bluuebunny/crossref_metadata_2025 huggingface dataset:
Peri-Tumoral Inflammatory Cell Infiltration in OSCC: A Reliable Marker of Local Recurrence and Prognosis? An Investigation Using Artificial Neural Networks
Authors: Campisi G. , Calvino F. , Carinci F. , Matranga D. , Carella M. , Mazzotta M. , Rubini C. , Panzarella V. , Santarelli A. , Fedele S. , Lo Muzio L.
Published: January 2017

The presence of inflammatory reaction in peri-tumoural connective tissue is generally considered as a defense mechanism against cancer, but inflammation tissue in malignant transformation and early steps of oncogenesis has been recently proven to play a supporting and aggravating role in some carcinomas. Aims of this retrospective study were to evaluate in OSCCs the independent association of peri-tumoral inflammatory infiltrate (PTI) with local recurrence (LR) or survival outcome, and to verify whether PTI can be considered a marker of prognosis. Data from 211 cases of OSCC, only surgically treated between 1990 and 2000, were collected and retrospectively analyzed for PTI and the event LR (5 yrs follow-up at least) by means of univariate-multivariate and neural networks analyses. Patients (mean age 65.3 ± 12.4 yrs, M/F = 2.98) showed presence of PTI in 68.2% (144/211): (+) in 27.0%, (++) in 25.6%, (+++) 15.6%; PTI was found reduced in 24.7% of cases and absent in 7.1%. In overall PTI+ve group (n=144), 66 were TNM Stage I, 33 Stage II, 45 Stage III, none Stage IV. LR (mean 6 ± 4 months) was present in 87/211 (41.2%) patients, of which 43/144 (29.8%) in OSCCs with PTI [23 (+),. 13 (++) and 7 (+++)] vs. 44/67 (65.7%) in OSCC with PTI -/+ or PTI–ve ones. By univariate analysis, PTI+ve cases showed a significant lower risk to have LR (p<0.0001; OR= 0.2297; CI= 0.1277:0.4134) vs PTI -/+ or –ve ones, especially among cases with higher PTI value (+++) (OR= 0.1718; CI= 0.0749:03939). Multivariate analyses (Logit model and neural networks) confirmed the same datum: presence of PTI was an independent predictive variable accounting for a better tumoural outcome without LR (Logit and neural networks values: OR' 0.226; CI= 0.113:0.454; ROC Area = 0.66, respectively). In terms of prognostic significance, elevated PTI was found to have an independent association with the poorest overall survival rate (P = 0.056). Our findings strongly suggest the importance to investigate routinely PTI in OSCCs, as useful marker of tumoral behavior and prognosis, and warrant further studies on its specific cellular nature.
Perioperative Allergy: Risk Factors
Authors: Caffarelli C. , Stringari G. , Pajno G. B. , Peroni D.G. , Franceschini F. , Iacono I. Dello , Bernardini R.
Published: January 2017

Perioperative anaphylactic as well as anaphylactoid reactions can be elicited by drugs, diagnostic agents, antiseptics, disinfectants and latex. In some individuals, allergic reactions occur in the absence of any evident risk factor. Previous history of specific safe exposure to a product does not permit to exclude the risk of having a reaction. We have systematically reviewed characteristics in the patient's history or clinical parameters that affect the risk of developing reactions during anesthesia. Evidence shows that patients with previous unexplained reaction during anesthesia are at risk for perioperative allergic reactions. An allergic reaction to an agent is associated with previous reaction to a product that is related with the culprit agent. Multiple surgery procedures, professional exposure to latex and allergy to fruit are associated with an increased frequency of latex allergy. It has been shown that in some instances, allergic perioperative reactions may be more common in atopic patients and in female.
Muscle Relaxants Allergy
Authors: Peroni D.G. , Sansotta N. , Bernardini R. , Crisafulli G. , Franceschini F. , Caffarelli C. , Boner A.L.
Published: January 2017

The most common agents that are responsible for intraoperative anaphylaxis are muscle relaxants. In fact, neuromuscular blocking agents (NMBAs) contribute to 50–70% of allergic reactions during anaesthesia. The main mechanism of hypersensitivity reactions to NMBAs is represented by acute type I allergic reactions and the most severe form is anaphylaxis. The rate of non IgE mediated immediate hypersensitivity reactions usually varies between 20 % and 35% of the reported cases in most large series. In a recent report, non allergic suspected reactions to NMBAs occurred with almost the same frequency as did those with an allergic component. Although the precise mechanisms of these reactions remain difficult to ascertain, they usually result from direct non specific mast cell and basophil activation. After diagnostic procedures, regardless of the specific IgE results, NMBAs are contraindicated if the skin tests were positive. In view of the constantly evolving anesthesiologic practices, and of the complexity of allergy investigation, an active policy to identify patients at risk and to provide any necessary support to anaesthetists and allergologists should be promoted. The high frequency of IgE anaphylactic reactions and the feasibility of skin tests in children justify systematic allergy testing whenever hypersensitivity reaction occurs during general anaesthesia.
Antibiotic Allergy
Authors: Caimmi S. , Caimmi D. , Lombardi E. , Crisafulli G. , Franceschini F. , Ricci G. , Marseglia G.L.
Published: January 2017

Antibiotics are commonly injected during the perioperative period and are responsible of 15% of the anaphylactic reactions. Anaphylaxis triggered by antibiotics primarily involves penicillin and cephalosporin. The management of patients with histories of allergic reactions to antibiotics is a common situation in clinical practice. The confirmation or invalidation of the allergic nature of the reported reaction is not based on in vitro tests, but on a rigorous allergological work-up based on detailed analysis of clinical history, skin tests and drug provocation test. Considering a possible cross-reactivity between penicillins, once an immediate penicillin allergy has been diagnosed, skin testing with the alternative molecule (cephalosporin, carbapenem, aztreonam) is mandatory and, if negative, the relevant drug should be given in an appropriate setting at increasing doses.
Clinical Modifications Induced by Drugs during the Perioperative Period
Authors: Franceschini F. , De Benedictis F.M. , Peroni D.G. , Marseglia G.L. , Cardinale F. , Caffarelli C. , Bernardini R.
Published: January 2017

Total intravenous anesthesia (TIVA) can be defined as a technique in which general anesthesia is induced and maintained using only intravenous agents. TIVA has become more popular in recent times because of the pharmacokinetic and pharmacodynamic properties of propofol, the availability of short acting synthetic opioids, and the development of delivery systems. Significant differences in anatomy and physiology in adults and children and special needs of younger patients have important consequences on many aspects of anesthesia. Airway and respiratory complications are the most common causes of morbidity during general anesthesia in children. Knowledge of the functional anatomy of airways in children forms the basis in the understanding of the pathological conditions that may occur.
Anesthesia in Children with Asthma and Rhinitis
Authors: Franceschini F. , De Benedictis F.M. , Peroni D.G. , Marseglia G.L. , Caffarelli C. , Crisafulli G. , Indinnimeo L.
Published: January 2017

The incidence of asthma is increasing worldwide, but morbidity and mortality are decreasing, because of improvements in medical care. Although the incidence of severe perioperative bronchospasm is relatively low in asthmatics undergoing anaesthesia, when it does occur it may be life-threatening. Preoperative assessment of asthma should include a specialized medical hystory and physical examination as well as pulmonary function testing. Potential trigger agents should be identified and avoided. In many asthmatic patients treatment with systemic corticosteroids and bronchodilators is indicated to prevent the inflammation and bronchocostriction associated with endotracheal intubation. Nonetheless, acute bronchospasm can still occur, especially at induction and emergence, and should be promptly and methodically managed.
Prevention of Allergic Reactions in Anesthetized Patients
Authors: Caffarelli C. , Stringari G. , Del Giudice M. Miraglia , Crisafulli G. , Cardinale F. , Peroni D.G. , Bernardini R.
Published: January 2017

Hypersensitivity reactions during perioperative period are increasing and may be potentially life-threatening. Therefore, major emphasis is given to prevention. We perform a review to examine which measures should be taken to prevent reactions to products used in elective and emergency surgery. Any patient with a history of previous anaphylaxis or severe reaction during anaesthesia should be referred to allergist for detection of the offending compound. However, the identification of the triggering agent is not always feasible because of the low accuracy of diagnostic tests. In these cases and when emergency surgery is required, it should be considered to replace all drugs administered before the onset of the reaction with alternatives. Furthermore, any cross-reacting agent and latex, especially in patients belonging to populations at-risk for latex allergy should be avoided. In susceptible patients, premedication with antihistamines and corticosteroids might reduce the severity of reaction to drugs or contrast material while it is unclear whether pre-treatment decreases incidence of anaphylactic reactions. There is no evidence that premedication prevents allergic reactions to latex. Overall, physicians should not rely on the efficacy of premedication.
Polytherapy in Bone Regeneration: Clinical Applications and Preliminary Considerations
Authors: Calori G.M. , Colombo M. , Ripamonti C. , Bucci M. , Fadigati P. , Mazza E. , Mulas S. , Tagliabue L.
Published: January 2017

Polytherapy, namely the simultaneous application of three fundamental elements necessary for bone regeneration (growth factors, osteogenic cells and osteocnductive scaffolds) seems to lead to a very high success rate in the treatment of complex non-union (NU) cases and critical bone defects. NU are reported in 5–10% of long bone fractures. The use of autologous bone grafts has been long-considered the gold standard for the treatment of these cases. However the harvesting procedure from the iliac crest increases surgery time and presents some donor site complications which may be elevated. In recent years, surgeons have some alternatives to autologous grafting such as: application of organic or synthetic bone substitute, application of mesenchymal stromal cells (MSC) or growth factors (GF). In the literature there are many studies available about their application in monotherapy, but unfortunately the healing rate doesn't exceed 90%. Polytherapy seems to be a logical option to improve the healing rate, nevertheless, there are not still extensive studies that validate this strategy and moreover, some questions are not resolved.
Pridie's Marrow Stimulation Technique Combined with Collagen Matrix for Cartilage Repair. A Study in a Still Growing Sheep Model
Authors: Giordano M. , Aulisa A.G. , Mastantuoni G. , Gigante A. , Guzzanti V.
Published: January 2017

The study assessed the spontaneous repair of large critical full-thickness defects (FTD) in not mature and still growing sheep model and compared repaired tissue after Pridie's technique to the same technique combined with type I collagen matrix. Thirty-six FTD were divided into group 1 (untreated), group 2 (treated according to Pridie's technique with 10.2 as value ratio of marrow stimulation), and group 3 (treated using Pridie's marrow stimulation technique, and covered by a type I collagen matrix). The histological exam at 12 months showed fibrous repair of the untreated defects. In group 2 the reparative tissue showed a prevalence of fibrocartilaginous tissue. The mean ICRS visual assessment scale score was 8.9. In group 3 the reparative tissue was similar to the normal surrounding cartilage. The mean ICRS visual assessment scale score was 14.7. Subchondral drilling with defined ratio between the stimulated marrow area and the lesion area could improve the quality of FTD repair in articular cartilage in not mature and still growing stifle sheep model if combined with type I collagen matrix.
Neuro-Immuno-Endocrine Processes in Vitiligo Pathogenesis
Authors: Miniati A. , Weng Z. , Zhang B. , Stratigos A.J. , Nicolaidou E. , Theoharides T.C.
Published: January 2017

Vitiligo is a cutaneous disorder of depigmentation, clinically characterized by well-demarcated, white macules of varying size and distribution. It can affect up to 2% of the population, especially younger ages. In spite of recent findings implicating genetic, immune and oxidative stress factors, the exact pathogenesis of vitiligo remains obscure. Here, we briefly discuss the prevailing theories, and offer new suggestions that could explain in part the damage of melanocyte in the vitiliginous lesions. Our emerging hypothesis is that neuropeptides released from peripheral nerve endings could synergize with new cytokines to adversely affect melanocyte function and viability. These may include corticotropin-releasing hormone (CRH) and neurotensin (NT), as well as interleukin 33 (IL-33) and thymic stromal lymphopoietin (TSLP). Such interactions could serve the basis for further research, possibly leading to new treatments.
Aberrant β-Catenin and Lef1 Expression May Predict the Clinical Outcome for Patients with Oropharyngeal Cancer
Authors: Papagerakis P. , Pannone G. , Shabana A-H. , Depondt J. , Santoro A. , Ghirtis K. , Berdal A. , Papagerakis S.
Published: January 2017

β-catenin, normally expressed on the epithelial cell surface, plays a crucial role in cadherin-mediated cell adhesion. Recent evidence suggests that β-catenin is also involved in other functions such as intracellular signaling via the Wnt pathway by creating a nuclear complex with members of the Lymphoid-Enhancer-Factor/T-Cell-Factor (LEF/TCF) family of transcription factors, and gene regulation that it is implicated in the development of several tumors. Little information is available on β-catenin expression and its main partner in the Wnt signaling pathway, LEF1, in oropharyngeal squamous cell carcinomas (OP-SCCs). The aim of this study is to investigate the expression of β-catenin and LEF1 expression in human primary OP-SCCs and to evaluate their clinical and prognostic significance. OP-SCCs and normal peritumoral areas were analyzed by immunohistochemistry, Western-blot and RT-PCR. β-catenin was overexpressed in tumors in comparison to normal peritumoral areas and displayed predominantly intracellular (cytosolic/nuclear) localization in 62% of the tumors. Immunoreactivity was correlated with clinicopathological parameters and long-term follow-up, and a significant association was found between protein expression and development of local recurrences (P =0.03). The OP-SCCs with poor clinical outcome, which displayed intracellular β-catenin expression, were also strongly positive for LEF1, with their co-expression statistically significant (P = 0.040). All (100%) advanced (stages 3+4) SCCs, 66.7% of the SCCs with positive lymph nodes and 80% of the SSCs that developed local recurrences were LEF1 positive. Cox regression analysis confirmed a poorer overall survival in cases with high expression of β-catenin and LEF1. Our results suggest that assessing intracellular β-catenin and LEF1 expression might help in patient risk stratification and outcome prediction, and serve as novel therapeutic targets in advanced OP-SCC.
Effects of Highly Active Antiretroviral Therapy on Platelet Activating Factor Metabolism in Naïve HIV-Infected Patients: II) Study of the Abacavir/Lamivudine/Efavirenz Haart Regimen
Authors: Chini M. , Tsoupras A.B. , Mangafas N. , Tsogas N. , Papakonstantinou V.D. , Fragopoulou E. , Antonopoulou S. , Gargalianos P. , Demopoulos C.A. , Lazanas M.C.
Published: January 2017

Human Immunodeficiency Virus (HIV)-infected patients are at increased risk for cardiovascular diseases partly due to chronic inflammation. Some antiretroviral drugs and Highly Active Anti-Retroviral Therapy (HAART) regimens seem to be related and amplify this increased risk, especially the ones containing abacavir. Platelet-Activating-Factor (PAF) is a potent inflammatory mediator that is implicated in both cardiovascular diseases and HIV-related manifestations. Our objective is to study the in vivo effect of the abacavir/lamivudine/efavirenz first-line HAART regimen on PAF metabolism in HIV-infected patients. The specific activities of PAF basic biosynthetic enzymes in leukocytes and platelets, PAF-cholinephosphotransferase (PAF-CPT) and lyso-PAF-acetyltransferase (Lyso-PAF-AT), but also those of PAF-basic catabolic enzymes, PAF acetylhydrolase (PAF-AH) in leukocytes and platelets and Lipoprotein-associated-Phospholipase-A2 (LpPLA2) in plasma, were measured in blood samples of 10 asymptomatic naïve male HIV-infected patients just before and after 1, 3 and 6 months of treatment. CD4 cell counts, viral load and several biochemical markers were also measured in the same blood samples of these patients. The repeated ANOVA measures and the Pearson r criterion were used for studying statistical differences and correlations - partial correlations respectively. Even though viral load was decreased and CD4 cell counts were beneficially increased after treatment with the abacavir/lamivudine/efavirenz regimen, the main enzyme of the remodelling PAF-synthesis that is implicated in pro-atherogenic inflammatory procedures, Lyso-PAF-AT activity, was increased at 3 months of treatment in both leukocytes and platelets, while the main enzyme of PAF-degradation, PAF-AH, was increased as a response only in leukocytes at the 3rd month. Although the abacavir/lamivudine/efavirenz HAART regimen exhibits very efficient antiretroviral activities, on the other hand it induces an in vivo transient increase in the inflammation-related remodeling PAF-biosynthetic pathway. This finding supports the hypothesis of inflammation-mediated increased cardiovascular risk in HIV-infected patients during the first months of abacavir-containing HAART.
Can the Association of Ciclosporine a and Methotrexate Maintain Remission/Low Disease Activity Induced by Etanercept in Early Rheumatoid Arthritis Patients? Evaluation by Magnetic Resonance Imaging
Authors: Diamanti A. Picchianti , Argento G. , Podestà E. , Germano V. , Fazi S. , Migliore A. , David V. , D'Amelio R. , Laganà B.
Published: January 2017

The opportunity to induce remission/low disease activity in Rheumatoid Arthritis (RA) patients has been achieved in recent years by the adoption of more sensitive diagnostic methods [Magnetic Resonance Imaging (MRI), ultrasonography] and early aggressive treatments (combination of biologics and synthetic DMARDs). On the other hand, data are still scarce and contrasting about the management of long-term remission. The aim of this preliminary study is to evaluate whether the association of Methotrexate + Ciclosporine A (MTX + CSA) therapy in early RA (eRA) patients is able to maintain remission/low disease activity and avoid structural progression, evaluated by MRI. Etanercept was suspended in patients who reached remission/low disease activity and CSA+MTX therapy was introduced (TO), all patients continued to receive MTX; at this time MRI showed mild/moderate synovitis and erosions in all the patients; 1-year after (T1), a slight reduction in mean synovitis, bone edema and total score was observed, whereas the erosion score was unchanged. The mean DAS44 remained stable from T0 to T1 and 6/7 patients maintained a low disease activity score. No side effects were reported. These results confirm the good clinical efficacy and safety of the combination therapy CSA+MTX in eRA patients and demonstrate a parallel arrest of structural damage evaluated by MRI 1-year after etanercept suspension.
Celastrus Treatment Modulates Antigen-Induced Gene Expression in Lymphoid Cells of Arthritic Rats
Authors: Yu H. , Venkatesha S.H. , Nanjundaiah S. , Tong L. , Moudgil K.D.
Published: January 2017

Rheumatoid arthritis (RA) is a debilitating autoimmune disease of global prevalence and the disease process primarily targets the synovial joints. Despite improvements in the treatment of RA over the past decade, there still is a need for new therapeutic agents that are efficacious, less expensive, and free of severe adverse reactions. Celastrus has been used in China for centuries for the treatment of rheumatic diseases. Furthermore, we previously reported that ethanol extract of Celastrus aculeatus Merr. (Celastrus) attenuates adjuvant-induced arthritis (AA) in rats. However, the mechanisms underlying the anti-arthritic activity of Celastrus have not yet been fully defined. We reasoned that microarray analysis might offer useful insights into the pathways and molecules targeted by Celastrus. We compared the gene expression profiles of the draining lymph node cells (LNC) of Celastrus-treated (Tc) versus water-treated (Tw) rats, and each group with untreated arthritic rats (T0). LNC were restimulated with mycobaterial heat shock protein-65 (Bhsp65). We identified 104 differentially expressed genes (DEG) (8 upregulated, 96 downregulated) when comparing Tc with T0 rats, in contrast to 28 (12 upregulated, 16 downregulated) when comparing Tw and T0 rats. Further, 20 genes (6 upregulated, 14 downregulated) were shared by both Tw and Tc groups. Thus, Celastrus treatment (Tc) significantly downregulated a large proportion of genes compared to controls (Tw). The DEG were mainly associated with the processes of immune response, cell proliferation and apoptosis, and cell signaling. These results provide novel insights into the mechanism of Celastrus anti-arthritic activity, and unravel potential therapeutic targets for arthritis.
Ethyl Pyruvate Administration Suppresses Growth and Invasion of Gallbladder Cancer Cells via Downregulation of Hmgb1-Rage Axis
Authors: Li M-L. , Wang X-F. , Tan Z-J. , Dong P. , Gu J. , Lu J-H. , Wu X-S. , Zhang L. , Ding Q-C. , Wu W-G. , Rao L-H. , Mu J-S. , Yang J-H. , Weng H. , Ding Q. , Zhang W-J. , Chen L. , Liu Y-B.
Published: January 2017

High mobility group box B1 (HMGB1)-receptor for advanced glycation endproducts (RAGE) axis has been previously known to be involved in carcinogenesis and development of multiple malignancies. Some studies have confirmed that Ethyl pyruvate (EP), a potent inhibitor of HMGB1, exerts the therapeutic effects on metastatic live tumor from gastric cancer. However, the effects and possible molecular mechanisms of EP on gallbladder cancer (GBC) need to be further explored. In the present study, human GBC cell lines (GBC-SD and SGC-996) were treated with different concentrations of EP. Then, the expression levels of HMGB1, RAGE and some transcription factors were identified by Real-time PCR and Western blot assays. Cell proliferative activities indicated by MTT assay, invasive potential by Transwell assay and cell apoptosis and cycle distribution were performed for functional analysis of GBC cell lines in vitro. As a result, EP decreased the expression of HMGB11, RAGE, PCNA and matrix metallopeptidase-9 (MMP-9), while it increased the expression of p53. Moreover, EP administration decreased GBC cell proliferation, inhibited the invasive potential, and induced apoptosis and cycle arrest in S phase in GBC cells. In conclusion, EP administration inhibits growth and invasion of gallbladder cancer cells possibly via down-regulation of the HMGB1-RAGE axis, suggesting that EP may play a critical role in the treatment of cancer in conjunction with other therapeutic agents.
The Lack and Cytomegalovirus-Specific Cellular Immune Response May Contribute to the Onset of Organ Infection and Disease in Lung Transplant Recipients
Authors: Costa C. , Saldan A. , Sinesi F. , Sidoti F. , Balloco C. , Simeone S. , Piceghello A. , Mantovani S. , Di Nauta A. , Solidoro P. , Cavallo R.
Published: January 2017

Cellular immune response has been demonstrated to play a role in the control of human cytomegalovirus (HCMV) replication in organ transplant recipients. Herein, HCMV-specific T-cell response and association to the onset of organ infection/disease were prospectively evaluated by EliSPOT assay in a population of 46 lung transplant (LT) recipients at 1, 3, 6, 9 and 12 months post-transplantation. According to our centre's practice, a combined prolonged antiviral prophylaxis (HCMV-IG for 12 months and ganciclovir or valganciclovir for 3 weeks from postoperative day 21) was given to all LT recipients. HCMV-DNA was concomitantly detected on bronchoalveolar lavage (BAL) and whole blood by real-time PCR. Approximately one third of patients resulted HCMV persistently non-responder; the rate of HCMV infection, as evaluated by HCMV-DNA positivity, tended to be higher in non-responders. Mean viral load on BAL was significantly higher in non-responders vs other patients (p <0.001). Temporal profile of infections appeared related to the HCMV responder status with a shorter time to onset of infection post-transplantation and a longer duration in non-responders. The occurrence of organ disease (i.e. pneumonia) tended to be higher in non-responders, with poor prognosis, as death occurred in one of three non-responder patients that developed HCMV pneumonia. The lack of HCMV-specific cellular response can contribute to the onset of organ infection and disease also in patients in which antiviral prophylaxis was adopted; this could be due to the potential occurrence of incomplete control of replication in lungs or a delayed priming of T-cell reconstitution.
Histomorphologic Alterations and Human Enamel after Repeated Applications of a Bleaching Agent
Authors: D'Amario M. , D'Attilio M. , Baldi M. , De Angelis F. , Marzo G. , Vadini M. , Varvara G. , D'Arcangelo C.
Published: January 2017

The objective of the study was to analyse the histomorphology of enamel after repeated applications of a professional bleaching regimen. Enamel specimens were obtained from buccal surfaces of 20 extracted human incisors. Two specimens were obtained for each tooth. Half of each tooth was maintained in distilled water and served as control; the other part was treated with a 38% hydrogen peroxide professional bleaching agent. The treated specimens were divided in four groups: in group 1, the professional bleaching protocol suggested by the manufacturer was applied once; in group 2, the same protocol was repeated twice; in group 3, three times; in group 4, four times. Between bleaching applications and before SEM evaluation, enamel specimens were maintained in artificial saliva for 1 week. Enamel specimens for each group were submitted to a qualitative scanning electron microscopy (SEM) analysis (200X, 500X, 1000X, 3000X), comparing the treated specimens with the related control enamel. Results of the SEM analysis showed no relevant alteration on the enamel surfaces, when the bleaching protocol was applied once or twice. However, significant changes of enamel surface morphology were SEM observed in groups 3 and 4, suggesting a predominance of depressions when bleaching procedure was repeated three or four times. From the results of this in vitro study, it is possible to state that bleaching procedures should not be carried out indiscriminately. SEM analysis showed important alterations of the prismatic structure of the enamel when the bleaching protocol was applied three and four times.
Heparin Protects BALB/c Mice from Mite-Induced Airway Allergic Inflammation
Authors: Fu L.S. , Tsai J.J. , Chen Y.J. , Lin H.K. , Tsai M.C. , Chang M.D.T.
Published: January 2017

More and more studies have demonstrated the anti-inflammatory effects of heparin. However, in the aspect of allergic airway inflammation, data about its daily use in animal model is scarce. To evaluate the efficacy of 22-day intranasal heparin administration in mite-induced airway allergic inflammation in BALB/c mice, the murine model of house dust-mite allergen-induced asthma was used to assess the effect of heparin (h) and low molecular weight heparin (1 mwh) administered intra-nasally (IN) throughout the full study period (22 days). Effects were monitored by histopathology, cell counts in broncho-alveolar lavage fluid (BALF), local cytokine production, serum, specific antibody levels, and airway resistance measurements. Compared to the positive control group, both hIN and lmwhIN groups had lower peri-bronchiolar/alveolar inflammatory pathology score and lower goblet cell scores ( p<0.01); lower eosinophil and neutrophil counts in BALF ( p<0.0001); and lower cytokine levels including IL-17A/F, IL-5, IL-13, IL-8 and eotaxin in lung tissue ( p <0.001). Serum Der p-specific IgE level was also lower in heparin-treated groups ( p<0.004). The two heparin-treated groups also revealed lower value of Penh after McH stimulation. In conclusion, heparin and lmw heparin decrease serum Der p-specific IgE level and possess anti-inflammatory effects on mite-induced airway allergic inflammation model in BALB/c mice.
Clinical Significance of Immunogenic Cell Death Biomarker Rage and Early Growth Response 1 in Human Primary Gastric Adenocarcinoma
Authors: Xu X-C. , Gao H. , Zhang W-B. , Abuduhadeer X. , Wang Y-H.
Published: January 2017

The receptor for advanced glycation end products (RAGE), a pattern recognition receptor that binds multiple ligands derived from a damaged cell environment, contributes to multiple pathologies including cancer. Early growth response 1 (EGR1) is a tumor suppressor gene or a tumor promoter involved in tumorigenesis and progression of some cancers. However, there is some lack of knowledge about the expression and clinical significance of RAGE and EGR1 in human primary gastric adenocarcinoma (GAC). The present study was aimed to investigate the expression and clinical significance of RAGE and EGR1 in human GAC. One hundred and twenty cases of GAC tissues, adjacent non-cancer tissues (ANCT) and metastatic lymph node (MLN) tissues were collected. The expression of RAGE and EGR1 was assessed using immunohistochemistry (IHC) through tissue microarray procedure. The clinicopathologic characteristics of all patients were analyzed. As a result, the expression of RAGE in GAC and MLN tissues showed the positive staining mainly in the cytoplasm, with lower reactivity rate compared with the ANCT (42.5% vs 82.5%, 65.0% vs 82.5%, P<0.001), while EGR1 expression had no significant difference between GAC, MLN tissues and ANCT ( P=0.565). Moreover, the positive expression of RAGE was closely associated with the N stage of GAC patients, but did not correlate with their age, gender, tumor size, tumor sites, T stage, and metastatic lymph node (each P>0.05). In addition, Spearman Rank correlation analysis showed the positive correlation of RAGE expression with EGR1 in GAC tissues (r=0.658). Taken together, the expression of RAGE is decreased in GAC and MLN tissues, and is associated with the N stage of GAC patients, suggesting that RAGE may represent a potential therapeutic target for the treatment of GAC.
Histopathological Features of Tissue Alterations Induced by Low Frequency Ultrasound with Cavitational Effects on Human Adipose Tissue
Authors: Pugliese D. , Maiorano E. , Pascone M.
Published: January 2017

Low frequency, high energy level ultrasound (US) induces physical effects on tissues called ultrasonic cavitation (UC). Endermic US therapy has recently been proposed as a method to reduce non-invasively the amount of adipose tissue. Very few published studies have dealt with the biological effects of such therapies on human adipose tissue. The aim of this study is to evaluate, through histopathological examination, the effects of various levels of ultrasonic radiation on supravital human adipose tissue. Four ex vivo human tissue samples were treated as follows: sample 1: no US radiation; sample 2: US radiation 2,5 W/cm2 for 15 minutes; sample 3: US radiation 5 W/cm2for 15 minutes; sample 4: infiltration of 30 ml physiological saline and US radiation, 5 W/cm2 for 15 minutes. For lower levels of ultrasonic energy, interruption of the adipocytic membranes was evident both in the surface and in the deeper cutaneous and subcutaneous layers, with focal dissolution and homogenization of the surface dermal fascia. For higher levels of ultrasonic energy, alterations of the adipocytes and of the collagen fibers were greater, resulting in the dissolution of the cells and of the interlobular fibrous septa. Both effects were amplified by tumescent saline infiltration. The histological lesions demonstrated in adipocytes confirm the theoretical premises of a possible usefulness in the treatment of localized adiposis. The alterations observed in the connective stroma could have positive effects on the structural re—organization and consequently on the in vivo external appearance of the treated areas.
Impact of Mast Cells on the Skin
Authors: Kritas S.K. , Saggini A. , Varvara G. , Murmura G. , Caraffa A. , Antinolfi P. , Toniato E. , Pantalone A. , Neri G. , Frydas S. , Rosati M. , Tei M. , Speziali A. , Saggini R. , Pandolfi F. , Cerulli G. , Theoharides T.C. , Conti P.
Published: January 2017

When through the skin a foreign antigen enters it provokes an immune response and inflammatory reaction. Mast cells are located around small vessels that are involved in vasaldilation. They mature under the influence of local tissue to various cytokines. Human skin mast cells play an essential role in diverse physiological and pathological processes and mediate immediate hypersensitive reaction and allergic diseases. Injection of anti-IgE in the skin or other agents that directly activate mast cells may cause the decrease in vascular tone, leakage of plasma and may lead to a fall in blood pressure with fatal anaphylactic shock. Skin mast cells are also implicated as effector cells in response to multiple parasites such as Leishmania which is primarily characterized by its tissue cutaneous tropism. Activated macrophages by IFNγ, cytotoxic T cells, activated mast cells and several cytokines are involved in the elimination of the parasites and immunoprotection. IL-33 is one of the latest cytokines involved in IgE-induced anaphylaxis and in the pathogenesis of allergic skin disorders. IL-33 has been shown in epidermis of patients with psoriasis and its skin expression causes atopic dermatitis and it is crucial for the development of this disease. Here we review the impact of mast cells on the skin.
Protective Effect of Alpha-Lipoic Acid on Cypermethrin-Induced Oxidative Stress in Wistar Rats
Authors: Mignini F. , Nasuti C. , Fedeli D. , Mattioli L. , Cosenza M. , Artico M. , Gabbianelli R.
Published: January 2017

Cypermethrin (CY), a class II pyrethroid pesticide, is globally used to control insects in the household and in agriculture. Despite beneficial roles, its uncontrolled and repetitive application leads to unintended effects in non-target organisms. In light of the relevant anti-oxidant properties of alpha-lipoic acid (ALA), in the work described herein we tested the effect of a commercially available ALA formulation on cypermethrin (CY)-induced oxidative stress in Wistar rats. The rats were orally administered with 53.14 mg/kg of ALA and 35.71 mg/kg of CY for 60 days. The treatment with CY did not induce changes in either locomotor activities or in body weight. Differences were observed on superoxide dismutase (SOD), catalase (CAT) and lipid peroxidation that were re-established by ALA treatment at similar levels of the placebo group. Furthermore, ALA formulation increased glutathione (GSH) level and glutathione peroxidase (GPx) activity. Because of the widespread use of CY, higher amounts of pesticide residues are present in food, and a diet supplementation with ALA could be an active free radical scavenger protecting against diseases associated with oxidative stress.
Differential Expression of Immune-Modulatory Molecule HLA-E in Non-Neoplastic and Neoplastic Lesions of the Thyroid
Authors: Zanetti B.R. , Carvalho-Galano D.F. , Feitosa N.L.F. , Hassumi-Fukasawa M.K. , Miranda-Camargo F.A. , Maciel L.M.Z. , Ribeiro-Silva A. , Soares E.G.
Published: January 2017

Human leukocyte antigen (HLA)—E is a non-classical molecule of the histocompatibility complex that functions as one of the main ligands of the Natural Killer (NK) cell inhibitory receptor CD94/NKG2A and inhibits its potent cytotoxic activity. Due to the important role of NK cells in combating neoplasm, we hypothesized that the differential expression of HLA-E could favor the progression of heterogeneous thyroid tumors. Using an immunohistochemistry technique in 143 biopsies of thyroid tumors, including benign and malignant neoplasms and goiters, we evaluated the expression of HLA-E among various tumor types and its association with the clinicopathological factors of diseases. We verified high HLA-E expression in all types of neoplastic tumors, although no significant differences between the groups were found. Low expression was observed in 95% of the goiter samples, showing significant differences between neoplastic and non-neoplastic lesions. Furthermore, a significant result was found with regard to the tumor size, with high HLA-E expression being related to smaller tumors. Therefore, our data suggest that an increase in HLA-E may be associated with the establishment of thyroid neoplasms, with either benign or malignant features.
Decreased Expression of Protease Inhibitor 9, a Granzyme B Inhibitor, in Celiac Disease: A Potential Mechanism in Enterocyte Destruction and Villous Atrophy
Authors: Pohjanen V-M. , Kokkonen T.S. , Arvonen M. , Augustin M.A. , Patankar M. , Turunen S. , Vähäsalo P. , Karttunen T.J.
Published: January 2017

The objective of this study was to assess the expression of protease inhibitor 9, a granzyme B inhibitor, in human small intestine, and to evaluate its cytoprotective role in the celiac disease of children. Twelve subjects with untreated celiac disease and thirteen healthy controls were examined by endoscopy. The expression of protease inhibitor 9 was analyzed immunohistochemically from duodenal biopsies and compared to granzyme B expression, apoptosis rate, number of intraepithelial lymphocytes and villus and crypt height data from the biopsies. We discovered that protease inhibitor 9 is expressed in the cytoplasm of the duodenal epithelial cells in the majority of cases. The enterocyte expression of protease inhibitor 9 was lower in celiac disease patients than in controls. Protease inhibitor 9 expression also showed a negative correlation with the number of apoptotic cells, overall density of granzyme B expressing intraepithelial lymphocytes, the height of the crypts and the severity of villous atrophy in duodenum. Therefore, we conclude that the protease inhibitor 9 is constantly expressed in the enterocytes of normal duodenum and the expression is decreased in celiac disease. These findings suggest that protease inhibitor 9 has a role in duodenal homeostasis and in the protection of enterocytes from misdirected granzyme B. Indeed, observed associations of lowered protease inhibitor 9 expression together with increased granzyme B expression, apoptosis rate and severity of villous atrophy suggest that impaired balance between granzyme B mediated cytotoxicity and its inhibition by protease inhibitor 9 forms an important factor in the pathogenesis of villous atrophy in celiac disease.
Mixed Type I and Type II Collagen Scaffold for Cartilage Repair: Ultrastructural Study of Synovial Membrane Response and Healing Potential versus Microfractures (A Pilot Study)
Authors: Enea D. , Guerra D. , Roggiani J. , Cecconi S. , Manzotti S. , Quaglino D. , Pasquali-Ronchetti I. , Gigante A.
Published: January 2017

The association between microfracture of the subchondral plate and a coverage scaffold has emerged as a promising strategy to treat cartilage lesions in a one-step procedure. Between different types of scaffolds (e.g. collagen, hyaluronic acid, polyglycolic acid) currently studied, type I collagen scaffold is the most used for this purpose, and is currently adopted for humans. The aim of this study was to test a novel scaffold made of mixed type I and II collagen (I-IICS) in order to define the immunological reaction of the synovial tissue and the repair capabilities induced by the collagen membrane when associated with microfracture. Eight New Zealand White rabbits, aged 180 days, were operated on bilaterally on the medial femoral condyle. A circular cartilage lesion was performed up to the calcified layer of the medial femoral condyle, and the centre of the lesion was microfractured. Randomly, one of the two lesions was covered with the I-IICS (treated), and the other was left uncovered (control). The synovial membrane reaction and the quality of the cartilage tissue repair were investigated at 2, 90, 180 and 270 days macroscopically, histomorphologically and ultrastructurally. Expression of tumor necrosis factor-alpha (TNF-α) in synovial tissue by immunocytochemistry analyses was also investigated. In the control group, at 2 days gold particles were localized mainly on synoviocyte type A, less on synoviocytes type B and on collagen bundles; in the treated group the reaction is more intense in cells in the matrix, but at 180 days controls and treated joints were very similar. The synovial membranes of the joints receiving the I-IICS did not reveal significant changes compared to the age-matched controls. Signs of inflammation were present at the 90-day time-point, and became less evident at afterwards. The degradation of the scaffolds was already evident at the 90-day time-point. The quality of the cartilage repair of the rabbits treated with the I-IICS was slightly better in 5 cases out of 6 in comparison to the controls. However, a statistically significant difference was not detected (p=0.06). Scaffolds made of mixed type I and II collagen exhibited good biocompatibility properties in vivo and favored cartilage restoration when associated with microfracture, as shown in this pilot study.
Allogeneic Adipose Tissue-Derived Mesenchymal Stem Cells in Combination with Platelet Rich Plasma are Safe and Effective in the Therapy of Superficial Digital Flexor Tendonitis in the Horse
Authors: Ricco' S. , Renzi S. , Del Bue M. , Conti V. , Merli E. , Ramoni R. , Lucarelli E. , Gnudi G. , Ferrari M. , Grolli S.
Published: January 2017

Overstrain tendonitis are common pathologies in the sport horses. Therapeutic approaches to tendon healing do not always result in a satisfactory anatomical and functional repair, and healed tendon is often characterized by functional impairment and high risk of reinjury. Recently, mesenchymal stem cells (MSCs) and platelet rich plasma (PRP) have been proposed as novel therapeutic treatments to improve the tendon repair process. MSCs are multipotent, easy to culture and being originated from adult donors do not pose ethical issues. To date, autologous MSCs have been investigated mainly in the treatment of large bone defects, cardiovascular diseases, osteogenesis imperfecta and orthopaedic injuries both in human and veterinary medicine. The clinical applications in which autologous MSCs can be used are limited because patient-specific tissue collection and cell expansion require time. For clinical applications in which MSCs should be used right away, it would be more practical to use cells collected from a donor, expanded in vitro and banked to be readily available when needed. However, there are concerns over the safety and the efficacy of allogeneic MSCs. The safety and efficacy of a therapy based on the use of allogeneic adipose tissue-derived mesenchymal stem cells (ASCs) associated to platelet rich plasma (PRP) were evaluated in 19 horses affected by acute or subacute overstrain superficial digital flexor tendonitis (SDFT). The application of allogeneic ASCs neither raised clinical sign of acute or chronic adverse tissue reactions, nor the formation of abnormal tissue in the long term. After a follow–up of 24 months, 89.5% horses returned to their previous level of competition, while the reinjury rate was 10.5%, comparable to those recently reported for SDFT treated with autologous bone marrow derived MSCs. This study suggests that the association between allogeneic ASCs and PRP can be considered a safe and effective strategy for the treatment of SDF tendonitis in the horse.
Cytochrome P450 Genetic Polymorphism in Neonatal Drug Metabolism: Role and Practical Consequences towards a New Drug Culture in Neonatology
Authors: Fanni D. , Ambu R. , Gerosa C. , Nemolato S. , Castagnola M. , Van Eyken P. , Faa G. , Fanos V.
Published: January 2017

The cytochrome P450 superfamily (CYP450) in humans is formed by 57 functional monooxygenases critical for the metabolism of numerous endogenous and exogenous compounds. The superfamily is organized into 18 families and 44 subfamilies. CYP nomenclature is based on the identity of amino acids. The most important functions of the CYP450 are related to metabolism of endogenous compounds, detoxification of exogenous xenobiotics and decomposition of the vast majority of currently used drugs. The expression of CYP450 enzymes in the human body is characterized by a marked substrate and tissue specificity, the most important being localized in the liver, but also present in kidney, lung, brain, breast, prostate and in the small intestine. The human cytochrome P450 3A gene family (CYP3A) accounts for the largest portion of CYP450 proteins in human liver and includes 4 genes: CYP3A4, CYP3A5, CYP3A7, CYP3A43. Multiple and complex genetic variations, marked interindividual, interethnic and gender variability have been reported regarding CYP3A isoform expression and activity. Multiple factors may affect CYP3A expression and activity, such as inducers like rifampicin, phenobarbital, 3-methylcholantrene, beta-naphtoflavone, and dexamethasone. The maturation of organ systems, paralleled by ontogeny of drug-metabolizing enzymes during fetal life and in the first months of postnatal life, surely exerts profound effects on drug disposition, probably being the predominant factor accounting for age-associated changes in drug clearance. In fact, drug dosage in the perinatal period represents a continuous challenge for neonatologists. The purpose of this article is to provide a brief review of the pharmacokinetic differences between neonates and adults, showing the peculiarities of liver CYP450-related drug metabolism in the perinatal period and at birth, and to report the toxic mechanisms of liver injury in neonates, due to the most frequently utilized drugs in NICU centers.
Is Osteopontin Involved in Cutaneous Fibroblast Activation? Its Hypothetical Role in Scleroderma Pathogenesis
Authors: Corallo C. , Volpi N. , Franci D. , Montella A. , Biagioli M. , Mariotti G. , D'Onofrio F. , Gonnelli S. , Nuti R. , Giordano N.
Published: January 2017

Osteopontin (OPN) is an extracellular matrix protein implicated in bone remodeling, but it presents also pro-inflammatory and pro-fibrotic properties. OPN expression also occurs upon exposure of cells to classical mediators of acute inflammation such as tumor necrosis growth factor alpha (TNF-α) and interleukin-1 beta (IL-1β), as well as fibrogenic cytokines such as transforming growth factor beta (TGF-β), although a detailed understanding of these regulatory pathways is still unknown. Plasma OPN levels in both limited and diffuse systemic sclerosis patients (ISSc and dSSc) were statistically higher compared to those of control subjects. Immunohistology demonstrated that high TGF-β levels, alpha smooth muscle actin (αSMA) levels and consequently high OPN levels were found in the affected skin of sclerodermic patients (ISSc and dSSc) compared to levels found in healthy skin. In order to better understand how OPN interferes with the fibrotic process, healthy skin fibroblasts were treated for 24 and 48 hours with bleomycin and with endothelin-1 (ET-1) plus TGF-β in order to induce the fibrogenesis. After 48 hours of stimulation, healthy treated fibroblasts showed statistically increased αSMA levels (index of differentiation into myofibroblasts) and simultaneously statistically increased OPN levels compared to healthy untreated ones. This study demonstrates that OPN levels increase simultaneously with the increasing of αSMA levels, therefore it is reasonable to hypothesize that OPN interferes in the pathogenesis of Systemic Sclerosis in the early stage of fibroblast differentiation process.