Potent anti-inflammatory effects of an H2 S-releasing naproxen (ATB-346) in a human model of inflammation.

ATB-346 is a hydrogen sulfide-releasing non-steroidal anti-inflammatory drug (H2 S-NSAID) derived from naproxen, which in preclinical studies has been shown to have markedly reduced gastrointestinal adverse effects. However, its anti-inflammatory properties in humans compared to naproxen are yet to be confirmed. To test this, we used a dermal model of acute inflammation in healthy, human volunteers, triggered by ultraviolet-killed Escherichia coli. This robust model allows quantification of the cardinal signs of inflammation along with cellular and humoral factors accumulating within the inflamed skin. ATB-346 was non-inferior to naproxen in terms of its inhibition of cyclooxygenase activity as well as pain and tenderness. ATB-346 significantly inhibited neutrophil infiltration at the site of inflammation at 4 h, compared to untreated controls. Subjects treated with ATB-346 also experienced significantly reduced pain and tenderness compared to healthy controls. Furthermore, both classical and intermediate monocyte subsets infiltrating the site of inflammation at 48 h expressed significantly lower levels of CD14 compared to untreated controls, demonstrating a shift toward an anti-inflammatory phenotype. Collectively, we have shown for the first time in humans that ATB-346 is potently anti-inflammatory and propose that ATB-346 represents the next generation of H2 S-NSAIDs, as a viable alternative to conventional NSAIDs, with reduced adverse effects profile.

Safety of anti-rheumatic drugs in men trying to conceive: A systematic review and analysis of published evidence.

There is limited evidence relating to the impact of disease modifying anti-rheumatic drugs (DMARDs) upon male fertility and peri-conception paternal exposure in men with rheumatic disease. Therefore, we conducted a systematic review of available evidence to update information on this subject and guide paternal counselling. A systematic search of PubMed and Embase was carried out up to September 2017, to find relevant peer-reviewed papers, using keywords for fertility/spermatogenesis/conception, men, and disease modifying or biologic drugs commonly prescribed in patients with rheumatic disease. The search yielded 724 papers, and the titles/abstracts were screened independently by 2 authors, duplicates removed and 233 potentially relevant papers selected for full text review. A total of 84 papers were included in the final analysis which covered the impact on fertility of over 611 male exposures to relevant drugs, and over 5986 pregnancies conceived during paternal exposure to (or within 3 months of stopping) these drugs. Aside from the known adverse impact of cyclophosphamide and sulfasalazine on spermatogenesis, overall there was no firm evidence of harm to fertility or pregnancy outcomes with paternal exposure to anti-TNF therapies, abatacept, rituximab, azathioprine, cyclosporine A, hydroxychloroquine, leflunomide, methotrexate or mycophenolate mofetil. There was no evidence found pertaining to the effects of male exposure to IVIG, tacrolimus, golimumab, anakinra or belimumab on fertility or pregnancy outcomes. These results provide further reassurance as to the safety of many DMARDs for men trying to conceive and will be useful when counselling men about risks of anti-rheumatic drugs to fertility and pregnancies, and following accidental conception.

Pro-resolving mediators promote resolution in a human skin model of UV-killed Escherichia coli-driven acute inflammation.

While the treatment of inflammatory disorders is generally based on inhibiting factors that drive onset of inflammation, these therapies can compromise healing (NSAIDs) or dampen immunity against infections (biologics). In search of new antiinflammatories, efforts have focused on harnessing endogenous pathways that drive resolution of inflammation for therapeutic gain. Identification of specialized pro-resolving mediators (SPMs) (lipoxins, resolvins, protectins, maresins) as effector molecules of resolution has shown promise in this regard. However, their action on inflammatory resolution in humans is unknown. Here, we demonstrate using a model of UV-killed Escherichia coli-triggered skin inflammation that SPMs are biosynthesized at the local site at the start of resolution, coinciding with the expression of receptors that transduce their actions. These include receptors for lipoxin A4 (ALX/FPR2), resolvin E1 (ChemR23), resolvin D2 (GPR18), and resolvin D1 (GPR32) that were differentially expressed on the endothelium and infiltrating leukocytes. Administering SPMs into the inflamed site 4 hours after bacterial injection caused a reduction in PMN numbers over the ensuing 6 hours, the phase of active resolution in this model. These results indicate that in humans, the appearance of SPMs and their receptors is associated with the beginning of inflammatory resolution and that their therapeutic supplementation enhanced the resolution response.

Novel translational model of resolving inflammation triggered by UV-killed E. coli.

Whilst numerous studies investigating the aetiology of inflammatory diseases have been performed in rodents, the applicability of these data to human pathophysiology is frequently debated. Regardless of the strengths and weaknesses of rodent models in biomedical research, there is a need to develop models of experimental inflammation in humans. Here, we describe a self-resolving acute inflammatory response triggered by the intradermal injection of UV-killed Escherichia coli into the forearm of healthy volunteers. Cells and exudates were harvested from onset to resolution by applying negative pressure over the inflamed site. Onset was characterized by high blood flow, neutrophilia and peak levels of pro-inflammatory cytokines, whilst resolution showed a decline in blood blow, reduction in neutrophils, increase in monocytes/macrophages and waning of classic pro-inflammatory cytokine levels. An anti-inflammatory effect, defined as suppression of onset phase events, was demonstrated by administering naproxen, a conventional non-steroidal anti-inflammatory drug. In summary, this model of resolving acute inflammation is minimally invasive, highly tractable and allows simultaneous investigation of the vascular response, cellular trafficking and chemical mediator profile of onset and resolution phases of acute inflammation in humans. It can serve as a translational platform to provide mechanistic insights and to test the clinical efficacy of novel anti-inflammatory and pro-resolving drugs, and also as a tool in patients to explore inherent defects in resolution pathways.

A case of good syndrome presumed secondary to metastatic pancreatic thymoma in a patient presenting with a myasthenic crisis postthymectomy.

INTRODUCTION: Myasthenia gravis (MG) is an autoimmune disorder characterized by autoantibodies against the postsynaptic nicotinic acetylcholine receptors, muscle-specific tyrosine kinase, low-density lipoprotein receptor-related protein 4, and agrin. The incidence of thymoma in MG is reported as ∼10%-15%. The incidence of extrathoracic metastatic thymoma is exceedingly rare and may present years after resection. Associations between thymoma and immunodeficiency have also been described, including Good syndrome. METHODS AND RESULTS: We describe the clinical course, investigations, and treatments performed in a patient presenting with a myasthenic crisis in the setting of acetylcholine receptor antibody-positive generalized MG 10 years postthymectomy. Computed tomography imaging revealed 2 pancreatic lesions, but no residual thoracic thymoma. Biopsy confirmed metastatic pancreatic thymoma, which was successfully resected. His course was further complicated by cytomegalovirus retinitis with a depressed CD4 count and perniosis. DISCUSSION: This presentation was felt to be consistent with Good immunodeficiency syndrome.

Outcomes using predominantly single-stage approach to interrupted aortic arch and associated defects.

BACKGROUND: Neonatal repair of interrupted aortic arch (IAA) involves an early choice between a single-stage or two-stage strategy. Risk factors for each are not yet fully investigated, especially as they relate to major associated cardiac malformations. We aimed to assess the outcome of neonates undergoing biventricular repair of IAA and associated congenital heart defects. METHODS: Preoperative assessment, operative management, and outcome were retrospectively reviewed for 18 consecutive patients undergoing biventricular IAA repair at Starship Children's Hospital from 2000 to 2005. RESULTS: Seventeen patients underwent a single-stage procedure and one patient weighing 970 g underwent a two-stage procedure. All but one had a ventricular septal defect. Major associated cardiac defects were present in 7 and included aortopulmonary window (1), truncus arteriosus (3), transposition of the great arteries (1), and aortic valve atresia (2). Those with major associated cardiac defects had longer procedural times but similar early mortality and intensive care unit and hospital stay. One patient required a pacemaker for complete heart block. Mean follow-up was 4.5 years with one late death and all survivors reporting normal functional status. Developmental delay was present in 5 (27%), 4 of whom had 22q deletion. Late reoperation was required in 4, including two Konno procedures and two pulmonary conduit changes. CONCLUSIONS: A good functional outcome and low reoperation rate can be achieved with a single-stage repair regardless of the presence of major additional cardiac abnormalities. Neonates with risk factors such as low birth weight and prematurity require an individualized approach.

Tuberculous osteomyelitis of the midfoot: a case report.

INTRODUCTION: The prevalence of tuberculosis is increasing and musculoskeletal tuberculosis, although currently rare, may become an important problem. CASE PRESENTATION: We report the case of a 20-year-old Somalian man, who presented with an inversion injury to his ankle. When further history was taken, it transpired that he had sustained trauma to his ankle in Somalia 4 years previously, complicated by a non-healing wound. His foot pain and swelling had been present ever since. Diagnosis of tuberculosis was made by bone biopsy, histology of which demonstrated caseating granulomas. Tissue culture yielded growth of tuberculous bacilli. The patient made a full recovery on anti-tuberculous treatment. CONCLUSION: Musculoskeletal tuberculosis can be difficult to diagnose as only about one third of patients have respiratory symptoms. Synovial fluid aspirate is relatively unlikely to lead to definitive diagnosis, and a bone biopsy should always be taken for culture and histological examination.

Diffuse lung cysts in lymphoid interstitial pneumonia: high-resolution CT and pathologic findings.

Lymphoid interstitial pneumonia is part of a spectrum of pulmonary lymphoproliferative disorders that range from benign, small, and airway-centered cellular infiltrates (follicular bronchiolitis, nodular lymphoid hyperplasia) to low-grade malignant lymphoma. Most of the cases occur in patients with underlying autoimmune disease or immunodeficiency. The characteristic high-resolution computed tomography findings consist of diffuse ground-glass opacities, ill-defined centrilobular nodules, bronchovascular thickening, interlobular septal thickening, and scattered thin-walled cysts. The cysts may be seen in up to 80% of the patients and are typically few in number and measure less than 3 cm in diameter. This case illustrates extensive cysts as the predominant high-resolution computed tomography finding of idiopathic lymphoid interstitial pneumonia in a 64-year-old man who underwent unilateral lung transplant. Such extensive cystic disease and lung transplantation treatment has not been previously described.

Aspergillus-related lung disease.

Aspergillus is a ubiquitous dimorphic fungus that causes a variety of human diseases ranging in severity from trivial to life-threatening, depending on the host response. An intact host defence is important to prevent disease, but individuals with pre-existing structural lung disease, atopy, occupational exposure or impaired immunity are susceptible. Three distinctive patterns of aspergillus-related lung disease are recognized: saprophytic infestation of airways, cavities and necrotic tissue; allergic disease including extrinsic allergic alveolitis, asthma, allergic bronchopulmonary aspergillosis, bronchocentric granulomatosis and chronic eosinophilic pneumonia; and airway and tissue invasive disease -- pseudomembranous tracheobronchitis, acute bronchopneumonia, angioinvasive aspergillosis, chronic necrotizing aspergillosis and invasive pleural disease. A broad knowledge of these clinical presentations and a high index of suspicion are required to ensure timely diagnosis and treatment of the potentially lethal manifestations of aspergillus-related pulmonary disease. In the present report, the clinical, radiographic and pathological aspects of the various aspergillus-related lung diseases are briefly reviewed.

Pulmonary candidiasis after hematopoietic stem cell transplantation: thin-section CT findings.

PURPOSE: To retrospectively evaluate thin-section computed tomographic (CT) findings in hematopoietic stem cell transplant (ie, bone marrow transplant) patients with histopathologically proved pulmonary candidiasis. MATERIALS AND METHODS: Ethical approval was obtained from the institutional review board of each of the three institutions; informed consent was not required. The study included 17 hematopoietic stem cell transplant recipients with proved pulmonary candidiasis. Histopathologic specimens were acquired at transbronchial biopsy (n = 8), open lung biopsy (n = 6), and autopsy (n = 3). The patients included seven men and 10 women (age range, 20-62 years; mean age, 37 years). The thin-section CT scans were retrospectively reviewed by two thoracic radiologists for the presence, appearance, and distribution of parenchymal abnormalities. RESULTS: Multiple nodules were present in 15 (88%) patients, including centrilobular nodules and tree-in-bud pattern in seven (41%) patients. Nodules were bilateral in 12 patients and unilateral in three. An associated halo of ground-glass opacity was identified in five (33%) patients. Nodules were the only CT finding in five patients (29%). Areas of air-space consolidation were identified in 11 (65%) patients. Areas of ground-glass opacity were seen in six (35%) of 17 patients and were always associated with other abnormalities. Other less common CT findings included pleural effusion (n = 3), thickening of the bronchial walls (n = 2), and cavitation (n = 1). CONCLUSION: The most common thin-section CT findings of pulmonary candidiasis in hematopoietic stem cell transplant patients are multiple bilateral nodular opacities often associated with areas of consolidation.

Aspergillus infection of the airways: computed tomography and pathologic findings.

Aspergillosis is a serious pathologic condition caused by Aspergillus organisms and is frequently seen in immunocompromised patients. In recent years, it has been shown that Aspergillus infection can result in a broad range of airway complications. In this article, we illustrate and review the characteristic computed tomography and pathologic findings of the different manifestations of Aspergillus infection involving the airways.

Drug-induced lung disease: high-resolution CT and histological findings.

AIM: To compare the parenchymal high-resolution computed tomography (HRCT) appearances with histological findings in patients with drug-induced lung disease and to determine the prognostic value of HRCT. MATERIALS AND METHODS: Drug history, HRCT features, histological findings and outcome at 3 months in 20 patients with drug induced-lung disease were reviewed retrospectively. The HRCT images were assessed for the pattern and distribution of abnormalities and classified as most suggestive of interstitial pneumonitis/fibrosis, diffuse alveolar damage (DAD), organizing pneumonia (OP) reaction, or a hypersensitivity reaction. RESULTS: On histopathological examination there were eight cases of interstitial pneumonitis/fibrosis, five of DAD, five of OP reactions, one of hypersensitivity reaction and one of pulmonary eosinophilia. The most common abnormalities on HRCT were ground-glass opacities (n = 17), consolidation (n = 14), interlobular septal thickening (n = 15) and centrilobular nodules (n = 8). HRCT interpretation and histological diagnosis were concordant in only nine (45%) of 20 patients. The pattern, distribution, and extent of HRCT abnormalities were of limited prognostic value: all eight patients with histological findings of OP, hypersensitivity reaction, or eosinophilic infiltrate improved on follow-up compared to only five of 13 patients with interstitial pneumonitis/fibrosis or DAD. CONCLUSION: In many cases of drug-induced lung injury HRCT is of limited value in determining the histological pattern and prognosis.