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Background: Short-term exposure to high Particulate Matter (PM) concentrations worsens several respiratory conditions., Objectives: We evaluated the relationship between short-term exposure to Particulate Matter and fine Particulate Matter (PM10 - PM2.5) and Emergency Department (ED) admissions and hospitalizations for COPD exacerbation observed at the University Hospital, Spedali Civili of Brescia, a city with some of the highest yearly levels of air pollution in Italy., Methods: We collected data from patients admitted to the ED with a COPD exacerbation diagnosis, starting from January 2014 to January 2016. Daily PM levels were collected from the Environmental Protection Regional Agency (ARPA). We performed a time-series analysis using the Poisson regression model with single and multiple day-lag. Results were expressed as Relative Risk (RR) and Excess of Relative Risk (ER) for COPD exacerbation-related ED admissions and hospitalizations, over a 10μg/m3 increase in PM concentration., Results: We collected data from 431 COPD patients. Both PM10 and PM2.5 were significantly associated with the risk of COPD exacerbation-related ED admission and hospitalization. Each increase of 10μg/m3 of PM10 and PM2.5 corresponded respectively to a RR for ED admissions of 1.06 and 1.08 at lag0-1; 1.06 and 1.09 at lag0-5 (p < 0.05). Similar results for COPD Exacerbation-related hospitalizations were found, with a RR of 1.07 and 1.10 at lag0-1 and 1.07 and 1.11 at lag0-5 for each increase of 10μg/m3 PM10 and PM2.5, respectively., Conclusions: Our findings show that in a highly polluted city of Northern Italy, short-term increase in exposure to PM10-PM2.5 is associated with a higher risk of ED admission and hospitalization due to COPD exacerbation with a greater incidence during the winter season., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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.

Background: Egg allergy is the second most prevalent form of food allergy in childhood. In spite of the evidence accumulated, inoculating egg allergy children with attenuated vaccines grown on chick embryo cell cultures, such as the measles, mumps, and rubella (MMR) vaccine, is regarded (erroneously) as potentially dangerous or even anaphylactogenic, by many. An issue perceived as particularly conflicting also by Health Professionals., Case Presentation: A 15-year-old boy, with a history of severe egg allergy in early infancy, who was still sensitized to egg allergens, including baked egg, had never received MMR vaccination, in fear of possible anaphylaxis, in spite of the fact that this vaccination is mandatory in the first year of life, in Italy. Because of that, he was not allowed to attend school, longer, and was referred to us in order to assess the potential risk of MMR vaccination. Upon thorough allergologic workup, sensitization to MMR vaccine components was excluded by an in vivo approach, consisting in skin prick tests, intradermal tests, and subcutaneous injection test, corroborated by vaccine-specific B-lymphocyte proliferation assay, ex vivo. T-cell proliferation in response to MMR vaccine was also excluded. Eventually, the boy was inoculated with MMR vaccine and was readmitted to school., Conclusions: The diagnostic strategy adopted appears feasible and easy-to-perform and may be adopted in controversial cases (as the one reported), characterized by previous severe allergic reactions to egg. The B-lymphocyte proliferation assay we developed may represent a useful and reliable tool not only in research but also in clinical practice.

In the last decade, an increasing number of randomized controlled trials (RCTs) on biologic therapy in patients with severe asthma have included patient-reported outcomes (PROs) as secondary efficacy measures. The majority of these RCTs showed a benefit in symptoms and quality of life. However, the magnitude of this benefit remains uncertain, because it rarely exceeded the minimal important difference (MID), owing to a significant improvement in the control group (placebo effect). Real-life studies on biologic therapies assessing PRO are scarce. They may support and integrate RCT results through their different experimental design. This real-life retrospective study provides data on 15 patients with difficult-to-treat severe eosinophilic asthma treated with benralizumab up to 6 months. Asthma quality of life questionnaire (AQLQ) and asthma control test (ACT) were assessed and administered at each visit to minimize the Hawthorne effect. Changes in general accepted efficacy measures, such as forced expiratory volume in 1 s (FEV 1 ), peak expiratory flux (PEF), exacerbation rate and blood eosinophils, from baseline were also assessed. AQLQ and ACT improved from 3.9 ± 0.4 to 5.2 ± 0.4 and from 15.6 ± 5.7 to 18.1 ± 5.6, respectively. FEV 1 increased of about 250 ml (+14%). PEF increased from 288 ± 107 to 333 ± 133 l/min. The number of exacerbations requiring OCS courses decreased from 2.8 ± 2.2 to 0.5 ± 0.8. Eosinophil counts dropped to 25.6 ± 15 cells/microliter. In conclusion, most patients reported improvements in AQLQ and ACT greater than MID, suggesting that these outcome represent a sensitive tool in real-life effectiveness studies. Our approach reduced the limitations of transition questions and the Hawthorne effect, increasing findings reliability., (Copyright © 2020. Published by Elsevier Ltd.)

Introduction: Severe asthma occurs in 5-10% of asthmatic patients, with nasal polyposis as one of the most frequent comorbidity. Benralizumab was recently marketed, thus we could analyse its effects in real-life in severe asthma, and compare the effects of the drug in patients with and without polyposis., Methods: Patients with severe asthma, receiving Benralizumab were enrolled in Italian asthma centres. The efficacy criteria for asthma (exacerbation rate, oral corticosteroid intake, hospitalizations, pulmonary function, exhaled nitric oxide) were evaluated at baseline and after 24 weeks of treatment. Patients were then sub-analysed according to the presence/absence of nasal polyposis., Results: Fifty-nine patients with severe uncontrolled asthma (21 males, age range 32-78) and treated with benralizumab for at least 24 weeks has been evaluated, showing significant improvements in asthma-related outcomes, except for pulmonary function and exhaled nitric oxide. This included a reduction in the sino-nasal outcome-22 score versus baseline of 13.7 points (p = .0037) in the 34 patients with nasal polyposis. Anosmia disappeared in 31% patients (p = .0034). When comparing the groups with and without nasal polyposis, a similar reduction of exacerbations was seen, with a greater reduction of the steroid dependence in patients with polyposis (-72% vs -53%; p < .0001), whereas lung function was significantly more improved (12% vs 34%, p = .0064) without polyposis patients., Conclusions: Benralizumab, after 6 months of treatment, confirmed its efficacy in severe asthma, and also in nasal polyposis, which is the most frequent comorbidity. The efficacy of Benralizumab in reducing steroid dependence was even higher in patients with polyposis., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Major scientific societies, such as the EAACI or the AAAAI, do not express any suggestion on which form of allergen immunotherapy (AIT) is to be preferred (subcutaneous immunotherapy, SCIT, vs sublingual immunotherapy, SLIT). This choice could depend on their relative pharmacoeconomic value., Objective: To assess the cost-effectiveness of AIT for grass pollen, administered as SCIT or SLIT., Methods: We created a Markovian Model, to evaluate, in a hypothetical cohort of adult patients suffering from moderate-to-severe rhino-conjunctivitis with or without allergic asthma, the cost-effectiveness of SLIT (tablets, Grazax ® and Oralair ® ) or SCIT (various currently available products, plus indirect nonmedical costs, such as travel and productivity costs) in addition to pharmacological therapy, assuming a 9-year horizon to capture AIT long-term effects. The incremental cost-effectiveness ratio (ICER) was calculated assuming pharmacological therapy as the reference comparator., Results: In the base case, SCIT was slightly more expensive, but more effective than SLIT, being the most cost-effective option (ICER for SCIT, €11 418; ICER for SLIT, €15 212). ICERs greater than €120 000 for both SCIT and SLIT were demonstrated in a scenario assuming that low treatment persistence rates, which are common in real-life, lead to absence of long-term AIT clinical benefit. Considering indirect nonmedical costs SLIT resulted more cost-effective than SCIT (ICER for SCIT, €17 318; ICER for SLIT, €15 212)., Conclusion: In daily practice, AIT for grass pollens may be a cost-effective option only in patients with low discontinuation rates. SCIT, which is less affected by this limitation than SLIT, seems the most cost-effective AIT form., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: The cerebral innate immune system has a critical role in control processes of viral replication in the brain after primary infactivo and immunologic disregulation and inflammation has been reported as a primary determinant of pathogenesis and prognosis of subsequent HSV-1 related encephalitis (HSE). Interaction linking LTR3-activated DCs is also represented by the killer Ig-like receptor (KIR) + pathways on NK cells. Only a few studies analyzed the role of of MMP-9 activity regulating genetic polymorphism on clinical outcome of viral infections. Susceptibility to symptomatic encephalitis depends on SNC viral invasion and BBB disruption. We hypothesize that certain KIR genes and MMP allele may help to characterize a risk profile of developing an acute encephalitis due to HSV 1., Aim of the Study: Analyze the frequency of KIR genes and the C(-1562)T MMP-9 allels in subjects with HSV-1 encephalitis and to analyze their interaction with regard of the risk of occurrence of a symptomatic encephalitis., Materials and Methods: Between November 2014 and January 2019, all consecutive patients with symptomatic acute encephalitis were recruited from three wards (Internal Medicine, Neurology, and Infectious Diseases) of "P. Giaccone" University Hospital, Palermo., Results: Patients with acute viral encephalitis in comparison to controls showed a higher frequency AA KIR haplotype, HLA-C2 and of HLA-A-Bw4 alleles. With regard of HLA allele frequency patients with acute viral encephalitis In comparison to controls also showed a higher frequency of HLA-C2 and of HLA-A-Bw4 alleles. With regard of MMP-9 alleles, subjects with acute viral encephalitis were more likely to have the TT genotype. The multiple logistic regression analysis considering variables predictive of the occurrence of acute viral encephalitis showed the detrimental effect of AA KIR, HLAC1, HLA-A-BW4 and HLA-B-BW4T and of TT aplotype of MMP-9 genotype., Conclusions: Our study shows that in immunocompetent adult subjects there is an association between some KIR genes, MMP-9 alleles and HLA-ligand alleles and susceptibility to develop a symptomatic acute viral encephalitis. Definition of the genetic and immunological background of acute viral encephalitis can play a key role to determine personalized medicine., Competing Interests: Declaration of Competing Interest All authors have no competing interest to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Allergic rhino-conjunctivitis (ARC) is an IgE-mediated disease that occurs after exposure to indoor or outdoor allergens, or to non-specific triggers. Effective treatment options for seasonal ARC are available, but the economic aspects and burden of these therapies are not of secondary importance, also considered that the prevalence of ARC has been estimated at 23% in Europe. For these reasons, we propose a novel flexible cost-effectiveness analysis (CEA) model, intended to provide healthcare professionals and policymakers with useful information aimed at cost-effective interventions for grass-pollen induced allergic rhino-conjunctivitis (ARC)., Methods: Treatments compared are: 1. no AIT, first-line symptomatic drug-therapy with no allergoid immunotherapy (AIT). 2. SCIT, subcutaneous immunotherapy. 3. SLIT, sublingual immunotherapy. The proposed model is a non-stationary Markovian model, that is flexible enough to reflect those treatment-related problems often encountered in real-life and clinical practice, but that cannot be adequately represented in randomized clinical trials (RCTs). At the same time, we described in detail all the structural elements of the model as well as its input parameters, in order to minimize any issue of transparency and facilitate the reproducibility and circulation of the results among researchers., Results: Using the no AIT strategy as a comparator, and the Incremental Cost Effectiveness Ratio (ICER) as a statistic to summarize the cost-effectiveness of a health care intervention, we could conclude that: SCIT systematically outperforms SLIT, except when a full societal perspective is considered. For example, for T = 9 and a pollen season of 60 days, we have ICER = €16,729 for SCIT vs. ICER = €15,116 for SLIT (in the full societal perspective).For longer pollen seasons or longer follow-up duration the ICER decreases, because each patient experiences a greater clinical benefit over a larger time span, and Quality-adjusted Life Year (QALYs) gained per cycle increase accordingly.Assuming that no clinical benefit is achieved after premature discontinuation, and that at least three years of immunotherapy are required to improve clinical manifestations and perceiving a better quality of life, ICERs become far greater than €30,000.If the immunotherapy is effective only at the peak of the pollen season, the relative ICERs rise sharply. For example, in the scenario where no clinical benefit is present after premature discontinuation of immunotherapy, we have ICER = €74,770 for SCIT vs. ICER = €152,110 for SLIT.The distance between SCIT and SLIT strongly depends on under which model the interventions are meta-analyzed., Conclusions: Even though there is a considerable evidence that SCIT outperforms SLIT, we could not state that both SCIT and SLIT (or only one of these two) can be considered cost-effective for ARC, as a reliable threshold value for cost-effectiveness set by national regulatory agencies for pharmaceutical products is missing. Moreover, the impact of model input parameters uncertainty on the reliability of our conclusions needs to be investigated further., Competing Interests: The authors have declared that no competing interests exist.

Background: Safety and treatment compliance are still considered important shortcomings of subcutaneous immunotherapy (SCIT)., Objective: To assess the rate of side effects (SE) to SCIT and treatment compliance at a hospital medically supervised facility., Methods: A retrospective review of patients with allergic rhino-conjunctivitis (ARC) with or without asthma, who received SCIT to mites and pollens from 1988 to 2018, was performed. The information was collected from patient's allergen immunotherapy forms that had been prospectically filled in by expert physicians., Results: Two thousand two hundred patients (50.2% males; mean age 29.4 ± 11.7 years) received 3037 SCIT courses. A total of 91,187 injections were given, with a mean SCIT duration of 2.5 ± 1.9 years. Nine hundred fifty-seven patients (43.5%) were compliant as they completed the minimally required treatment duration of 3 years. A total of 1087 SE (1.2% of all injections; 76.8% local reactions) were reported in 513 patients (23.3%). There were 42 anaphylactic reactions (in 29 patients) during the study period; two of these were severe. Adrenalin was administered only once. No anaphylactic shock was reported. Only 39 patients (1.8%) discontinued SCIT because of SE, the majority of whom (24; 61.5%) because of systemic reactions (urticaria, asthma, anaphylaxis). Parietaria vaccines were the most frequently associated to SE. Female gender, number of vaccines administered (2 vaccine vs. 1 vaccine) and year of SCIT inception (1996-2018 vs. 1988-1995) were independently associated to SE., Conclusion: SCIT, although not absolutely free of risk, is safe and well tolerated. There is still room for improvement of treatment compliance., Competing Interests: Declaration of competing interest We declare that we have no conflict of interest., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Iron deficiency is the main cause of anemia in both sexes, with women being more commonly affected. Iron therapy is currently considered an effective and safe remedy to replenish the iron storages. Iron can be administrated both orally and intravenously. In particular, intravenous (IV) iron therapy is widely used when oral iron preparations are either not tolerated or ineffective. Indeed, IV iron improves iron stores more rapidly. Two main immunological responses have been described for iron hypersensitivity reactions (HSRs): IgE-mediated allergy and complement activation-related pseudo-allergy. Here, we report 3 cases of adult patients with iron allergy, who were successfully treated with two different desensitization procedures, respectively. Analysis of these cases demonstrates that, in the presence of HSRs to iron products, desensitization is an effective and safe procedure that prevents treatment discontinuation and hence allows therapeutic target achievement., (© 2020 S. Karger AG, Basel.)

Purpose of Review: Although allergen immunotherapy (AIT) for fungi has been performed for many years, evidence clearly demonstrating its clinical benefit are still lacking. Here, we reviewed the available studies assessing efficacy and safety of AIT for molds., Recent Findings: Studies on AIT for fungi were performed only for the two predominating mold species in the external environment, namely Cladosporium and Alternaria. There is no evidence for other mold species. Recent finding in the literature are lacking; the 2 most recent studies on AIT for molds were published in 2011. Overall, 13 studies were identified (the first was published in 1986), but only nine of these compared AIT to placebo. The studies are small (median study sample size, 27 patients) and of low quality, owing to several defects leading to moderate-to-high risk of bias. Symptoms improvement and medication use reduction, which are the main outcome measures of the studies, were inconsistently demonstrated. There are some concerns about safety with Cladosporium extracts, whereas vaccines with Alternaria extracts seem to be safe and well tolerated., Summary: Low strength evidence suggests that mold AIT is efficacious for the treatment of respiratory allergies. High-quality studies with an adequate sample size are needed.

DNA damage and the generation of reactive oxygen species (ROS) are key mechanisms of apoptotic cell death by commonly used genotoxic drugs. However, the complex cellular response to these pharmacologic agents remains yet to be fully characterized. Several studies have described the role of transcription factor octamer-1 (Oct-1)/Pit-1, Oct-1/2, and Unc-86 shared domain class 2 homeobox 1 (POU2F1) in the regulation of the genes important for cellular response to genotoxic stress. Evaluating the possible involvement of other POU family transcription factors in these pathways, we revealed the inducible expression of Oct-6/POU3F1, a regulator of neural morphogenesis and epidermal differentiation, in cancer cells by genotoxic drugs. The induction of Oct-6 occurs at the transcriptional level via reactive oxygen species (ROS) and ataxia telangiectasia mutated- and Rad3-related (ATR)-dependent mechanisms, but in a p53 independent manner. Moreover, we provide evidence that Oct-6 may play a role in the regulation of cellular response to DNA damaging agents. Indeed, by using the shRNA approach, we demonstrate that in doxorubicin-treated H460 non-small-cell lung carcinoma (NSCLC) cells, Oct-6 depletion leads to a reduced G2-cell cycle arrest and senescence, but also to increased levels of intracellular ROS and DNA damage. In addition, we could identify p21 and catalase as Oct-6 target genes possibly mediating these effects. These results demonstrate that Oct-6 is expressed in cancer cells after genotoxic stress, and suggests its possible role in the control of ROS, DNA damage response (DDR), and senescence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Introduction: In humans, a major component of natural killer (NK) and T cell target recognition depends on the surveillance of human leukocyte antigen (HLA) class I molecules by killer immunoglobulin-like receptors (KIRs)., Aims: To implement the knowledge about the immunological genetic background of acute ischemic stroke susceptibility in relation to the frequency of the KIR genes and HLA alleles., Methods: Subjects with acute ischemic stroke and subjects without stroke were genotyped for the presence of KIR genes and of the three major KIR ligand groups, HLA-C1, HLA-C2, and HLA-Bw4, both HLA-B and HLA-A loci., Results: Between November 2013 and February 2016, consecutive patients with acute ischemic stroke were recruited. As healthy controls, we enrolled subjects without acute ischemic stroke. Subjects with acute ischemic stroke in comparison with controls showed a higher frequency of 2DL3, 2DL5B, 2DS2, and 2DS4 KIR genes and a lower frequency of HLA-B-Bw4 I alleles. Subjects without acute ischemic stroke showed a higher frequency of interaction between KIR 2DS2 and HLAC2. We also observed a higher frequency of 2DL3 and 2 DL4 KIR genes in subjects with atherosclerotic (LAAS) subtype. Multiple logistic regression analysis showed a protective effect towards stroke of HLA-B-Bw4 I and interaction between KIR 2DL2 and HLAC1 and 2DS2-HLAC2 and a detrimental effect of 2DL2-HLA-C1&#95;A interactions., Conclusion: Our findings of a higher frequency of activating KIR genes seem to be consistent with findings previously reported patients with coronary syndrome. This higher frequency of "proinflammatory" genes in subjects with ischemic stroke could also explain the immunoinflammatory activation of the acute phase of stroke.

The outcome of host-virus interactions is determined by a number of factors, some related to the virus, others to the host, such as environmental factors and genetic factors. Therefore, different individuals vary in their relative susceptibility to infections. Human cytomegalovirus (HCMV) is an important pathogen from a clinical point of view, as it causes significant morbidity and mortality in immunosuppressed or immunosenescent individuals, such as the transplanted patients and the elderly, respectively. It is, therefore, important to understand the mechanisms of virus infection control. In this review, we discuss recent advances in the immunobiology of HCMV-host interactions, with particular emphasis on the immunogenetic aspects (human leukocyte antigens, HLA; killer cell immunoglobulin-like receptors, KIRs; immunoglobulin genetic markers, GM allotypes) to elucidate the mechanisms underlying the complex host-virus interaction that determine various outcomes of HCMV infection. The results, which show the role of humoral and cellular immunity in the control of infection by HCMV, would be valuable in directing efforts to reduce HCMV spurred health complications in the transplanted patients and in the elderly, including immunosenescence. In addition, concerning GM allotypes, it is intriguing that, in a Southern Italian population, alleles associated with the risk of developing HCMV symptomatic infection are negatively associated with longevity.

Introduction: Onion (Allium cepa) handling can induce contact dermatitis, rhinoconjunctivitis and asthma. However, only sporadic reports exist on allergic reactions to onion consumption., Aim: We describe herein a case of a 35-year-old man who had an episode of anaphylaxis following cooked onion ingestion. We evaluated onion-specific IgE, the possible cross-reactivity between onion and peach and lymphocyte proliferation in response to onion., Material and Methods: Specific IgE was evaluated using two techniques: skin test and ImmunoCAP technology. Cross-reactivity between onion and peach was evaluated by IgE-ELISA inhibition test. As for lymphocyte proliferation, blood mononuclear cells were stained with CFSE dye and cultured with an in-house onion extract. Proliferation and phenotype was assessed by flow-cytometry., Results: The skin test and ImmunoCAP confirmed the IgE-dependent response towards onion. The incubation of the patient serum with increasing concentrations of the peach extract reduced only scarcely (~30%) onion-specific IgE. Interestingly, B cells but not T cells showed proliferation in response to onion extract., Conclusions: In conclusion, our report shows that cooked onion can induce severe allergic reactions, suggesting the presence of thermostable components. Moreover, we applied for the first time a B-cell-based approach to the diagnosis of food allergy. This latter approach might also be applied to other allergic conditions., Competing Interests: The authors declare no conflict of interest.

Allergen-specific immunotherapy (AIT) is the only allergy treatment that confers long-term symptom amelioration for patients suffering from allergy. The most frequently used allergen application route is subcutaneous injection (SCIT), commonly taken as the gold standard, followed by sublingual (SLIT) or oral (OIT) application of allergen preparations. This is an up-to-date review of the clinical evidence for a novel route of allergen application, i.e., directly into lymph nodes - intralymphatic immunotherapy (ILIT). The major advantages of ILIT over the current AIT approaches are its short duration and the low allergen doses administered. The whole treatment consists of merely 3 ultrasound-guided injections into inguinal lymph nodes 1 month apart. While the number of patients included in randomised controlled trials is still limited, the clinical results for ILIT are encouraging, but more clinical trials are needed, as well as more preclinical work for optimising formulations., (© 2018 S. Karger AG, Basel.)

Background: It is well known that long living individuals are a model of successful ageing and that the identification of both genetic variants and environmental factors that predispose to a long and healthy life is of tremendous interest for translational medicine., Methods: We present the preliminary findings obtained from an ongoing study on longevity conducted on a sample of Sicilian long-lived individuals., Results: We review the characteristics of longevity in Sicily, taking into account lifestyle, environment, genetics, hematochemical values, body composition and immunophenotype. In addition, we discuss the possible implications of our data for the prevention and/or treatment of age-related diseases., Conclusion: As widely discussed in this review, the explanation of the role of genetics and lifestyle in longevity can provide important information on how to develop drugs and/or behaviours that can slow down or delay ageing. Thus, it will be possible to understand, through a "positive biology" approach, how to prevent and/or reduce elderly frailty and disability., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Allergen immunotherapy (AIT) with mould extracts has been performed for many years but the final demonstration of its clinical efficacy is still missing, due to the small number of studies and their inconsistent results., Objective: To systematically review efficacy and safety of AIT for the treatment of respiratory allergies to moulds., Design: The primary outcomes were safety and reduction of symptoms (Symptom Score, SS) and medication use (Medication Score, MS) in patients treated with AIT compared to controls. 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., Data Sources: Medline, Web of Science and the Cochrane Library (through September 2017) supplemented with manual searches of reference lists., Eligibility Criteria: Randomized studies of intervention comparing AIT to placebo/pharmacotherapy. Studies not reporting on our outcome of interest or without a control population were excluded., Results: Nine studies (168 children, 99 adults; median sample size, 27) met the inclusion criteria. The risk of bias was moderate-to-high in all but one study. Low strength evidence supports the assumption that AIT is effective in reducing symptoms and medication use, with only four of nine studies reporting higher benefit of AIT vs. comparators. The highest benefit of AIT compared to pharmacotherapy/placebo was reported in studies with a longer follow-up (SMD for MS from -3.96 to -3.97 in favour of AIT) and low risk of bias (VAS for SS: 66.3 ± 13 in AIT group; 186.6 ± 39 in comparators; P < 0.05). No difference was reported with respect to study sample size, route of administration, age of participants. Generalised adverse reactions were reported in 12.5% of participants treated with sublingual immunotherapy, and 37.2% of participants treated with subcutaneous immunotherapy., Conclusions: Low strength evidence suggests that mould AIT is efficacious for the treatment of respiratory allergies. High-quality studies with an adequate sample size are needed., (© 2018 John Wiley & Sons Ltd.)

Background: Brentuximab vedotin (BV) is an antibody-drug conjugate formed by an anti-CD30 chimeric IgG 1 conjugated with monomethyl-auristatin-E. BV targets the CD30 + cells, which characterize Hodgkin lymphoma as well as anaplastic large cell lymphoma. Once bound to the CD30 + cells BV exerts its cytotoxic effect via the monomethyl-auristatin-E moiety. So far, accounts on immediate adverse reactions to BV remain anecdotal. Moreover, few reports exist on desensitization for BV., Case Presentation: A 20-year old male patient was diagnosed with Hodgkin lymphoma in July 2014. The first line treatment with adriblastine, bleomicine, vinblastine and dacarbazine lead to a partial remission. Thus, a treatment with BV was started. However, during the second BV infusion, he developed generalized urticaria and dyspnea. In order not to discontinue the treatment with BV, we performed a thorough allergological workup and designed a 12-step rapid desensitization protocol. Overall the desensitization procedure was well tolerated and no major adverse reactions occurred., Conclusion: Rapid desensitization is a suitable and safe option in the case of BV allergy and prevents the BV treatment withdrawal.

Interventions to extend life span represent the new perspective in aging investigation. Healthy dietary habits are important modifiable factors that can favor a healthy aging phenotype. Many studies have demonstrated benefits for metabolic syndrome and type 2 diabetes mellitus resulting from the traditional Mediterranean foods. Opuntia Ficus Indica (OFI), widespread in the Mediterranean basin, belongs to the Cactaceae family. It is known for its antioxidant and anti-inflammatory properties. Moreover, products containing extracts from OFI fruits or cladodes have been used to control obesity and other metabolic parameters, such as glycemia and lipid profile. The aim of this study was to analyze the antioxidant and anti-inflammatory effect of pasta with 3% of OFI cladode extracts added to show its beneficial effect in human health. We performed a single arm longitudinal intervention study in 42 healthy volunteers, administrating 500 g/week of this functional pasta for 30 days. Our pasta had antioxidant and anti-inflammatory properties with putative effect on the aging process and related metabolic diseases. We also demonstrated a hypoglycemic effect. The results are preliminary, but it is possible to speculate that our pasta could be considered an effective food for the prevention of age-related metabolic disorders.

Introduction: The HLA genes, as well as the innate immune KIR genes, are considered relevant determinants of viral outcomes but no study, to our knowledge, has evaluated their role in the clinical setting of acute viral encephalitis., Results: Subjects with acute viral encephalitis in comparison to subjects without acute viral encephalitis showed a significantly higher frequency of 2DL1 KIR gene and AA KIR haplotypes and of HLA-C2 and HLA-A-Bw4 alleles. Subjects without acute viral encephalitis showed a higher frequency of interaction between KIR2DL2 and HLAC1. Multiple logistic regression analysis showed the detrimental effect of HLA-A haplotype and HLA-C1, HLA-A-BW4 HLA-B-BW4 T alleles, whereas multiple logistic regression showed a protective effect of AB+BB KIR haplotype and a detrimental effect of interaction between KIR3DL1 and HLA-A-Bw4., Discussion: Our findings of a lower frequency of activating receptors in patients with acute encephalitis compared to controls could result in a less efficient response of NK cells. This finding could represent a possible pathogenetic explanation of susceptibility to acute symptomatic encephalitis in patients with viral infection from potentially responsible viruses such as Herpes virus., Materials and Methods: 30 Consecutive patients with symptomatic acute viral encephalitis and as controls, 36 consecutive subjects without acute encephalitis were analyzed. The following KIR genes were analyzed, KIR2DL1, 2DL2, 2DL3, 2DL5, 3DL1, 3DL2, 3DL3, 2DL4, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5, 3DS1, 2 pseudogenes (2DP1 and 3DP1) and the common variants of KIR2DL5 (KIR2DL5A, KIR2DL5B)., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Natural killer (NK) cells provide a major defence against human cytomegalovirus (HCMV) infection through the interaction of their surface receptors, including the activating and inhibitory killer immunoglobulin-like receptors (KIRs), and human leucocyte antigen (HLA) class I molecules. Also γ marker (GM) allotypes, able to influence the NK antibody-dependent cell-mediated cytotoxicity, appear to be involved in the immunological control of virus infections, including HCMV. In some cases, their contribution requires epistatic interaction with other genes of the immune system, such as HLA. In the present report, with the aim of gaining insight into the immune mechanisms controlling HCMV, we have studied the possible associations among humoral and NK responses, and HCMV infections. In a previous study we assessed whether the KIR and HLA repertoire might influence the risk of developing symptomatic (n = 60) or asymptomatic (n = 60) disease after primary HCMV infection in the immunocompetent host. In the present study, the immunocompetent patients with primary symptomatic HCMV infection were genotyped for GM3/17 and GM23 allotypes, along with the 60 participants with a previous asymptomatic infection as controls. Notwithstanding the presence of missing data record, advanced missing data recovery techniques were able to show that individuals carrying the GM23 allotypes, both homozygous and heterozygous, GM17/17, HLA-C2 and Bw4 T KIR-ligand groups are associated with the risk of developing symptomatic infection. Our findings on the role of both cellular and humoral immunity in the control of HCMV infection should be of value in guiding efforts to reduce HCMV-associated health complications in the elderly, including immunosenescence, and in transplantation., (© 2017 John Wiley & Sons Ltd.)

Recently, the role of killer cell immunoglobulin-like receptor (KIR) in autoimmune diseases has received increasing attention. The present study was undertaken to determine the association of KIR genes and the human leukocytes antigen (HLA) ligands with Systemic Lupus Erythematosus (SLE) and accompanying oxidative stress. Presence or absence of 17 KIR and 5 HLA loci was performed using the polymerase chain reaction-sequence specific primer (PCR-SSP) method by case-control study. A total of 45 SLE patients, and 60 healthy controls, all of Sicilian descent, were enrolled. Plasma values of the anti-oxidant molecule Taurine were determined in all subjects by capillary electrophoresis UV detection. The carrier frequency of the KIR2DS2 gene was significantly increased in SLE patients compared to healthy controls (73.3 versus 45.0%; OR = 3.36; 95% CI = 1.46-7.74; p = .005) suggesting a role of KIR2DS2 gene in the susceptibility to disease. We also observed a strong positive association between the presence of HLA-C1 ligands group and the disease (82.2% in SLE patients versus 41.7% in controls; OR = 6.47, 95% CI = 2.58-16.26; p < .0001). Stepwise logistic regression analysis supported the effect of the HLA-C1 ligands in SLE patients (OR = 7.06, 95% CI = 0.07-2.19; p = .002), while the KIR genes were no longer significant. Interestingly, we found that SLE patients HLA-C1 positive showed significantly decreased plasma levels of antioxidant activity marker Taurine (69.38 ± 28.49 μmol/L) compared to SLE patients HLA-C1 negative (108.37 ± 86.09 μmol/L) (p = .03). In conclusion, HLA-C1 ligands group was significantly associated with an increased risk of SLE as well as an increased oxidative stress status overall in SLE patients., (Copyright © 2018 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Background: Hymenoptera venom immunotherapy (VIT) is a clinically effective treatment. However, little is known about its long-term clinical efficacy and biological effects. Several mechanisms have been proposed to account for VIT efficacy, including reduction of specific IgE and induction of allergen-specific IgG 4 , but the overall picture remains elusive. We investigated Vespula VIT clinical efficacy up to 8 years after discontinuation and the kinetics of Vespula -specific IgE and IgG 4 . Out of 686 consecutive patients we retrospectively selected and analysed a series of 23 patients with Vespula allergy that underwent a 5-year IT course, followed by a prolonged follow-up., Methods: Clinical efficacy of VIT was assessed as number and severity of reactions to Vespula re-stinging events. The presence of Vespula -specific IgE and IgG 4 was also monitored over time., Results: During the VIT treatment, patients were protected, reporting no reactions or mild reactions in occasion of re-stinging events. This protection was entirely maintained during the follow-up, up to 8 years. Skin reactivity (reflecting mast cell-bound Vespula -specific IgE) and circulating Vespula -specific IgE levels declined substantially during VIT. Notably, this reduction was maintained over time during the follow-up. Moreover, all the patients were analysed for IgG 4 . A robust induction of Vespula -specific IgG 4 was observed during the VIT course, with a substantial decline during the follow-up., Conclusions: We conclude that Vespula VIT is a clinically effective treatment, which induces long-term protection after discontinuation. The reduction of specific IgE, assessed by skin tests and RAST, closely matches the VIT- induced protection, while the IgG 4 induction seems not to be associated with VIT clinical efficacy in the long term.

Killer immunoglobulin-like receptors (KIRs) regulate the activation of natural killer cells through their interaction with human leucocyte antigens (HLA). KIRs and HLA loci are highly polymorphic, and some of their combinations have been found to protect against viral infections or to predispose to autoimmune disorders. In particular, some activating KIRs profiles may be detrimental in autoimmune pathogenesis, and specific KIRs may be particularly aggressive in the clearance of different microorganisms, protecting individuals in the control of a given pathogen. So, considering that in the pathogenesis of many autoimmune disorders and infections innate immunity plays a key role, the recent development for KIRs characterization, diseases monitoring, and treatment becomes obvious. Here, we reviewed a growing body of evidence supporting the influence of KIRs variants and their interaction with ligands in the development of the main human autoimmune and viral diseases, highlighting the main applications in clinical practice., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

A better hygiene, a Westernized diet, air pollution, climate changes, and other factors that influence host microbiota, a key player in the induction and maintenance of immunoregulatory circuits and tolerance, are thought to be responsible for the increase of allergic diseases observed in the last years. The increase of allergic diseases in elderly is related to the presence of other factors as several comorbidities that should interfere with the development and the type of allergic reactions. A central role is played by immunosenescence responsible for modifying response to microbiota and triggering inflamm-ageing. In addition, in elderly there is a shift from Th1 responses vs. Th2, hence favouring allergic responses. Better understanding of the mechanisms of immunosenescence and its effects on allergic inflammation will most certainly lead to improved therapy., Competing Interests: Not applicableNot applicableThe authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: Randomized Controlled Trials showed that omalizumab exhibited a good safety and tolerability profile in patients with moderate-to-severe asthma. However, safety data of long-term treatment with omalizumab are scarce. Our aim was to assess the safety of omalizumab in patients under long-term treatment in a real-life setting., Methods: Difficult-to-control asthmatic patients treated with omalizumab up to 9 years were retrospectively evaluated. Mild to severe adverse events any and reasons for discontinuation were recorded., Results: Ninety-one patients (26.4% males, mean age 49.9 ± 14.9 years) were included: mean treatment length, 3.8 ± 2.6 years; mean individual monthly dose, 514.5 ± 345.7 mg (range, 150-1200 mg). A total of 10,472 single injections were given cumulatively to the 91 patients (115 single injections per patients, on average, over a treatment period up to 9 years). Fifty-nine patients (64.8%) were treated for a period of time from 3 to 9 years, 14 of whom from 6 to 9 years. A high proportion of patients who discontinued treatment dropped out within the first year (18, 39.1%), mainly for reasons unrelated to treatment. Six patients (6.6%) discontinued omalizumab for treatment-related adverse events: arthralgia/myalgia (3 patients); urticaria, angioedema (1 patients); metrorrhagia (1 patient); relapsing herpes labialis (1 patient). Four other patients complained of mild adverse events (rhinitis/conjunctivitis, injection site reaction, fatigue, thrombosis) but continued the treatment. Anaphylaxis was not reported., Conclusions: Long-term treatment with omalizumab appears remarkably safe and well tolerated in real-life setting. Prolonged omalizumab treatment for many consecutive years did not increase the risk of side effects, particularly anaphylaxis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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., Competing Interests: The authors have declared that no competing interests exist.

Background: Chylomicronemia syndrome is a metabolic condition characterized by severe fasting hypertrigliceridemia (≥ 1000 mg/dL) and other clinical features including chronic abdominal pain and recurrent acute pancreatitis. In patients with acute or recurrent pancreatitis, plasma exchange (PEx) is indicated for the treatment of acute disease and prevention of recurrence. The use of plasma instead of albumin as replacement fluid has been suggested for its putative ability to replace the deficient enzyme possibly leading to better clinical improvement., Case Report: A 40-year-old man with chylomicronemia syndrome due to a newly identified loss-of-function mutation in the lipoprotein lipase (LPL) gene (IVS2, c.250-1G/C) has been treated at our hospital since the age of 13. From age 18 to age 34, the patient had five episodes of acute pancreatitis while his triglyceride (TG) levels were extremely high (2500-4000 mg/dL). As the TG levels remained stable over 4000 mg/dL despite the maximum medical treatment, the patient started long-term PEx treatment on a weekly basIs. Both albumin and plasma have been used as replacement solution. Thirty months from the beginning of this treatment, no episode of acute pancreatitis has been reported, and the chronic abdominal pain fully disappeared. No differences were observed between the use of albumin or plasma as replacement solution., Conclusion: Long-term PEx is effective in preventing the recurrence of acute pancreatitis and in treatment of chronic abdominal pain in this patient with chylomicronemia syndrome. Plasma is not more effective than albumin in lipid reduction, likely because of its extremely low enzyme content. Therefore, in patients with LPL deficiency serum albumin should be preferred to plasma as replacement fluid because of the low rate of side effects and reduced costs., (© 2015 AABB.)

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., Competing Interests: The authors report no conflicts of interest.

Background: Adherence to a Mediterranean Diet appears to reduce the risk of cardiovascular disease, cancer, Alzheimer's disease, and Parkinson's disease, as well as the risk of death due to cardiovascular disease. No study has addressed the association between diagnostic subtype of stroke and its severity and adherence to a Mediterranean Diet in subjects with acute ischemic stroke., Aim: To evaluate the association between Mediterranean Diet adherence, TOAST subtype, and stroke severity by means of a retrospective study., Methods: The type of acute ischemic stroke was classified according to the TOAST criteria. All patients admitted to our ward with acute ischemic stroke completed a 137-item validated food-frequency questionnaire adapted to the Sicilian population. A scale indicating the degree of adherence to the traditional Mediterranean Diet was used (Me-Di score: range 0-9)., Results: 198 subjects with acute ischemic stroke and 100 control subjects without stroke. Stroke subjects had a lower mean Mediterranean Diet score compared to 100 controls without stroke. We observed a significant positive correlation between Me-Di score and SSS score, whereas we observed a negative relationship between Me-Di score and NIHSS and Rankin scores. Subjects with atherosclerotic (LAAS) stroke subtype had a lower mean Me-Di score compared to subjects with other subtypes. Multinomial logistic regression analysis in a simple model showed a negative relationship between MeDi score and LAAS subtype vs. lacunar subtype (and LAAS vs. cardio-embolic subtype)., Conclusions: Patients with lower adherence to a Mediterranean Diet are more likely to have an atherosclerotic (LAAS) stroke, a worse clinical presentation of ischemic stroke at admission and a higher Rankin score at discharge., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

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.

Some studies have shown that polymorphisms in the insulin growth factor-1 (IGF-1) signaling pathway genes could influence human longevity. However, the results of different studies are often inconsistent. Our aim was to investigate by systematic review and meta-analysis the association of the common polymorphisms defining the genetic variability of the IGF-1 signaling pathway associated with human longevity. Eleven studies investigating the association between the polymorphisms in the IGF-1 signaling pathway genes (IGF-1, IGF-1 receptor (IGF-1R), Forkhead box O3A (FOXO3A) and Silent mating type Information Regulation 1 (SIRT1) and longevity were found and analyzed. The modelfree approach was applied to meta-analyze these studies. No association was reported between the single nucleotide polymorphisms (SNPs) of IGF-1 and longevity in the only available study. The meta-analysis of available data from four studies, showed a significant association with the IGF-1R polymorphism rs2229765, suggesting that subjects with the Abearing genotype have a greater chance of longevity. Concerning the five studies on FOXO3A SNPs, for the rs2764264 a significant association with longevity was observed for C allele when only males were included in the analysis. Statistically significant results were obtained for other SNPs as well, i.e. rs2802292 (G allele), rs9400239 and rs479744 (T and A alleles, respectively). For rs9400239 the association was observed in long lived males with a lower odds ratio than in centenarians, while in rs479744 a significant association was highlighted in centenarians. Concerning SIRT1, no association between the SNPs under study and longevity was observed in the only available report. Current findings suggest that both IGF-1R and FOXO3A polymorphisms could be associated with longevity. The high degree of between-study heterogeneity and the low number of available studies underline the need for further methodologically adequate analyses to confirm this evidence.

Background: Subcutaneous (SCIT) and sublingual (SLIT) immunotherapy are the 2 most prescribed routes for administering allergen-specific immunotherapy. They were shown to be effective in control of symptoms and in reducing rescue medication use in patients with allergic diseases, but their effectiveness has to be balanced against side effects. In recent years, SLIT has been increasingly prescribed, instead of SCIT, because of improved safety and easy administration., Objective: We assessed which route is the most effective in the treatment of patients with seasonal allergic rhinitis to grass pollen., Methods: An indirect meta-analysis-based comparison between SCIT and SLIT was performed. Treatment efficacy was determined as the standardized mean difference (SMD) in symptom and medication scores obtained with active treatment, SCIT or SLIT, compared with placebo. Studies were included if they were double-blind randomized controlled trials comparing SCIT or SLIT with placebo. Thirty-six randomized controlled trials (3014 patients; 2768 controls) were analyzed., Results: The overall effect size of SCIT for symptom score (SMD, -0.92; 95%CI, -1.26 to -0.58) was significantly higher than SLIT, both administered via drops (SMD, -0.25; 95% CI, -0.45 to -0.05) and tablets (SMD, -0.40; 95%CI, -0.54 to -0.27). Similar results were reported for medication score (SCIT: SMD, -0.58; 95% CI, -0.86 to -0.30. SLIT drops: SMD, -0.37; 95% CI, -0.74 to -0.00. SLIT tablets SMD, -0.30; 95% CI, -0.44 to -0.16)., Conclusions: Our results provide indirect but solid evidence that SCIT is more effective than SLIT in controlling symptoms and in reducing the use of antiallergic medications in seasonal allergic rhinoconjuntivitis to grass pollen., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Cytomegalovirus primary infection is considered dangerous for some kinds of patients: immunocompromised (HIV-infected and transplanted patients), newborns with congenital infection, and immunocompetent patients in critical condition. CMV infection is usually asymptomatic or only mildly symptomatic in immunocompetent hosts. We collected all cases of acute CMV infection that came to our attention during the period November 2009 - May 2011 to analyze their clinical features. Immunoenzymatic methods (ELISA) were used for the detection of specific IgM and IgG antibodies in every case. We observed 73 cases of acute CMV infection. The male-female ratio was 1.5/1. The average age was 36.4. All the patients had fever, 16 (22%) pharyngitis, only 9 (12.3%) lymphadenopathy. The most common complications were hepatitis, encephalitis, pericarditis and pneumonia. Unknown genetic factors may greatly influence the clinical expression of the illness.

Background: Allergic rhinitis (AR) and nonallergic rhinitis (NAR) may present with different clinical and laboratory characteristics., Methods: A total of 1,511 consecutive patients, aged 18-81 years, diagnosed with rhinitis, 56% females and 44% males, underwent complete allergic evaluation including skin prick test, blood eosinophil counts, nasal eosinophil counts, peak nasal inspiratory flow (PNIF) measurement and evaluation of nasal symptoms using a visual analog scale (VAS)., Results: A total of 1,107 patients (73%)had AR, whereas 404 (27%) had NAR. Patients with NAR were older and predominantly female. A higher nasal eosinophils count was associated with AR and a lack of clinical response to antihistamines. AR patients had more sneezing and nasal pruritus, whereas NAR was characterized mainly by nasal obstruction and rhinorrhea. AR patients had more severe symptoms and recurrent conjunctivitis, whereas NAR patients had slightly more frequent episodes of recurring headaches as well as olfactory dysfunction. PNIF, blood eosinophil counts and VAS of nasal symptoms were higher in patients with AR. In a final logistic regression model, 10 variables were statistically different between AR and NAR: age [OR 0.97 (95% CI 0.96-0.98)], sneezing [OR 4.09 (95% CI 2.78-6.00)], nasal pruritus [OR 3.84 (95% CI 2.60-5.67)], mild symptoms [OR 0.21 (95% CI 0.09-0.49)], intermittent/severe nasal symptoms [OR 3.66 (95% CI 2.06-6.50)], VAS [OR 1.06 (95% CI 1.04-1.08)], clinical response to antihistamines [OR 22.59 (95% CI 13.79-37.00)], conjunctivitis [OR 4.49 (95% CI 2.86-7.05)], PNIF [OR 1.01 (95% CI 1.00-1.01)] and nasal eosinophil counts [OR 1.14 (95% CI 1.10-1.18)]. Receiver operating characteristic analysis showed high predictive accuracy for a model including these variables independently of the diagnosis of AR/NAR (cutoff <0.74)., Conclusions: We showed that the several clinical and laboratory parameters reported above may help to reinforce or exclude the diagnosis of AR obtained with skin prick test., (Copyright © 2011 S. Karger AG, Basel.)

Background: The benefit of sublingual immunotherapy (SLIT) with grass allergens for seasonal allergic rhinitis has been extensively studied, but data on efficacy are still equivocal., Objective: To assess the effectiveness of SLIT with grass allergens in the reduction of symptoms and medication in patients with seasonal allergic rhinitis to grass pollen., Methods: Computerized bibliographic searches of MEDLINE (1995-2010) were supplemented by hand searches of reference lists. Studies were included if they were double-blind randomized controlled trials (RCTs) comparing SLIT to placebo and if they included patients with history of allergy to grass pollen treated with natural grass pollen extracts. Nineteen RCTs with 2971 patients were analyzed. The outcomes assessed were symptom and medication scores., Results: Using a random-effects model, SLIT with grass allergens significantly reduces both symptoms (standardized mean difference, -0.32; 95% CI, -0.44 to -0.21) and medication use (standardized mean difference, -0.33; 95% CI, -0.50 to -0.16) compared with placebo. The treatment is more efficacious in adults than in children. Prolonging duration of preseasonal treatment for more than 12 weeks improves the treatment efficacy., Conclusion: This meta-analysis found that SLIT with grass allergens is effective in patients with seasonal allergic rhinitis compared with placebo. The benefit is clinically modest, and criteria are needed to identify patients most likely to benefit from SLIT., (Copyright (c) 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

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 well as exploring the related therapeutic possibilities, i.e., nonsteroidal antiinflammatory drugs, cytokine blocking antibodies, immunotherapy, diet, and curcumin.

In this paper, we consider the role of the genetics of inflammation in the pathophysiology of prostate cancer (PCa). This paper is not an extensive review of the literature, rather it is an expert opinion based on data from authors' laboratories on age-related diseases and inflammation. The aim is the detection of a risk profile that potentially allows both the early identification of individuals at risk for disease and the possible discovery of potential targets for medication. In fact, a major goal of clinical research is to improve early detection of age-related diseases, cancer included, by developing tools to move diagnosis backward in disease temporal course, i.e., before the clinical manifestation of the malady, where treatment might play a decisive role in preventing or significantly retarding the manifestation of the disease. The better understanding of the function and the regulation of inflammatory pathway in PCa may help to know the mechanisms of its formation and progression, as well as to identify new targets for the refinement of new treatment such as the pharmacogenomics approach.

It has been hypothesized that polymorphisms of Tumor Necrosis Factor (TNF)-alpha gene affect the risk of developing 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 TNF-alpha gene with AD risk. Hence, the results being stated are of a meta-analysis across studies, and that this meta-analysis does not invalidate the results of the individual studies previously performed. Seventeen studies that investigated the association between 5 TNF-alpha polymorphisms (-850, -308, -863, -238, and -1031) and AD were retrieved and analyzed. The model-free approach was applied to meta-analyze these case-control genetic association studies. Available data suggested a significant association between -850 polymorphism and AD risk (TT vs. TC+CC: pooled odds ratio [OR], 1.61; 95% confidence interval [CI], 1.08-2.29; p=0.02) with no evidence of between-study heterogeneity (chi(2), p>0.1). Subgroup analysis suggested that the possession of T allele significantly increased the risk of AD associated with carriage of the apolipoprotein E epsilon 4 allele in Caucasian Australians and Northern Europeans (TT+TC vs. CC: OR, 1.95; 95% CI, 1.45-2.62; p=0.00001; p>0.1; chi(2) for heterogeneity, p>0.1). No significant difference in genotype distribution of -308 polymorphism in AD was found, with a high degree of between-study heterogeneity. For the -863 and -1031 polymorphisms we did not find an association with AD, but significant between-study heterogeneity discouraged genotype data pooling. Only four studies investigated the -238 variant and the results were not significant. Current findings support an association between -850 C>T polymorphism and the risk of developing AD; hence, they strengthen the suggestion of a potential role for anti-TNF therapy to maintain physiologic levels of TNF-alpha.