Incidental Pharmacogenetics Findings in an HLA‐related Research: Considerations for Primary Prevention

Abstract

Hypersensitivity drug reactions (HDRs) are an immense public health problem where significant proportions may lead to mortality. HDRs can manifest in various phenotypes, mainly cutaneous reactions that range from the mild; i.e. exanthem, urticaria, and angioedema to the critical; i.e. severe cutaneous adverse reactions (SCARs). SCARs are life‐threatening reactions that include Stevens‐Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) or drug‐induced hypersensitivity syndrome (DIHS) and less commonly, acute generalized exanthematous pustulosis (AGEP). Previously, these reactions were unavoidable as they are linked to the intrinsic properties of drugs and an individual's genetic predisposition. Nevertheless, with the advent of pharmacogenomics and the vast pharmacogenetic studies performed in the last two decades, this is set to change in future.

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Dietary fats, olive oil and respiratory diseases in Italian adults: a population‐based study

Abstract

Background

Fat intake has been associated with respiratory diseases, with conflicting results.

Objective

We studied the association between asthma and rhinitis with dietary fats, and their food sources in an Italian population.

Methods

Clinical and nutritional information was collected for 871 subjects (aged 20–84) from the population‐based multi‐case control study Genes Environment Interaction in Respiratory Diseases (GEIRD): 145 with Current Asthma (CA), 77 with Past Asthma (PA), 305 with Rhinitis and 344 Controls. Food intake was collected using the EPIC (European Investigation into Cancer and Nutrition) Food Frequency Questionnaire. The associations between fats and respiratory diseases were estimated by multinomial models. Fats and their dietary sources were analyzed both as continuous variables and as quartiles.

Results

Monounsaturated fatty acids, and oleic acid were associated with a reduced risk of CA in both continuous (RRR=0.68, 95%CI: 0.48; 0.96; RRR=0.69; 95%CI: 0.49;0.97, per 10g, respectively) and per‐quartile analyses (p for trend=0.028 and 0.024, respectively). Olive oil was associated with a decreased risk of CA (RRR=0.80; 95%CI: 0.65;0.98 per 10g). An increased risk of rhinitis was associated with moderate total fat and SFA intake.

Conclusions

High dietary intakes of oleic acid and of olive oil are associated with a lower risk of asthma but not of rhinitis.

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Impaired immunoregulatory network of the cd4 t lymphocytes in refractory asthma

Abstract

Background

The immunopathogenesis of severe asthma has been associated with an inefficient regulatory response. There are a few studies about the CD4 T cells profile among individuals with severe asthma refractory to treatment.

Objective

To evaluate the CD4 T lymphocyte profile from individuals with severe asthma according to their response to treatment, relating to their atopy status and age of asthma onset.

Methods

We evaluated nineteen individuals with severe asthma refractory to treatment (SAR), 21 with well‐controlled or partly controlled severe asthma (CSA) and 23 with mild to moderate asthma (MMA). Lymphocytes were obtained from PBMC and the frequency of expression of different molecules in this population was assessed using the flow cytometry.

Results

We observed the frequency of CD4⁺IFN‐γ⁺T cells was higher in atopic individuals with SAR than with CSA. In addition, among the atopic and early onset asthma (EOA), the frequency of CD4⁺CTLA‐4⁺T cells was lower in the SAR group than the CSA group. In relation to non‐atopic and late onset asthma (LOA) phenotypes, we noted the frequency of CD4⁺FoxP3⁺T cells was lower in individuals with SAR than with CSA. We also observed among the LOA patients, the frequency of CD4⁺TGF‐β⁺ T cells was decreased in SAR group than the in CSA group.

Conclusion & Clinical Relevance

Our data suggest that refractoriness to treatment in asthma is associated with a lower expression of distinct regulatory molecules by CD4 T cells between those who are atopic and have EOA and those who are non‐atopic and have LOA. Thus, these results may contribute to the identification of new regulatory strategies to treat asthma according to their phenotypes.

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Angiopoietin‐1 haploinsufficiency affects the endothelial barrier and causes hereditary angioedema

Abstract

Backgound

Different mutations of the angiopoietin‐1 gene (ANGPT1) have been associated with the occurrence of Hereditary Angioedema (HAE).

Objective

The purpose of the study is to clarify whether the ANGPT1 A119S variant plays its role via haploinsufficiency or a dominant negative effect.

Methods

The ability of ANGPT1 A119S variant to affect the endothelial barrier function was assessed by immunocytochemistry. Inter‐endothelial gap formation molecules primarily responsible for cell‐cell adhesions of HUVECs, vascular endothelial (VE)‐cadherin and β‐catenin, and reorganization of the F‐actin cytoskeletal were evaluated.

Results

In in vitro conditions mimicking the heterozygous state, the p.A119S variant significantly reduced the capability to bind its natural receptor (80.7% of normal), less than the homozygous condition (59.1%). After stimulation of VEGF or bradykinin, the addiction of equimolar amounts of wtANGPT1 and ANGPT1 p.A119S clearly reduced the expression of VE‐cadherin on the endothelial cell surface (31% and 24% respectively). Likewise, cell surface expression of β‐catenin was reduced and severe gap formation between adjacent HUVECs developed. In cultured cells, β‐catenin expression was mostly observed along the cell surface. Treatment with equimolar amounts of wtANGPT1 and ANGPT1 p.A119S failed to restore the reorganization of the F‐actin cytoskeletal elements. ANGPT1 p.A119S variant in homozygous condition further diminished VE‐cadherin and β‐catenin expression and failed to reduce stress fiber formation significantly affecting the endothelial barrier functionality.

Conclusions & Clinical Relevance

Present data show that in a heterozygous state the p.A119S substitution results in a pathogenic loss of function of the protein due to a mechanism of haploinsufficiency. the ANGPT1 reduced ability to counteract the increment of endothelial permeability produced by inducers, such as VEGF and Bradykinin, stimulate vascular leakage and reorganization of the F‐actin cytoskeletal elements. As a result, a partial impairment of the ANGPT1 functionality, like when dominant mutations occur, represents a pathophysiological cause of HAE.

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A Rainbow of Colors and Spectrum of Textures: An Approach to Oral Mucosal Entities

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Erythematous and Vascular Oral Mucosal Lesions: A Clinicopathologic Review of Red Entities

Abstract

Erythematous lesions of the oral mucosa are common and can reflect a variety of conditions, ranging from benign reactive or immunologically-mediated disorders to malignant disease. Together with vascular abnormalities, which can vary from reddish to bluish-purple in color, the differential diagnosis for erythematous oral mucosal change is quite diverse. This review focuses on salient clinical features and histopathologic findings of selected conditions which clinically present as red or vascular-like oral mucosal alterations, including oral vascular malformations and neoplasms, pyogenic granuloma, localized juvenile spongiotic gingival hyperplasia, denture stomatitis, benign migratory glossitis (geographic tongue), orofacial granulomatosis, granulomatosis with polyangiitis (Wegener granulomatosis), megaloblastic anemia, and erythroplakia. Recognition of the characteristic clinical features of these conditions, in conjunction with thorough patient history, will allow clinicians to narrow the differential diagnosis and guide appropriate clinical decision making, including the need for tissue biopsy, in order to complete the diagnostic process and initiate optimal patient care.

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Left or right? An Australian study of the laterality of skin cancers

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