Modest genetic influence on bronchodilator response: a study in healthy twins

Aim

To determine the reasons for large standard deviation of bronchodilator response (BDR) and establish whether there is a potential heritable component in healthy subjects.

Methods

67 monozygotic and 42 dizygotic adult twin pairs were assessed for bronchodilator response (%change in FEV₁ after inhaling 400 µg salbutamol). Univariate quantitative genetic modeling was performed.

Results

Multiple regression modeling showed a significant association between BDR and sex and baseline FEV1 (P < 0.05), while no association was found with smoking habits, body mass index, or age. Within pair correlation in monozygotic twins was modest (0.332), but higher than in dizygotic twins (0.258). Age-, sex-, and baseline FEV1-adjusted genetic effect accounted for 14.9% (95% confidence interval, CI 0%-53.1%) of the variance of BDR, shared environmental effect for 18.4% (95% CI 0%-46.8%), and unshared environmental effect for 66.8% (95% CI 46.8%-88.7%).

Conclusion

Our twin study showed that individual differences in BDR can be mostly explained by unshared environmental effects. In addition, it is the first study to show low, insignificant hereditary influences, independently from sex, age, and baseline FEV1.The assessment of the reversibility of airway obstruction is a key element in the diagnosis of airway diseases and can also be a sign of the potential therapeutic effect of a specific inhaled drug (1,2). Bronchodilator response (BDR) is tested after the inhalation of a drug and is defined as the change in spirometric parameters including forced vital capacity (FVC), forced expiratory volume in 1 second (FEV₁), and mid-expiratory flow 25%-75%. Although no consensus exists, the latest American Thoracic Society (ATS)/European Respiratory Society (ERS) guideline recommends that, during a single testing session, an increase in FEV₁ or FVC>12% and ≥200 mL from baseline is considered a significant BDR (3).Large population studies proposed a different threshold of BDR that has a role in clinical interpretation of airway response to a bronchodilator (4,5). However, underlying reasons for the large variation of BDR and a potential heritable component in healthy population are still unclear. It is known that certain genetic polymorphisms are associated with BDR in asthmatic (6,7) and non-asthmatic (8,9) individuals. This is supported by the fact that there are differences in BDR among different nations (10). These studies strongly support a hereditary influence on BDR, but they cannot fully describe the relationship of hereditary and environmental factors on the development of BDR. Assessing familial aggregation of BDR, Niu et al found a modest familial clustering (11).Family design can determine inter-generation resemblance or difference, but, in contrast to the twin study design, it does not determine the influence of outside factors such as family, environment, and culture (12). Accordingly, family studies cannot reliably distinguish the influence of heritability from common environmental effects. Numerous twin studies examined airway hyperresponsiveness (AHR) (13-18), but none of them investigated BDR. Although BDR is usually associated with AHR in obstructive airway diseases (19), previous twin results on AHR cannot simply be extended to BDR. Therefore, the first aim of this study is to determine which factors affect BDR in a healthy twin population. As a second aim we investigated whether the large standard deviation of BDR in healthy asymptomatic subjects could be attributable to genetic or environmental factors.     

Corrosive effects of fluoride on titanium: investigation by X-ray photoelectron spectroscopy, atomic force microscopy, and human epithelial cell culturing

High fluoride (F(-)) concentrations and acidic pH impair the corrosion resistance of titanium (Ti). Effects of F(-)-containing caries-preventive prophylactic rinses, and gels on Ti were investigated by X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM). Human epithelial cell attachment and proliferation were investigated by dimethylthiazol-diphenyl tetrazolium bromide (MTT) and protein content assays. Aqueous 1% NaF solution (3800 ppm F(-), pH 4.5) or high (12,500 ppm) F(-) content gel (pH 4.8) strongly corroded the surface and modified its composition. XPS revealed formation of a strongly bound F(-)-containing complex (Na(2)TiF(6)). AFM indicated an increase in roughness (R(a)) of the surfaces: 10-fold for the NaF solution and smaller for the gel or a mouthwash (250 ppm F(-), pH 4.4). MTT revealed that cell attachment was significantly increased by the gel, but was not disturbed by either the mouthwash or the NaF. Cell proliferation determined by MTT decreased significantly only for the NaF-treated samples; protein content assay experiments showed no such effect. This study indicates that epithelial cell culturing results can depend on the method used, and the adverse effects of a high F(-) concentration and low pH should be considered when prophylactic gels are applied by patients with Ti implants or other dental devices.     

The presence of pacemaker HCN channels identifies theta rhythmic GABAergic neurons in the medial septum

The medial septum (MS) is an indispensable component of the subcortical network which synchronizes the hippocampus at theta frequency during specific stages of information processing. GABAergic neurons exhibiting highly regular firing coupled to the hippocampal theta rhythm are thought to form the core of the MS rhythm-generating network. In recent studies the hyperpolarization-activated, cyclic nucleotide-gated non-selective cation (HCN) channel was shown to participate in theta synchronization of the medial septum. Here, we tested the hypothesis that HCN channel expression correlates with theta modulated firing behaviour of MS neurons by a combined anatomical and electrophysiological approach. HCN-expressing neurons represented a subpopulation of GABAergic cells in the MS partly overlapping with parvalbumin (PV)-containing neurons. Rhythmic firing in the theta frequency range was characteristic of all HCN-expressing neurons. In contrast, only a minority of HCN-negative cells displayed theta related activity. All HCN cells had tight phase coupling to hippocampal theta waves. As a group, PV-expressing HCN neurons had a marked bimodal phase distribution, whereas PV-immunonegative HCN neurons did not show group-level phase preference despite significant individual phase coupling. Microiontophoretic blockade of HCN channels resulted in the reduction of discharge frequency, but theta rhythmic firing was perturbed only in a few cases. Our data imply that HCN-expressing GABAergic neurons provide rhythmic drive in all phases of the hippocampal theta activity. In most MS theta cells rhythm genesis is apparently determined by interactions at the level of the network rather than by the pacemaking property of HCN channels alone.     

Selection of features within and without objects: effects of gestalt appearance and object-based instruction on behavior and event-related brain potentials

We studied how physical and instructed embedding of features in gestalts affects perceptual selection. Four ovals on the horizontal midline were either unconnected or pairwise connected by circles, forming ears of left and right heads (gestalts). Relevant to responding was the position of one colored oval, either within its pair or relative to fixation ("object-based" or "fixation-based" instruction). Responses were faster under fixation- than object-based instruction, less so with gestalts. Previously reported increases of N1 when evoked by features within objects were replicated for fixation-based instruction only. There was no effect of instruction on N2pc. However P1 increased under the adequate instruction, object-based for gestalts, fixation-based for unconnected items, which presumably indicated how foci of attention were set by expecting specific stimuli under instructions that specified how to bind these stimuli to objects.     

Cholesteryl Ester Transfer Protein Gene Polymorphism (I405V) and Risk of Ischemic Stroke

Background

Cholesteryl ester transfer protein (CETP) plays a major role in the metabolism of high-density lipoprotein. Polymorphisms in the CEPT gene can affect susceptibility to atherosclerosis and cardiovascular disease. The aim of this study was to evaluate the association of the CETP I405V polymorphism with ischemic stroke.