bluuebunny/crossref_metadata_2025 huggingface dataset:
Soluble Interleukin-2 Receptor as an Indicator of Immunological Disturbance Found in Silicosis Patients
Authors: Hayashi H. , Maeda M. , Murakami S. , Kumagai N. , Chen Y. , Hatayama T. , Katoh M. , Miyahara N. , Yamamoto S. , Yoshida Y. , Nishimura Y. , Kusaka M. , Fujimoto W. , Otsuki T.
Published: January 2017

Silicosis patients (SILs) possess not only respiratory disorders but also alterations in autoimmunity. To determine an early indicator of immunological disturbance in SILs, the role of serum-soluble interleukin (IL)-2 receptor (sIL-2R) was analyzed. Of ten SILs, immunological clinical parameters such as immunoglobulin (Ig) G, complements, the titer of autoantibodies including anti-nuclear antibodies (ANA), anti-Scl-70 antibody (Ab) and anti-centromere (CM) Ab, and experimental indicators such as serum-soluble Fas, serum IL-2, CD25+ cells in CD4+ or CD8+ fractions, and sIL-2R were divided from respiratory parameters such as % vital capacity (%VC), percentage of forced expiratory volume in 1 second (FEV1.0%) and v25/Ht (liter/second/m(body height) by a correlation assay. Additionally, a stepwise regression test showed that sIL-2R was correlated with Ig G, ANA and anti-CM Ab. Furthermore, factor analysis revealed that sIL-2R contributed to the subpopulation of SILs with poorer immunological status in the absence of alterations in respiratory status. By defining healthy donors as 1, SILs as 2 and patients with systemic sclerosis as 3 for immunopathological progression status as metric variables, sIL2R and ANA showed a strong positive correlation. This suggests that sIL-2R is a good clinical indicator of immunological disturbance found in SILs without clinical manifestations of any disturbance in autoimmunity. Further analysis using a large-scale number of patients should be performed to confirm these findings.
In Vitro Evaluation of the Efficacy of a New Laser Surface Implant: Cellular Adhesion and Alkaline Phosphatase Production Tests
Authors: Berardi D. , De Benedittis S. , Polimeni A. , Malagola C. , Cassinelli C. , Perfetti G.
Published: January 2017

Bone tissue reacts in different ways to implant surfaces with different patterns. The aim of this study is to understand which laser generated surface pattern produces the best cell adhesion in vitro, evaluating both the activity of the alkaline phosphatase and the cells adhering to titanium samples. Tests were carried out on titanium samples with sandblasted surfaces with laser-produced holes with diameters of 5, 10, and 20 μm, and on sandblasted titanium cylinders without holes as controls. The samples were inserted into culture medium containing SaOS-2 cells for 3, 7 and 10 days. The results showed that at days 3 and 7 the laser surfaces stimulated a higher production of alkaline phosphatase (ALP) compared to the data from the control group. At day 10 there were no significant differences between the test group and the control group.
Plant-Derived Recombinant Fl, V, and F1-V Fusion Antigens of Yersinia Pestis Activate Human Cells of the Innate and Adaptive Immune System
Authors: Del Prete G. , Santi L. , Andrianaivoarimanana V. , Amedei A. , Domarle O. , D'Elios M.M. , Arntzen C.J. , Rahalison L. , Mason H.S.
Published: January 2017

Plague is still endemic in different regions of the world. Current vaccines raise concern for their side effects and limited protection, highlighting the need for an efficacious and rapidly producible vaccine. F1 and V antigens of Yersinia pestis, and F1-V fusion protein produced in Nicotiana benthamiana administered to guinea pigs resulted in immunity and protection against an aerosol challenge of virulent Y. pestis. We examined the effects of plant-derived F1, V, and F1-V on human cells of the innate immunity. F1, V, and F1-V proteins engaged TLR2 signalling and activated IL-6 and CXCL-8 production by monocytes, without affecting the expression of TNF-α, IL-12, IL-10, IL-1β, and CXCL10. Native F1 antigen and recombinant plant-derived F1 (rF1) and rF1-V all induced similar specific T-cell responses, as shown by their recognition by T-cells from subjects who recovered from Y. pestis infection. Native F1 and rF1 were equally well recognized by serum antibodies of Y. pestis-primed donors, whereas serological reactivity to rF1-V hybrid was lower, and that to rV was virtually absent. In conclusion, plant-derived F1, V, and F1-V antigens are weakly reactogenic for human monocytes and elicit cell-mediated and humoral responses similar to those raised by Y. pestis infection.
Effect of SP3 Silencing on Cytokeratin Expression Pattern in HPV-Positive Cells
Authors: Lucchese A. , Serpico R.
Published: January 2017

In an attempt to understand the molecular factors underlying squamous cell carcinogenesis in HPV-infected oral and cervical tissues, we examined the Sp3-dependent cytokeratin expression in HPV-positive CaSki cells. Two sets of cytokeratins were examined: the simple epithelial CK 7, 8, 18, 19, and 20, which are generally expressed in simple epithelia and CK4, 10, 13, and 17, which are expressed in squamous epithelia. Two additional CK pairs, i.e. CK6/CK16 and CK4/CK13 were analyzed as controls of the proliferation/differentiation cell status, respectively. We report that Sp3 gene silencing specifically hits CK18 and CK19, which are markers of oral and cervical squamous tumors. These data may be of help in immunopathological definition of squamous carcinogenesis.
Vaccination with Trichinella Spirallis Antigens Increases CD8+ Peripheral T Cells and Enhances the TH2 Immune Response in Leishmania Infantum Challenged MICE
Authors: Daoudaki M. , Diakou A. , Frydas S. , Fouzas I. , Karagounp E. , Vavatsi N. , Haralabidis S.
Published: January 2017

In this study we investigate the effect of Trichinella spiralis vaccination on immune responses elicited in BALB/c mice challenged subcutaneously with 0.5 ×106 of Leishmania infantum promastigotes. Secretion of specific anti- L. infantum antibodies and changes in the number of CD4+, CD8+ T cell and CD19+ B cells in the peripheral blood were tested for the evaluation of immune responses. Immunization with low amounts of T. spiralis antigens induced depression in anti- Leishmania specific antibodies of the IgG1 isotype, while no changes in the number of CD4+ and CD8+ T cell subpopulations or CD19+ B cells were observed. In contrast, high amounts of T. spiralis antigens induced an enhancement in anti- Leishmania specific antibodies of total IgG and IgGl isotype, increase of CD8+ T cell number and activation of CD19+ B cells, indicated by the co-expression of CD69 marker. Our results suggest that immunization with a certain dose of T. spiralis antigens in experimentally challenged mice with L. infantum leads to an increase of peripheral CD8+ T cells which are responsible for the control of L. infantum infection, although a simultaneous enhancement in Th2-type of immune response is also observed.
Expression of Internalin a and Biofilm Formation among Listeria Monocytogenes Clinical Isolates
Authors: Franciosa G. , Maugliani A. , Scalfaro C. , Floridi F. , Aureli P.
Published: January 2017

Internalin A (InlA), a cell wall-bound protein of Listeria monocytogenes, is among the major components involved in the adhesion to and invasion of host cells expressing specific forms of E-cadherin. Some L. monocytogenes strains secrete truncated non-functional forms of InlA. The purpose of this study is to compare the biofilm-forming abilities of L. monocytogenes strains from clinical sources expressing InlA proteins in the different forms. A total of 70 L. monocytogenes strains were examined using SDS-PAGE, Western blot, DNA sequencing, and microtitre plate biofilm formation assays. We found that 8 of the 70 strains expressed truncated InlA, and that this group of strains exhibited significantly enhanced biofilm-forming ability compared to the group expressing full-length InlA. Further experiments showed that: (i) L. monocytogenes biofilms were detached by treatment with protease K; (ii) protein fragments resulting from proteolysis, rather than intact proteins, are responsible for biofilm enhancement, because biofilm formation was impaired by the protease inhibitor a2-macroglobulin; (iii) truncated and/or proteolytically cleaved InlA are likely involved in the biofilm enhancement, based on the effects that anti-InlA monoclonal antibodies produced on the biofilm formation of L. monocytogenes strains expressing either truncated or full-length InlA. These data provide a basis for further investigation of the molecular structure and composition of L. monocytogenes biofilms.
Analysis of Memory and Effector CD8+ T Cell Subsets in Chronic Graft-versus-Host Disease
Authors: D'Asaro M. , Salerno A. , Dieli F. , Caccamo N.
Published: January 2017

In humans, the selective depletion of CD8+ cells may prevent GVHD after allogeneic transplantation. These cells can infiltrate and damage target tissues. It is of interest to investigate the phenotypical characteristics and cytotoxic properties of the different CD8+ subsets in cGVHD patients. In a preliminary study we found that patients with cGVHD had a markedly elevated percentage of peripheral blood CCR7−/CD45RA+ cells compared to patients without cGVHD; conversely, the CCR7+/CD45RA+ subsets of CD8+ cells was significantly decreased. In this study, we report in depth on the phenotype of effector T cell subsets in cGVHD patients, as well as their proliferative capability, cytotoxic properties and cellular turnover. We confirm a predominance of effector T cell subsets in cGVHD patients and show that a large fraction of these cells down-regulate CCR7 and re-express CD45RA, thus approaching end-stage differentiation. Moreover CD8+ cells of cGVHD patients have low CD8 coreceptor expression, reduced proliferative potential and a high content of perforin and granzyme A. They also have a lower cell turnover and have more propensity to apoptosis, as demonstrated by BrdU incorporation. Taken together, our findings indicate a perturbation of the balance between naive/memory and effector/CD45RA+ CD8+ T cells, and suggest an involvement of the latter compartment characterized by a high content of cytotoxic equipment, in the pathogenesis of cGVHD.
Duodenal Intraepithelial Lymphocytes of Children with Cow Milk Allergy Preferentially Bind the Glycan-Binding Protein Galectin-3
Authors: Mercer N. , Guzman L. , Rua E. Cueto , Drut R. , Ahmed H. , Vasta G.R. , Toscano M.A. , Rabinovich G.A. , Docena G.H.
Published: January 2017

A breakdown in intestinal homeostasis results in inflammatory bowel diseases including coeliac disease and allergy. Galectins, evolutionarily conserved β-galactoside-binding proteins, can modulate immune-epithelial cell interactions by influencing immune cell fate and cytokine secretion. In this study we investigated the ‘glycosylation signature’ as well as the regulated expression of galectin-1 and −3 in human duodenal samples of allergic and non-allergic children. Whereas galectin-1 was predominantly localized in the epithelial compartment (epithelial cells and intraepithelial lymphocytes) and the underlying lamina propria (T cells, macrophages and plasma cells), galectin-3 was mainly expressed by crypt epithelial cells and macrophages in the lamina propria. Remarkably, expression of these galectins was not significantly altered in allergic versus non-allergic patients. Investigation of the glycophenotype of the duodenal inflammatory microenvironment revealed substantial α2–6-linked sialic acid bound to galactose in lamina propria plasma cells, macrophages and intraepithelial lymphocytes and significant levels of asialo core 1 O-glycans in CD68+ macrophages and enterocytes. Galectin-1 preferentially bound to neutrophils, plasma cells and enterocytes, while galectin-3 binding sites were mainly distributed on macrophages and intraepithelial lymphocytes. Notably, galectin-3, but not galectin-1 binding, was substantially increased in intraepithelial gut lymphocytes of allergic patients compared to non-allergic subjects, suggesting a potential role of galectin-3-glycan interactions in shaping epithelial-immune cell connections during allergic inflammatory processes.
A Multicenter Open-Label Experience on the Response of Psoriasis to Adalimumab and Effect of Dose Escalation in Non-Responders: The Aphrodite Project
Authors: Vena G.A. , Galluccio A. , De Simone C. , Mastrandrea V. , Buquicchio R. , La Greca S. , Dattola S. , Guerra A. Puglisi , Donato L. , Cantoresi F. , De Pità O. , Pezza M. , D'Agostino M. , Vernaci R. , Miracapillo A. , Valenti G. , Cassano N.
Published: January 2017

There is much evidence to show the efficacy of adalimumab, a human monoclonal antibody targeting tumour necrosis factor-alpha, in the treatment of plaque psoriasis. In this open-label experience, 147 high-need patients suffering from plaque psoriasis, with a mean Psoriasis Area and Severity Index (PASI) of 18.8, and concomitant psoriatic arthritis (PsA) received subcutaneous injections of 40 mg of adalimumab every other week (EOW). This was actually the dosage regimen recommended for PsA, as the drug had not then been approved for psoriasis at the time of the patients' enrolment. At week 12, an improvement of at least 50% of the PASI (PASI-50) was observed in 111 (77%) patients. Continuation of treatment in responders with adalimumab 40 mg EOW led to a sustained response, with the PASI-50 achieved by 97% of patients in the as-treated analysis at week 24 (PASI-75 in 82% and PASI-90 in 45% out of 109 patients who received EOW injections up to week 24). Thirty subjects who failed to attain the PASI-50 response at week 12 were treated with adalimumab 40 mg every week for a further 12 weeks. At week 24, 80% of these patients obtained a PASI-50 response after dose escalation. Tolerability was good in the majority of patients. Only two patients discontinued treatment because of an adverse event (repeated flu-like episodes and a pleuropericarditis of unknown origin, respectively).
Specific Immunotherapy for Allergic Rhinitis in Italy: The Patients' Points of View
Authors: Larosa M. , Ciprandi G. , Tesi C.F. , Cadario G. , Fiocchi A. , Frati F. , Romano A.
Published: January 2017

Specific immunotherapy (SIT) is the unique causal treatment for allergy, but its use is quite limited. A perspective, cross-sectional telephone interview survey was carried out in Italy to evaluate the characteristics of 500 patients with allergic rhinitis (250 of whom treated with SIT). Relevant differences were found concerning therapeutic management of allergic rhinitis, mainly regarding the use of drugs and co-morbidities. The allergist is the most important consultant who prescribes SIT. This study therefore provides evidence that the course of allergic rhinitis may depend on the therapy prescribed by and the level of allergy awareness of the physician.
Specific Immunotherapy for Allergic Rhinitis in Italy: The Doctors' Points of View
Authors: Larosa M. , Ciprandi G. , Tesi C.F. , Cadario G. , Fiocchi A. , Frati F. , Romano A.
Published: January 2017

Specific immunotherapy (SIT) is the unique causal treatment for allergy, but its prescription is quite restricted. A perspective and cross-sectional survey based on telephone interviews was carried out in Italy to evaluate the profile of doctors prescribing SIT for allergic rhinitis. A total of 540 doctors were interviewed, 200 of whom are GPs, 60 allergists, 60 ENT specialists, 100 familial paediatricians, 60 hospital paediatricians and 60 pulmonologists. Significant differences concern diagnostic and therapeutic management of allergic rhinitis, mainly regarding SIT prescription. The allergist is the most important consultant who prescribes SIT, as opposed to the paediatrician. This study therefore provides the evidence that doctors' behaviour towards SIT depends on the type of graduate studies.
Chronic Lymphocytic Leukemia-Associated Pure Red Cell Aplasia
Authors: D'Arena G. , Cascavilla N.
Published: January 2017

Pure red cell aplasia (PRCA) is a well-known marrow failure which may be acquired or constitutional/congenital, as the Diamond-Blackfan syndrome. Acquired PRCA may show as a primary hematological disorder or secondary to an associated disease, infection or drug. PRCA rarely complicates chronic lymphocytic leukemia (CLL), may occur anytime in the course of the disease and, in this context, it is a minority of total PRCA. Anemia due to PRCA in CLL patients must be carefully evaluated and differentiated from other causes (autoimmune hemolytic anemia, neoplastic lymphocyte infiltration of bone marrow, chemotherapy) that require a different therapeutic approach. PRCA is thought to be an immunologically mediated disorder, but there is no uniformity in the setting of the management. Immunosuppressive therapy is frequently given, such as steroids and cyclosporin-A. Recently, anecdotal cases have been published on the effectiveness of monoclonal antibodies rituximab and alemtuzumab.
Effects of Rich-in-Fat Diets and Highly Selective COX-2 Inhibitors on 7,12-Dimethylbenz-(A)-Anthracene-Induced Tumor Growth
Authors: Miliaras S. , Anogeianaki A. , Meditskou S. , Kefala V. , Koutsonikolas D. , Liangouris J. , Anogianakis G. , Miliaras D.
Published: January 2017

The effects of diet, of non-steroidal anti-inflammatory drugs, or of their combination on carcinogenesis continue to be a case for controversy. Diets that are high in fat have been linked to increased risk of various tumors. At the same time there is substantial, but not conclusive, evidence that the risk of breast and colon cancer correlates with total fat intake rather than a specific type of fat. On the other hand, non-steroidal anti-inflammatory drugs (NSAIDs) have been studied extensively because they appear to delay or inhibit the development of malignant and pre-malignant lesions. 7,12-Dimethylbenz-(a)-anthracene (DMBA) has been used for a long time to induce carcinogenesis in a number of rat animal models. The present study attempts to identify the effects on DMBA-induced tumor growth (a) of diets rich in fat and (b) of the highly selective COX-2 inhibitor Celecoxib, which has been claimed to offer substantial protection against carcinogenesis.
Two Weeks of Permanence in Negatively-Charged Air Conditions Causes Alteration of Natural Killer Cell Function
Authors: Takahashi K. , Otsuki T. , Mase A. , Kawado T. , Kotani M. , Nishimura Y. , Maeda M. , Murakami S. , Kumagai N. , Hayashi H. , Chen Y. , Shirahama T. , Miura Y. , Morimoto K.
Published: January 2017

The effects of negatively-charged air conditions were analyzed as one of the approaches to improve health and quality of life. We previously reported that the use of a charcoal coating and application of an electric voltage yielded predominantly negatively-charged particles in an experimental room, and that 2.5 hours of living in these conditions caused a slight activation of the immune system (slight elevation of serum interleukin (IL)-2), regulated blood flow, and stabilized the autonomic nervous system when compared with control conditions (no dominance of negatively-charged particles). In this study, we expanded the previous study and placed 15 subjects in negatively-charged air conditions for two weeks during the night and analyzed various biological parameters. Although individual biological reactions differed from subject to subject, natural killer (NK) cell activity increased significantly following living in negatively-charged air conditions. Taken together, the results of the previous investigation and those of this study show that repeated elevation of IL-2 (although it immediately returned to the baseline level) causes chronic and recurrent stimulation to NK cells and results in the steady activation of NK cells. Negatively-charged air particles may be a good tool to improve health and quality of life.
Reciprocal Modulation of Circulating CD4+CD25+bright T Cells Induced by Extracorporeal Photochemotherapy in Cutaneous T-Cell Lymphoma and Chronic GRAFT- Versus-Host-Disease Patients
Authors: Quaglino P. , Comessatti A. , Ponti R. , Peroni A. , Mola F. , Fierro M.T. , Savoia P. , Novelli M. , Bernengo M.G.
Published: January 2017

The mechanisms of action of extracorporeal photochemotherapy (ECP) in cutaneous T-cell lymphoma (CTCL) are poorly understood. Recently, ECP has been shown to induce an increase in regulatory T cell (Treg) expression and functional activities in Graft-versus-host-disease (GvHD), whereas no data are available in CTCL patients. The aim of this study is to evaluate whether ECP is able to modulate the expression levels of the circulating CD4+CD25+bright subset in CTCL patients and whether these modifications are related to the disease course. The patient population included 43 CTCL and 15 chronic GvHD patients treated by ECP at our institutions since 1992. The expression of the circulating CD4+CD25+bright subset was analysed at baseline and sequentially during treatment by flow-cytometry. Fifty healthy donors were used as controls. The baseline circulating CD4+CD25+bright percentage values in CTCL (median: 4.3%) were similar to those of healthy donors, whereas GvHD showed significantly lower values (median: 1.5%; p<0.001). During treatment, CTCL patients were characterised by an early decrease (from 4.3% to 2.4% median after 6 months). The CD4+CD25+bright decrease was associated to the disease course, as it occurred in 91.3% of responding but in only 25% of PD patients (p=0.0001). On the other hand, a significant increase of CD4+CD25+bright cells was observed in GvHD. ECP induces a reciprocal modulation of the circulating CD4+CD25+bright cells in CTCL and GvHD, with a downregulation in CTCL potentially associated with the response mechanisms.
Angiogenesis in Psoriatic Skin and its Modifications after Administration of Etanercept: Videocapillaroscopic, Histological and Immunohistochemical Evaluation
Authors: Campanati A. , Goteri G. , Simonetti O. , Ganzetti G. , Giuliodori K. , Giuliano A. , Sabato S. , Stramazzotti D. , Gulini E. , Dusi D. , De Blasio S. , Fabris G. , Offidani A.
Published: January 2017

Several studies suggest that microangiopathy plays a crucial role in the pathogenesis of psoriasis. TNF-alpha up-regulates the genetic transcription of VEGF, a pro-angiogenetic cytokine over-expressed in psoriatic skin, which promotes micrangiopathic modifications in psoriatic plaque. Etanercept is a chimeric protein used in the treatment of psoriasis and other immunomediated disorders, which blocks inflammatory response by interfering in the binding of TNF-alpha to its receptors. Starting from this data, we retain that Etanercept can improve microangiopathy in psoriatic skin by reducing the synthesis of pro-angiogenetic chemokine VEGF. The aims of the study are: to verify the effect of Etanercept on cutaneous en plaque capillaries in vivo using intra-vital videocapillaroscopy analysis, to evaluate the relation between the en plaque videocapillaroscopic pattern and the immunohistochemical cutaneous expression of VEGF in psoriasis, and finally to correlate all these in data with clinical disease activity. Eighteen patients (10 male and 8 female, mean age 51, range 21–60) suffering from stable, en plaque type psoriasis, involving at least 10% of body surface area (BSA), and not responsive to conventional therapy were included in the study. All the enrolled patients received Etanercept 50mg/twice/week, subcutaneously, for 12 weeks, and were carefully followed up for clinical response with PASI score and DLQI index both before (T0) and after 12 weeks (T12) of treatment with Etanercept. A well-demarcated psoriatic plaque of the extensor surface of upper extremities was chosen to perform an intra-vital videocapillaroscopy analysis (IVCP), and a skin biopsy for immunohistochemical study both at T0 and T12in all the included patients, in order to evaluate the presence of microangiopathy and its modification after therapy. All the patients experienced a clinical improvement of cutaneous disease with a significant decrease of PASI score (p0.0001) and DLQI level (p0.0001), throughout the twelve weeks of treatment. On IVCP analysis, microangiopathy dramatically decreased (p0.0001), this modification being significantly related with PASI and DLQI decrease at T12. Immunohistochemical expression of VEGF decreased significantly from T0 to T12 (p0.0001), and was related with a reduction of psoriatic microangiopathy at T12. The results of our videocapillaroscopic and immunohistochemical investigation confirm that the therapeutic potentiality of Etanercept is based also on its capability to promote the regression of psoriatic microangiopathy. Moreover, according to these considerations, videocapillaroscopic evaluation of psoriatic plaque, both before and after treatment with Etancercept, may be a useful tool to objectively demonstrate its effect on microcirculation.
Functional Characterization of Muscle Fibres from Patients with Chronic Fatigue Syndrome: Case-Control Study
Authors: Pietrangelo T. , Toniolo L. , Paoli A. , Fulle S. , Puglielli C. , Fano G. , Reggiani C.
Published: January 2017

Chronic fatigue syndrome (CFS) is a disabling condition characterized by unexplained chronic fatigue that impairs normal activities. Although immunological and psychological aspects are present, symptoms related to skeletal muscles, such as muscle soreness, fatigability and increased lactate accumulation, are prominent in CFS patients. In this case-control study, the phenotype of the same biopsy samples was analyzed by determining i) fibre-type proportion using myosin isoforms as fibre type molecular marker and gel electrophoresis as a tool to separate and quantify myosin isoforms, and ii) contractile properties of manually dissected, chemically made permeable and calcium-activated single muscle fibres. The results showed that fibre-type proportion was significantly altered in CSF samples, which showed a shift from the slow- to the fast-twitch phenotype. Cross sectional area, force, maximum shortening velocity and calcium sensitivity were not significantly changed in single muscle fibres from CSF samples. Thus, the contractile properties of muscle fibres were preserved but their proportion was changed, with an increase in the more fatigue-prone, energetically expensive fast fibre type. Taken together, these results support the view that muscle tissue is directly involved in the pathogenesis of CSF and it might contribute to the early onset of fatigue typical of the skeletal muscles of CFS patients.
Antibodies to Ganglioside Complexes in Guillain-Barré Syndrome: Clinical Correlates, Fine Specificity and Complement Activation
Authors: Notturno F. , Luciani M. , Caporale C.M. , Ciarelli A. , Uncini A.
Published: January 2017

In the Schwann cells and neuronal plasma membranes the gangliosides are organized in clusters forming complexes of gangliosides in the microdomains termed lipid rafts. We investigated frequency, clinical correlates, fine specificity and pro-inflammatory properties of antibodies to ganglioside complexes (GSCs) in a Guillain Barré syndrome (GBS) population. In 63 patients with different GBS variants we performed an ELISA for antibodies to Campylobacter Jejuni ( C. jejuni), gangliosides and GSCs. We studied the fine specificity of antibodies to GSCs by immunoabsorption study and performed a complement activation assay. Twenty-seven percent of patients had antibodies to GSCs and 71% had antibodies either to single gangliosides or to GSCs. Patients with antibodies to GSCs had more frequent involvement of cranial nerves but did not present more frequent antecedent respiratory, gastrointestinal or C. jejuni infection, did not have a preferential demyelinating or primary axonal GBS variant and did not develop greater disability at six months. The absorption study showed in 2 sera that antibodies to the complex GD1a/GD1b did not react with the gangliosides forming the complex or other single gangliosides, suggesting that antibodies to GSCs are targeted to new conformational glycoepitopes different from the ones displayed by the single gangliosides. Antibody anti-GSCs activated the complement more frequently than antibodies to single gangliosides. Complement activation indicates that antibodies to GSCs have high avidity, pro-inflammatory properties and may exert a pathogenic role in GBS.
The Transplant of the White Man's Leg: A Novel Representation of Cosma and Damian's Miracle
Authors: Lippi D.
Published: January 2017

The history of the miracle performed by the patron saints of medicine Cosma and Damian is well known: physicians and historians have dealt with this subject on many occasions, giving rise to a large range of literature. The Author brings up the problem again, on the ground of a novel Spanish painting which has never previously been taken into consideration from a medical point of view but which reserves some surprises and offers a possible psychological consideration of the matter.
Association between Familial Mediterranean Fever and Retroperitoneal Fibrosis: Retroperitoneal Fibrosis Regression after Colchicine Therapy
Authors: De Socio G. , Cerquaglia C. , Curigliano V. , Fonnesu C. , Giovinale M. , Verrecchia E. , Marino G.M.E. , Natale L. , Gasbarrini G.B. , Manna R.
Published: January 2017

Retroperitoneal fibrosis (RPF) is a disease characterized by inflammatory fibrotic processes affecting the retroperitoneal structures. Familial Mediterranean Fever (FMF) is an autosomal recessive disorder, characterized by fever and attacks of sterile serositis. Colchicine is the only suitable drug for prevention of acute episodes. We describe a case of association between RPF and FMF in a 48-year-old male, in whom therapy with colchicine, besides preventing acute episodes, allowed RPF regression. To date the association between FMF and RPF and the use of colchicine therapy alone for RPF has not been described.
Efficacy and Safety of Anti-TNF-α Therapy Combined with Cyclosporine a in Patients with Rheumatoid Arthritis and Concomitant Hepatitis C Virus Infection
Authors: Giannitti C. , Benucci M. , Caporali R. , Manganelli S. , Bellisai F. , Sebastiani G.D. , Galeazzi M.
Published: January 2017

This study further expands our previous observation demonstrating the usefulness of combination therapy of anti-TNF-alpha and Cyclosporine A in the treatment of rheumatoid arthritis and concurrent hepatitis C virus infection, as well its efficacy and safety in controlling HCV viremia and liver toxicity. Seven patients were included in the study; transaminase levels remained unchanged, HCV RNA serum levels decreased significantly and DAS 28 significantly improved after twelve month follow-up. No side effects were registered.
Systemic Sclerosis and Cancer
Authors: Marasini B. , Conciato L. , Belloli L. , Massarotti M.
Published: January 2017

To review recent advances and current controversies on the association between systemic sclerosis (SSc) and cancer, PUBMED was searched from 1966 to the present using the terms: systemic sclerosis, cancer, morphoea, sclerotic diseases. Malignancies, mainly in lung and breast, coexist with idiopathic SSc or with SSc-like disorders, but not with localized forms of scleroderma (morphoea), with the exception of squamous cell carcinoma in patients with pansclerotic morphoea and skin ulcers. The mechanisms connecting SSc and malignancies are unknown. The occurrence of different cancer types with SSc or SSc-like disorders suggest different underlying mechanisms, including altered immune response, common genetic and environmental links, disease-dependent factors, tumor-derived biologic substances and therapies. The process of sclerosis itself may favour cancer in certain sites, and a reaction between T cells and neoantigens formed during irradiation has been suggested to explain the frequent development of morphoea after breast irradiation. Radiotherapy, especially when used for breast cancer, may trigger idiopathic SSc or morphoea and influence the severity of preexisting SSc, with the consequence that SSc is considered a relative contraindication to breast radiotherapy. In conclusion, cancer and SSc may be associated, but it is still controversial as to whether there is a causal relationship. Continuing interest in these associations, in particular in the different modalities of associations, may help to understand the underlying biological mechanisms and to identify patients at risk.
Release of Palladium from Biomechanical Prostheses in Body Fluids Can Induce or Support PD-Specific IFNγ T Cell Responses and the Clinical Setting of a Palladium Hypersensitivity
Authors: Cristaudo A. , Bordignon V. , Petrucci F. , Caimi S. , De Rocco M. , Picardo M. , Fei P. Cordiali , Ensoli F.
Published: January 2017

The increased use of Palladium (Pd) for biomedical applications, which has more than doubled in the last ten years, appears to be associated with an increased frequency of adverse reactions to Pd. The aim of this study is to investigate the relationship between the implant of a biomechanical apparatus containing Pd and the setting of a hypersensitivity to Pd by determining the levels of the metal released in biological fluids, assessing the effects of Pd on peripheral blood mononuclear cell (PBMC) cytokine production and exploring the clinical setting of skin sensitization. Of a total of 3,093 subjects examined in 2006, sensitization to Pd alone or in association with nickel (Ni) was observed in 1.6% and 13.03% of the individuals, respectively. Of these, a group of six subjects positive to Pd and negative to Ni at patch testing were selected on the basis of the oral clinical symptoms in order to measure both the levels of Pd in biological fluids and the degradation of the dental prostheses. Specific Pd measurements were carried out on salivary fluid, urine and serum samples by High Resolution Inductively Coupled Plasma-Mass Spectrometry. In addition, the degradation of the dental prostheses was assessed by both a “leaching test” and an analysis of the micro morphology of orthodontic prostheses. The induction of IFN-γ production by Pd was assessed in PBMC by the ELISpot assay. Skin sensitization to Pd was evaluated by patch testing and clinical examination. Ten healthy subjects were comparatively tested as controls. We found a specific induction of an IFN-γ response by Pd in PBMC collected from all the subjects positive to Pd at patch testing. On the contrary, control subjects did not show any response to Pd as assessed by IFN-γ ELISpot assay or by skin testing. Remarkably, the levels of Pd in all biological samples (saliva, sera, urine) were significantly higher in Pd-sensitized patients than in those collected from controls, reaching the highest concentrations in the urine. The leaching studies gave additional evidence that the dental appliances can release measurable levels of Pd in saliva. Oral clinical symptoms in patients with Pd dental prostheses were associated with measurable levels of Pd in the biological fluids, the induction of Pd-specific IFN-γ responses in PBMC and the clinical evidence of skin sensitization to Pd. These data suggest that dental appliances may represent an active source of Pd in the body, and this, in turn, can favour the clinical setting of a hypersensitivity to this metal.
Sequence Uniqueness as a Molecular Signature of HIV-1-Derived B-Cell Epitopes
Authors: Lucchese A. , Serpico R. , Crincoli V. , Shoenfeld Y. , Kanduc D.
Published: January 2017

The complex pathophysiology of human immunodeficiency virus (HIV) infection and the relatively high mutation rate of the retrovirus make it challenging to design effective anti-HIV vaccines. Several attempts have been made during the last decades to elucidate the enigmatic immunology of HIV infection and to predict potential immunogenic peptides for active vaccination using bioinformatic analysis methods. The results obtained to date to address this important problem are scarce. In this study, we exploit available HIV databases and analyse previously characterized HIV-encoded linear B-cell epitopes for their amino acid sequence similarity to the human or murine host proteome. We obtained further documentation that the HIV-derived antibody-targeted sequences mostly coincide with peptide areas rarely shared with the host proteins. In toto, our past and present data give clear-cut support to the statement that low-similarity to the host proteome is a major mechanism in defining viral peptide immunogenicity and indicate a possible way for inducing effective, high-titer, and non-cross-reactive antibodies to be used in anti-HIV vaccine therapy.
Immunogenicity of Allo-Vesicle Carrying ERBB2 Tumor Antigen for Dendritic Cell-Based Anti-Tumor Immunotherapy
Authors: Napoletano C. , Rughetti A. , Landi R. , Pinto D. , Bellati F. , Rahimi H. , Spinelli G.P. , Pauselli S. , Sale P. , Dolo V. , De Lorenzo F. , Tomao F. , Benedetti-Panici P. , Frati L. , Nuti M.
Published: January 2017

Dendritic cells (DCs) are able to orchestrate innate and acquired immunity and can activate and sustain a long-lasting anti-tumor immune response in vivo when used as anti-tumor cell therapy. The selection of the antigen and the choice of its formulation are key points in designing anti-cancer DC-based vaccines. Cell released vesicles/exosomes have been shown to transfer antigens, HLAI/peptide complexes and co-stimulatory molecules to recipient cells. In this study we describe the generation of an allogenic microvesicle cell factory in which the expression of a specific tumor antigen was combined to the expression of co-stimulatory and allogeneic molecules. The DG75 lymphoblastoid cell line was selected as microvesicle producer and transfected with ErbB2, as tumor antigen prototype. The shed microvesicles transferred antigenic components to recipient DCs, increasing their immunogenicity. DC pulsing resulted in cross-presentation of ErbB2 both in HLAI and HLAII compartments, and ErbB2-specific CD8+ T cells from cancer patients were activated by DCs pulsed with vesicle-bound ErbB2. The microvesicle cell factory proposed may represent a source of cell free immunogen to be used for DC-based cancer therapy.
Chlamydia Pneumoniae Induces T Cell Apoptosis through Glutathione Redox Imbalance and Secretion of TNF-α
Authors: Sessa R. , Di Pietro M. , Schiavoni G. , Macone A. , Maras B. , Fontana M. , Zagaglia C. , Nicoletti M. , Del Piano M. , Morrone S.
Published: January 2017

Chlamydia pneumoniae persistent infection has been implicated in the pathogenesis of several chronic inflammatory diseases including atherosclerosis, and we hypothesized that modulation of the apoptosis of macrophages and/or T cells by C. pneumoniae infection may contribute to the development of such diseases. We therefore evaluated apoptosis, cytokine response, and redox status in human primary T cells and macrophages infected with C. pneumoniae. In addition, co-cultures of T cells and macrophages infected with C. pneumoniae were also carried out. Apoptosis, and levels of glutathione (GSH), glutathione disulfide (GSSG), and tumour necrosis factor (TNF)-α were measured by flow cytometry, high performance liquid chromatography and enzyme-linked immunosorbent assay. C. pneumoniae induced apoptosis in T cells as well as in co-cultures of T cells and infected macrophages by marked decrease in GSH/GSSG ratio and increased production of TNF-α, respectively. The results demonstrate that interaction of C. pneumoniae with T cells and/or macrophages characterized by interference with redox status, and secretion of tumour necrosis factor TNF-α culminates in the induction of T cell apoptosis and survival of infected macrophages. In conclusion, the inappropriate T cell response against C. pneumoniae and survival of infected macrophages could explain the persistence of this intracellular obligate pathogen in the host-organism; it may contribute to the development of chronic inflammatory diseases, although further studies are needed to clarify such a complex mechanism.
Regulation of CREB Activation by P38 Mitogen Activated Protein Kinase during Human Primary Erythroblast Differentiation
Authors: Di Giacomo V. , Sancilio S. , Caravatta L. , Rana R.A. , Di Pietro R. , Cataldi A.
Published: January 2017

Among the molecular events underlying erythroid differentiation, we analyzed the signalling pathway leading to cAMP response element binding (CREB) nuclear transcription factor activation. Normal donor blood light density cells differentiated to pro-erythroblasts during the proliferative phase (10 days) of the Human Erithroblast Massive Amplification (HEMA) culture, and to orthochromatic erythroblasts, during the differentiative phase (4 additional days) of the culture. Since erythropoietin was present all over the culture, also pro-erythroblasts left in proliferative medium for 14 days continued their maturation without reaching the final steps of differentiation. p38 Mitogen Activated Protein Kinase (p38 MAPK) and CREB maximal activation occurred upon 4 days of differentiation induction, whereas a lower activation was detectable in the cells maintained in parallel in proliferative medium (14 days). Interestingly, when SB203580, a specific p38 MAPK inhibitor, was added to the culture the percentage of differentiated cells decreased along with p38 MAPK and CREB phosphorylation. All in all, our results evidence a role for p38 MAPK in activating CREB metabolic pathway in the events leading to erythroid differentiation.
Angiogenic Potential of Human Dental Pulp Stromal (STEM) Cells
Authors: Marchionni C. , Bonsi L. , Alviano F. , Lanzoni G. , Di Tullio A. , Costa R. , Montanari M. , Tazzari P.L. , Ricci F. , Pasquinelli G. , Orrico C. , Grossi A. , Prati C. , Bagnara G.P.
Published: January 2017

Dental pulp is a heterogeneous microenviroment where unipotent progenitor and pluripotent mesenchymal stem cells cohabit. In this study we investigated whether human Dental Pulp Stromal (Stem) Cells (DP-SCs) committed to the angiogenic fate. DP-SCs showed the specific mesenchymal immunophenotypical profile positive for CD29, CD44, CD73, CD105, CD166 and negative for CD14, CD34, CD45, in accordance with that reported for bone marrow-derived SCs. The Oct-4 expression in DP-SCs, evaluated through RT-PCR analysis, increased in relation with the number of the passages in cell culture and decreased after angiogenic induction. In agreement with their multipotency, DP-SCs differentiated toward osteogenic and adipogenic commitments. In angiogenic experiments, differentiation of DP-SCs, through Vascular Endothelial Growth Factor (VEGF) induction, was evaluated by in vitro matrigel assay and by cytometric analysis. Accordingly, endothelial-specific markers like Flt-1 and KDR were basally expressed and they increased after exposure to VEGF together with the occurrence of ICAM-1 and von Willebrand Factor positive cells. In addition, VEGF-induced DP-SCs maintained endothelial cell-like features when cultured in a 3-D fibrin mesh, displaying focal organization into capillary-like structures. The DP-SC angiogenic potential may prove a remarkable tool for novel approaches to developing tissue-engineered vascular grafts which are useful when vascularization of ischemic tissues is required.
Immunological Parameters to Define Infection Progression and Therapy Response in a Well-Defined Tuberculosis Model in Mice
Authors: De Steenwinkel J.E.M. , De Knegt G.J. , Ten Kate M.T. , Van Belkum A. , Verbrugh H.A. , Hernandez-Pando R. , Van Soolingen D. , Bakker-Woudenberg I.A.J.M.
Published: January 2017

To evaluate novel approaches for tuberculosis (TB) diagnostics and treatment, well-validated animal TB models are needed. Especially the emergence and spread of drug resistant TB requires innovative therapy and accurate parameters for monitoring success or failure of therapy. We developed a TB model in BALB/c mice, in which Mycobacterium tuberculosis (Mtb) infection was induced through the natural respiratory route, mimicking human TB infection. The lung showed a mild inflammatory infiltrate consisting of granulomas in the first phase of infection, followed by progressive increase of pneumonic lesions resulting in extensive lung consolidation in the chronic phase. Dissemination to the extra-pulmonary sites was observed. The model was validated in terms of therapeutic outcome. The 26-week standard therapy administered in human pharmacokinetic-equivalent doses, resulted in complete elimination of Mtb in all infected organs, without relapse of infection in the post-treatment period. However, a 13-week therapy, simulating patient non-adherence resulted in relapse of infection. In our quest to find biomarkers for monitoring success or failure of therapy, the concentrations of various cytokines in serum and lung, determined by Cytometric Bead Array (CBA), were evaluated in relation to the in situ cytokine expression in the lung, assessed by immunohistochemistry. The level of IFN-γ concentration in serum increased with infection progression, and decreased during effective therapy, and as such appeared to be an appropriate immunological parameter for success or failure of therapy. Relapse of infection, after inappropriate therapy, manifested as an increase in the serum IFN-γ concentration.
Immunohistochemical Expression of Prostate Stem Cell Antigen in Cystoprostatectomies with Incidental Prostate Cancer
Authors: Mazzucchelli R. , Barbisan F. , Santinelli A. , Lopez-Beltran A. , Cheng L. , Scarpelli M. , Montironi R.
Published: January 2017

High expression of Prostate Stem Cell Antigen (PSCA) has been shown to be associated with adverse prognostic features in clinically-diagnosed prostate cancer. The aim of this study is to analyze PSCA expression in cystoprostatectomies with incidental prostate carcinoma (PCa). PSCA expression was evaluated immunohistochemically in normal-looking epithelium (NEp), high-grade prostatic intraepithelial neoplasia (HGPIN) and pT2a Gleason score 6 acinar adenocarcinoma. The evaluation was carried out on 20 cystoprostatectomies (CyPs) with incidental PCa from men with bladder urothelial carcinoma (UC), and 20 radical prostatectomies (RPs) with hormonally untreated PCa from men with clinically detected PCa. Ki-67 was also investigated. The percentages of PSCA positive cells in HGPIN were significantly higher than in NEp (NEp: CyP, mean 2.92% ± standard deviation 6.26%; RP, 3.5% ± 6.46%. HGPIN: CyP, 13.67% ± 12.78%; RP, 14.67% ± 11.34%) (p<0.001). The proportions of positive cells in PCa were greater than in HGPIN (CyP, 20.25% ± 15.96%; RP, 22.58% ± 13.67%) (p0.001). For Ki-67 labeling, the proportions of positive nuclei in the CyPs significantly increased from NEp through HGPIN to PCa. A similar trend was seen in the RPs. In the CyPs the percentages of PSCA and Ki67 positive cells were lower than in the RPs, the differences between the CyP and RP compartments being not statistically significant. Our findings suggest that PSCA is a marker associated with neoplastic transformation of prostate cells, both in CyPs and RPs. However, there are no significant differences between CyPs with incidental prostate carcinoma and RPs with clinically diagnosed cancer.