bluuebunny/crossref_metadata_2025 huggingface dataset:
APP/PS1 Transgenic Mice Treated with Aluminum: An Update of Alzheimer's Disease Model
Authors: Zhang Q.L. , Jia L. , Jiao X. , Guo W.L. , Ji J.W. , Yang H.L. , Niu Q.
Published: January 2017

There is still no animal model available that can mimic all the cognitive, behavioral, biochemical, and histopathological abnormalities observed in patients with Alzheimer's disease (AD). We undertook to consider the interaction between genetic factors, including amyloid precursor protein (APP) and presenilin-1 (PS1), and environmental factors, such as Aluminum (Al) in determining susceptibility outcomes when studying the pathogenesis of AD. In this article, we provide an AD model in APP/PS1 transgenic mice triggered by Al. The animal model was established via intracerebral ventricular microinjection of aluminum chloride once a day for 5 days in APP/PS1 transgenic mice. Twenty wild type (WT) mice and 20 APP/PS1 transgenic (TG) mice were separately divided into 2 groups (control and Al group), and a stainless steel injector with stopper was used for microinjection into the left-lateral cerebral ventricle of each mouse. The Morris water maze task was used to evaluate behavioral function of learning and memory ability on the 20th day after the last injection. This AD model's brain was analyzed by: (1) amyloid β immunohistochemical staining; (2) Tunnel staining; (3) apoptotic rates; (4) caspase-3 gene expression. Here, decrease of cognitive ability and neural cells loss were shown in APP/PS1 transgenic mice exposed to Al, which were more extensive than those in APP/PS1 TG alone and WT mice exposed to Al alone. These findings indicate that there is a close relationship between over-expression of APP and PS1 genes and Al overload. It is also suggested that APP/PS1 TG mice exposed to Al have potential value for improving AD models.
Gitr-Expressing Regulatory T-Cell Subsets are Increased in Tumor-Positive Lymph Nodes from Advanced Breast Cancer Patients as Compared to Tumor-Negative Lymph Nodes
Authors: Krausz L.T. , Fischer-Fodor E. , Major Z.Zs. , Fetica B.
Published: January 2017

Lymph node (LN) infiltration by neoplastic process involves important changes in lymph node immune microenvironment. In particular, regulatory T cells (Treg) seem to have a key role in altering the immunoediting function of the immune system which leads to the elusion of the tumor from immune surveillance. In this study, we evaluate the expression of T-cell markers in CD4+ and CD8+ subsets from tumor-positive and tumor-negative lymph nodes from the same, advanced stage breast cancer patient. The study was carried out on 3 patients and similar results were obtained. Flow cytometric analysis of CD8+ cells demonstrated a significant difference in the expression of CD25, CD45RA, CD45RO, and GITRL (Glucocorticoid-Induced TNF receptor-Related ligand). Flowcytometric analysis of CD4+ cells demonstrated a significant difference in the expression of GITR (Glucocorticoid-Induced TNF receptor-Related), CD25, FoxP3 (Forkhead box P3), CD28, and CD45RA. Multiple staining allowed the identification of two Treg subpopulations, CD4+CD25highGITR+CD127−/low and CD4+CD25lowGITR+CD127+ cells, proving that both are increased in the positive nodes in comparison with the negative nodes from the same patient. We identified for the first time the CD4+CD25lowGITR+CD127+ Treg subpopulation in cancer, and the 2.6 fold increase in positive LN suggests that this Treg subpopulation could be a key player in metastasis. We also found GITRL expression in the CD8 lymphocytes, which may also contribute to the changes of metastatic lymph node microenvironment. These findings make both GITR and GITRL good possible co-candidates for future therapeutical intervention against metastasis and perhaps also as disease evolution biomarkers.
Comparison of Immuno-Phenotypes of Stem Cells from Human Dental Pulp and Periodontal Ligament
Authors: Ponnaiyan D. , Bhat K.M. , Bhat G.S.
Published: January 2017

It has been established that human dental pulp and periodontal ligament contain a population of mesenchymal stem cells (MSCs). However, the phenotypic analysis in terms of putative stem cell markers expressed by these stem cell populations is incomplete. It is relevant to understand whether stem cells derived from closely related tissues are programmed differently. The aim of the present study is to analyze whether these stem cells depict distinct characteristics by gaining insight into differences in their immunophenotype. Dental pulp and periodontal ligament tissue samples were obtained from extracted impacted wisdom teeth. Cell cultures were analyzed for surface and intracellular markers by indirect immunoflourescence. Detailed immunophenotype analysis was carried out by flow cytometry using relevant markers. The present study data shows dental pulp stem cells (DPSCs) and periodontal ligament stem cells (PDLSCs) expressed embryonic stem (ES) cell markers Oct-4, Nanog and mesodermal marker Vimentin by indirect immunoflourescence. PDLSCs, however, had a weak expression of Nanog. Immunophenotyping revealed strong expression of MSC markers (CD73, CD90) in DPSCs and PDLSCs. Differences were observed in expression of sternness-related markers. DPSCs displayed increased percentages of SSEA4, CD13 and CD166 and decreased CD9 expression compared to PDLSCs. Both stem cells express common MSC markers, different levels of expression suggests there might be more than one stem cell population existing within these tissues which differ in their embryonic status, and DPSCs are a more primitive stem cell population in comparison to PDLSCs.
Protective Activity of the Ethanol Extract of Cynanchum Paniculatum (Bunge) Kitagawa on Treating Herpes Simplex Encephalitis
Authors: Li X.-F. , Guo Y.-J. , Zhang D.-M. , Chen Z. , Wei X. , Li Y.-H. , Zhang S.-L. , Tao J.-Y , Dong J.-H. , Mei Y.-W. , Li L.-L. , Zhao L.
Published: January 2017

To date there has been no valid treatment for herpes simplex encephalitis (HSV). This study explores the protective activity of ethanol extract of Cynanchum paniculatum (bunge) kitagawa for treatment of HSV. Cell models and animal models were established and divided into 4 groups: normal group, virus group, cynanchum paniculatum group and Dexamethasone group. Flow cytometry was employed to detect apoptosis of cell model and TUNEL assay was chosen to detect apoptosis of animal tissues. The survival time of the animal models was observed. ELISA was used to measure TNF-α expression and the Greiss method to measure Nitric Oxide (NO) expression in the mouse brain. As a result, it was found that extract of Cynanchum paniculatum can improve the survival rate of HSV-infected mice. The extract could prevent apoptosis in the neuron cell model and reduce apoptosis rate in brain tissue after HSV infection. With the extract intervention, TNF-α and NO levels in brain tissue were significantly decreased in the animal model. In conclusion, the extract of Cynanchum paniculatum can prevent HSV-inducing impairment in the cell and animal model of HSE.
Clinical and Histological Outcome Predictors in Renal Limited Pauci-Immune Crescentic Glomerulonephritis: A Single Centre Experience
Authors: Gigante A. , Salviani C. , Giannakakis K. , Rosato E. , Barbano B. , Amoroso A. , Gasperini M.L. , Nofroni I. , Salsano F. , Cianci R. , Pugliese F.
Published: January 2017

Renal-limited vasculitis is a pauci-immune crescentic glomerulonephritis with no signs of systemic involvement, representing one of the most common causes of rapidly progressive glomerulonephritis. The study aims to examine clinical and histological features in twenty-four patients with RLV diagnosed by the Nephrology Department of Sapienza University of Rome, Italy, evaluating the role of these parameters in predicting renal survival. Patients details, clinical and histological features and outcomes were recorded at the time of renal biopsy and over a mean follow-up period of 36±6 months. In our study, serum creatinine at presentation was significantly higher in patients who had a poor outcome than in those who survived with independent renal function (6.3±2.47 mg/dl vs 2.84±2.01 mg/dl, P= 0.002). The presence of C3c was found in the area of glomerular fibrinoid necrosis and in small arteries and arterioles with fibrinoid necrosis in 17 patients (P= 0.018). In conclusion, serum creatinine at presentation and focal C3c depositions in areas of glomerular and arteriolar fibrinoid necrosis were the best determinants of poor renal outcome, maybe underlining the pathogenic role of alternative pathway activation of complement system but also demonstrating the focal distribution of necrotizing lesions.
Mitochondrial Alterations, Oxidative Stress and Neuroinflammation in Alzheimer's Disease
Authors: Verri M. , Pastoris O. , Dossena M. , Aquilani R. , Guerriero F. , Cuzzoni G. , Venturini L. , Ricevuti G. , Bongiorno A.I.
Published: January 2017

Alzheimer's disease (AD) is a multifactorial disorder characterized by the progressive deterioration of neuronal networks. The primary cause and sequence of its progression are only partially understood but abnormalities in folding and accumulation of insoluble proteins such as β-amyloid and Tau-protein are both associated with the pathogenesis of AD. Mitochondria play a crucial role in cell survival and death, and changes in mitochondrial structure and/or function are related to many human diseases. Increasing evidence suggests that compromised mitochondrial function contributes to the aging process and thus may increase the risk of AD. Dysfunctional mitochondria contribute to reactive oxygen species which can lead to extensive macromolecule oxidative damage and the progression of amyloid pathology. Oxidative stress and amyloid toxicity leave neurons chemically vulnerable. The mitochondrial toxicity induced by β-amyloid is still not clear but may include numerous mechanisms, such as the increased permeability of mitochondrial membranes, the disruption of calcium homeostasis, the alteration of oxidative phosphorylation with a consequent overproduction of reactive oxygen species. Other mechanisms have been associated with the pathophysiology of AD. Inflammatory changes are observed in AD brain overall, particularly at the amyloid deposits, which are rich in activated microglia. Once stimulated, the microglia release a wide variety of pro-inflammatory mediators including cytokines, complement components and free radicals, all of which potentially contribute to further neuronal dysfunction and eventually death. Clinically, novel approaches to visualize early neuroinflammation in the human brain are needed to improve the monitoring and control of therapeutic strategies that target inflammatory and other pathological mechanisms. Similarly, there is growing interest in developing agents that modulate mitochondrial function.
Psoriasiform Dermatitis in a Non-Psoriatic Patient Treated with Adalimumab
Authors: Tammaro A. , Persechino S. , Abruzzese C. , Narcisi A. , Cortesi G. , Parisella F.R. , Laganà B.
Published: January 2017

Anti-TNF drugs may be associated with various adverse reactions including cutaneous ones. We describe the case of a 45-year-old woman affected by undifferentiated spondylarthritis who presented a localized psoriasiformis dermatitis during treatment with adalimumab, without any medical history of psoriasis.
Jugulodigastric Lymph Node Inflammation Derived from Chronic Atypical Oropharyngeal Phlogosis Recurring Annually after Flu Virus Vaccination: A Holistic Vision and a Clinical Case Solved after Chlamydicidal Antibiotic Therapy
Authors: Neri G. , Del Boccio M. , Pennelli A. , Martinotti S. , Tenaglia R. , Pugliese M. , Toniato E. , Croce A. , Gallenga P.E.
Published: January 2017

In this report, we evaluated the case history of a patient with longstanding chronic pharyngitis who had periodic clinical manifestation for three years after a flu vaccine administration, and after various treatments tried to resolve the chronic pharyngitis with unsuccessful antibiotic and anti-inflammatory therapies. The patient occasionally presented a slight ocular inflammation, while dysuria occurred after sexual activity. The search for common pathogens by use of pharyngeal swabs resulted only in Corynebacterium ulcerans growth. After this first result, we focused our investigations on ocular and uro-genital infections of Chlamydiaceae (Ct and Cp) and Mycoplasmataceae (Mh and Uu) families. We examined the patient's pharynx using molecular and culture techniques from three different sites. Although several infectious agents, including viruses and bacteria, causing chronic pharyngitis are reported in the literature, these ocular and uro-genital pathogens are seldomly routinely investigated in the same patient in ORL. Furthermore, while episodes of chronic pharyngitis is one of the most common clinical manifestation in ENT patients, these atypical pharyngitis represent ever-increasing infections which must always be considered and researched by suitable instruments such as PCR. Only from the collection of detailed medical history and careful observations of clinical manifestation, indicative of an oral chronic pathologic phenomenon of low intensity initiated several years previously, starting with sudden outbreak and relapse like a bout of flu', we suggest to study these atypical infecting agents frequently localized in the urogenital human area, awhich would allow to highlight and to recognize these clinical cases that manifest themselves as chronic inflammation of jugulodigastric lymph nodes, remaining still unrecognized and rarely associated to chlamydial infection, confused with the response to flu vaccination. After several specific cycles of antibiotic therapy, the patient's health improved considerably and showed almost complete regression of jugulodigastric lymph node inflammation.
Il-18 Level in Patients Undergoing Coronary Artery Bypass Grafting Surgery or Valve Replacement: Which Link with Epicardial Fat Depot?
Authors: Dozio E. , Dogliotti G. , Malavazos A.E. , Bandera F. , Cassetti G. , Vianello E. , Zelaschi R. , Barassi A. , Pellissero G. , Solimene U. , Morricone L. , Sigruener A. , Tarabin V. , Schmitz G. , Menicanti L. , Romanelli M.M. Corsi
Published: January 2017

Interleukin-18 (IL-18) is a member of the interleukin-1 family of cytokines produced constitutively by different cell types and by adipose tissue. Due to the link between obesity, inflammation and cardiovascular diseases, we aimed to measure IL-18 circulating level in patients undergoing open-heart surgery both for elective coronary artery bypass grafting (CABG) or for valve replacement (VR), and we also evaluated whether epicardial adipose tissue (EAT) depot may be a potential source of IL-18. Circulating IL-18 protein was quantified by enzyme-linked immunosorbent assay. IL-18, IL-18 receptor 1 (IL-18 Rl) and IL-18 receptor accessory protein (IL-18-RAP) gene expression in EAT depot were evaluated by one colour microarray platform. EAT thickness was measured by echocardiography. In this study we found that all cardiovascular patients (CABG and VR) have increased circulating IL-18 level compared to healthy control subjects (p < 0.0001), but no statistical significant difference was observed between CABG and VR groups (p = 0.35). A great increase in the gene expression of IL-18 (p < 0.05), IL-18 R1 (p < 0.01) and IL-18 RAP (p < 0.001) was observed in EAT samples obtained from CABG vs VR patients. In conclusion, CABG and VR patients had similar increased level of circulating IL-18 protein, but in EAT depots isolated from CABG gene expression of IL-18, IL-18 R1 and IL-18-RAP resulted higher than in VR patients. Future investigation on local IL-18 protein production, its autocrine-paracrine effect and its correlation with plasmatic IL-18 level could give more information on the relationship between IL-18 and coronary artery disease.
Metabolic Syndrome and Chronic Simvastatin Therapy Enhanced Human Cardiomyocyte Stress before and after Ischemia- Reperfusion in Cardio-Pulmonary Bypass Patients
Authors: Corsetti G. , Pasini E. , Ferrari-Vivaldi M. , Romano C. , Bonomini F. , Tasca G. , Dioguardi F.S. , Rezzani R. , Assanelli D.
Published: January 2017

Metabolic syndrome (MetS) is a set of metabolic alterations including high levels of low-density lipoprotein (LDL), which increase the risk of cardiomyopathy often leading to surgery. Despite inducing myopathy, statins are widely used to lower LDL. Cardiopulmonary bypass (Cpb) causes oxidative stress and metabolic injury, altering mitochondrial expression (Grp75) and endoplasmic reticulum (Grp78) chaperones, apoptotic enzymes (Bcl2 family) and increasing cardiomyocyte lipid/lipofuscin storage. We believe that cardiomyocytes from patients with MetS may be more sensitive to surgical stress, in particular after simvastatin therapy (MetS+Stat). The study group included ten patients with MetS, ten patients with Mets+Stat and ten healthy subjects. Myocardial biopsies were obtained both before and after-Cpb. Grp75, Grp78, Bax, Bcl2, lipids, lipofuscin and fibrosis were evaluated by immuno/histochemistry. MetS cardiomyocytes had higher Grp75, Bax, fibrosis and lipofuscin. MetS+Stat had lower Grp75 and higher Grp78 expressions, high Bax, fewer fibrosis and higher lipofuscin content. Cpb did not vary the fibrosis and lipids/lipofuscin content, although it influenced the chaperones and Bax expression in all groups. These changes were more profound in patients with MetS and even more so in patients with MetS+Stat. The results suggest that MetS and MetS+Stat cardiomyocytes were more highly stressed after-Cpb. Interestingly, simvastatin caused high stress even before-Cpb.
A Pilot Study to Compare Two Different Hyaluronic Acid Compounds for Treatment and Knee Osteoarthritis
Authors: Iannitti T. , Rottigni V. , Palmieri B.
Published: January 2017

Osteoarthritis is characterized by progressive articular cartilage degeneration, changes in subchondral bone and synovial inflammation, leading to pain and disability. Viscosupplementation with hyaluronic acid has been widely investigated due to the viscoelastic properties of this compound to manage pain improving the ability to perform daily activities in patients affected by osteoarthritis. In the present study we investigated the clinical effectiveness of viscosupplementation with a new highly cross-linked hyaluronic acid, Variofill®, in patients affected by bilateral knee osteoarthritis in comparison with the widely used Synvisc®. A total of 20 patients, aged between 24–74 years and affected by bilateral knee osteoarthritis, participated in this pilot randomized triple-blind clinical study. They received two injections (2 ml each) of Synvisc® in their left knee and 2 injections (2 ml each) of Variofill® in their right knee spaced 15 days apart. Visual Analogue Scale and Western Ontario McMaster Universities Osteoarthritis Index score were used to evaluate the efficacy of hyaluronic acid injections before and 3 and 6 months after treatment. Both treatment regimens resulted in a significant improvement vs baseline in all endpoints at 3 and 6 months (p < 0.001). Treatment with Variofill® resulted in a high percentage improvement in Visual Analogue Scale pain, Western Ontario McMaster Universities Osteoarthritis Index score pain and physical activity, when compared to Synvisc® viscosupplementation, at 6 months (p < 0.05). These results are encouraging for larger clinical trials with Variofill® in larger cohorts of patients affected by osteoarthritis of the knee.
Effects and Trimethyltin on Hippocampal Dopaminergic Markers and Cognitive Behaviour
Authors: Mignini F. , Nasuti C. , Artico M. , Giovannetti F. , Fabrizi C. , Fumagalli L. , Iannetti G. , Pompili E.
Published: January 2017

The triorganotin compound trimethyltin (TMT) is a highly toxic molecule which has a great impact on human health. The aim of this study was to investigate the specific alteration of dopamine receptors and transporters in the hippocampus of TMT-treated rats. The TMT-treated group showed impaired spatial reference memory in a Morris water maze task compared to the control group, whereas memory consolidation tested 24 hours after the last training session was preserved. In the open field, TMT-treated rats showed a decrease in time spent in rearing episodes reflecting a lower interest to explore a novel environment. In the hippocampal area of the TMT-treated group, we observed a reduction in neuronal viability accompanied by a significant decrease in the expression of the dopamine receptors (D1 and D2), and dopamine transporters (DAT, VMAT1 and VMAT2). A less pronounced reduction was observed for D3 and D5 while D4 did not change. These data were confirmed by RT-PCR analysis. The present study on TMT-induced neurodegeneration highlights the link between hippocampal asset of dopamine receptors and transporters and the impaired performance of rats in a spatial reference memory task.
Pharmacokinetics and Colchicine in Pediatric and Adult Patients with Familial Mediterranean Fever
Authors: Berkun Y. , Wason S. , Brik R. , Butbul Y. , Ben-Chetrit E. , Hashkes P.J. , Livneh A. , Ozen S. , Ozdogan H. , Faulkner R. , Davis M.W.
Published: January 2017

This study sought to determine the appropriate starting dose of colchicine in children aged 2 to 4 years with familial Mediterranean fever (FMF) based on steady-state pharmacokinetics in pediatric patients with FMF ⩾2 to <16 years and adult patients with FMF ⩾16 to ⩽65 years. Outpatients received colchicine for 90 days starting with a fixed dose for 14 days (blood sampling days 14 and 15). After starting doses of colchicine (0.6 mg/day [⩾2 to <4 years], 0.9 mg/day [⩾4 to <6 years], 0.9 mg/day [⩾6 to <12 years], 1.2 mg/day [⩾12 to <16 years], and 1.2 mg/day [⩾16 to ⩽65 years]), the observed steady-state pharmacokinetic parameters were comparable across age groups, despite the higher doses of colchicine on a mg/kg/day basis in the younger age groups. An exception occurred with once-daily colchicine, whereby mean Cmax for colchicine was higher in patients 4 to <6 years (9.4 ng/mL) compared with the younger and older age groups (6.1–6.7 ng/mL). Mean AUC0-24h values in children 2 to <4, 6 to <12, and 12 to <16 years were similar to those in adults. However, mean AUC0-24h values in children 4 to <6 years were 25% higher than those observed in adults. The results show that the recommended starting dose for children 2–4 years and 4–6 years should be 0.6 mg/day (half the US adult dose). Children aged 6 to <12 years should receive 0.9 mg/day (i.e. three-quarters of the US adult dose). The safety of colchicine in children 2 to <4 years was comparable to that in older children and adults.
Comparitive Effectiveness and Finasteride Vs Serenoa Repens in Male Androgenetic Alopecia: A Two-Year Study
Authors: Rossi A. , Mari E. , Scarnò M. , Garelli V. , Maxia C. , Scali E. , Iorio A. , Carlesimo M.
Published: January 2017

The objective of this open label study is to determine the effectiveness of Serenoa repens in treating male androgenetic alopecia (AGA), by comparing its results with finasteride. For this purpose, we enrolled 100 male patients with clinically diagnosed mild to moderate AGA. One group received Serenoa repens 320 mg every day for 24 months, while the other received finasteride 1 mg every day for the same period. In order to assess the efficacy of the treatments, a score index based on the comparison of the global photos taken at the beginning (T0) and at the end (T24) of the treatment, was used. The results showed that only 38% of patients treated with Serenoa repens had an increase in hair growth, while 68% of those treated with finasteride noted an improvement. Moreover finasteride was more effective for more than half of the patients (33 of 50, i.e. 66%), with level II and III alopecia. We can summarize our results by observing that Serenoa repens could lead to an improvement of androgenetic alopecia, while finasteride confirmed its efficacy. We also clinically observed, that finasteride acts in both the front area and the vertex, while Serenoa repens prevalently in the vertex. Obviously other studies will be necessary to clarify the mechanisms that cause the different responses of these two treatments.
Detection of Bovine Alpha-S1-Casein in Term and Preterm Human Colostrum with Proteomic Techniques
Authors: Orrù S. , Di Nicola P. , Giuliani F. , Fabris C. , Conti A. , Coscia A. , Bertino E.
Published: January 2017

Due to increased social awareness of allergens and population hyper-sensitization, the reported incidence of allergic reactions to food allergens has increased over the past two decades. Cow's milk proteins (CMPs) are among the most common food allergens. The aim of this study was to use proteomics techniques to investigate cow's milk allergens in both full-term human colostrum and in preterm newborns' mothers - where both groups showed no prior allergen detection – in order to understand whether cow's milk allergens could be a cause of sensitization established through lactation. The most relevant finding was the detection of the intact bovine alpha-S1-casein in both term and preterm colostrum. Using techniques detailed in this paper and which allowed for direct protein identification, β-lactoglobulin was not detected in any of the colostrum samples. According to our results, bovine alpha 1 casein is considered a major cow's milk allergen, is readily secreted in human milk, and so could be considered a possible cause of sensitization in exclusively breastfed infants.
Establishment of a Low Dose Canine Endotoxemia Model to Test Anti-Inflammatory Drugs: Effects of Prednisolone
Authors: De Vries F. , Leuschner J. , Jilma B. , Derhaschnig U.
Published: January 2017

Infusion of low doses of lipopolysaccharide (LPS) in human volunteers provides a standardised model to study novel anti-inflammatory drugs. However, low dose endotoxemia is not well characterised in animals larger than rodents and trials with immunomodulating substances are scarce. We conducted a dose-finding study to establish a canine endotoxemia model combining optimal cytokine response with minimal burden for the animals. We thereafter evaluated the pharmacodynamics and pharmacokinetics (PK) of prednisolone. For dose-finding, dogs randomly received a single bolus of 0.03, 0.1 or 1.0μg/kg BW LPS i.v. The second part was a randomised, placebo controlled trial with 4 parallel groups. Either 0.25, 0.5 or 5mg/kgBW prednisolone or placebo were given for 3 days. On day 3, all animals received 0.1μg/kg BW LPS i.v. Blood was sampled to measure interleukin 6 (IL-6) and tumor necrosis factor (TNF)-α, C-reactive protein, prednisolone and cortisol concentrations. In accordance with human endotoxemia, LPS substantially and dose-dependently increased IL-6 and TNF-α several 1000-fold. Prednisolone significantly attenuated the LPS-induced IL-6 and TNF-α responses by a maximum of 96% (p<0.03 for all treatment groups) and significantly reduced peak cortisol concentrations in a dose-dependent way (p<0.004 for all treatment groups). PK showed a non-linear kinetic. In conclusion, this dog model could provide a reliable setting to test experimental drugs for canine or human use.
Clinically-Irrelevant Positivity for Serum Proteinase 3-ANCA in HIV Disease
Authors: Romano C. , Sellitto A. , Restivo L. , Adinolfi L.E.
Published: January 2017

Diagnosis of small-vessel vasculitides (granulomatosis with polyangiitis, microscopic polyangiitis, Churg-Strauss syndrome, and their localized forms) is aided by the detection of serum antineutrophil cytoplasmic antibodies (ANCA). However, serum ANCA positivity does not always mean vasculitis. Here, we report on a 61-year-old female patient with very high serum levels of proteinase 3 ANCA, marked hypergammaglobulinemia, low complement levels, and a 16-mm lung nodule on chest CT scan, who was referred to our Institution with a provisional diagnosis of possible granulomatosis with polyangiitis. On admission, history-taking disclosed two recent episodes of viral reactivation (namely, cytomegalovirus and varicella-zoster virus), while physical examination revealed lingual and nail involvement suggestive of Candida infection. An immunodeficiency disorder was eventually suspected. Search for antibodies against human immunodeficiency virus (HIV) 1 and 2 turned positive. Western blot analysis confirmed HIV infection. Thus, although ANCA detection may be helpful in diagnosing small-vessel vasculitis in the appropriate clinical scenario, screening for HIV infection should sometimes be considered to discriminate clinically irrelevant serum ANCA positivity.
Pharmacological Management of Pediatric Kerion Celsi
Authors: Pranteda G. , Muscianese M. , Grimaldi M. , Tuzi M. , Pranteda G. , Fidanza L. , Tamburi F. , Bottoni U. , Nisticò S.
Published: January 2017

We report a case of severe tinea capitis, treated successfully with griseofulvin. In our opinion, the treatment of this severe dermatophytosis with griseofulvin is safe and effective. Other treatments, such as itraconazole pulsed therapy, failed, despite an initial improvement, leading to an aggressive recurrence of the lesion. We chose griseofulvin for its well-known large spectrum activity, also against uncommon species, like Microsporum Gypseum, which are responsible for the most severe cases.
Latent Virus Reactivation Risk and Biological Drugs: Chronic Inflammatory and Immune-Mediated Disorders
Authors: Nardis C.
Published: January 2017

Psoriasis vulgaris, psoriatic arthritis and rheumatoid arthritis are chronic inflammatory and immune-mediated disorders, widely distributed in the population and induced by several environmental factors in genetically predisposed individuals. Different therapies are currently used to treat these diseases. Since these pathologies are characterized by an altered production of proinflammatory cytokines and chemokines, and biological therapy is based on the development of monoclonal antibodies or recombinant proteins against these molecules, this therapy represents an important option. Nevertheless, it was recently reported that biological agents have been associated with serious life-threatening infections. This article aims to summarize literature data on viral reactivation risk that clinicians need to take into account when selecting the most appropriate biological therapy for such patients.
Role of Steroid Therapy in Pseudoxanthoma Elasticum-like Papillary Dermal Elastolysis
Authors: Pranteda G. , Muscianese M. , Marmo G. , Fidanza L. , Pranteda G. , Tamburi F. , Bottoni U. , Nisticò S.
Published: January 2017

Pseudoxanthoma Elasticum-like Papillary Dermal Elastolysis (PXE-PDE) is a peculiar idiopathic elastolytic disorder that clinically resembles Psudoxanthoma elasticum (PXE). It is histologically characterized by a total or partial loss of elastic fibers in the papillary dermis. It more often affects elderly women and is characterized by asymptomatic and symmetrical yellowish papules localized predominantly on the neck, supraclavicular regions, and flexural areas. After analyzing a series of cases and the recent literature suggesting that glucocorticoids may down-regulate the elastin gene expression and elastin mRNA, in cultured human skin fibroblasts, we think that high dose and prolonged steroid therapy may contribute to the appearance of PXE-PDE lesions.
Immunomodulatory and Protective Properties of Tacrolimus in Experimental Scorpion Envenomation
Authors: Kabrine M. , Laraba-Djebari F.
Published: January 2017

Involvement of imbalance between pro- and anti-inflammatory events has been reported in the developed pathogenesis after scorpion envenomation. The immunosuppressive and anti-inflammatory properties of tacrolimus (FK-506) have been investigated: i) to better understand evolution of signaling pathways which are involved in the immune system ii) to reduce observed clinical signs while keeping a balance between pro- and anti-inflammatory cytokines. Naval Medical Research Institute (NMRI) mice received tacrolimus (1 mg/kg every 12 hours per os) for 21 days before envenomation with a sublethal dose (10 μg/20 g body weight) of Androctonus australis hector venom (Aah). Cell migration, pulmonary edema, exudation, Myeloperoxydase (MPO), Eosinophil peroxydase (EPO), C-reactive protein (CRP), C3, Creatine phosphokinase (CPK), aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), and hyperglycemia were analyzed 30 min, 3 and 24 hours after injection of Aah venom. Histological analysis of lung parenchyma was undertaken 24 hours after envenomation. Aah lethality was evaluated on mice with or without pretreatment with tacrolimus. (Fab')2 fragments (40 mg/kg) were also used as specific treatment in all protocols. Tacrolimus significantly inhibited cell migration, pulmonary edema, exudation, CRP and hyperglycemia. It also decreased MPO and EPO activities and prevented tissue damage in lung tissue, balancing seric parameter levels (CPK, ASAT and ALAT). The pretreated animals seemed to be protected by this macrolide against the venom lethality. These findings suggest that the overactivation of the immune system is one of the causes involved in the aggravation of the pathophysiological effects induced after envenomation. The obtained results showed that the use of F(ab')2 fragments as specific treatment cannot reduce the induced inflammatory response.
Systemic Nickel Allergy Syndrome: Epidemiological Data from Four Italian Allergy Units
Authors: Ricciardi L. , Arena A. , Arena E. , Zambito M. , Ingrassia A. , Valenti G. , Loschiavo G. , D'Angelo A. , Saitta S.
Published: January 2017

The prevalence of nickel hyper-sensitivity varies widely in different countries, nevertheless it is the leading cause of contact dermatitis. The presence of nickel in the diet (mainly plant foods) in some nickel-sensitive subjects can provoke/aggravate eczema and systemic contact dermatitis as well as cause extra-cutaneous symptoms (respiratory, gastrointestinal, neurological). These symptoms, correlated to the ingestion of nickel-containing foods and beverages, in nickel patch test positive individuals, defines the so called “systemic nickel allergy syndrome (SNAS)”, a condition successfully treated by oral desensitization. Although numerous studies have investigated the prevalence of contact nickel allergy or addressed the relationship between nickel intake and onset of systemic symptoms, to our knowledge no epidemiological studies have attempted to estimate the prevalence of SNAS. Therefore, we decided to evaluate consecutive patients (1,696), afferent to four allergy units in Sicily, a region of southern Italy, from October 2010 to March 2011. SNAS was confirmed in 98 patients (5.78%) of the 1,696 studied, suggesting that this clinical entity may be an emergent allergological condition rather than an occasional finding. The most common symptoms complained of in our population were cutaneous (51 patients), gastrointestinal (87 patients) and other systemic clinical manifestations (37 patients). Furthermore, 16 out of the 98 SNAS patients (16.3%) presented IgE-mediated food allergy with a statistically significant association ( X2=16.950; P<.0001), therefore suggesting underlying cross-facilitating pathways. These findings need confirmation on wider populations but may help allergists to suspect, during common clinical practice, that cutaneous and extra-cutaneous symptoms may be referred to nickel intake and deserve specific in-depth investigation.
C-Reactive Protein (CRP) Modulates Lymphocyte Proliferation VIA Affecting Activation Step
Authors: Wiktorowicz K. E. , Kotecki M. , Mackiewicz S. H. , Morkowski J. , Kapcinska M. , Mackiewicz A.
Published: January 2017

The effect of CRP on lymphocyte activation and proliferation in vitro was estimated on the basis of measurement of 3H-thymidine incorporation, analysis of distribution of subsequent cell divisions and analysis of IL-2 receptor expression. Low doses of CRP (less than 3μg/ml) stimulated and high doses (over 5μg/ml) inhibited lymphocyte activation, with little effect on proliferating lymphoblasts. The presence of foetal bovine serum or autologous serum modified CRP action on lymphocytes. The inhibitory effect of CRP on lymphocyte proliferation was similar in cultures stimulated by PHA or by allogeneic cells. On the basis of results obtained, CRP is considered a possible immunomodulator.
Effect of Interleukin-4 on Cytolytic T Cells
Authors: Mondelli M.U.
Published: January 2017

Recent studies indicate that interleukin-4 (IL-4) is a potent T-cell growth factor which may have a significant stimulatory effect on alloreactive cytolytic T lymphocytes (CTL). In this study, it was found that exposure of a recombinant retrovirus (RVpC)-specific, MHC-restricted, polyclonal CTL line to IL-4 resulted in the generation of CTL which efficiently lysed RVpC-infected as well as uninfected autologous target cells. A number of CTL cloned lines was generated from the parental line grown for 2 weeks with autologous stimulator cells in IL-4-containing media which again lysed RVpC-expressing as well as uninfected autologous target cells but not their allogeneic HLA-mismatched counterparts.

These results extend previous observations in allogeneic systems and suggest that, in a syngeneic system, IL-4 may stimulate the recruitment of autoreactive CTL in vitro. This is a previously unrecognised property of IL-4, the in vivo significance of which remains to be established.
Modulation of Cytotoxic Processes by Platelet-Activating Factor
Authors: Pignol B. , Coulomb H. , Hénane S. , Mencia-Huerta J.M. , Braquet P.
Published: January 2017

The effect of platelet-activating factor (PAF) on rat NK cell activity, rat macrophage cytotoxicity and TNF production by rat macrophages and human monocytes was investigated. After a 4-h incubation period, PAF enhanced rat NK cell activity at the effector/target cell ratios of 50/1 and 25/1 in a bell-shape fashion and with a peak effect at 1 nM. After 24 h incubation with 1 μM PAF, rat macrophage cytotoxicity, as assessed at the 20/1 effector/target cell ratio, was also increased. Addition of PAF and lipopolysaccharide (LPS) to rat macrophages or human monocytes markedly enhanced TNF production, whereas PAF alone was ineffective. This enhancement of the LPS-induced TNF production by PAF followed a bell-shape pattern and significant increases were noted at the 30 μM and 1 μM concentrations, as compared the release observed with human monocytes and rat macrophages stimulated with LPS alone, respectively. The effect of PAF on the LPS-induced TNF release from human monocytes appears to be mediated via the interaction of the autacoid with a specific receptor. Indeed, addition of the PAF antagonist, BM 52021 (10 μM), to the incubation medium inhibited by about 50% the enhancing effect fo the autacoid. The bulk of these results indicate that PAF may play a regulatory role in various cytotoxic processes.
Immunomodulating Effects of Various Phenothiazines and Related Tricyclic Compounds in Vitro and in Vivo
Authors: Lilius Esa-Matti , Bakay Marta , Berencsi Klara , Petri I. , Földeak S. , Molnar J.
Published: January 2017

A biotechnological approach to the immunomodulating ability of various phenothiazines and related tricyclic compounds in vitro and in vivo was made. The effect of these compounds was studied on various mononuclear leukocyte functions such as antibody-dependent cell-mediated cytotoxicity, blast transformation of lymphocytes by three mitogens, phytohemagglutinin, concanavalin A and pokeweed mitogen (PWM), rosette formation with erythrocytes and with antibody coated erythrocytes (EA), as well as on polymorphonuclear leukocyte functions including phagocytosis and chemiluminescence emission. Moreover, the ability of these compounds to modulate the bioluminescence emission capacity of Escherichia coli cloned with lux genes was measured. Also in vivo studies were made by measuring the number of haemolytic plaque forming cells in the spleen of mice after drug administration.

The electrochemical structure of these tricyclic compounds was shown to be in good correlation with their immunomodulating activity on all the functions except EA rosette formation and on blast transformation by PWM showing the role of charge transfer complex formation in the drug-target cell interaction.

These results suggest that the biological effectiveness of phenothiazines and related tricyclic compounds can be presumed from their electrochemical properties and a tricyclic compound with a given biological effect can be theoretically designed.
The Complement System
Authors: Agostoni A. , Cicardi M. , Gardinali M. , Bergamaschini L.
Published: January 2017

The human complement system (C) acts to lyse susceptible cells, to promote phagocytosis of target particles, and to solubilize immune-complexes, its activation generates peptides that mediate features of the inflammatory response. It is comprised of a series of plasma zymogens, activated by proteolytic cleavage in a cascade manner, and of plasma and cell membrane control proteins. Activation is achieved by two independent routes: the classical pathway, started by immunoglobulins, and the alternative pathway, started by cell membrane components. Both of them promote the generation of an enzyme-complex (C3 convertase) able to cleave the pivotal protein of the complement system, C3, thus initiating the common pathway with the formation of the lytic complex (Figure 1).

In this paper we will briefly review the physiologic phenomena related to the complement activation and its role in pathogenesis of illness particularly focusing on the studies carried out in our laboratory.
The Effect of C-Reactive Protein (CRP) on Respiratory Burst of Human Peripheral Blood Phagocytes
Authors: Cofta J. , Lacki J.K. , Mackiewicz S.H. , Wiktorowicz K.E.
Published: January 2017

The effect of C-reactive protein (CRP) on the oxidative response of human peripheral blood monocytes and granulocytes was investigated. The respiratory burst of phagocytes induced by phorbol-myristate-13-acetate (PMA), phytohaemagglutinin (PHA) or opsonized zymosan (OZ) was measured in luminol-enhanced chemiluminescence.

The effect of CRP on PMA-induced monocyte chemiluminescence (CL) depended both on CRP concentration and incubation time. A short incubation of cells with CRP (15–30 min.) enhanced the oxidative burst. Preincubation of cells for 1h (or longer) with low doses of CRP (about 2 μg/ml) increased, while with higher (>10 μg/ml) inhibited PMA-stimulated chemiluminescence. CRP reduced also PHA or OZ-induced monocyte respiratory response. CRP diminished PMA, PHA, and OZ-induced granulocyte chemiluminescence, except the response to PHA in the presence of low doses CRP (about 5 μg/ml).

The action of CRP on phagocytes probably involves activation of some intracellular mechanisms. During immune response, CRP could protect tissues against damage by excess of free oxygen and its biological active derivatives.
The Presence and Clearance of Immune Complexes in the Untreated Generalised Psoriasis
Authors: Ahangari G. , Rakhshan M. , Farhoudi A. , Eslami M. B. , Mortazavi H. , Pakzad P.
Published: January 2017

Psoriasis is a hyperproliferative inflammatory disease and 70% of patients develop a chronic plaque form of the disease. The pathogenesis of psoriasis is not known but evidence exists that changes in micro vascular occur. There are micro vascular abnormalities in the capillaries which display a multilayer basement membrane with fenestration. Study of involved synovium in psoriatic arthritis reveals endothelial cell swelling, thickening of the vessel walls and inflammatory cell infiltration. Investigation on expression of CD35 molecules that clear the immune complexes were carried out in this study. CD35 is single chain glycoprotein (MW160–240 kD) and is located on the long arm of the chromosome 1. FACScan was used as laser flow cytometer. Initially 40 blood samples from normal individuals, 35 untreated Lupus Erythematosus Systemic and 35 Rheumatoid arthritis patients were studied as controls for reference values of CD35, Circulating immune Complexes (CIC), Complement C3 & C4. Next 34 patients suffering from psoriasis were studied for, Circulating immune Complexes (CIC), Complement C3 & C4. Comparison of these results with those of reference values normal ranges showed significant increase of CIC (P<0.05) and decrease of CD35 (P<0.001). Where as, the complement component levels C3 (P>0.05) and C4(P>0.05) indicates werenot significantly altered. This study shows that the decrease in expression of CD35 on Red blood cells in psoriasis patients is more crucial than C3 and C4 levels. Thus decrease of CD35 molecule in psoriasis may cause increased levels of CIC in patients' sera and promotion of inflammatory responses.
Interleukin-12, a New Anti-Tumor Cytokine
Authors: Mier James W. , Gollob Jared A. , Atkins Michael B.
Published: January 2017

Of the numerous cytokines that have been isolated and characterized over the last several years, few have attracted as much attention as Interleukin-12 (IL-12). Since its discovery ten years ago, the intracellular signaling pathways activated by IL-12 have been identified, the individual components of the receptor cloned, and many of its effects on cellular immune function documented. Recombinant murine IL-12 has been subjected to extensive investigation in animal models of cancer and parasitic infection and shown great promise as an antitumor agent and a potential treatment for leishmaniasis. Preclinical data suggest that it may also be useful in the treatment of antibiotic-resistant tuberculosis and AIDS. Recombinant human IL-12 (rhIL-12) has recently entered Phase I and II clinical testing in cancer patients. The following is a brief review of the immunologic effects of IL-12, the results of animal studies, and data from recently completed clinical trials.
Are Animal Studies of Antipsychotics Appropriately Dosed?: Lessons from the Bedside to the Bench
Authors: Kapur Shitij , Wadenberg Marie-Louise , Remington Gary
Published: January 2017

Animal models are crucial for understanding the mechanism of action of antipsychotics. However, the dose of an antipsychotic in animal studies is often arbitrarily chosen, with haloperidol 1 mg/kg being a rather common standard. Recent clinical positron emission tomography (PET) studies in patients show all antipsychotics to block dopamine D2 receptors, and most are effective at doses that lead to 60% to 80% D2 occupancy. When occupancy exceeds 80%, the incidence of side effects rises sharply. To use this “bedside” information to inform the “bench,” we measured D2 occupancy in rats using a method similar in principle to the [11 C]-raclopride PET method in humans. We found that: 1) as in humans, haloperidol is effective in animal models of antipsychotic action when D2 occupancy > 70% and leads to effects in models of extrapyramidal side effects when D2 occupancy is > 80%; 2) very low doses, 0.06 mg/kg/sc, cause acute D2 occupancy of 75%; 3) and even doses that acutely saturate D2 receptors give little D2 occupancy after 24 hours due to the very short half-life of haloperidol in rats (2.5 hours versus 24 hours in humans). We conclude that most previous animal studies of antipsychotics have used doses giving rise to inappropriately high acute D2 occupancy and inappropriately low D2 occupancy between doses. We exemplify how this dosing confounder could lead to inappropriate conclusions. Data from the bedside translated to the bench—using D2 occupancy as a mediating variable—will lead to more valid animal models.