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Asthma is a chronic respiratory disease in which airway inflammation is a key feature, even in the milder expressions of the disease. The conventional pharmacological approach to mild asthma has long relied on reliever therapy with as-needed short-acting beta-agonists (SABAs), while anti-inflammatory maintenance with inhaled corticosteroids (ICSs) has been reserved for patients with more persistent asthma. Poor adherence to maintenance treatment is an important issue in asthma management, and can partly explain suboptimal symptom control. Over-reliance on SABA bronchodilators for rapid symptom relief is common in real life and potentially leads to an increased risk of asthma morbidity and mortality. Combined anti-inflammatory and reliever medications in a single inhaler have the potential to overcome these limitations. Recent studies in patients with mild asthma have shown that anti-inflammatory reliever therapy with budesonide-formoterol, given on an as-needed basis, is superior to SABA in ensuring asthma control and non-inferior to budesonide maintenance therapy in preventing exacerbations. To address the implications of these important findings for the management of patients with asthma, Italian specialists convened at a series of meetings held during the second half of 2018 across Italy. This article presents their position on these topics and includes a review of the evidence supporting the use of anti-inflammatory reliever therapy in mild asthma and the implementation of this novel approach in clinical practice.

Recently, dupilumab, an anti-IL-4Rα antibody, has become available for the treatment of moderate-to-severe atopic dermatitis (AD).1-4 Baseline patient characteristics that can be used as predictors of response to dupilumab treatment in AD patients have not yet been identified.

Hyperthermia represents an interesting therapeutic strategy for the treatment of tumors. Moreover, it is able to regulate several aspects of the immune response. Fas (APO-1/CD95) and its ligand (FasL) are cell surface proteins whose interaction activates apoptosis of Fas-expressing targets. In T cells, the Fas-Fas-L system regulates activation-induced cell death, is implicated in diseases in which lymphocyte homeostasis is compromised, and plays an important role during cytotoxic and regulatory actions mediated by these cells. In this study we describe the effect of hyperthermia on activation of the fas-L gene in T lymphocytes. We show that hyperthermic treatment enhances Fas-L-mediated cytotoxicity, fas-L mRNA expression, and fas-L promoter activity in activated T cell lines. Our data indicate that hyperthermia enhances the transcriptional activity of AP-1 and NF-κB in activated T cells, and this correlates with an increased expression/nuclear translocation of these transcription factors. Moreover, we found that heat shock factor-1 is a transactivator of fas-L promoter in activated T cells, and the overexpression of a dominant negative form of heat shock factor-1 may attenuate the effect of hyperthermia on fas-L promoter activity. Furthermore, overexpression of dominant negative mutants of protein kinase Cε (PKCε) and PKCθ partially inhibited the promoter activation and, more importantly, could significantly reduce the enhancement mediated by hyperthermia, indicating that modulation of PKC activity may play an important role in this regulation. These results add novel information on the immunomodulatory action of heat, in particular in the context of its possible use as an adjuvant therapeutic strategy to consider for the treatment of cancer.

BACKGROUND Dupilumab has been demonstrated to be an effective treatment for patients with moderate-to-severe atopic dermatitis (AD) in clinical trials. However, evidence of real-world experience with dupilumab in a broader population is limited to date. METHODS Adult patients with moderate-to-severe AD, defined as an Eczema Area Severity Index (EASI) score of 24 or higher, treated with dupilumab at ten Italian academic centers, were included in the study. Physician-reported outcome measures (EASI), patient-reported outcome measures (pruritus and sleep score, Dermatology Life Quality Index, DLQI) and serological markers [immunoglobulin (Ig) E and eosinophil count] after 16 weeks were analyzed. RESULTS We enrolled 543 patients with moderate-to-severe AD. Two patients (0.4%) discontinued treatment. The median ± interquartile percentage change from baseline to 16 weeks of treatment in the EASI score was -87.5±22.0 (p

Background: Benralizumab is effective in severe eosinophilic asthma (SEA), but suboptimal responses are observed in some patients. Although several factors have been associated with benralizumab response, no cluster analysis has yet been undertaken to identify different responsiveness sub-phenotypes. Objective: To identify SEA sub-phenotypes with differential responsiveness to benralizumab. Methods: One hundred and five patients diagnosed with SEA who had completed 6months of benralizumab treatment were included in a hierarchical cluster analysis based on a set of clinical variables that can be easily collected in routine practice (age, age at disease onset, disease length, allergen sensitization status, blood eosinophil count, IgE levels, FEV1% predicted, nasal polyposis, bronchiectasis). Results: Four clusters were identified: Clusters 2 and 3 included patients with high levels of both IgE and eosinophils (type-2 biomarkers high), whereas Clusters 1 and 4 included patients with only one type-2 biomarker at a high level: IgE in Cluster 1 and eosinophils in Cluster 4. Clusters 2 and 3 (both type-2 biomarkers high) showed the highest response rate to benralizumab in terms of elimination of exacerbations (79% and 80% respectively) compared to Clusters 1 and 4 (52% and 60% respectively). When super-response (the absence of exacerbation without oral corticosteroid use) was assessed, Cluster 2, including patients with more preserved lung function than the other clusters, but comparable exacerbation rate, oral corticosteroid use and symptom severity, was the most responsive cluster (87.5% of patients). Conclusions: Our cluster analysis identified benralizumab differential response sub-phenotypes in SEA, with the potential of improving disease treatment and precision management.

Dupilumab, an inhibitor of interleukin (IL)-4/13 activity, is a biological agent approved for the treatment of moderate-to-severe atopic dermatitis (AD)1 . Our aim was to assess the long-term effectiveness and safety of dupilumab in a clinical real-life setting.

Introduction There is, so far, no universal definition of severe asthma. This definition usually relies on: number of exacerbations, inhaled therapy, need for oral corticosteroids, and respiratory function. The use of such parameters varies in the different definitions used. Thus, according to the parameters chosen, each patient may result in having severe asthma or not. The aim of this study was to evaluate how the choice of a specific definition of severe asthma can change the allocation of patients. Methods Data collected from the Severe Asthma Network Italy (SANI) registry were analyzed. All the patients included were then reclassified according to the definitions of U-BIOPRED, NICE, WHO, ATS/ERS, GINA, ENFUMOSA, and TENOR. Results 540 patients, were extracted from the SANI database. We observed that 462 (86%) met the ATS/ERS criteria as well as the GINA criteria, 259 (48%) the U-Biopred, 222 (41%) the NICE, 125 (23%) the WHO, 313 (58%) the Enfumosa, and 251 (46%) the TENOR criteria. The mean eosinophil value were similar in the ATS/ERS, U-Biopred, and Enfumosa (528, 532 and 516 cells/mcl), higher in WHO and Tenor (567 and 570 cells/mcl) and much higher in the NICE classification (624 cells/mcl). Lung function tests resulted similarly in all groups, with WHO (67%) and ATS/ERS-GINA (73%), respectively, showing the lower and upper mean FEV1 values. Conclusions The present observations clearly evidence the heterogeneity in the distribution of patients when different definitions of severe asthma are used. However, the recent definition of severe asthma, provided by the GINA document, is similar to that indicated in 2014 by ATS/ERS, allowing mirror reclassification of the patients examined. This lack of homogeneity could complicate the access to biological therapies. The definition provided by the GINA document, which reflects what suggested by ATS/ERS, could partially overcome the problem.

Background and aims Severe asthma is burdened by frequent exacerbations and use of oral corticosteroids (OCS) which worsen patients’ health and increase healthcare spending. Aim of this study was to assess the clinical and economic effect of adding mepolizumab (MEP) for the treatment of these patients. Methods Patients >18 years old, referred to 8 asthma clinics, starting MEP between May 2017 and December 2018, were enrolled and followed-up for 12 months. Information in the 12 months before mepolizumab were collected retrospectively. The evaluation parameters included: OCS use, number of exacerbations/hospitalizations, concomitant therapies, comorbidity, and annual number of working days lost due to the disease. The primary objective was to compare the annual total cost per patient pre- and post-MEP. Secondary outcomes included rates of exacerbations and number of OCS-dependent patients. Results 106 patients were enrolled in the study: 46 male, median age 58 years. Mean annual cost pre- and post-MEP (cost of biologic excluded) was €3996 and €1,527, respectively. Total savings due to MEP resulted in €2469 (95%CI 1945–2993), 62% due to exacerbations reduction and 33% due to productivity increase. Such savings could fund about 22% of the total cost of MEP for one year. The introduction of MEP induced a clinical benefit by reducing both OCS-dependent patients (OR = 0.12, 95%CI 0.06–0.23) and exacerbation rate (RR = 0.19, 95%CI 0.15–0.24). Conclusions Patients with severe eosinophilic asthma experienced a clinical benefit in asthma control adding MEP to standard therapy. Biologic therapy can be, partially, funded by the savings produced by patients’ improvement.

Background: Rising pollution plays a crucial role in worsening several respiratory diseases. Particulate Matter (PM)-induced asthma exacerbations are one of the most dangerous events. Objectives: To assess the correlation between progressive particulate matter short-term exposure and asthma exacerbations, we investigated the role of PM levels on Emergency Department (ED) admissions and hospitalizations for these events in Brescia, an important industrial city located in northern Italy with high yearly levels of air pollution. Methods: We analyzed 1050 clinical records of ED admissions for suspected asthma exacerbation, starting from January 2014 to December 2017. Daily PM levels were collected from the Environmental Protection Regional Agency. We performed a time-series analysis using a Poisson regression model with single and multiple day-lag. Results were expressed as Relative Risk (RR) and Excess of Relative Risk (ERR) of severe asthma exacerbation over a 10 µg/m3 increase in PM10 and PM2.5 concentration. Results: We selected and focused our analysis on 543 admissions for indisputable asthma exacerbation in ED and hospital. The time-series study showed an increase of the RR (CI95%) for asthma exacerbation-related ED admissions of 1.24 with an ERR of 24.2% for PM2.5 at lag0–1 (p < 0.05). We also estimated for PM2.5 a RR (CI95%) of 1.12 with an ERR of 12.5% at lag0–5 (p ≤ 0.05). Again, for PM2.5, an increase of the RR (CI95%) for asthma exacerbation-related hospitalizations of 1.31 with an ERR of 30.7% at lag0–1 (p < 0.05) has been documented. These findings were confirmed and even reinforced considering only the population living in the city. Conclusions: Short-term PM exposure, especially for PM2.5, plays a critical role in inducing asthma exacerbation events leading to ED admission or hospitalization.

Coronavirus disease 2019 (COVID-19) is induced by SARS-CoV-2 and may arise as a variety of clinical manifestations, ranging from an asymptomatic condition to a life-threatening disease associated with cytokine storm, multiorgan and respiratory failure. The molecular mechanism behind such variability is still under investigation. Several pieces of experimental evidence suggest that genetic variants influencing the onset, maintenance and resolution of the immune response may be fundamental in predicting the evolution of the disease. The identification of genetic variants behind immune system reactivity and function in COVID-19 may help in the elaboration of personalized therapeutic strategies. In the frenetic look for universally shared treatment plans, those genetic variants that are common to other diseases/models may also help in addressing future research in terms of drug repurposing. In this paper, we discuss the most recent updates about the role of immunogenetics in determining the susceptibility to and the history of SARS-CoV-2 infection. We propose a narrative review of available data, speculating about lessons that we have learnt from other viral infections and immunosenescence, and discussing what kind of aspects of research should be deepened in order to improve our knowledge of how host genetic variability impacts the outcome for COVID-19 patients.

Hepatitis B virus (HBV) infection causes a self-limiting disease in most individuals. However

Mediterranean spotted fever (MSF) is endemic in Italy, where Rickettsia conorii subsp. conorii was thought to be the only pathogenic rickettsia and Rhipicephalus sanguineus the vector and main reservoir. R. conorii subsp. israelensis, which belongs to the R. conorii complex, is the agent of Israeli spotted fever (ISF); apart from Israel, it has also been found in Italy (Sicily and Sardinia) and in different regions of Portugal. We describe here two severe cases of ISF which occurred in otherwise healthy Italian adults. Their characteristics are analyzed and discussed in the light of other 91 cases found through a systematic review of international literature.

Bitter taste receptors (TAS2R) are involved in a variety of non-tasting physiological processes, including immune-inflammatory ones. Therefore, their genetic variations might influence various traits. In particular, in different populations of South Italy (Calabria, Cilento, and Sardinia), polymorphisms of TAS2R16 and TAS238 have been analysed in association with longevity with inconsistent results. A meta-analytic approach to quantitatively synthesize the possible effect of the previous variants and, possibly, to reconcile the inconsistencies has been used in the present paper. TAS2R38 variants in the Cilento population were also analysed for their possible association with longevity and the obtained data have been included in the relative meta-analysis. In population from Cilento no association was found between TAS2R38 and longevity, and no association was observed as well, performing the meta-analysis with data of the other studies. Concerning TAS2R16 gene, instead, the genotype associated with longevity in the Calabria population maintained its significance in the meta-analysis with data from Cilento population, that, alone, were not significant in the previously published study. In conclusion, our results suggest that TAS2R16 genotype variant is associated with longevity in South Italy.

Background Guidelines and position papers indicate that allergen immunotherapy (AIT) is the only disease-modifying treatment, including prevention of the onset of new allergen sensitizations. However, this preventive effect was shown by only a few observational studies. Our aim was to systematically review the efficacy of AIT in preventing the onset of new allergen sensitizations. Methods Computerized bibliographic searches of MEDLINE, EMBASE, and the Cochrane Library (through June 2015) were supplemented with manual searches of reference lists. Observational studies or randomized controlled trials with a long-term observation period were included. Paired reviewers extracted data about study characteristics and assessed biases. The end-point was the risk difference in the onset of new allergen sensitizations between patients treated with AIT and pharmacotherapy. The strength of the evidence was graded based on the risk of bias, consistency, and magnitude of effect, according to the GRADE Working Group's guide. Results Eighteen studies (1,049 children, 10,057 adults) met the inclusion criteria. The risk of bias was high in all but one study. Low evidence supports the position that AIT prevents the onset of new allergen sensitizations, with 10 out of 18 studies reporting a reduction of the onset of new sensitizations in patients treated with AIT vs. placebo. Small studies and studies with a shorter follow-up showed the highest benefit of AIT. Conclusions The overall evidence provides a low-grade level of the evidence supporting the efficacy of AIT in preventing the onset of new allergen sensitizations, but high-quality studies could change this estimate. This article is protected by copyright. All rights reserved

Killer immunoglobulin-like receptors (KIRs) regulate the activation of Natural Killer cells through their interaction with human leukocyte antigens (HLA). KIR and HLA loci are highly polymorphic and certain HLA-KIR combinations have been found to protect against viral infections. In this study we analyzed whether the KIR/HLA repertoire may influence the course of hepatitis B virus (HBV) infection. Fifty-seven subjects with chronic hepatitis B (CHB), 44 subjects with resolved HBV infection, and 60 healthy uninfected controls (HC) were genotyped for KIR and their HLA ligands. The frequency of the HLA-A-Bw4 ligand group was higher in CHB (58%) than subjects with resolved infection (23%) (crude OR, 4.67; P< 0.001), and HC (10%) (crude OR,12.38; P< 0.001). Similar results were obtained for the HLA-C2 ligand group, more frequent in CHB (84%), than subjects with resolved infection (70%) (crude OR, 2.24; P< 0.10), and HC (60%) (crude OR, 3.56; P< 0.01). Conversely, the frequency of KIR2DL3 was lower in CHB (81%) than in subjects with resolved infection (98%) (crude OR,0.10; P< 0.05). These results suggest a detrimental role of HLA-A-Bw4 and HLA-C2 groups, which are associated with the development of CHB, and a protective role of KIR2DL3. A stepwise variable selection procedure, based on multiple logistic regression analysis, identified these three predictive variables as the most relevant, featuring high specificity (90.9%), and positive predictive value (87.5%) for the development of CHB. Our results suggest that a combination of KIR/HLA gene/alleles is able to predict the outcome of HBV infection

Immunological mechanisms involved in the genesis of the immune response against viral infections take into account the activation of both innate adaptative response. Innate immune defenses trigger a rapid local response, which is often sufficient to control viral infection, and promotes the subsequent activation of specific immune defenses. Natural killer (NK) cells that constitute a subpopulation of lymphocyte-related cells are a key factor of innate immune response and play a role in defense against viral infections by killing infected cells or by producing cytokines and interacting with adaptative immune system's cells. Killer immunoglobulin-like receptors (KIRs) regulate the activation of NK cells through their interaction with human leukocyte antigens (HLA). KIRs and HLA loci are highly polymorphic and certain HLA-KIRs combinations have been found to protect against viral infections. In this study we review how the KIRs/HLA repertoire may influence the course of hepatitis B virus (HBV), hepatitis C virus (HCV), cytomegalovirus (CMV) and Herpes Simplex Virus 1 (HSV-1) infection. Results of our study suggest that a combination of KIRs/HLA gene/alleles is able to predict the outcome of viral infection and allows to plan successful customized therapeutic strategies.

Introduction Patients with chronic liver diseases are usually thin as a result of hypermetabolism and malnutrition expressed by reduced levels of leptin and impairment of other adyponectins such as visfatin. Aims We evaluated the metabolic and inflammatory effects of intravenous high-dose furosemide plus hypertonic saline solutions (HSS) compared with repeated paracentesis and a standard oral diuretic schedule, in patients with cirrhosis and refractory ascites. Methods 59 consecutive cirrhotic patients with refractory ascites unresponsive to outpatient treatment. Enrolled subjects were randomized to treatment with intravenous infusion of furosemide (125-250mg⁄bid) plus small volumes of HSS from the first day after admission until 3 days before discharge (Group A, n:38), or repeated paracentesis from the first day after admission until 3 days before discharge (Group B, n: 21). Plasma levels of ANP, BNP, Leptin, visfatin, IL-1β, TNF-a, IL-6 were measured before and after the two type of treatment. Results Subjects in group A were observed to have a significant reduction of serum levels of TNF-α, IL-1β, IL-6, ANP, BNP, and visfatin, thus regarding primary efficacy endpoints, in Group A vs. Group B we observed higher Δ-TNF-α, Δ-IL-1β, Δ-IL-6, Δ-ANP, Δ-BNP, Δ-visfatin, Δ-Leptin at discharge. Discussion Our findings underline the possible inflammatory and metabolic effect of saline overload correction in treatment of cirrhosis complications such as refractory ascites, suggesting a possible role of inflammatory and metabolic-nutritional variables as severity markers in these patients.

UNLABELLED It has been hypothesized that polymorphisms of interleukin (IL)-10 genes affect the risk of developing late onset Alzheimer's disease (AD). However, results of different studies are often inconsistent. Our aim was to investigate by meta-analysis the association of the common polymorphisms comprehensively defining the genetic variability of the IL-10 gene with AD risk. Fifteen studies investigating the association between IL-10 polymorphisms (-1082, -819, -592) and AD were found and analyzed. The model-free approach was applied to meta-analyze these case-control genetic association studies. Available data suggested an association between -1082 polymorphism and AD risk with a marginal statistical significance (GG versus AG/AA pooled odds ratio [OR]: 0.82, 95% confidence interval CI: 0.65-1.02) and evidence of a moderate degree of between-study heterogeneity (χ2 = 27.13, d.f. = 13, p = 0.01, I2 = 52%). For the -819 and -592 polymorphisms, we did not find an association with AD, but significant between-study heterogeneity made genotype data pooling unacceptable. Analysis by IL-10 haplotype showed that the -1082G/-819C/-592C haplotype is associated with a lower risk of AD, although with a marginal statistical significance, probably due to the low number of studies included (GCC versus other genotypes: OR: 0.61, 95% CI: 0.32-1.15; I2: 85%). Current findings suggest a possible association between -1082 A > G polymorphism and the risk of developing AD; this effect is more evident in the oldest patients. The high degree of between-study heterogeneity, due to several underpowered studies and to other methodological problems of individual studies underlies the need for further methodologically adequate studies.

Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disease which in Western society mainly accounts for clinical dementia. AD has been linked to inflammation and oxidative stress. Neuro-pathological hallmarks are senile plaques, resulting from the accumulation of several proteins and an inflammatory reaction around deposits of amyloid, a fibrillar protein, Abeta, product of cleavage of a much larger protein, the beta-amyloid precursor protein (APP) and neurofibrillary tangles. Inflammation clearly occurs in pathologically vulnerable regions of AD and several inflammatory factors influencing AD development, i.e. environmental factors (pro-inflammatory phenotype) and/or genetic factors (pro-inflammatory genotype) have been described. Irrespective of the source and mechanisms that lead to the generation of reactive oxygen species, mammalian cells have developed highly regulated inducible defence systems, whose cytoprotective functions are essential in terms of cell survival. When appropriately activated, each one of these systems has the possibility to restore cellular homeostasis and rebalance redox equilibrium. Increasing evidence, support the notion that reduction of cellular expression and activity of antioxidant proteins and consequent augment of oxidative stress are fundamental causes for ageing processes and neurodegenerative diseases., including AD. The better understanding of different molecular and cellular inflammatory mechanisms is crucial for complete knowledge of AD pathophysiology, hence for its prevention and drug therapy. Accordingly, two lines of preventive therapeutics can be outlined, the first based on anti-inflammatory drugs, the second one on anti-oxidative properties.

Statins have beneficial effects on cerebral circulation and brain parenchyma during ischemic stroke and reperfusion. The primary hypothesis of this randomized parallel trial was that treatment with 80 mg/day of atorvastatin administered early at admission after acute atherosclerotic ischemic stroke could reduce serum levels of markers of immune-inflammatory activation of the acute phase and that this immune-inflammatory modulation could have a possible effect on prognosis of ischemic stroke evaluated by some outcome indicators. We enrolled 42 patients with acute ischemic stroke classified as large arteries atherosclerosis stroke (LAAS) randomly assigned in a randomized parallel trial to the following groups: Group A, 22 patients treated with atorvastatin 80 mg (once-daily) from admission day until discharge; Group B, 20 patients not treated with atorvastatin 80 mg until discharge, and after discharge, treatment with atorvastatin has been started. At 72 hours and at 7 days after acute ischemic stroke, subjects of group A showed significantly lower plasma levels of tumor necrosis factor-α, interleukin (IL)-6, vascular cell adhesion molecule-1, whereas no significant difference with regard to plasma levels of IL-10, E-Selectin, and P-Selectin was observed between the 2 groups. At 72 hours and 7 days after admission, stroke patients treated with atorvastatin 80 mg in comparison with stroke subjects not treated with atorvastatin showed a significantly lower mean National Institutes of Health Stroke Scale and modified Rankin scores. Our findings provide the first evidence that atorvastatin acutely administered immediately after an atherosclerotic ischemic stroke exerts a lowering effect on immune-inflammatory activation of the acute phase of stroke and that its early use is associated to a better functional and prognostic profile.

IMPORTANCE: Randomized clinical trials (RCTs) and meta-analyses of sublingual immunotherapy (SLIT) for the treatment of seasonal allergic rhinoconjunctivitis (SARC) have shown a modest clinical benefit compared with placebo. Furthermore, indirect comparison by meta-analyses showed that subcutaneous immunotherapy is more effective than SLIT. Despite these data, SLIT has become the most prescribed treatment of SARC in Europe in recent years, and it was approved by the US Food and Drug Administration for the treatment of SARC to grass pollen in the United States on April 1, 2014. OBJECTIVE: To assess the efficacy and safety of the grass pollen sublingual tablets licensed as drugs in the treatment of patients with SARC to grass pollen. DATA SOURCES: Computerized bibliographic searches of MEDLINE, EMBASE, the Cochrane Library, and ClinicalTrials.gov (from inception to April 30, 2014) were supplemented with a manual search of reference lists. STUDY SELECTION: Randomized clinical trials were included if they compared the grass pollen SLIT tablets approved by regulatory authorities in the European Union and the United States for SARC with placebo. DATA EXTRACTION AND SYNTHESIS: Data on populations, interventions, and outcomes were extracted from each RCT according to the intent-to-treat method by 2 independent observers and were combined using the method by DerSimonian and Laird. MAIN OUTCOMES AND MEASURES: The primary end point was the difference in the symptom score and medication score between SLIT and placebo. We pooled data using random-effects meta-analysis, with standardized mean differences (SMDs) and 95% CIs reported. RESULTS: Data were available in 13 RCTs for the symptom score (4659 patients) and in 12 RCTs for the medication score (4558 patients). We found a small treatment benefit in the symptom score (SMD, -0.28; 95% CI, -0.37 to -0.19; P < .001) and in the medication score (SMD, -0.24; 95% CI, -0.31 to -0.17; P < .001). Adverse events were reported in 1384 of 2259 patients (61.3%) receiving SLIT and in 477 of 2279 patients (20.9%) receiving placebo. Seven patients in the SLIT group reported treatment-related adverse events requiring epinephrine. CONCLUSIONS AND RELEVANCE: Findings show a small benefit of the grass pollen sublingual tablets in reducing symptoms and in decreasing the use of symptomatic medication (antihistamines and corticosteroids) in patients with SARC. Considering the low magnitude of the benefit, the convenience and easy administration do not seem to be sufficient reasons for the choice of SLIT.

BACKGROUND/AIMS: Unresponsiveness to IFN-alpha is common in chronic hepatitis C. Since conditions associated with an increased oxidative stress (advanced age, steatosis, fibrosis, iron overload, and alcohol consumption) reduce the likelihood of response, we hypothesized that oxidative stress may affect the antiviral actions of IFN-alpha. METHODS: We examined in a human hepatocellular carcinoma cell line (Huh-7) the effect of hydrogen peroxide (H2O2), as a generator of oxidative stress, on the IFN-alpha signaling pathway. RESULTS: Pretreatment of Huh-7 cells with 0.5-1 mM H2O2 resulted in the suppression of the IFN-alpha-induced antiviral protein MxA and of IRF-9 mRNA expression. The reduced expression of these genes was associated to H2O2 -mediated suppression of the IFN-alpha-induced assembly of signal transducer and activator of transcription (STAT) factors to specific promoter motifs on IFN-alpha-inducible genes. This was accomplished by preventing the IFN-alpha-induced tyrosine phosphorylation of STAT-1 and STAT-2 through the inactivation of the upstream receptor associated tyrosine kinases, JAK-1 and Tyk-2. The suppression was fast, occurring within 5mins of pretreatment with H2O2, and did not require protein synthesis. CONCLUSIONS: In conclusion, oxidative stress impairs IFN-alpha signaling and might cause resistance to the antiviral action of IFN-alpha in chronically HCV infected patients with high level of oxidative stress in the liver.

Background: The benefit of neoadjuvant chemoradiotherapy in oesophageal cancer has been extensively studied but data on survival are still equivocal. Objective: To assess the effectiveness of chemoradiotherapy followed by surgery in the reduction of mortality in patients with resectable oesophageal cancer. Methods: Computerised bibliographic searches of MEDLINE and CANCERLIT (1970–2002) were supplemented with hand searches of reference lists. Study selection: Studies were included if they were randomised controlled trials (RCTs) comparing preoperative chemoradiotherapy plus surgery with surgery alone, and if they included patients with resectable histologically proven oesophageal cancer without metastatic disease. Six eligible RCTs were identified and included in the meta-analysis. Data extraction: Data on study populations, interventions, and outcomes were extracted from each RCT according to the intention to treat method by three independent observers and combined using the DerSimonian and Laird method. Results: Chemoradiotherapy plus surgery compared with surgery alone significantly reduced the three year mortality rate (odds ratio (OR) 0.53 (95% confidence interval (CI) 0.31–0.93); p = 0.03) (number needed to treat = 10). Pathological examination showed that preoperative chemoradiotherapy downstaged the tumour (that is, less advanced stage at pathological examination at the time of surgery) compared with surgery alone (OR 0.43 (95% CI 0.26–0.72); p = 0.001). The risk for postoperative mortality was higher in the chemoradiotherapy plus surgery group (OR 2.10 (95% CI 1.18–3.73); p = 0.01). Conclusions: In patients with resectable oesophageal cancer, chemoradiotherapy plus surgery significantly reduces three year mortality compared with surgery alone. However, postoperative mortality was significantly increased by neoadjuvant chemoradiotherapy. Further large scale multicentre RCTs may prove useful to substantiate the benefit on overall survival.

Killer Immunoglobulin like Receptors (KIR) are membrane proteins expressed on Natural Killer (NK) cells and on a small subset of CD8 lymphocytes. They influence the activation or inhibition of both cell types through interaction with their ligands, represented by Human Leukocyte Antigen (HLA) class I molecules. Several studies have shown that KIR/HLA interactions are involved in the pathogenesis and progression of different diseases as viral infections, autoimmune-disorders, or cancer, conditioning susceptibly to or protection against the outcome of the disease. HBV infection represents a major health problem with 2 billion people infected and 3 hundred and fifty million people with chronic diseases worldwide. The aim of this study is to assess whether KIR/HLA interaction is involved in immune response against hepatitis B infection. We are conducting a case-control study in Sicilian population, comparing subjects with chronic hepatitis B with subjects with previous HBV infection (HBc-Ab with or without HBeAb or HBsAb) as controls. A second control population was represented by HBcAb negative subjects. Peripheral blood samples were collected and genomic DNA was extracted from leukocytes and typed, using PCR-SSP, for KIR and HLA Preliminary data showed that HLA-A Bw4 was more frequent in cases than controls (1. cases, 23/35, 66%, vs. HBcAb positive controls, 8/35, 23%, OR 6.47, p=0.0003, and 2. cases, 23/35, 66%, vs. HBcAb negative controls, 6/60, 10%, OR 17.25, p=0.00001). No difference have been found in the frequencies HLA-C1, HLA-C2, HLA-Bw4I, and HLA-Bw4T; no difference have also been reported in the number of KIRs, both activating and inhibitory, and haplotype A and B between groups. Our data suggest that the HLA-A Bw4, likely through its interaction with the inhibitory KIR3DL1, is associated to the risk of developing chronic hepatitis B. Data on HBcAb negative subjects suggest also the possibility of selective genetic pressure.

Background: T-cells expressing the KIR2DS2 activating receptor were found to be prevalent in the coronary culprit atherosclerotic plaque in patients with acute coronary syndromes (ACS), suggesting a possible cytolytic activity against the endothelium of the plaque, leading to plaque rupture and in turn to superimposed thrombosis and sudden occlusion of the artery. To explore if a similar pathogenetic mechanism occurs in acute ischemic stroke, we analyzed the possible association between the genetic KIR and HLA repertoire and the susceptibility to ischemic stroke. Methods: Fourteen patients with ischemic stroke and ten controls with atherosclerotic disease without ischemic stroke matched for sex and age were genotyped for KIR and their HLA ligands, using PCR-SSP. Results: The frequency of the homozygous A haplotype (only KIR2DS4 as activating KIR) was 57% in patients and 80% controls (OR=0.33). The total number of activating and inhibitory KIR was not significantly different between cases and controls. The HLA-A was present in four cases and one control. The HLABw4T and HLABw4I alleles, as well as either the homozygous or the heterozygous form, were present in 12 cases and 6 controls, respectively. The putative interaction between HLABw4T/I allele and the KIR3DL1 inhibitory receptor was reported in 12 cases and 6 controls (OR=4). Conclusions: This descriptive preliminary analysis shows that subjects with ischemic stroke have a lower frequency of the A-haplotype, a higher frequency the HLABw4T or HLABw4I allele and a higher frequency of the HLABw4T/I-KIR3DL1 inhibitory interaction compared to controls, suggesting a stronger potential inhibition on NK activation.

Background: Dietary intervention and genetic alterations in gene encoding proteins involved in nutrient-sensing pathways can modulate lifespan, influencing longevity. It depends on under/over-expression of regulatory molecules that lead to different expression of homeostatic genes. Insulin/IGF-1 pathway was associated with longevity and lifespan modulation in model organisms. In humans, a key molecule in this pathway is FOXO3A that acts as a TF on homeostatic genes in response to decreased signaling increasing life span. Interestingly, other genes that increase lifespan interact with FOXO3A such as SIRT1, which modulates the oxidative stress response. Methods: We used meta-analytical and candidate-gene approaches to investigate the association of SNPs encoding proteins involved in Insulin/IGF-1 pathway with ageing and longevity. Results: Our study confirmed previous results related to the association between FOXO3A, IGF-1R, KLOTHO and longevity. No association was reported between IGF-1 and SIRT1 although all IGF-1 SNPs could affect its serum levels, known to modulate ageing and longevity. Moreover, we showed a new association between SHIP2 SNPs and longevity. Conclusions: Our results showed that specific SNPs of IGF-1R, FOXO3A, SHIP2 and KLOTHO influence ageing and longevity in different ethnic populations and that FOXO3A could be the most relevant gene in lifespan extension, particularly in males. Moreover, it could be speculated that a reduction of insulin signaling may decrease the activation of NF-kB slowing down inflammatory gene transcription. Thus, the intervention on ageing and longevity should be based both on nutrient-sensing and inflammatory pathways. The first simple step could be represented by the adherence to the Mediterranean diet with low glycaemic index and low animal proteins.

Alzheimer disease (AD) is a heterogeneous and progressive neurodegenerative disease, which in Western society mainly accounts for senile dementia. Today many countries have rising aging populations and are facing an increased prevalence of age-related diseases, such as AD, with increasing health-care costs. Understanding the pathophysiology process of AD plays a prominent role in new strategies for extending the health of the elderly population. Considering the future epidemic of AD, prevention and treatment are important goals of ongoing research. However, a better understanding of AD pathophysiology must be accomplished to make this objective feasible. In this paper, we review some hot topics concerning AD pathophysiology that have an important impact on therapeutic perspectives. Hence, we have focused our attention on inflammation, cytokines, immune response, apolipoprotein E (APOE), cholesterol, oxidative stress, as welll as exploring the related therapeutic possibilities, i.e., nonsteroidal antiinflammatory drugs, cytokine blocking antibodies, immunotherapy, diet, and curcumin.

Background: Appropriate treatment of acute hepatitis C is still a matter of controversy due to the lack of large controlled trials. Aim: To assess the effectiveness of interferon as treatment for acute hepatitis C by meta-analysis. Methods: MEDLINE search (1985-2002) was supplemented with manual searches of reference lists. Studies were included if they were controlled trials comparing interferon to no treatment and if they included patients with either post-transfusion or sporadic acute hepatitis C. Twelve trials were analyzed (414 patients). The outcome assessed was the sustained virological response (SVR) rate (undetectable hepatitis C virus RNA in serum at least 6 months after cessation of therapy). Results: Interferon significantly increased the SVR (risk difference 49%; 95% confidence interval 32.9-65%) in comparison to no treatment. The risk difference of SVR increased from 5 to 90% when trials were ordered by increasing interferon weekly dose. Delaying therapy by 8-12 weeks after the onset of disease does not compromise the SVR rate. Conclusions: Current evidence is sufficient to recommend interferon treatment of patients with acute hepatitis C. A later initiation of therapy yields the same likelihood of response as early treatment. A daily induction dose during the 1st month is the best option of treatment. © 2003 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Highlights • Autosomal dominant polycystic kidney disease is the most common among inherited cystic kidney diseases. • Patients with HIV infection are at risk of developing acute kidney injury and chronic kidney disease. • We provide the first report of HIV infection in a patient with polycystic kidney disease. • Lymphopenia should not contraindicate kidney transplantation in patients with HIV infection., Here we describe the case of a HIV-infected patient with polycystic kidney disease and end stage renal diseases not transplantable due to the persistence of a CD4 count

BACKGROUND: Endothelial dysfunction is an early marker of cardiovascular disease so endothelial and arterial stiffness indexes are good indicators of vascular health. We aimed to assess whether the presence of diabetic foot is associated with arterial stiffness and endothelial function impairment. METHODS: We studied 50 subjects with type 2 diabetes mellitus and diabetic foot syndrome (DFS) compared to 50 diabetic subjects without diabetic foot, and 53 patients without diabetes mellitus, by means of the mini mental state examination (MMSE) administered to evaluate cognitive performance. Carotid-femoral pulse wave velocity (PWV) and augmentation index (Aix) were also evaluated by Applanation tonometry (SphygmoCor version 7.1), and the RH-PAT data were digitally analyzed online by Endo-PAT2000 using reactive hyperemia index (RHI) values. RESULTS: In comparison to diabetic subjects without diabetic foot the subjects with diabetic foot had higher mean values of PWV, lower mean values of RHI, and lower mean MMSE. At multinomial logistic regression PWV and RHI were significantly associated with diabetic foot presence, whereas ROC curve analysis had good sensitivity and specificity in arterial PWV and RHI for diabetic foot presence. CONCLUSIONS: Pulse wave velocity and augmentation index, mean RHI values, and mean MMSE were effective indicators of diabetic foot. Future research could address these issues by means of longitudinal studies to evaluate cardiovascular event incidence in relation to arterial stiffness, endothelial and cognitive markers.