The Variants in the 3′ Untranslated Region of the Matrix Metalloproteinase 9 Gene as Modulators of Treatment Outcome in Children with Asthma

Purpose

The maintaining of asthma control is difficult due to high variability in response to therapy among patients. Since matrix metalloproteinase 9 (MMP9) is implicated in inflammation and remodeling of asthmatic airways, it could be associated with adequate response to asthma therapy. The aim of this study was to investigate whether variants in 3′ end of the MMP9 gene are associated with clinical phenotype and responsiveness to treatment in children with asthma.

Methods

The study included 127 asthmatic children from Slovenia. Variants in the 3′ end of the MMP9 gene were analyzed by direct DNA sequencing and the obtained results were correlated with clinical parameters.

Results

Two variants were detected, rs13925 and rs20544. For the variant rs20544, statistically significant difference in airway hyperresponsiveness (p?=?0.011) and asthma control (p?=?0.049) between genotypes was found. Patients with TT genotype had lower airway sensitivity, and after 12 months of treatment showed significant improvement in Asthma Control Test (ACT) scores compared to CC and CT genotype. For the variant rs13925, the association with lung function was observed. The carriers of A allele showed noticeable improvement of lung function after the first 6 months of treatment in comparison to the carriers of G allele (p?=?0.046).

Conclusion

The main finding of our study is the association of MMP9 genotypes rs20544 TT and rs13925 AA and AG with better asthma control, and indirectly better response to treatment. Based on these results, MMP9 deserves further research as a potential predictive biomarker for asthma.

     

Heritability of the Human Craniofacial Complex

Quantifying normal variation and the genetic underpinnings of anatomical structures is one of the main goals of modern morphological studies. However, the extent of genetic contributions to normal variation in craniofacial morphology in humans is still unclear. The current study addresses this gap by investigating the genetic underpinnings of normal craniofacial morphology. The sample under investigation consists of 75 linear and angular measurements spanning the entire craniofacial complex, recorded from lateral cephalographs of 1,379 participants in the Fels Longitudinal Study. Heritabilities for each trait were estimated using SOLAR, a maximum‐likelihood variance components approach utilizing all pedigree information for parameter estimation. Trait means and mean effects of the covariates age, sex, age², sex × age, and sex × age² were simultaneously estimated in the analytic models. All traits of the craniofacial complex were significantly heritable. Heritability estimates ranged from 0.10 to 0.60, with the majority being moderate. It is important to note that we found similar ranges of heritability occurring across the different functional/developmental components of the craniofacial complex, the splanchnocranium, the basicranium, and the neurocranium. This suggests that traits from different regions of the craniofacial complex are of comparable utility for the purposes of population history and phylogeny reconstruction. At the same time, this genetic influence on craniofacial morphology signals a caution to researchers of nongenetic studies to consider the implications of this finding when selecting samples for study given their project design and goals. Anat Rec, 298:1535–1547, 2015. © 2015 Wiley Periodicals, Inc.     

Interaction between warfarin and cannabis

Delta‐9‐tetrahydrocannabinol (THC), the main psychoactive cannabinoid in cannabis, may inhibit the cytochrome P450 enzyme CYP2C9. Consequently, cannabis use might infer a risk of drug‐drug interaction with substrates for this enzyme, which includes drugs known to have a narrow therapeutic window. In this study, we describe a case report of a 27‐year‐old man treated with warfarin due to mechanical heart valve replacement who presented with elevated international normalized ratio (INR) value (INR = 4.6) following recreational cannabis use. We conducted a review of the available literature, using the PubMed and EMBASE databases while following PRISMA guidelines. Following screening of 85 articles, three eligible articles were identified, including one in vitro study and two case reports. The in vitro study indicated that THC inhibits the CYP2C9‐mediated metabolism of warfarin. One case study reported of a man who on two occasions of increased marijuana use experienced INR values above 10 as well as bleeding. The other case study reported of a patient who initiated treatment with a liquid formulation of cannabidiol for the management of epilepsy, ultimately necessitating a 30% reduction in warfarin dose to maintain therapeutic INR values. The available, although sparse, data suggest that use of cannabinoids increases INR values in patients receiving warfarin. Until further data are available, we suggest patients receiving warfarin be warned against cannabis use.     

Scoring accuracy of automated sleep staging from a bipolar electroocular recording compared to manual scoring by multiple raters

Objectives

Electroencephalography (EEG) assessment in research and clinical studies is limited by the patient burden of multiple electrodes and the time needed to manually score records. The objective of our study was to investigate the accuracy of an automated sleep-staging algorithm which is based on a single bipolar EEG signal.

Methods

Three raters each manually scored the polysomnographic (PSG) records from 44 patients referred for sleep evaluation. Twenty-one PSG records were scored by Rechtschaffen and Kales (R&K) criteria (group 1) and 23 PSGs were scored by American Academy of Sleep Medicine (AASM) 2007 criteria (group 2). Majority agreement was present in 98.4% of epochs and was used for comparison to automated scoring from a single EEG lead derived from the left and right electrooculogram.

Results

The κ coefficients for interrater manual scoring ranged from 0.46 to 0.89. The κ coefficient for the auto algorithm vs manual scoring by rater ranged from 0.42 to 0.63 and was 0.61 (group 1, κ = 0.61 and group 2, κ = 0.62) for majority agreement for all studies. The mean positive percent agreement across subjects and stages was 72.6%, approximately 80% for stages wake (78.3%), stage 2 sleep (N2) (80.9%), and stage 3 sleep (N3) (78.1%); the percentage slightly decreased to 73.2% for rapid eye movement (REM) sleep and dropped to 31.9% for stage 1 sleep (N1). Differences in agreement were observed based on raters, obstructive sleep apnea (OSA) severity, medications, and signal quality.

Conclusions

Our study demonstrated that automated scoring of sleep obtained from a single-channel of forehead EEG results in agreement to majority manual scoring are similar to results obtained from studies of manual interrater agreement. The benefit in assessing auto-staging accuracy with consensus agreement across multiple raters is most apparent in patients with OSA; additionally, assessing auto-staging accuracy limited disagreements in patients on medications and in those with compromised signal quality.     

Alzheimer’s disease and type 2 diabetes: the association study of polymorphisms in tumor necrosis factor-alpha and apolipoprotein E genes

Type 2 diabetes (T2D) and Alzheimer??s disease (AD) are two progressive disorders with high prevalence worldwide. Polymorphisms in tumor necrosis factor-alpha (TNF-??) and apolipoprotein E (ApoE) genes might be associated with both T2D and AD, representing possible genetic markers for the development of the AD in subjects with T2D. The aim was to determine ApoE and G-308A TNF-?? gene polymorphisms in unrelated Croatian Caucasians: 207 patients with sporadic AD, 196 T2D patients and 456 healthy controls. Patients with AD had higher frequency of ApoE4 allele compared to T2D patients and controls. The significant association, observed between ApoE2 allele and T2D, disappeared after the data were adjusted for age and sex. The genotype or allele frequencies of G-308A TNF-?? gene polymorphism were similar among the patients with AD, T2D and healthy controls. In conclusion, these results do not support the hypothesis that the A allele of G-308A TNF-?? gene polymorphism is associated either with AD or T2D. Our data confirm the association between the ApoE4 allele and AD, and point out the E2 allele of ApoE gene as the possible risk factor for T2D.