Differential effect of p47phox and gp91phox deficiency on the course of Pneumococcal Meningitis.

Bacterial meningitis is a severe inflammatory disease of the central nervous system and is characterized by massive infiltration of granulocytes into the cerebrospinal fluid (CSF). To assess the role of NADPH oxidase-derived reactive oxygen species (ROS) in pneumococcal meningitis, mice deficient in either the gp91 subunit (essential for functioning of the phagocyte enzyme) or the p47 subunit (essential for functioning of homologous enzymes in nonphagocytic cells) were intracisternally infected with live Streptococcus pneumoniae, and defined disease parameters were measured during the acute stage of infection. While none of the parameters measured (including CSF bacterial titers) were significantly different in gp91(-/-) and wild-type mice, the infection in p47(-/-) mice was associated with significantly increased inflammation of the subarachnoid and ventricular space, disruption of the blood-brain barrier, and the presence of interleukin-1 beta, tumor necrosis factor alpha, and matrix metalloproteinase 9 in the cortex. These changes were associated with approximately 10-fold-higher CSF bacterial titers in p47(-/-) mice than in wild-type mice (P < 0.001). In contrast to infection with live bacteria, the inflammatory response, including CSF leukocytosis, was significantly attenuated in p47(-/-) mice (but not gp91(-/-) mice) challenged with a fixed number of heat-inactivated pneumococci. Impairment of the host defense appeared to be responsible for the higher bacterial titers in p47(-/-) mice. Therefore, these results indicate that ROS generated by a gp91-independent NADPH oxidase(s) are important for establishing an adequate inflammatory response to pneumococcal CSF infection.

Multiple Sclerosis: Current Knowledge and Future Outlook

Background: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination and axonal loss. The etiology of MS is unknown; however, environmental and genetic factors play a key role in the development of MS. Diagnostic criteria have been adapted to facilitate earlier diagnosis with increased sensitivity and specificity. Our understanding of the pathophysiology of MS has deepened considerably in recent years, resulting in different therapies to modify the disease course. Furthermore, several drugs have lately shown efficacy in phase III studies and their approval is expected in the near future. As treatment options expand, a future challenge will be to find the optimal treatment for the individual patient. Summary: This mini-review gives an overview of the current knowledge of MS with emphasis on the latest diagnostic criteria and both current and upcoming treatment options. Key Messages: Treatment of MS changes rapidly as the knowledge and therapeutic options in MS expand. Clinical Impact: Diagnosis of MS is based on McDonald criteria. MS therapy can be divided into relapse, disease-modifying and symptomatic treatment. Relapses are commonly treated with intravenous methylprednisolone. First-line therapy consists of either interferon-β, glatiramer acetate or teriflunomide. In general, agents used as escalation therapies (natalizumab, fingolimod and mitoxantrone) are more potent than the agents used for first-line therapy; however, these have potentially serious side effects and should be used with care.

The role of adipokines in periodontal infection and healing.

Periodontitis is a chronic inflammatory disease of the periodontium, which is caused by pathogenic bacteria in combination with other risk factors. The bacteria induce an immunoinflammatory host response, which can lead to irreversible matrix degradation and bone resorption. Periodontitis can be successfully treated. To achieve regenerative periodontal healing, bioactive molecules, such as enamel matrix derivative (EMD), are applied during periodontal surgery. Recently, it has been shown that obesity is associated with periodontitis and compromised healing after periodontal therapy. The mechanisms underlying these associations are not well understood so far, but adipokines may be a pathomechanistic link. Adipokines are bioactive molecules that are secreted by the adipose tissue, and that regulate insulin sensitivity and energy expenditure, but also inflammatory and healing processes. It has also been demonstrated that visfatin and leptin increase the synthesis of proinflammatory and proteolytic molecules, whereas adiponectin downregulates the production of such mediators in periodontal cells. In addition, visfatin and leptin counteract the beneficial effects of EMD, whereas adiponectin enhances the actions of EMD on periodontal cells. Since visfatin and leptin levels are increased and adiponectin levels are reduced in obesity, these adipokines could be a pathomechanistic link whereby obesity and obesity-related diseases enhance the risk for periodontitis and compromised periodontal healing. Recent studies have also revealed that adipokines, such as visfatin, leptin and adiponectin, are produced in periodontal cells and regulated by periodontopathogenic bacteria. Therefore, adipokines may also represent a mechanism whereby periodontal infections can impact on systemic diseases.

A mouse model for S. typhimurium-induced enterocolitis.

Salmonella typhimurium has emerged as a model pathogen that manipulates host cells in a complex fashion, thus causing disease. In humans, S. typhimurium causes acute intestinal inflammation. Intriguingly, type III secreted virulence proteins have a central role in this process. At the cellular level, the functions of these factors are well characterized; at present, animal models are required for elucidating how these factors trigger inflammatory disease in vivo. Calf infection models have been employed successfully and, recently, a mouse model was identified: in streptomycin-pretreated mice, S. typhimurium causes acute colitis. This mouse model provides a new avenue for research into acute intestinal inflammation because it enables the manipulation and dissection of both the bacterial and host contributions to the disease in unsurpassed detail.

Imaging of the Sclera in Patients with Scleritis and Episcleritis using Anterior Segment Optical Coherence Tomography

PURPOSE To evaluate the sclera and episclera in patients with scleritis and episcleritis using anterior segment optical coherence tomography (AS-OCT). METHODS Cross-sectional prospective case series of 11 consecutive patients with episcleral or scleral inflammatory disease located anterior to the equator. The thickness of the ocular wall (sclera and the episclera) was measured using AS-OCT and compared to the contralateral healthy eye. RESULTS Eleven patients with a mean age of 49.5 years presented with symptomatic scleritis or episcleritis. The mean thickness of the ocular wall in the affected eye was 982 ± 56 μm compared to 790 ± 23 μm (p < 0.05) in the fellow eye. Enhanced-depth AS-OCT showed that the thickening occurred mainly in the episcleral layer in both scleritis and episcleritis. CONCLUSION Enhanced-depth AS-OCT may be a useful tool for imaging scleritis or episcleritis and may serve to monitor therapeutic success in these patients.

Escalating incidence of eosinophilic esophagitis in Canton of Vaud, Switzerland, 1993-2013: a population-based study.

BACKGROUND Eosinophilic esophagitis (EoE) is a chronic, inflammatory disease of the esophagus with a rapidly increasing incidence. However, population-based epidemiologic data on EoE are rare and limited to regions with less than 200 000 inhabitants. We evaluated the incidence and prevalence of EoE over time in Canton of Vaud, Switzerland. MATERIALS AND METHODS Canton of Vaud lies in the French-speaking, Western part of Switzerland. As of December 2013, it had a population of 743 317 inhabitants. We contacted all pathology institutes (n = 6) in this canton to identify patients that have been diagnosed with esophageal eosinophilia between 1993 and 2013. We then performed a chart review in all adult and pediatric gastroenterology practices to identify patients with EoE. RESULTS Of 263 patients with esophageal eosinophilia, a total of 179 fulfilled the diagnostic criteria for EoE. Median diagnostic delay was 4 (IQR 1-9) years. No patient was diagnosed with EoE prior to 2003. Incidence of EoE increased from 0.16/100 000 inhabitants in 2004 to 6.3/100 000 inhabitants in 2013 (P < 0.001). The cumulative EoE prevalence in 2013 was 24.1/100 000. The incidence in males was 2.8 times higher (95% CI 2.01-3.88, P < 0.001) when compared to that in females. The annual EoE incidence was 10.6 times higher (95%-CI 7.61-14.87, P < 0.001) in the period from 2010 to 2013 when compared to that in the period from 1993 to 2009. CONCLUSIONS The incidence and cumulative prevalence of EoE in Canton of Vaud, Switzerland, has rapidly increased in the past 10 years.

Perturbation of the T cell repertoire in rheumatoid arthritis

Aberrations in the T cell repertoire with the emergence of oligoclonal populations have been described in patients with rheumatoid arthritis (RA). However, the extent of the repertoire perturbations as well as the underlying mechanisms are not known. We now have examined the diversity of the peripheral CD4 T cell repertoire by determining the frequencies of arbitrarily selected T cell receptor (TCR) β-chain sequences. Healthy individuals displayed a highly diverse repertoire, with a median frequency of individual TCR β-chain sequences of 1 in 2.4 × 107 CD4 T cells. In RA patients, the median TCR β-chain frequency was increased 10-fold, indicating marked contraction of the repertoire (P < 0.001). The loss in TCR diversity was not limited to CD4 memory T cells but also involved the compartment of naive T cells, suggesting that it reflected an abnormality in T cell repertoire formation and not a consequence of antigen recognition in the synovium. Also, control patients with chronic inflammatory disease such as hepatitis C expressed a diverse repertoire indistinguishable from that of normals. Telomere length studies indicated an increased replicative history of peripheral CD4 T cells in RA patients, suggesting an enhanced turnover within the CD4 compartment. Compared with age-matched controls, terminal restriction fragment sizes were 1.7 kilobases shorter (P < 0.001). These data demonstrate an altered CD4 T cell homeostasis in RA that may contribute to the autoimmune response as well as to the immunodeficiency in these patients.

A genome-wide search for susceptibility genes in human systemic lupus erythematosus sib-pair families

Systemic lupus erythematosus (SLE) is an autoimmune multisystem inflammatory disease characterized by the production of pathogenic autoantibodies. Previous genetic studies have suggested associations with HLA Class II alleles, complement gene deficiencies, and Fc receptor polymorphisms; however, it is likely that other genes contribute to SLE susceptibility and pathogenesis. Here, we report the results of a genome-wide microsatellite marker screen in 105 SLE sib-pair families. By using multipoint nonparametric methods, the strongest evidence for linkage was found near the HLA locus (6p11-p21) [D6S257, logarithm of odds (lod) = 3.90, P = 0.000011] and at three additional regions: 16q13 (D16S415, lod = 3.64, P = 0.000022), 14q21–23 (D14S276, lod = 2.81, P = 0.00016), and 20p12 (D20S186, lod = 2.62, P = 0.00025). Another nine regions (1p36, 1p13, 1q42, 2p15, 2q21–33, 3cent-q11, 4q28, 11p15, and 15q26) were identified with lod scores ≥1.00. These data support the hypothesis that multiple genes, including one in the HLA region, influence susceptibility to human SLE.

Pericellular mobilization of the tissue-destructive cysteine proteinases, cathepsins B, L, and S, by human monocyte-derived macrophages.

Human macrophages are believed to damage host tissues in chronic inflammatory disease states, but these cells have been reported to express only modest degradative activity in vitro. However, while examining the ability of human monocytes to degrade the extracellular matrix component elastin, we identified culture conditions under which the cells matured into a macrophage population that displayed a degradative phenotype hundreds of times more destructive than that previously ascribed to any other cell population. The monocyte-derived macrophages synthesized elastinolytic matrix metalloproteinases (i.e., gelatinase B and matrilysin) as well as cysteine proteinases (i.e., cathepsins B, L, and S), but only the cathepsins were detected in the extracellular milieu as fully processed, mature enzymes by either vital fluorescence or active-site labeling. Consistent with these observations, macrophage-mediated elastinolytic activity was not affected by matrix metalloproteinase inhibitors but could be almost completely abrogated by inhibiting cathepsins L and S. These data demonstrate that human macrophages mobilize cysteine proteinases to arm themselves with a powerful effector mechanism that can participate in the pathophysiologic remodeling of the extracellular matrix.

Orbscan Topography in Primary Open-Angle Glaucoma

Purpose: To compare anterior and posterior corneal curvatures between eyes with primary open-angle glaucoma (POAG) and healthy eyes. Methods: This is a prospective, cross-sectional, observer-masked study. A total of 138 white subjects (one eye per patient) were consecutively recruited; 69 eyes had POAG (study group), and the other 69 comprised a group of healthy control eyes matched for age and central corneal pachymetry with the study ones. Exclusion criteria included any corneal or ocular inflammatory disease, previous ocular surgery, or treatment with carbonic anhydrase inhibitors. The same masked observer performed Goldmann applanation tonometry, ultrasound pachymetry, and Orbscan II topography in all cases. Central corneal thickness, intraocular pressure, and anterior and posterior topographic elevation maps were analyzed and compared between both groups. Results: Patients with POAG had greater forward shifting of the posterior corneal surface than that in healthy control eyes (p < 0.01). Significant differences in anterior corneal elevation between controls and POAG eyes were also found (p < 0.01). Conclusions: Primary open-angle glaucoma eyes have a higher elevation of the posterior corneal surface than that in central corneal thickness–matched nonglaucomatous eyes.

Rinite alérgica e suas principais comorbilidades : asma, conjuntivite alérgica e sinusite

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Omalizumab uma nova arma terapêutica na dermatite atópica refratária?

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Rinite ocupacional : investigar, prevenir, diagnosticar e tratar

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Étude sur le rôle de SIGIRR chez les cas pédiatriques dans la maladie de Crohn

Il est admis que la maladie de Crohn (MC) résulte de facteurs immunologiques, environnementaux et génétiques. SIGIRR, un récepteur anti-inflammatoire, n’a jamais été étudié dans le contexte de la MC, et de nombreuses découvertes à son sujet ont mené plusieurs à s’intéresser quant à son utilité dans l’atténuation de maladies inflammatoires. Récemment, l’IL-37 a été identifié comme ligand d’un complexe formé de SIGIRR-IL-18Rα. SIGIRR et l’IL-37 pourraient alors être des acteurs de la dérégulation de l’inflammation retrouvée chez la MC. Nous les avons étudiés dans le contexte de la MC pédiatrique, afin d’y caractériser leurs effets. Nous avons identifié une diminution de l’expression de SIGIRR sur certains types de cellules immunitaires. De plus, les personnes atteintes de la MC ont des concentrations de protéines altérées, soit SIGIRR soluble, l’IL-37, l’IL-18BP, et l’IL-18, et tendent à revenir à la normale lorsque l’inflammation est contrôlée par médication. De plus, la concentration de l’IL-18 libre suit le même patron. Par analyse de régression linéaire de SIGIRR soluble et l’IL-37, de l’IL-18BP et l’IL-18, ainsi que l’IL-37 et l’IL-18, des tendances divergentes ont été identifiées entre les patients non traités aux contrôles et patients traités. Nos résultats suggèrent que le système IL-37-SIGIRR est compromis chez les patients de la MC. Étant donné que ce système est un facteur crucial dans la régulation négative de l’inflammation, il sera intéressant de déterminer si SIGIRR et l’IL-37 peuvent constituer des cibles thérapeutiques importantes dans l’atténuation et la résolution de l’inflammation chez les patients atteints de la MC.