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Concept: Granuloma

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BACKGROUND: Sarcoidosis is a systemic disease characterized by the formation of noncaseating granulomas in various tissues. Cutaneous involvement occurs in 20 to 35 percent of the patients and may be the initial manifestation of the disease. Our study was performed to discriminate the clinical, laboratory, and prognostic differences between patients with specific and nonspecific cutaneous involvement. The second aim was to asses the diagnostic usefulness of punch biopsy in sarcoidosis. METHODS: The clinical, laboratory, pathological features, and skin biopsy results of 120 patients with cutaneous sarcoidosis were evaluated. The patients fulfilled clinical, radiologic or both features of sarcoidosis supported by the histopathologic evidence of noncaseating granulomas.Skin involvement was the initial finding in 30% of the patients. Erythema nodosum and lupus pernio were the most common skin lesions. Almost all of the patients with LP were either stage 0 or 1. Respiratory symptoms occurred in 72.2% of the patients with specific skin involvement. BronchoalveolarLavage (BAL) lymphocytosis, high ratio of CD4/CD8 and elevated serum Angiotensin Converting Enzyme (ACE) were more frequent in patients with specific cutaneous lesions. The frequency of progressive disease was significantly higher in this group. Punch skin biopsy was diagnostic in 81.6% of the patients with a complication rate of 4%. CONCLUSIONS: Specific cutaneous lesions along with BAL lymphocytosis, high CD4/CD8 ratio and elevated serum ACE levels may be predictors of progressive disease in sarcoidosis. Punch biopsy is a simple technique with a high diagnostic yield and a low complication rate for cutaneous sarcoidosis.

Concepts: Medical terms, Biopsy, Pathology, Sarcoidosis, Granuloma, Skin biopsy, Erythema nodosum, Lupus pernio

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BACKGROUND: Leprosy is a contagious and chronic systemic granulomatous disease caused by Mycobacterium leprae. In the pathogenesis of leprosy, granulomas play a key role, however, the mechanisms of the formation and maintenance of M. leprae granulomas are still not clearly understood. METHODS: To better understand the molecular physiology of M. leprae granulomas and the interaction between the bacilli and human host cells, we developed an in vitro model of human granulomas, which mimicked the in vivo granulomas of leprosy. Macrophages were differentiated from human monocytes, and infected with M. leprae, and then cultured with autologous human peripheral blood mononuclear cells (PBMCs). RESULTS: Robust granuloma-like aggregates were obtained only when the M. leprae infected macrophages were co-cultured with PBMCs. Histological examination showed M. leprae within the cytoplasmic center of the multinucleated giant cells, and these bacilli were metabolically active. Macrophages of both M1 and M2 types co-existed in the granuloma like aggregates. There was a strong relationship between the formation of granulomas and changes in the expression levels of cell surface antigens on macrophages, cytokine production and the macrophage polarization. The viability of M. leprae isolated from granulomas indicated that the formation of host cell aggregates benefited the host, but the bacilli also remained metabolically active. CONCLUSIONS: A simple in vitro model of human M. leprae granulomas was established using human monocyte-derived macrophages and PBMCs. This system may be useful to unravel the mechanisms of disease progression, and subsequently develop methods to control leprosy.

Concepts: Immune system, Monocyte, Tuberculosis, Mycobacterium, PBMC, Granuloma, Leprosy, Mycobacterium leprae

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Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis.

Concepts: Vasculitis, Wegener's granulomatosis, Autoimmune diseases, Arthritis, Granuloma, Anti-neutrophil cytoplasmic antibody, Proteinase 3, Vascular-related cutaneous conditions

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Background: The results of endonasal dacryocystorhinostomies (DCR) with transillumination and intubation are presented.Materials and Methods: In the period from 1999 to 2009 follow-up examinations of 50 endonasal DCRs were carried out. All patients over 18 were included. The files were systematically evaluated. The follow-up examinations were performed after a minimum of 6 months with anamnesis of epiphora.Results: 50 endonasal DCRs were performed on 40 patients. Initial surgery was performed on 27 lacrimal ducts, 16 patients had already had operations. Corrective surgery was required in 8 cases (7 endonasal DCRs, 1 external DCRs). 78 % women and 22 % men were included. The median age at the time of operation was 48 years; the median duration of preoperative symptoms was 24 months. In 42 % of the cases a chronic dacryocystitis was found. Pre-existing conditions were sarcoidosis in three cases and one case of Wegener’s granulomatosis. As well as lacrimal duct obstruction, additional pathologies were treated in the same session [septoplasty (n = 12), sinus operations (n = 10), and cauterisation of the nasal concha (n = 7), removal of a dacryocele (n = 1), conchectomy (n = 1)]. 20 operations were performed on the right side, 26 on the left side and two bilateral. The median duration of the operation was 51 minutes. No operative complications were encountered. The length of stay in hospital was on average four days. The median of follow-up was 23 months. The success rate was 78 %.Discussion: The success rate of endonasal DCRs is about 70 to 95 %. Thus, the achieved rate in this study is acceptable, especially as 16 of 40 patients underwent revision surgery. Probably this is attributed to the technique of transillumination. The safe intraoperative localisation of the lacrimal sac with a light probe seems to have a positive effect on the removal of obstructions.

Concepts: Hospital, Surgery, Wegener's granulomatosis, Granuloma, Lacrimal canaliculi, Lacrimal sac, Lacrimal apparatus, Nasolacrimal duct

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An epizootic of ulcerative to nodular ventral dermatitis was observed in a large breeding colony of 8-month to 5-year-old leopard geckos (Eublepharis macularius) of both sexes. Two representative mature male geckos were euthanized for diagnostic necropsy. The Chrysosporium anamorph of Nannizziopsis vriesii (CANV) was isolated from the skin lesions, and identification was confirmed by sequencing of the internal transcribed spacer region of the rRNA gene. Histopathology revealed multifocal to coalescing dermal and subcutaneous heterophilic granulomas that contained septate fungal hyphae. There was also multifocal epidermal hyperplasia with hyperkeratosis, and similar hyphae were present within the stratum corneum, occasionally with terminal chains of arthroconidia consistent with the CANV. In one case, there was focal extension of granulomatous inflammation into the underlying masseter muscle. This is the first report of dermatitis and cellulitis due to the CANV in leopard geckos.

Concepts: Pathology, Ribosomal RNA, Anatomical pathology, Skin, Granuloma, Eublepharis, Gekkonidae, Leopard gecko

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INTRODUCTION: Wegener’s granulomatosis presenting as diffuse alveolar hemorrhage is uncommon. However, the recognition of multisystem disease involving joints, kidney, eye and lung is critical for diagnosing Wegener’s vasculitis. This is not the first report of this kind in the literature. CASE PRESENTATION: A 51-year-old Croatian woman presented to our Emergency Department with a history of progressively worsening productive cough and shortness of breath, epistaxis and two episodes of hemoptysis. She developed respiratory failure due to diffuse alveolar hemorrhage, which was successfully treated with high-dose steroids, cyclophosphamide and plasmapheresis. Her clinical course was complicated with methicillin-resistant Staphyloccocus aureus pneumonia, which has been associated with Wegener’s granulomatosis flares. CONCLUSION: The recognition of multisystem disease is critical for diagnosing Wegener’s vasculitis. Diffuse alveolar hemorrhage can be a fulminant manifestation of Wegener’s granulomatosis, in which case immediate and aggressive treatment with pulse steroids, high-dose cyclophosphamide and plasma exchange can be life-saving.

Concepts: Pulmonology, Pneumonia, Vasculitis, Wegener's granulomatosis, Arthritis, Granuloma, Plasmapheresis, Hemoptysis

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OBJECTIVE: To report the occurrence of actinic granuloma of the conjunctiva in young women. DESIGN: Retrospective case series. PARTICIPANTS: Three eyes of 3 young women with a unilateral conjunctival mass of recent onset. METHODS: Three young women (21, 23, and 23 years of age) sought treatment for painless red masses of the conjunctiva that were thought clinically to be pingueculitis, actinic keratosis, or ocular surface squamous neoplasia (OSSN), but were diagnosed histopathologically as actinic granuloma. Special stains were performed to exclude infectious and autoimmune causes of granulomatous inflammation, followed by dermatologic work-up and systemic investigations. Diagnosis of actinic granuloma of the conjunctiva was confirmed. MAIN OUTCOME MEASURES: Patients' characteristics (age, sex, early onset), clinical presentation, same geographical location, typical histopathologic features, and lack of systemic association. RESULTS: All 3 cases were in young women with a rapid-onset conjunctival growth with conjunctival feeder vessels and intrinsic vessels; however, there was no surface keratin, and rose bengal stain results were negative. Histopathologic analysis of all 3 cases revealed elastolysis and granulomatous inflammation characterized by multinucleated giant cells, some of which displayed elastophagocytosis that was highlighted by Verhoeff-van Giesen elastic stain. There was absence of cytologic atypia of surface epithelium. Mucin stains and special stains for an infectious cause demonstrated negative results. Serologic investigations and systemic work-up results were negative, which excluded any systemic associations with this condition. This led to the final diagnoses of actinic granuloma of the conjunctiva. CONCLUSIONS: Conjunctival actinic granuloma is an underrecognized entity. We present 3 cases of this condition to highlight its occurrence in young women and the role of histopathologic examination to avoid misinterpretation of this condition. Both clinician and pathologist should consider this entity as a differential diagnosis of benign conjunctival lesions and OSSN. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Concepts: Diagnosis, Pathology, Anatomical pathology, Medical diagnosis, Granuloma, Actinic keratosis, Cytopathology, Pinguecula

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Granulomas are complex lung lesions that are the hallmark of tuberculosis (TB). Understanding antibiotic dynamics within lung granulomas will be vital to improving and shortening the long course of TB treatment. Three fluoroquinolones (FQs) are commonly prescribed as part of multi-drug resistant TB therapy: moxifloxacin (MXF), levofloxacin (LVX) or gatifloxacin (GFX). To date, insufficient data are available to support selection of one FQ over another, or to show that these drugs are clinically equivalent. To predict the efficacy of MXF, LVX and GFX at a single granuloma level, we integrate computational modeling with experimental datasets into a single mechanistic framework, GranSim. GranSim is a hybrid agent-based computational model that simulates granuloma formation and function, FQ plasma and tissue pharmacokinetics and pharmacodynamics and is based on extensive in vitro and in vivo data. We treat in silico granulomas with recommended daily doses of each FQ and compare efficacy by multiple metrics: bacterial load, sterilization rates, early bactericidal activity and efficacy under non-compliance and treatment interruption. GranSim reproduces in vivo plasma pharmacokinetics, spatial and temporal tissue pharmacokinetics and in vitro pharmacodynamics of these FQs. We predict that MXF kills intracellular bacteria more quickly than LVX and GFX due in part to a higher cellular accumulation ratio. We also show that all three FQs struggle to sterilize non-replicating bacteria residing in caseum. This is due to modest drug concentrations inside caseum and high inhibitory concentrations for this bacterial subpopulation. MXF and LVX have higher granuloma sterilization rates compared to GFX; and MXF performs better in a simulated non-compliance or treatment interruption scenario. We conclude that MXF has a small but potentially clinically significant advantage over LVX, as well as LVX over GFX. We illustrate how a systems pharmacology approach combining experimental and computational methods can guide antibiotic selection for TB.

Concepts: Bacteria, Antibiotic resistance, In vivo, Tuberculosis, In vitro, Granuloma, Leprosy

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A 13-year-old boy presented with a 9-month history of episodic unilateral swelling of the face and oral pain. He reported having loose, nonbloody stools. Granulomatous inflammation consistent with Crohn’s disease was found on histopathological examination.

Concepts: Inflammation, Histopathology, Crohn's disease, Inflammatory bowel disease, Face, Granuloma, Abscess

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Granulomatous lung diseases are a heterogeneous group of disorders that have a wide spectrum of pathologies with variable clinical manifestations and outcomes. Precise clinical evaluation, laboratory testing, pulmonary function testing, radiological imaging including high-resolution computed tomography and often histopathological assessment contribute to make a confident diagnosis of granulomatous lung diseases. Differential diagnosis is challenging, and includes both infectious (mycobacteria and fungi) and noninfectious lung diseases (sarcoidosis, necrotising sarcoid granulomatosis, hypersensitivity pneumonitis, hot tub lung, berylliosis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, rheumatoid nodules, talc granulomatosis, Langerhans cell histiocytosis and bronchocentric granulomatosis). Bronchoalveolar lavage, endobronchial ultrasound-guided transbronchial needle aspiration, transbronchial cryobiopsy, positron emission tomography and genetic evaluation are potential candidates to improve the diagnostic accuracy for granulomatous lung diseases. As granuloma alone is a nonspecific histopathological finding, the multidisciplinary approach is important for a confident diagnosis.

Concepts: Pulmonology, Pathology, Positron emission tomography, Anatomical pathology, Tuberculosis, Medical diagnosis, Sarcoidosis, Granuloma