bluuebunny/crossref_metadata_2025 huggingface dataset:
Deficiency of INFγ Producing Cells in Adenoids of Children Exposed to Passive Smoke
Authors: Avanzini M.A. , Ricci A. , Scaramuzza C. , Semino L. , Pagella F. , Castellazzi A.M. , Marconi M. , Klersy C. , Pistorio A. , Boner A.L. , Marseglia G.L.
Published: January 2017

Exposure to passive smoke is a very common event associated with increased susceptibility to respiratory tract infections. Many related adverse effects result from the ability of cigarette smoke extracts to interfere with the immune system, but the mechanism is not yet completly understood. The aim of the present study is to evaluate the intracellular cytokine profile in adenoids and peripheral blood cells of children exposed to passive smoke. Children undergoing adenoidectomy exposed or not exposed to passive smoke were studied. The intracellular cytokine profile of lymphocyte subsets in adenoids and in peripheral blood were evaluated by flow cytometry analysis. Children exposed to tobacco smoke showed a significantly lower percentage of INF-γ producing CD4+ and CD8+ cells in adenoids. Moreover a significant correlation was observed between the quantity of exposure and reduction in Th1 (CD4+INFγ+ and CD8+INFγ +) cells in adenoids. This reduction may be a contributing factor in the increasing susceptibility to respiratory tract infection in children exposed to tobacco smoke.
Immunity to Extracellular Matrix Antigens is Associated with Ultrastructural Alterations of the Stroma and Stratified Epithelium Basement Membrane in the Skin of Hashimoto's Thyroiditis Patients
Authors: Bei R. , Mentuccia D. , Trono P. , Masuelli L. , Cereda V. , Palumbo C. , Marzocchella L. , Mrozek M.A. , Pallotta P. , Di Lella G. , Modesti M. , Cerilli M. , Frajese G.V. , Frajese G. , Zambruno G. , Modesti A.
Published: January 2017

Employing purified extracellular matrix (ECM) proteins, i.e. type I, III, IV and V collagens (CI, CHI, CIV, CV), laminin (LM) and fibronectin (FN), as antigen sources we detected autoantibodies to conformational and/or denatured ECM antigens among 34 of 50 sera obtained from Hashimoto's thyroiditis (HT) patients and 6 of 51 control sera obtained from non-autoimmune thyroid disease patients and healthy donors (HT sera vs. control sera p=4×10−9). Reactivity to conformational antigens, mostly due to autoantibodies of the IgG isotype, was observed in 30/50 HT sera and in 6/51 control sera (p=3.5×10−7) and was not always concomitant with that to linear antigens, found in 23/50 HT and in 6/51 control sera (p=1.6×10−4). Ultrastructural analysis of skin biopsies obtained from 18 HT patients without symptomatic cutaneous diseases revealed defects of the stratified squamous epithelium basement membrane in 11/18, alterations of the stroma in 13/18 and both basement membrane and stromal defects in 9/18. Interestingly, 13/13 (p=0.012) and 9/11 (p=0.012) patients with stromal and basement membrane defects respectively, exhibited serum antibodies to at least one ECM antigen involved in the organization of the altered tissue compartment. Lastly, 10/18 skin biopsies presented immunoglobulin (Ig) and/or complement (C3) deposits along the cutaneous basement membrane zone (BMZ) or in the papillary dermis and 9/10 sera from the same patients simultaneously showed antibodies to at least one ECM antigen involved in the organization of these two skin compartments. Besides, 8/11 HT patients with basement membrane defects exhibited Ig or C3 deposits along the BMZ. Our findings suggest that autoantibodies to ECM molecules might contribute to the development of asymptomatic extra-thyroid skin diseases in HT patients.
Mast Cell Deficient W/Wv Mice Have Lower Serum IL-6 and Less Cardiac Tissue Necrosis Than Their Normal Littermates following Myocardial Ischemia-Reperfusion
Authors: Bhattacharya K. , Farwell K. , Huang M. , Kempuraj D. , Donelan J. , Papaliodis D. , Vasiadi M. , Theoharides T.C.
Published: January 2017

Myocardial ischemia-reperfusion (IR) injury complicates all forms of coronary artery revascularization. Circulating interleukin-6 (IL-6) has been implicated in cell death following a variety of stimuli. Macrophages, platelets, neutrophils and the endothelium have been shown to release IL-6 after IR injury. Cardiac mast cells have been implicated in IR; however, their involvement has never been quantified. In this randomized, prospective study, we compared cardiac tissue susceptibility and serum IL-6 changes between mast cell deficient (W/Wv) mice and their normal littermates (+/+). Twenty-eight male W/Wv mice (n=14) and their +/+ littermates (n=14) were anaesthetized with 2.5% isofluorane. The left coronary artery (LCA) was ligated for 30 minutes or a sham procedure was performed. After 6 hours of reperfusion, the animals were sacrificed. The muscle viability was assessed on fresh whole-mount slices by nitroblue tetrazolium (NBT) histochemical assay and serum IL-6 concentrations measured by ELISA. Cardiac muscle viability was significantly higher in W/Wv mice than the +/+ mice. Serum IL-6 levels were higher in the +/+ sham mice (465 ± 32 pg/ml, n=6) than the W/Wv mice (185 ± 31 pg/ml, n=6), p < 0.001. The IL-6 levels increased significantly after reperfusion only in the +/+ mice (698 ± 41 pg/ml, n=8, p = 0.001), while it remained similar in the W/Wv mice (202 ± 48 pg/ml, n=8, p = 0.783). These results show that the absence of mast cells reduces the myocardial damage associated with IR injury. Furthermore, there is an attenuation in the inflammatory response, as measured by serum IL-6 levels, following this local insult. This finding entertains the prospect of developing prophylactic therapy - targeting selective inhibition of cardiac mast cell activation, in clinical situations involving medical or surgical myocardial revascularization.
Serum and Mucosal Cytokine Profiles in Patients with Active Helicobacter Pylori and Ischemic Heart Disease: Is There a Relationship?
Authors: Di Bonaventura G. , Piccolomini R. , Pompilio A. , Zappacosta R. , Piccolomini M. , Neri M.
Published: January 2017

This study is designed to investigate, for the first time, circulating and gastric mucosal levels of IL1-α, IL-6, IL-8 and TNF-α in patients with ischemic heart disease (IHD) and matched controls, according to the presence or absence of active Helicobacter pylori infection. Furthermore, in order to evaluate whether modified lipid profile was associated to an increased cardiovascular risk, this was determined in the same groups. Cytokine levels were measured using ELISA in 58 patients with IHD and 52 controls. Active H. pylori infection was assessed if either culture of H. pylori or rapid urease test gave a positive result. Our findings indicate increasing cytokine mucosal levels in H. pylori-positive patients compared to H. pylori-negative subjects. However, the increase was statistically significant only for IL-6 and TNF-α in the gastric mucosa of IHD patients. In H. pylori-positive controls, IL-8 mucosal levels positively correlated with both IL-1α (r = 0.98; P = 0.0003) and IL-6 (r = 0.83; P = 0.03) levels. Circulating cytokine levels were comparable in IHD and healthy subjects, regardless of H. pylori status. There were no correlations between mucosal and circulating cytokine levels. Active H. pylori infection was not associated with a modified lipid profile in either controls or IHD patients, although ApoAI levels were significantly higher in H. fly/ort'-positive controls compared to those H. pylori-negative. Taken together, the results of the present study provide evidence that active H. pylori infection may play a role as a trigger factor in the pathophysiology of IHD by inducing an inflammatory cascade concentrated on gastric mucosa.
Recognition Sites for Microbes and Components of the Immune System on Human Mast Cells: Relationship to CD Antigens and Implications for Host Defense
Authors: Mayerhofer M. , Aichberger K.J. , Florian S. , Valent P.
Published: January 2017

Traditionally, mast cells (MCs) have been considered to play an important role in allergic disorders and helminth infections. More recently, MCs have been implicated in a variety of different infectious diseases including life-threatening disorders caused by viruses and bacteria. Apart from recognition through specific IgE, MCs are considered to recognize such bacteria and viruses via specific cell surface binding sites. In addition, MCs interact with diverse components and cells of the immune system and thereby may facilitate the targeting and the elimination of invading microbes in the tissues. The current article provides an overview on MC antigens contributing to microbe recognition and targeting as an important element of natural host-defense.
Immunopathology of Leishmaniasis: An Update
Authors: Mansueto P. , Vitale G. , Di Lorenzo G. , Rini G.B. , Mansueto S. , Cillari E.
Published: January 2017

Leishmaniasis represents a severe, increasing, public health problem. The perspective of its control is highly dependent on research progress, on therapeutic manipulations of the immune system, and on vaccine development. There is a correlation between the clinical outcome of Leishmania infection and the cytokine response profile. While a protective immune response against Leishmania has been clearly identified to be related to the influence of a type-1 response and IFN-γ production, the precise role of T helper (TH) 2 cytokines in non-healing infections requires further exploration. IL-4 and IL-13 (TH2 cytokines) can promote disease progression in cutaneous leishmaniasis, whereas IL-4 would appear to enhance protective type-1 responses in visceral leishmaniasis. Thus, the TH1/TH2 paradigm of resistance/susceptibility to intracellular parasites is probably an oversimplification of a more complicated network of regulatory/counter regulatory interactions. Moreover, the presence of antigen specific regulatory T cell subsets may provide an environment that contributes to the balance between TH1 and TH2 cells. Finally, the involvement of CD8+ T cells has been described, but the modality of their function in this kind of infection has not been so far elucidated.
Effect of Propofol, Sevoflurane and Desflurane on Systemic Redox Balance
Authors: Cinnella G. , Vendemiale G. , Dambrosio M. , Serviddio G. , Pugliese P.L. , Aspromonte G. , Altomare E.
Published: January 2017

We studied the effects of Propofol, Desflurane, and Sevoflurane on the systemic redox balance in patients undergoing laparohysterectomy. We measured blood concentration of glutathione (GSH), plasma antioxidant capacity (Trolox Equivalent Antioxidant Capacity-TEAC), and lipid peroxidation products (malondialdehyde (aMDA) and 4-hydroxynonenal (aHNE) protein adducts). Sixty patients were randomly placed into three groups of twenty people each. In Group P anesthesia was induced with Propofol 2 mg/kg and maintained with 12–10–8 mg/kg/min; in Groups S and D anesthesia was induced with 3 mg/kg Sodium Thiopental and maintained with 2% Sevoflurane and 6% Desflurane, respectively. Blood samples were collected prior to induction (T0bas), 60min and 24h postoperatively (T160' and T224 h). In Group P, GSH increased on T160' (p<0.02) and returned to baseline on T24h, while TEAC remained unmodified; in Groups S, GSH and TEAC decreased on T160' (p<0.01 vs. T0bas, p<0.03 vs. T0bas, respectively); in Group D, on T160' there was a slight decrease of GSH and TEAC. The levels of aMDA slightly decreased throughout the study periods in Group P, increased in Group D, and remained stable in Group S. Propofol showed antioxidant properties, while Sevoflurane and Desflurane seemed to shift the redox balance towards oxidation, yet without inducing overt oxidative damage.
Effect of Etanercept on Insulin Sensitivity in Nine Patients with Psoriasis
Authors: Marra M. , Campanati A. , Testa R. , Sirolla C. , Bonfigli A.R. , Franceschi C. , Marchegiani F. , Offidani A.
Published: January 2017

Metabolic syndrome is associated to chronic low grade inflammation, characterized by increased levels of inflammatory cytokines, such as Tumor Necrosis Factor-α (TNF-α) and Interleukin-6 (IL-6). In particular, TNF-α causes a decrease in the insulin-stimulated kinases related to the early phases of the insulin cascade, thereby leading to insulin resistance. Etanercept is a human fusion protein used in the treatment of psoriasis and inflammatory arthritis. It blocks inflammatory response by interfering in the binding of TNF-α to its receptors. The aim of this case report study is to verify the effect of Etanercept on insulin sensitivity, lipid profile and inflammatory status in psoriatic patients. Nine psoriatic patients with stable, active, plaque type psoriasis were enrolled and treated with Etanercept for 24 weeks. We found an improvement in the metabolic assessment with a significant reduction of insulin plasma levels. In particular, this treatment allows to maintain their euglycemic state with lower insulin plasma levels, as confirmed by the improved Homeostasis Model Assessment (HOMA) index. We conclude that Etanercept, probably acting on inflammation, improves insulin sensitivity in psoriatic subjects.
Effects of Nanoparticles on Lung Physiology in the Presence or Absence of Antigen
Authors: Inoue K. , Takano H. , Yanagisawa R. , Sakurai M. , Abe S. , Yoshino S. , Yamaki K. , Yoshikawa T.
Published: January 2017

Ambient particulate matter (PM) exacerbates allergic airway diseases. Our previous study showed that diesel exhaust particles, the main constituents in urban PM, enhance airway hyperresponsivness in mice. In addition, health effects of PM with a diameter of less than 100 nm, called nanoparticles, have been reported, and we have also demonstrated that carbon nanoparticles exacerbate antigen-related airway inflammation. The present study investigates the effects of pulmonary exposure to two sizes of carbon nanoparticles on lung physiology and lung expression of Muc5ac in the presence or absence of antigen in mice. Nanoparticles alone or ovalbumin (OVA) alone moderately enhanced cholinergic airway reactivity, as assessed by total respiratory system resistance (R) and Newtonian resistance (Rn). In the nanoparticle + OVA groups, all the parameters for lung responsiveness, such as R, compliance, elastance, Rn, tissue damping, and tissue elastance, were worse than those in the vehicle group, the corresponding nanoparticle groups or the OVA group. The lung mRNA level for Muc5ac was significantly higher in the OVA group than in the vehicle group, and further increased in the nanoparticle + OVA groups than in the OVA or the nanoparticle groups. These data suggest that carbon nanoparticles can enhance lung hyperresponsiveness, especially in the presence of antigen. The effects may be mediated, at least partly, through the enhanced lung expression of Muc5ac.
Vertical Hepatitis C Virus Transmission is not Related to Mother-Child Class-1 HLA Concordance
Authors: Azzari C. , Indolfi G. , Betti L. , Moriondo M. , Massai C. , Becciolini L. , Bertelli L. , Poggi G.M. , De Martino M. , Resti M.
Published: January 2017

Mother-child human leukocyte antigen (HLA) diversity is protective for vertical transmission of some viruses. The aim of this study is to evaluate the role of mother-child HLA diversity on hepatitis C virus (HCV) vertical transmission. Forty consecutive HCV infected and 46 consecutive control uninfected children born to HCV-RNA positive mothers were evaluated for HLA class-1 type concordance with their mothers. No significant difference in the degree of HLA concordance was found between HCV infected and uninfected children both when A, B, C ( p=0.30) and when only A and B alleles were evaluated ( p=0.59). Mother-infant HLA concordance does not affect HCV vertical transmission.
Safety and Tolerability of Infliximab Therapy: Suggestions and Criticisms Based on Wide Clinical Experience
Authors: Vultaggio A. , Matucci A. , Parronchi P. , Rossi O. , Palandri F. , Romagnani S. , Maggi E.
Published: January 2017

Infliximab, an IgG1 monoclonal chimeric antibody against tumor necrosis factor (TNF)-α, represents the main biological drug employed for the treatment of several immuno-mediated inflammatory disorders. Infliximab infusion can be complicated by clinically heterogeneous adverse reactions, potentially interfering with the course of treatment. We analysed the adverse events recorded in 49 patients affected by different chronic inflammatory disorders (rheumatoid arthritis, seronegative spondiloarthritis, Behçet's disease, Wegener's granulomatosis, Churg-Strauss' syndrome, Cogan's disease) who were receiving a total of 709 infliximab infusions, in order to correlate the development of infliximab reactions and their features to some potential risk factors. We displayed a lower frequency of infusion reactions (1.5%; 11 out of 709 infusions) than those previously reported. However, patients suffering from rheumatoid arthritis and/or patients who underwent re-treatment after a long period, showed a higher prevalence of infliximab-related reactions. In conclusion, in our experience infliximab treatment is rarely complicated by adverse reactions which are, more importantly, almost always mild. Some good clinical practices, such as the low rate of infusion, pre-treatment with anti-histamine and prednisone in all patients, chronic immunosuppressive therapy and avoidance of long intervals between infusions may represent a combined useful strategy to reduce the frequency of infliximab reactions and to increase safety.
Colifagina, a Novel Preparation of 8 Lysed Bacteria Ameliorates Experimental Colitis
Authors: Vetrano S. , Correale C. , Borroni E.M. , Pagano N. , Savino B. , Locati M. , Malesci A. , Repici A. , Danese S.
Published: January 2017

Immune reactivity towards the bacterial intestinal flora plays an important part in the pathogenesis of inflammatory bowel disease. Administration of probiotic bacteria has beneficial effects on infectious and inflammatory diseases, principally in bowel disorders. However, little is known about the administration of soluble bacterial antigens in intestinal inflammation. We investigated the therapeutic effects of colifagina in experimental colitis. To assess this effect, C57BL/6 mice with dextran sulphate sodium-induced colitis were treated with colifagina, or with a placebo, for a period of 10 days. The mice were monitored, and inflammation was assessed by disease activity index (DAI). Analysis of fecal IgA concentration and measurement of IgA and inflammatory chemokine production in organ colonic culture was performed by ELISA. Clinically and histologically, bacterial-lysate-treated mice revealed significantly fewer DAI and a reduction of colonic histological inflammation. Treatment of healthy mice with colifagina significantly increased the fecal concentration of IgA and IgA production in organ culture. Colifagina administration in DSS-treated mice significantly increased the fecal concentration of IgA and IgA production in organ culture. MIP-1, MIP-2 and RANTES concentrations in colonic organ culture were significantly lower in colifagina-treated mice than in the placebo group. The use of colifagina is effective in amelioration of murine colitis.
Chemokines and Bone Remodeling
Authors: Galliera E. , Locati M. , Mantovani A. , Corsi M.M.
Published: January 2017

Bone remodeling is characterized by spatial and temporal coupling of bone resorption and formation and is necessary for skeletal growth and normal bone structure maintenance. Imbalance of this process is related to metabolic bone disorders such as osteoporosis or rheumatoid arthritis. For this reason, bone remodeling is under the control of several local and systemic factors, including molecules of the immune system. The importance of the interplay of both the skeletal and immune systems is reflected by the emerging interdisciplinary research field, called osteoimmunology, focused on common aspects of osteology and immunology. This review focuses on the role of inflammatory mediators, such as cytokines in bone remodeling and, in particular, a subfamily of chemotactic cytokines or chemokines which are involved not only in several aspects of physiological bone remodeling but also in pathological bone disorders, such as rheumatoid arthritis or osteoporosis. Understanding the role of inflammation and chemokines will provide new insights for the treatment of diseases affecting both skeletal and immune systems, by the development of new therapeutic strategies targeting common inflammatory mediators.
Interferon γ-Signature Transcript Profiling and IL-23 Upregulation in Response to Helicobacter Pylori Infection
Authors: Vivas J.R. , Régnault B. , Michel V , Bussière F.I. , Avé P. , Huerre M. , Labigne A. , D'Elios M.M. , Touati E.
Published: January 2017

Helicobacter pylori infection is the major cause of gastroduodenal pathologies including gastric cancer. The long persistence of bacteria and the type of immune and inflammatory response determine the clinical issue. In this study, the global gene expression profile after 6 and 12 months of H. pylori infection was investigated in the mouse stomach, using the Affymetrix GeneChip Mouse Expression Array A430. Genes related to the inflammatory and immune responses were focused. Levels of selected transcripts were confirmed by reverse transcription polymerase chain reaction. Twenty-five and nineteen percent of the differentially expressed genes observed at 6 and 12 months post-infection respectively, were related to immune response. They are characterized by an interferon (IFN)γ-dependent expression associated to a T helper 1 (Th1) polarised response. In-depth analysis revealed that an up-regulation of IL-23p19, took place in the stomach of H. pylori infected-mice. Strong IL-23p19 levels were also confirmed in gastric biopsies from H. pylori-infected patients with chronic gastritis, as compared to healthy subjects. Our microarray analysis revealed also, a high decrease of H+K+-ATPase transcripts in the presence of the H. pylori infection. Association of gastric Th1 immune response with hypochlorhydria through the down-regulation of H+K+-ATPase contributes to the genesis of lesions upon the H. pylori infection. Our data highlight that the up-regulation of IL-23 and of many IFNγ signature transcripts occur early on during the host response to H. pylori, and suggest that this type of immune response may promote the severity of the induced gastric lesions.
Murine Models of Anaemia of Inflammation: Extramedullary Haematopoiesis Represents a Species Specific Difference to Human Anaemia of Inflammation That Can Be Eliminated by Splenectomy
Authors: Schubert T.E.O. , Obermaier F. , Ugocsap P. , Männel D.N. , Echtenacher B. , Hofstädter F. , Haerle P.
Published: January 2017

In contrast to humans, mice physiologically exhibit extramedullary haematopoiesis in the spleen. In spite of this crucial species specific difference not much is known about the contribution of extramedullary haematopoiesis to overall erythropoiesis in models of anaemia of inflammation (AI). The objective of this study is to characterize murine AI with respect to extramedullary haematopoiesis and to develop a model more closely resembling human AI. Three different models of AI [caecal ligation and puncture (CLP), collagen induced arthritis (CIA) and DSS induced chronic colitis (DSSC)] were characterized with respect to red blood parameters, iron metabolism and extramedullary haematopoiesis. Arthritic animals were splenectomised to prevent extramedullary haematopoiesis. Anaemia caused by systemic inflammation was found in all three models. Splenic extramedullary haematopoiesis was markedly increased as reflected by increment in spleen weights and increase of the red pulp resulting in increased reticulocyte counts. Splenectomised arthritic animals did not show increased reticulocyte counts indicating that most of the reticulocytes were produced in the spleen. Our results demonstrate that murine AI differs from human AI with respect to increased splenic extramedullary haematopoiesis. Our data demonstrate that induction of AI in splenectomised mice represents a good way to model human AI.
Quantification of Sirolimus and Everolimus by Immunoassay Techniques: Test Specificity and Cross-Reactivity Evaluation
Authors: Pieri M. , Miraglia N. , Gentile A. , Polichetti G. , Castiglia L. , Federico S. , Sabbatini M. , Basile V. , Tarantino G. , Acampora A. , Capone D.
Published: January 2017

The possible cross-reactivity of immunoassays with structurally-related drugs was investigated. Innofluor® Certican® (FPIA) calibrators were measured by using IMx® Sirolimus assay (MEIA) and MEIA Sirolimus calibrators were analysed by using FPIA Certican® assay. Drug concentrations were measured in 95 and 100 samples from renal transplanted patients (RTP) on sirolimus or everolimus treatment by using immunoassays and LC/ESI-MSMS. A high cross-reactivity was found both for MEIA and FPIA. High correlation degrees, confirmed by the Bland-Altman and the Eksborg tests, were found between drug concentrations measured in real samples by both immunoassays (r=0.909 and r=0.970, respectively). LC/ESI-MSMS analysis of samples containing sirolimus showed no positivity for everolimus. Similarly, samples from patients on treatment with everolimus resulted negative as far as regards sirolimus. MEIA and FPIA could be considered mutually reliable and accurate alternatives for the specific-drug immunoassay. It should be noticed that in patients switching from one drug to the other unreal overestimation of the blood levels of the current administered immunosuppressant can occur.
Consequences of Long-Lasting Persistent Allergic Rhinitis in Adolescents
Authors: Marseglia G.L. , Grignani M. , Civallero P. , Colombo B. , Di Gioacchino M. , Marchi A. , Perrone A. , Ciprandi G.
Published: January 2017

While it is well known that asthma is characterized by airway remodelling, only few studies have investigated this issue in patients affected by allergic rhinitis (AR). The aim of the present study is to investigate functional and structural consequences of long-lasting persistent AR (PER) in a cohort of adolescents. Eighty patients, forty with short-lasting and forty with long-lasting PER were prospectively and consecutively evaluated both clinically and by performing skin prick test, nasal cytology, and rhinomanometry. Eosinophils were significantly higher in patients presenting with long-lasting PER rather than in those with short-lasting PER (P<.0001). The degree of inflammation was significantly associated with impaired nasal airflow (rs= −0.81). This study provides evidence that adolescents with long-lasting PER may show a progressive worsening of nasal function depending on the inflammation.
Celiac Disease in the 21st Century: Issues of Under-and Over-Diagnosis
Authors: Gasbarrini G. , Miele L. , Malandrino N. , Grieco A. , Addolorato G. , Gasbarrini A. , Cammarota G. , Bonvicini F.
Published: January 2017

Until the 1960s celiac disease (CD) or sprue was considered a pediatric disease that was rarely diagnosed in adulthood. Thanks to greater awareness of the disease and the availability of improved diagnostic tools (above all, sophisticated endoscopic techniques and the development of reliable serological markers), the prevalence of CD in Western countries has been increasing steadily, and it is now recognized as a common disorder, even in adults. However, many cases of this disease still go undiagnosed, especially among the elderly and in patients with atypical clinical presentations (which are by no means uncommon). On the other hand, the frequency of unfounded diagnoses of CD is also on the rise. This reflects a tendency toward exclusively symptomatic diagnosis as well as the growing use of invalidated tests for CD (e.g., the cytotoxic test, the sublingual or subcutaneous provocation/neutralization test, etc.). As a result, public healthcare spending is being increased in several countries (Italy included) by the growing number of prescriptions for gluten-free diets. This editorial discusses the problems of under- and over-diagnosis of CD and provides an algorithm for management of suspected cases designed to minimize both problems with particular importance to morphologic aspects of small bowel (also in electron microscopy), in basal conditions or in gluten-free diets.
The Erythromycin-Resistance in S. Pyogenes Does Not Limit the Human Polymorphonuclear Cell Antimicrobial Activity
Authors: Cuffini A.M. , Tullio V. , Banche G. , Allizond V. , Mandras N. , Roana J. , Scalas D. , Carlone N.A.
Published: January 2017

In order to highlight the potential erythromycin immunomodulatory properties related to different antibiotic resistance patterns in Streptococcus spp., we evaluated the influence of the macrolide on the PMNs primary functions against erythromycin-susceptible (Ery-S) and erythromycin-resistant (Ery-R) S. pyogenes strains. A total of 438 S. pyogenes were isolated over the period 2005–2007. On the basis of the triple disk testing, 345 out of 438 S. pyogenes isolates were Ery-S and 93 were Ery-R; among the resistant strains, 65 displayed the cMLSB phenotype, 23 had the M phenotype and 5 had iMLSB phenotype. Concerning antibacterial activity of PMNs, our results showed that erythromycin did not modify bacterial uptake, but significantly increased the phagocyte intracellular killing, compared with controls, for both Ery-S and Ery-R strains. Consequently, this report underlines that in immunocompetent hosts the dichotomy between the in vitro resistance and clinical trial data for antimicrobial agents should be thoroughly re-evaluated.
Successful Cyclosporine Treatment in a Case of Amicrobial Pustulosis Associated with Immunological Abnormalities
Authors: Frigerio E. , Ramoni S. , Franchi C. , Garutti C. , Garavaglia M. , Splnelli M. , Capsoni F. , Altomare G.F.
Published: January 2017

Amicrobial pustulosis associated with autoimmune diseases (APAD) is a clinical entity which was described only recently and few cases are reported in the literature. This condition is characterized by recurrent acute onset with pustular lesions predominantly involving skin folds, genitals, scalp and external auditory canals of young women. The etiopathogenesis of APAD is unknown and the most effective therapeutic treatment seems to be systemic corticosteroids. We describe the case of a 16-year old female patient suffering from APAD successfully treated with cyclosporine A.
Aerosol Antibiotic Therapy in Children with Chronic Upper Airway Infections: A Potential Alternative to Surgery
Authors: Macchi A. , Castelnuovo P.
Published: January 2017

Tonsillectomy and adenoidectomy remain the first choice treatment of chronic or recurrent acute infections of the upper respiratory tract in children. The aim of this study is to investigate the efficacy of the combination of thiamphenicol glycinate acetylcysteinate plus beclomethasone, administered as aerosol, in children awaiting tonsillectomy and/or adenoidectomy. The study comprised 204 children, aged 1 to 12 years, with chronic adenotonsillitis who had been listed for surgery due to obstructive symptoms and recurrent acute infections. Patients were randomized to treatment with thiamphenicol glycinate acetylcysteinate, dosage 250 mg/day in 2 administrations plus beclomethasone with a dosage of 400 μg/day in 2 administrations, or no treatment, control group, unless required. The drugs were administered by aerosol for 10 days/month over a period of 6 months. Clinical visits were at 4, 7 and 12 months after the start of treatment. The primary efficacy outcome was the reduction in the number of patients requiring surgery. Secondary efficacy measures were the reduction of nasal obstruction, the decrease in the number of infectious episodes and the tolerability of the treatment. Aerosol treatment with thiamphenicol glycinate acetylcysteinate plus beclomethasone resulted in a significantly lower proportion of patients requiring surgery (29 of 101; 29%) compared to patients in the control group (100 of 103; 97%) (p < 0.0001). Treatment was also associated with a reduction of nasal obstruction and a decrease in the number of infectious episodes. No treatment-related adverse events were reported and the aerosol therapy proved easy to administer to children. The aerosol therapy with the combination of thiamphenicol glycinate acetylcysteinate plus beclomethasone was able to prevent or postpone surgery in a substantial percentage of patients, without adverse events. These preliminary results suggest that this novel approach could play a role in the antibiotic prophylaxis of chronic infectious diseases of the upper airways.
Inflammasomes are Differentially Expressed in Cardiovascular and other Tissues
Authors: Yin Y. , Yan Y. , Jiang X. , Mai J. , Chen N.C. , Wang H. , Yang X-F.
Published: January 2017

To determine the expression of components in Toll-like receptors (TLRs)/Nod-like receptors (NLRs)/inflammasome/caspase-1/interleukin (IL-1)-β pathway, we examined the expression profiles of those genes by analyzing the data from expression sequence tag cDNA cloning and sequencing. We made several important findings: firstly, among 11 tissues examined, vascular tissues and heart express fewer types of TLRs and NLRs than immune and defense tissues including blood, lymph nodes, thymus and trachea; secondly, brain, lymph nodes and thymus do not express proinflammatory cytokines IL-1β and IL-18 constitutively, suggesting that these two cytokines need to be upregulated in the tissues; and thirdly, based on the expression data of three characterized inflammasomes (NALP1, NALP3 and IPAF inflammasome), the examined tissues can be classified into three tiers: the first tier tissues including brain, placenta, blood and thymus express inflammasome(s) in constitutive status; the second tier tissues have inflammasome(s) in nearly-ready expression status (with the requirement of upregulation of one component); the third tier tissues, like heart and bone marrow, require upregulation of at least two components in order to assemble functional inflammasomes. Our original model of three-tier expression of inflammasomes would suggest a new concept of tissue inflammation privilege, and provides an insight to the differences among tissues in initiating acute inflammation in response to stimuli.
Placenta Growth Factor is a Survival Factor for Human Malignant Mesothelioma Cells
Authors: Albonici L. , Doldo E. , Palumbo C. , Orlandi A. , Bei R. , Pompeo E. , Mineo T.C. , Modesti A. , Manzari V.
Published: January 2017

Placenta growth factor (PlGF) is a key regulator of pathological angiogenesis and its overexpression has been linked to neoplastic progression. To assess whether PlGF could have a role in malignant mesothelioma (MM), we analyzed the expression of PlGF, VEGF, and their cognate receptors (VEGF-R1 and VEGF-R2) and co-receptors (neuropilin-1 and neuropilin-2) in MM cell lines as well as in resected MM tissues, hyperplastic/reactive mesothelium and normal mesothelium. MM cell cultures expressed both ligands and the associated receptors to a variable extent and released different amounts of PlGF. As assessed by immunohistochemistry, PlGF expression was switched on in hyperplastic/reactive compared to normal mesothelium. Moreover, 74 and 94% of MM tissues overexpressed PlGF and VEGF-R1, respectively ( p<0.05 MM vs normal mesothelium). Administration of recombinant PlGF-2 did not elicit a significant stimulation of MM cell growth, while it was associated with a transient phosphorylation of Akt, suggesting that PlGF-2 could activate downstream effectors of proliferative and cytoprotective signals via VEGF-R1 in MM cells. Indeed, the administration of an anti-PlGF antibody was found to cause a significant reduction of MM cell survival. In conclusion, our data demonstrate that, by acting as a survival factor, PlGF can play a role which goes beyond the stimulation of angiogenesis in MM. This evidence could help the rational design of new therapeutic interventions for this aggressive tumor.
The Role of Interleukin-6 and Transforming Growth Factor-β1 in Predicting Restenosis within Stented Infarct-Related Artery
Authors: Szkodzinski J. , Blazelonis A. , Wilczek K. , Hudzik B. , Romanowski W. , Gasior M. , Wojnar R. , Lekston A. , Polonski L. , Zubelewicz-Szkodzinska B.
Published: January 2017

Despite high efficacy of percutaneous coronary intervention (PCI), in-stent restenosis proves to be a significant problem of therapy. Restenosis concerns around 30% of patients. Studies have suggested that restenosis is initiated by cells which participate in intense inflammatory reaction caused by stent implantation. Atherosclerotic plaque rupture during stent implantation and PCI-associated injury of the vessel wall lead to hemorrhage and release of various cytokines. They are probably responsible for quick recurrence of vascular lumen stenosis (restenosis). Interleukin-6 (IL-6) is known as a main pro-inflammatory cytokine, whereas Transformig Growth Factor-β1 (TGF-β1) has anti-inflammatory properties. The study population comprised 36 patients with myocardial infarction treated with PCI with stent implantation. They underwent control coronary angiography after 12 months. At this time plasma concentration of IL-6 and TGF-β was measured in peripheral blood. Serum IL-6 concentration in the analyzed population correlates with lumen loss (p<0.01) and the severity of stenosis (p<0.001). No such correlation was found between serum TGF-β1 concentration and lumen loss (p=NS) or the severity of stenosis (p=NS). The IL-6 plasma concentration may be a marker of in-stent restenosis in patients after PTCA, while the concentration of TGF-β1 is not associated with the occurrence of restenosis at one year of follow-up.
Thalidomide Prevents Formation of Multinucleated Giant Cells (Langhans-Type Cells) from Cultured Monocytes: Possible Pharmaceutical Applications for Granulomatous Disorders
Authors: Yasui K. , Yashiro M. , Nagaoka Y. , Manki A. , Wada T. , Tsuge M. , Kondo Y. , Morishima T.
Published: January 2017

Thalidomide is an effective drug for chronic inflammatory diseases, but the mechanism underlying its immunomodulatory action remains uncertain. Thalidomide has been reported to clinically improve chronic inflammatory granulomatous disorders. In such disorders, the granulomas consist of epithelioid cells, scattered lymphocytes and multinucleated giant cells (MNGC; Langhans-type cells). The present experimental approach permitted the reproduction of MNGC formation from peripheral blood monocytes and examination of thalidomide's effect on it. MNGC can be effectively generated from monocytes cultured in the presence of interleukin-4 (IL-4) and macrophage colony-stimulating factor (M-CSF) for 14 days. Thalidomide can inhibit the formation of MNGC in a dose-dependent manner. MNGC formation was partly inhibited by the presence of neutralizing TNF-α antibody in the responses induced by IL-4 and M-CSF. Autocrinal TNF-α production and modulation of cadhelin expression to regulate cell adhesion might be involved in this inhibitory action of thalidomide. Our results support thalidomide's clinical efficacy in the treatment of chronic granulomatous disorders (granulomatosis).
Role of the Netrin System of Repellent Factors on Synovial Fibroblasts in Rheumatoid Arthritis and Osteoarthritis
Authors: Schubert T. , Denk A. , Mägdefrau U. , Kaufmann S. , Bastone P. , Lowin T. , Schedel J. , Bosserhoff A-K.
Published: January 2017

Changes in the expression of repellent factors, i.e., Netrins and their receptors, may be responsible for the invasive behavior of the synovial tissue cells in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). This study was carried out to analyze the expression of Netrins and their receptors in synovial cells of patients with RA, OA, and control subjects without synovial inflammation. Quantitative RT-PCR was performed to measure the expression of Netrin-1, −3, −4, Neogenin, DCC, UNC5A-D. The influence of Netrin-1 on synovial fibroblasts (SF) was analyzed by determining proliferation, migration, and their ability to organize collagen. SF expressed all repellent factors of the Netrin family. When comparing SF of healthy donors to patients with RA and OA, a stronger expression of UNC5B (4 fold) and UNC5C (769 fold) in RA and OA was found, whereas expression of the other molecules revealed no significant differences. Treating the SF-cells with recombinant Netrin-1 resulted in inhibition of migration of RA- and OA-SFs whereas control cells were not affected. The stronger expression of UNC5B and UNC5C receptors might contribute to the disordered phenotype of RA- and OA-SFs. Addition of Netrin-1 reduces the migratory ability of SFs, potentially by repulsion, as seen in neuronal cells in embryonic development. Due to its function, Netrin-1 may constitute a novel target in the treatment of OA and RA.
No Association between Polymorphisms in Cubilin, a Gene of the Homocysteine Metabolism and the Risk of Non-Syndromic Cleft Lip with or without Cleft Palate
Authors: Martinelli M. , Carinci F. , Morselli P.G. , Palmieri A. , Girardi A. , Riberti C. , Scapoli L.
Published: January 2017

Epidemiological studies have correlated lower maternal periconceptional levels of plasma folate and cobalamin with increased risk of delivering offspring presenting congenital malformations such as cleft lip with or without cleft palate (CL/P) or neural tube defects. A number of genetic studies aimed at correlating these biochemical levels or the occurrence of malformations with specific genetic defects or polymorphisms have been successfully performed. The cubilin gene (CUBN) codes for a carrier that plays a crucial role in cobalamin cell internalization. CUBN polymorphisms were previously found to be associated with spina bifida occurrence. In this work, a family-based association study was performed to test CUBN involvement in CL/P. A sample of 391 CL/P triads was investigated with three single nucleotide polymorphisms mapping on the cubilin gene. Association tests indicated no significant association between CL/P and marker alleles or marker haplotypes. No evidence of maternal effect and imprinting were obtained. These data suggest that CUBN is not involved in CL/P onset in the investigated Italian population.
Evidence of LEF1 Fetal-Maternal Interaction in Cleft Lip with or without Cleft Palate in a Consistent Italian Sample Study
Authors: Martinelli M. , Carinci F. , Morselli P.G. , Caramelli E. , Palmieri A. , Girardi A. , Riberti C. , Scapoli L.
Published: January 2017

Epithelial mesenchymal transformation is considered a cardinal process in orofacial development. Several molecular players appear to be involved in this delicate mechanism; the activation of LEF1 transcription factor by transforming growth factor beta 3 seems to be a key step for the correct flow of events. The failure of orofacial processes during embryonic development may provoke cleft lip and/or cleft palate malformations. The scope of the present investigation was to verify whether genetic variants at LEF1 could influence the risk of orofacial clefting. The approach was a family based association study involving a total of 512 Italian patients and their parents, 401 having cleft lip with or without cleft palate (CL/P) and 111 with cleft palate only (CPO). Haplotype association analysis provided moderate evidence of an association with clefting (p 0.01). A log-linear likelihood-based method was used to verify maternal and foetal-maternal association. An association between the maternal genotype and the occurrence of CL/P was observed at two polymorphic loci, at rs10022956 (P = 0.0049) and rs10025431 (P = 0.0065) respectively, while a foetal-maternal effect modulating the risk of clefting was found at locus rs10025431 (P = 0.0071). These data further corroborate the importance of the mother's genotype with regard to susceptibility to malformations and early-onset diseases.
Histomorphic-Metric Evaluation of an Implant Retrieved from Human Maxilla after 13 Years
Authors: Traini T. , Danza M. , Altavilla R. , Zollino I. , Lucchese A. , Sollazzo V. , Trapella G. , Brunelli G. , Carinci F.
Published: January 2017

Fixture fracture is the most catastrophic failure of implant components because it usually causes the loss of the implant. Nevertheless, the osseointegrated fractured implants represent a very useful opportunity to study in humans the effects of loading to the peri-implant bone microstructure. The aim of the present study was to evaluate the interplay between microstructure and function of the bone around an implant retrieved from human maxilla after 13 years. There was 1 fractured Dental Implant Line (sand blasted surface from a patient placed in the anterior region of the maxillary bone (2.1) after a bone augmentation procedure, and it was processed for histology. The specimen was analyzed under the scanning electron microscope (SEM), the confocal scanning laser microscope (CSLM) and brightfield light microscope (LM) equipped with circularly polarized light (CPL). The BIC rate of the implant retrieved after 13 years was (mean ±SD) 68.7 ± 3.7. The crestal bone down the implant platform damage appeared to be under modeling process. The transverse collagen fiber orientation (CFO) (mean ±SD) under the lower flank of the threads was 20.4 ± 3.5 × 104 pixel while the longitudinal CFO was 19.8 ± 2.8 × 104 pixel (P>.05). In the inter-threads region the transverse CFO (mean ±SD) was 15.0 ± 4.0 × 104 pixel while the longitudinal CFO was 21.4 ± 3.0 × 104 pixel (P>.05). The osteocytes numbers (mean ±SD) was 130 ± 34. Under SEM with back scattered electrons (BSE) signal the peri-implant bone appears mainly lamellar and highly mature with several osteons organized in the implant inter-threads areas. The fracture of the implant was most probably correlated to a fatigue of the material mainly associated to a damage of the internal coil. Surprisingly, it was noted a lack of implant site-specific CFO of the bone extracellular matrix facing the threaded dental implant notwithstanding the high level of BIC rate.
Reciprocal Altered Expression of E-Cadherin and P-Cadherin in Mucous Membrane Pemphigoid
Authors: Santarelli A. , Di Fede O. , Carinci F. , Rubini C. , Ganzetti G. , Perrone D. , Simonetti O. , Offidani A. , Re M. , Perrone D. , Pannone G. , Lo Muzio L.
Published: January 2017

E- and P- cadherins are involved in the selective adhesion of epidermal cells. To gain insight into the role of cadherins on the acantholysis of keratinocytes and further investigate the pathogenesis of Mucous Membrane Pemphigoid, we examined the expression of P-cadherin and E-cadherin, in normal human oral mucosa, lesional and peri-lesional mucosa in MMP. Twenty-nine samples from paraffin-embedded specimens of MMP were used for the study. Five specimens of healthy oral mucosa were evaluated as control group. To evaluate the E- and P-Cadherin expression, a mean percentage of positive cells was determined from the percentage of positive cells derived from the analysis of 100 cells in ten random areas at x400 magnification. It was observed that E-cadherin was weakly and discontinuously expressed on the epithelial layers of pemphigoid mucosa, while it was intensively expressed on all keratinocytes in normal human skin. In contrast, P-cadherin was strongly expressed throughout the entire epidermal layer in MMP samples, although its expression is restricted to the basal cell layer in normal human skin. Statistical analyses showed that the percentage of E-cadherin positive cells in the epithelium of pemphigoid cases was significantly decreased compared with that in normal human mucosa. There was a significant increase in the percentage of P-cadherin positive cells in the epithelial layers of MMP compared with normal human mucosa. The present study showed that there is downregulation of E-cadherin expression and upregulation of P-cadherin expression in MMP mucosa, which may be involved in the pathogenesis of MMP.