Biomarkers of immunotherapy response in patients with allergic rhinitis

Introduction: Allergen immunotherapy represents the only disease-modifying therapy available for immunoglobulin E-mediated diseases such as allergic rhinitis and asthma. Allergen immunotherapy induces allergen tolerance by interfering with the immune-pathogenic mechanisms of the allergic response and is potentially able to provide long-term relief of symptoms of allergic rhinitis and asthma and alter the natural course of allergic diseases.

Areas covered: Since allergen immunotherapy (AIT) is actually considered an individualized treatment on patient’s clinical and immunological profile, the identification of specific biomarkers, which may guide diagnosis, management, and predict response to AIT treatment in allergic rhinitis (AR) patients, is essential and is currently an active field of research.

Expert commentary: The identification and validation of biomarkers of successful AIT for AR is an urgent need to definitively establish the role of AIT as a therapeutic tool of personalized medicine.     

Real-life clinical practice and management of polysensitized patients with respiratory allergies: a large,global survey of clinicians prescribing allergen immunotherapy

Background: The allermix survey was conducted to gain insights into the most frequently diagnosed allergies worldwide, the use of allergen immunotherapy (AIT) in clinical practice, and to identify current clinical approaches for the management of polyallergic patients.

Methods: The survey was conducted in 19 countries worldwide during 2016. Clinicians currently prescribing AIT completed an online questionnaire, designed to gather data on their daily clinical practice, most commonly diagnosed and treated allergies among their patients, awareness and adherence to recommendations and guidelines on AIT, the AIT format(s) that they choose to prescribe, and management of polyallergic patients.

Results: Respondents (N = 1029) considered a clinical demonstration of safety and effectiveness, and quality and standardization of allergen extract, as key factors influencing their choice of which AIT formulation to prescribe. 98% of respondents reported managing polyallergic patients; 58% were treated with single-allergen AIT and 42% with multiple-allergen AIT. 74% of respondents were aware of latest AIT practice guidelines, while 67% had an awareness of recent recommendations for pharmaceutical manufacturers.

Conclusion: These findings highlight the need for high-quality AIT products that are supported by robust efficacy and safety data, and address the treatment habits of allergy specialists in their real-life clinical practice.     

New opportunities for allergen immunotherapy using synthetic peptide immuno-regulatory epitopes (SPIREs)

Introduction: Allergen immunotherapy (AIT) reduces allergic rhinoconjunctivitis (ARC) symptoms, but long-term efficacy requires treatment for 3–5 years. Synthetic peptide immuno-regulatory epitopes, a new class of AIT, are allergen peptides with a shorter, more convenient treatment regimen that could potentially have benefits on adherence and outcomes.

Areas covered: Phase 2 trials of therapies derived from cat, house dust mite, grass, and ragweed allergen peptides demonstrated significant reduction in ARC symptoms after short-course treatment; improvement was sustained for 18–24 months posttreatment. We conducted a PubMed literature search for clinical publications using the search terms AIT; allergen peptides; ARC; cat, grass, house dust mite, and ragweed allergy; SCIT; SLIT; and synthetic peptides.

Expert commentary: Long-term disease modification is a realistic goal of AIT. The inconvenience of conventional AIT regimens negatively impacts long-term persistence and, thus, efficacy. In comparison, SPIREs have a more convenient treatment regimen that could potentially have benefits on adherence and outcomes.     

Comparison of allergenic extracts from different origins: the value of the FDA’s bioequivalent allergy unit (BAU)

Introduction: Allergy immunotherapy (AIT) is the only disease-modifying intervention for the treatment of allergic diseases. The clinical effectiveness of AIT is clearly dose-dependent, so it is important that clinicians can assess and compare the potency of the various products available. However, this is not possible in practice, because manufacturers use different methods to determine potency. Therefore, a clear need exists for adoption of a ‘gold-standard’ measure of allergenicity. The bioequivalent allergy unit (BAU) is thus far the only allergen unit approved by a regulatory agency (the US Food and Drug Administration), with European regulatory authorities yet to adopt a common unit.

Areas covered: Using PubMed, we performed a review of the literature on measures of allergen extract potency, use of the BAU, and BAU assessment for grass pollen tablets.

Expert commentary: There is an obvious benefit to allergists and patients for having a single, comparable unit across products, and we strongly support the adoption of a single, ‘gold-standard’ unit of measurement for all products. Use of the BAU allows a clear comparison of the potency of allergen products from different manufacturers, and enables better understanding of the potential reasons for any differences in administration and dosing protocols between these products.     

Systematic overview of neuroanatomical differences in ADHD: Definitive evidence

Objectives: This article seeks to identify neuroanatomical differences in ADHD through an overview of systematic reviews that report encephalic differences compared to a control group in volume, area, activation likelihood or chemical composition.

Methods: We conducted a systematic search using Cochrane guidelines and PRISMA criteria in PubMed, Scopus, Web of Science, Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects.

Results: Results revealed broad encephalic involvement that includes a functional frontal and cingulate hypoactivation and structural differences in corpus callosum, cerebellum and basal nuclei.

Conclusions: ADHD symptoms might be due to a multi-network unbalanced functioning hypothesis.     

High numbers of myeloid derived suppressor cells in peripheral blood and ascitic fluid of cirrhotic and HCC patients

Background: Hepatocellular carcinoma (HCC) is the 3rd most common cause of cancer-related death worldwide. It has evolved different immune escape mechanisms, which might include emergence of lymphoid and myeloid regulatory cells.

Aim of this work: To determine the numbers of Myeloid-derived suppressor cells (MDSCs) in peripheral blood and ascitic fluid in cirrhosis and HCC and their relation to IFN-γ and α-fetoprotein (α-FP).

Patients and methods: Sixty individuals were enrolled in this study; forty cirrhotic patients with ascites; twenty without HCC (Group I), and twenty with HCC (group II) as well as twenty healthy individuals as a control group (group III). The phenotype and numbers of MDSCs were analyzed in peripheral blood of all the individuals and ascitic fluid of the patients using flow cytometry. Intracellular IFN-γ and serum alfa-fetoprotein were measured.

Results: Significant increases in the relative and the mean number of peripheral blood MDSCs were found in the cirrhosis and HCC groups than in the control group, with the HCC group showing the highest number. MDSC count was negatively correlated with IFN-γ levels, while α-FP was positively correlated with MDSC% in the HCC group. MDSC count was low in ascitic fluid of both HCC and cirrhosis groups with no significant difference between the 2 groups.

Conclusion: A high frequency of MDSCs was detected in the peripheral blood of cirrhotic and HCC patients, indicating presence of immunosuppressive arms. These cells could be targeted to develop a new effective immunotherapy or an adjuvant to current therapies.     

Clinical use of adjuvants in allergen-immunotherapy

Introduction: Allergen-specific Immunotherapy (AIT) is the only available treatment aimed to tackle the underlying causes of allergy. The active components of subcutaneous vaccines traditionally consist of natural or modified allergen extracts which can be combined with adjuvant platforms. In recent years new targets have been further developed in an attempt to raise the safety and efficacy profile of AIT.

Areas covered: In this review, we discuss the desirable attributes of adjuvants and delivery systems from empiricism to rational design, for current and future clinical applications in AIT.

Expert commentary: The introduction of novel adjuvants, in combination with active targets, has been demonstrated to reduce symptoms of AIT, increase clinical efficacy of allergy treatment and reduce the number of doses. The evolution of vaccine development for AIT is entering a phase of scientific progress that challenges dogmas. Over the past century the traditional concept of immunotherapy, entailing long-course administration of native extract preparations and first generation adjuvants, has seen evolution in the past decade from proof-of-concept to clinical development pipelines encompassing the advent of second generation adjuvants and delivery systems forming essential components of modern AIT development.     

ALK protein expression in pulmonary adenocarcinoma of Tunisian patients

Background. It is now necessary to determine ALK status in order to use targeted therapy. Aim: herein, we assess immunohistochemical profile of ALK protein in a series of Tunisian patients with pulmonary adenocarcinoma.

Materials and Methods. ALK protein expression was studied applying the D5F3 antibody with a fully automated Ventana CDx technique on a series of 19 patients.

Results. Positive ALK expression was found in one case (5.2%) corresponding to a papillary adenocarcinoma which showed a strong granular and homogenous cytoplasmic staining. The patient was a 30-years-old woman.

Conclusion. The frequency of positive ALK expression based on immunohistochemistry in our series was similar to that reported in the world literature.     

Allergen immunotherapy in atopic dermatitis

Introduction: Atopic dermatitis (AD) is a chronic relapsing skin disease, characterized by flare-up due to the exposure to allergens in patients sensitized to them. Currently, therapy of AD is mainly based on symptomatic treatment and avoidance of irritating/allergenic factors, house dust mites being particularly important. Allergen immunotherapy (AIT) is suggested to be the only etiologic treatment, to modify the natural history of the disease.

Areas covered: The aim of this review is investigating the putative role of AIT in AD through the evaluation of the most recent scientific literature. Several studies have been conducted since 1970, with promising results in improving the clinical outcome of AD, but they often lack the necessary scientific rigorousness. Moreover, heterogeneity of the studies makes it very difficult to compare and to analyze data in a systematic review or meta-analysis.

Expert commentary: As a result of the above-mentioned limitations, the treatment of AD with causative aeroallergen can nowadays be suggested only as an add-on therapy in selected patients who are non-responsive to the traditional therapy.     

Allergic rhinitis management: what’s next?

Introduction: Allergic rhinitis (AR) is characterized by the presence of congestion, postnasal drainage, sneezing and rhinorrhea. AR contributes to reduced productivity and significant morbidity worldwide.

Areas covered: We review data emphasizing that the most effective therapy to alter the course of AR is allergen-specific immunotherapy, either subcutaneous or sublingual. However, significant advancements in developing alternative forms of therapies have opened the door for potential novel avenues of treating patients with AR. We discuss novel therapies currently under investigation or recently approved, which may provide a more effective and safer treatment option.

Expert commentary: Novel therapies for this common disorder which causes significant impaired quality of life are under investigation and will hopefully lead to better therapeutic options.     

The Orientalisation of North Africa: New hints from the study of autosomal STRs in an Arab population

Background: Recent genomic analyses suggest that the current North African gene pool was mainly influenced by population flow coming from the East that altered the genetic structure of autochthonous Berber populations. Such genetic flow has not been extensively addressed yet using North African populations of Middle-eastern origin as reference.

Aim: To discern the Middle-eastern component in the genetic background of Tunisian Arabs and evaluate the extent of gene flow from the Middle East into North African autochthonous Berber populations.

Subjects and methods: This study has examined 113 Tunisians of well-known Arabian origin from Kairouan region, using 15 autosomal Short Tandem Repeats (STRs) loci.

Results: No deviations from Hardy-Weinberg equilibrium were observed and all loci presented high levels of heterozygosity. Principal coordinate and STRUCTURE analyses were consistent in clustering together North African and Middle Eastern populations, likely reflecting the recent gene flow from the East dating back to the Arab conquest period. This demographic migration and the Arabisation process that submerged the original Berber language and customs seems to have be accompanied by substantial gene flow and genetic admixture.

Conclusion: This study represents an additional step to obtain a comprehensive understanding of the complex demographic history of North African populations.     

Testing times: identifying puberty in an identified skeletal sample

Background: Identifying the onset of puberty in skeletal remains can provide evidence of social changes associated with the onset of adulthood.

Aim: This paper presents the first test of a skeletal method for identifying stages of development associated with the onset of puberty in a skeletal sample of known age and cause of death.

Materials and methods: Skeletal methods for assessing skeletal development associated with changes associated with puberty were recorded in the identified skeletal collection in Coimbra, Portugal. Historical data on the onset of menarche in this country are used to test the method.

Results: As expected, females mature faster than their male counterparts. There is some side asymmetry in development. Menarche was found to have been achieved by an average age of 15.

Conclusions: Asymmetry must be taken into account when dealing with partially preserved skeletons. Age of menarche is consistent, although marginally higher, than the age expected based on historical data for this time and location. Skeletal development in males could not be tested against historical data, due to the lack of counterpart historical data. The ill health known to be present in this prematurely deceased population may have delayed skeletal development and the onset of puberty.     

Correlation of Proteinuria with Podocyte Foot Process Effacement in IgA Nephropathy: An Ultrastructural Study

Background: Proteinuria is an uncommon clinical manifestation of IgA nephropathy and is usually seen in cases with severe lesions like endocapillary proliferation. However, it is occasionally seen even with cases with mild glomerular manifestations and may even be of nephrotic range.

Predictor: Podocyte foot process effacement.

Outcome: Severity of proteinuria.

Measurements: Podocyte foot process effacement was measured. Morphometric analysis was performed on transmission electron microscope images using a computerized digital photomicrograph system (BioWizard 4.2 Image analysis software, New Delhi, India). Proteinuria was measured quantitatively assigned into five grades.

Results: It was found that as the extent of proteinuria increased, the effacement ratio also increased, and this was most significant between “no” proteinuria and the rest of the categories.

Conclusion: Nephrotic presentation in IgA nephropathy is a known phenomenon and in certain cases may show near normal glomerular morphology with severe foot process effacement on EM being the only significant finding to explain the proteinuria. Proteinuria in these cases shows a significant correlation with degree of foot process effacement. Renal biopsy is important in these cases because they are known to have a better prognosis and are usually steroid responsive.     

Evaluating mtDNA patterns of genetic isolation using a re-sampling procedure: A case study on Italian populations

Background: A number of studies which have investigated isolation patterns in human populations rely on the analysis of intra- and inter-population genetic statistics of mtDNA polymorphisms. However, this approach makes it difficult to differentiate between the effects of long-term genetic isolation and the random fluctuations of statistics due to reduced sample size.

Aim: To overcome the confounding effect of sample size when detecting signatures of genetic isolation.

Subjects and methods: A re-sampling based procedure was employed to evaluate reduction in intra-population diversity, departure from surrounding genetic background and demographic stationarity in 34 Italian populations subject to isolation factors.

Results: Signatures of genetic isolation were detected for all three statistics in seven populations: Pusteria valley, Sappada, Sauris, Timau settled in the eastern Italian Alps and Cappadocia, Filettino and Vallepietra settled in the Appenines. However, this study was unable to find signals for any of the statistics analysed in 19 populations. Finally, eight populations showing signals of isolation were found for one or two statistics.

Conclusion: The analysis revealed that the use of population genetic statistics combined with re-sampling procedure can help detect signatures of genetic isolation in human populations, even using a single, although highly informative, locus like mtDNA.     

Y-Chromosome haplotypes reveal relationships between populations of the Arabian Peninsula,North Africa and South Asia

Background: The United Arab Emirates (UAE) is positioned at the crossroads of human migration out of Africa and through to Asia and Europe.

Aim: To compare the degree of genetic diversity of the Arabian UAE population with populations in other countries from the Middle East, South Asia and North Africa.

Subjects and methods: Twenty-seven Y-STR were analysed in 217 individuals. Y-STR haplotypes from this study were compared to population data stored in YHRD, using MDS and AMOVA.

Results: Two hundred and twelve haplotypes were observed in the 217 individuals studied. Although the reduction in Y-STR loci from 27 to 17 resulted in a decrease in discriminatory power, comparisons of populations were possible. The UAE population clustered closer with other populations of the Middle East. The South Asian and North African populations were separated by Middle Eastern populations in between both clusters.

Conclusion: This is the first study to report the diversity of a population of the Arabian Peninsula using 27 Y-STR. MDS plots show that Middle Eastern populations are positioned in the centre, with African, Asian and European populations around the Arab population cluster. The findings of this study are consistent with this region being at the epicentre of human migration between continents.     

Matrix Metalloproteinase-9 rs17576 Gene Polymorphism and Behçet’s Disease: Is There an Association?

Background: Clinical studies have reported a significant association between matrix metalloproteinases (MMP), particularly (MMP-9), and inflammatory diseases including Behçet’s disease (BD).

Purpose: To study the relationship between MMP-9 rs17576 gene polymorphism and the development of BD, and its relation to disease activity among Egyptian patients.

Methods: A total of 100 BD patients and 100 healthy control volunteers were genotyped for MMP-9 rs17576 polymorphism with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), followed by the confirmation of our results in random subgroups using direct DNA sequencing technique.

Results: The frequency of the GG genotype and G allele was significantly higher in BD patients as compared to the normal controls (p = 0.011, OR 8.61; p = 0.03, OR 1.65, respectively). There was no significant association between the MMP-9 rs17576 polymorphism and the clinical outcomes of BD.

Conclusion: our study suggests a significant association of the MMP-9 rs17576 A/G polymorphism with increased risk of BD development in Egyptian patients.     

Relation of socioeconomic status to overweight and obesity: a large population-based study of Chinese adults

Background: China has been going through significant changes in social and economical aspects and with great socioeconomic disparity in different regions. However, data on the association between socioeconomic status (SES) and obesity are not available in Tianjin, China.

Aim: This study aimed to investigate the association between SES and high adiposity among the adult population in Tianjin.

Subjects and methods: A total of 7351 individuals aged 20–79 were included in this study. Socioeconomic information was collected through an interview following a structured questionnaire. Waist circumference, body weight and height were measured following standard procedures. Overweight and obesity were defined according to the criteria of the Working Group on Obesity in China. Data were analysed using multinomial logistic regression with adjustment for potential confounders.

Results: Stratified analysis showed that higher monthly income and education were related to decreased odds of abdominal overweight/obesity in women, while high education was associated with increased odds of general overweight/obesity in men. Retirement increased the odds of abdominal overweight and obesity and non-manual work was associated with low odds of abdominal obesity in women.

Conclusions: SES was associated with general and abdominal overweight/obesity and sex may play a role in such an association.     

Do patients with different psychiatric disorders show altered social decision-making? A systematic review of ultimatum game experiments in clinical populations

Background: Impairments in social functioning are a common feature of psychiatric disorders. Game paradigms pose a unique way for studying how people make decisions in interpersonal contexts. In the last decade, researchers have started to use these paradigms to study social decision-making in patients with psychiatric disorders.

Purpose: The aim of this systematic literature review is to summarise the currently available evidence on the behaviour of patients with psychiatric disorders in the commonly used Ultimatum Game (UG).

Method: A systematic literature search including MEDLINE, PsycINFO, PSYNDEXplus Tests, PSYNDEXPLUS Literature, EBM Reviews—Cochrane Central Register of Controlled Trials, Embase and PASCAL was performed via the Ovid interface.

Results: We found evidence for alterations in UG behaviour for patients with frontotemporal dementia, schizophrenia, affective disorders, alcohol, cocaine, heroin and 3,4-methylenedioxymethamphetamine consumption, alcohol dependence, anxiety disorders, borderline personality disorder, autism, Tourette syndrome and oppositional defiant disorder.

Conclusion: There is some evidence that different psychiatric disorders might go along with alterations in social decision-making. However, in general, data are currently limited and studies are hard to compare due to differences in methodologies.