 24 papers were meta-analyzed. In the current study, the demographic information of 1133 patients with HIES, which was mentioned in 24 articles enrolled in the project, was collected, and the information related to patients who had malignancy was analyzed and meta-analyzed. A total of 96 patients out of 1133 studied patients had at least one type of malignancy, the overall prevalence of malignancies reported in the articles was 6.5% (95% confidence interval 4.1-9%), and the total prevalence of malignancy in patients with NHL type and patients with squamous cell carcinoma (SCC) was 2.9% (95% confidence interval 1.7-4.4%) and 2.2% (95% confidence interval 0.3-4.1%), respectively. The results of this study indicated that in 6.5% of cases, HIES was complicated with malignancy, and considering the higher rate of these malignancies in women as well as in DOCK8 mutation sufferers, it is necessary for physicians to be aware of this association and includes malignancy screening in follow-up and periodic examinations of these patients. Indeed, more studies in this field will help to clarify the precise figures and predisposing factors of the relationship between HIES and malignancy.
Topics: Humans; Female; Job Syndrome; Prevalence; Neoplasms; Immunoglobulin E; Lymphoma; Mutation; Guanine Nucleotide Exchange Factors
PubMed: 37924455
DOI: 10.1007/s10238-023-01228-5 -
European Radiology Jun 2024Our objective in this review is to familiarize radiologists with the spectrum of initial and progressive CT manifestations of pulmonary complications observed in adult... (Review)
Review
Our objective in this review is to familiarize radiologists with the spectrum of initial and progressive CT manifestations of pulmonary complications observed in adult patients with primary immunodeficiency diseases, including primary antibody deficiency (PAD), hyper-IgE syndrome (HIES), and chronic granulomatous disease (CGD). In patients with PAD, recurrent pulmonary infections may lead to airway remodeling with bronchial wall-thickening, bronchiectasis, mucus-plugging, mosaic perfusion, and expiratory air-trapping. Interstitial lung disease associates pulmonary lymphoid hyperplasia, granulomatous inflammation, and organizing pneumonia and is called granulomatous-lymphocytic interstitial lung disease (GLILD). The CT features of GLILD are solid and semi-solid pulmonary nodules and areas of air space consolidation, reticular opacities, and lymphadenopathy. These features may overlap those of mucosa-associated lymphoid tissue (MALT) lymphoma, justifying biopsies. In patients with HIES, particularly the autosomal dominant type (Job syndrome), recurrent pyogenic infections lead to permanent lung damage. Secondary infections with aspergillus species develop in pre-existing pneumatocele and bronchiectasis areas, leading to chronic airway infection. The complete spectrum of CT pulmonary aspergillosis may be seen including aspergillomas, chronic cavitary pulmonary aspergillosis, allergic bronchopulmonary aspergillosis (ABPA)-like pattern, mixed pattern, and invasive. Patients with CGD present with recurrent bacterial and fungal infections leading to parenchymal scarring, traction bronchiectasis, cicatricial emphysema, airway remodeling, and mosaicism. Invasive aspergillosis, the major cause of mortality, manifests as single or multiple nodules, areas of airspace consolidation that may be complicated by abscess, empyema, or contiguous extension to the pleura or chest wall. CLINICAL RELEVANCE STATEMENT: Awareness of the imaging findings spectrum of pulmonary complications that can occur in adult patients with primary immunodeficiency diseases is important to minimize diagnostic delay and improve patient outcomes. KEY POINTS: • Unexplained bronchiectasis, associated or not with CT findings of obliterative bronchiolitis, should evoke a potential diagnosis of primary autoantibody deficiency. • The CT evidence of various patterns of aspergillosis developed in severe bronchiectasis or pneumatocele in a young adult characterizes the pulmonary complications of hyper-IgE syndrome. • In patients with chronic granulomatous disease, invasive aspergillosis is relatively frequent, often asymptomatic, and sometimes mimicking or associated with non-infectious inflammatory pulmonary lesions.
Topics: Humans; Adult; Tomography, X-Ray Computed; Lung Diseases; Immunologic Deficiency Syndromes; Primary Immunodeficiency Diseases
PubMed: 37935849
DOI: 10.1007/s00330-023-10334-7 -
Industrial Health Dec 2023Brugada syndrome (BrS) is an inherited arrhythmogenic disorder predisposing patients to a high risk of sudden cardiac death. Specific guidelines on the health...
Brugada syndrome (BrS) is an inherited arrhythmogenic disorder predisposing patients to a high risk of sudden cardiac death. Specific guidelines on the health surveillance of BrS workers are lacking. We report here three cases requiring assessment of specific job capacity, investigated with an interdisciplinary protocol including 24-h Holter electrocardiography with modified precordial leads, pharmacological test with ajmaline, molecular genetic analysis, electrophysiological study with ventricular stimulation, risk stratification, and occupational medicine evaluation: (1) a female 42-yr-old company manager with positive ajmaline test and CACNA1C gene mutation (judged fit for the job with limitations regarding work-related stress); (2) a male 44-yr-old welder with positive ajmaline test, SCN5A gene mutation, and associated OSAS (obstructive sleep apnea syndrome), who was advised to refrain from night shifts and driving company vehicles; (3) a male 45-yr-old electrical technician with inducible ventricular tachyarrhythmia, who was implanted with a biventricular cardioverter defibrillator, and therefore recommended to avoid exposure to electromagnetic fields and working at heights. We conclude that the collaboration between the cardiologist and the occupational physician allows defining the functional capabilities and the arrhythmogenic risk of BrS workers, to optimize job fitness assessment.
Topics: Humans; Male; Female; Brugada Syndrome; Electrocardiography; Ajmaline; Death, Sudden, Cardiac; Electrocardiography, Ambulatory
PubMed: 36724992
DOI: 10.2486/indhealth.2022-0205 -
Revista Brasileira de Medicina Do... 2023Characterized by high levels of emotional exhaustion and depersonalization and reduced professional accomplishment, burnout syndrome has been a major cause of psychic...
INTRODUCTION
Characterized by high levels of emotional exhaustion and depersonalization and reduced professional accomplishment, burnout syndrome has been a major cause of psychic illness in nursing workers, with a serious impact on the quality of services and on patient safety.
OBJECTIVES
To analyze the correlation between organizational climate, job satisfaction, and burnout in nursing workers.
METHODS
This is a cross-sectional study with a sample of 534 Brazilian nursing workers. We used the Organizational Climate Scale for Health Organizations, the Job Satisfaction Questionnaire (S20/23), and the Maslach Burnout Inventory. An analytical descriptive analysis of the data was performed using relative and absolute frequencies, mean, standard deviation, minimum, maximum, and correlation test between the variables.
RESULTS
Organizational climate and job satisfaction were evaluated as regular. With regard to burnout, moderate levels of emotional exhaustion, low levels of depersonalization, and high levels of professional accomplishment were observed. A strong positive correlation was found between job satisfaction and organizational climate; in addition to a moderate negative correlation between emotional exhaustion and both organizational climate and job satisfaction, and a moderate negative correlation between depersonalization and job satisfaction.
CONCLUSIONS
Organizational climate and job satisfaction had a negative correlation with burnout dimensions, representing possible protective factors.
PubMed: 38313086
DOI: 10.47626/1679-4435-2022-867 -
Cutaneous and Ocular Toxicology Dec 2023It was reported that pseudoexfoliative material deteriorates iris, brain, heart and lung functions. This material is also found in the skin.
BACKGROUND
It was reported that pseudoexfoliative material deteriorates iris, brain, heart and lung functions. This material is also found in the skin.
AIMS
The purpose of this study was to investigate the possible effects of pseudoexfoliation material on the aging of the facial skin.
STUDY DESIGN
Cross-sectional study.
METHODS
Forty pseudoexfoliation syndrome (PES) cases and 40 age- and gender-matched controls were evaluated. Job, cigarette use and the presence of any systemic diseases as well as the duration of sun exposure for all the cases were recorded. All of the cases underwent facial skin examination with Wrinkle Assessment Scale as per Lemperle G et al. and Pinch Test.
RESULTS
Wrinkle Assessment Scale scores of the groups also were compared for all 8 facial locations. There were statistically significant differences found between Wrinkle Assessment Scale scores in PES and Control Group for all 8 locations. Mean Wrinkle Assessment Scale scores of women were 4.12 ± 0.74 in Control Group and 4.75 ± 0.37 in PES group (p = 0.0001). For men, mean Wrinkle Assessment Scale scores were 3.77 ± 0.72 in Control group and 4.54 ± 0.36 in PES group (p = 0.002).
CONCLUSION
These results implies that there is quicker progression in aging of facial skin in PES than normals.
Topics: Male; Humans; Female; Exfoliation Syndrome; Cross-Sectional Studies; Aging; Face; Skin Aging
PubMed: 37417936
DOI: 10.1080/15569527.2023.2234024 -
Current Opinion in Infectious Diseases Aug 2024The purpose of this focused review is to discuss unusual presentations of viral infections in the context of specific inborn errors of immunity. We will discuss hyper... (Review)
Review
PURPOSE OF REVIEW
The purpose of this focused review is to discuss unusual presentations of viral infections in the context of specific inborn errors of immunity. We will discuss hyper immunoglobulin E (IgE) syndromes, epidermodysplasia verruciformis, and X-linked agammaglobulinemia as examples of inborn errors of immunity associated with specific presentations of viral infection and disease.
RECENT FINDINGS
Advances in both genetic and viral diagnostics have broadened our understanding of viral pathogenesis in the setting of immune dysfunction and the variable phenotype of inborn errors of immunity. Dedicator of cytokinesis 8 (DOCK8) deficiency is now recognized as an inborn error of immunity within the hyper IgE syndrome phenotype and is associated with unusually aggressive cutaneous disease caused by herpes simplex and other viruses. Studies of patients with epidermodysplasia verruciformis have proven that rarely detected human papillomavirus subtypes may cause malignancy in the absence of adequate host defenses. Finally, patients with X-linked agammaglobulinemia may remain at risk for severe and chronic viral infections, even as immune globulin supplementation reduces the risk of bacterial infection.
SUMMARY
Susceptibility to viral infections in patients with inborn errors of immunity is conferred by specific, molecular defects. Recurrent, severe, or otherwise unusual presentations of viral disease should prompt investigation for an underlying genetic defect.
Topics: Humans; Agammaglobulinemia; Virus Diseases; Genetic Diseases, X-Linked; Epidermodysplasia Verruciformis; Job Syndrome; Guanine Nucleotide Exchange Factors
PubMed: 38747352
DOI: 10.1097/QCO.0000000000001021