The rs579459 ABO gene polymorphism and risk of incident cardiovascular events in obstructive sleep apnea: a pilot study.

PURPOSE: We have previously shown that the TT genotype (rs579459 location of the ABO gene) is significantly associated with circulating levels of e-selectin in patients with suspected obstructive sleep apnea (OSA). We hypothesized that this genotype would be associated with incident cardiovascular disease (CVD). METHODS: Patients with suspected OSA who had a full diagnostic polysomnogram from 2003 to 2011 were recruited; CV events occurring within 8 years of polysomnography were identified by linkage to provincial health databases. Cox proportional hazards models were used to evaluate the incidence of first CV events as a function of the rs579459 genotype. RESULTS: In this targeted study, 408 patients were studied, and 39 incident events were identified. A larger proportion of patients with the TT genotype had an event (31/247; 12.6%) than the CT and CC genotypes (8/161; 5.0%); in univariate analysis, the TT genotype was significantly associated with CV events (HR = 2.53; 95% CI = 1.16-5.51, p = 0.02). After adjustment for age, AHI, sex, smoking, diabetes, statin use, and BMI, the TT genotype remained a significant predictor (HR = 2.35; 95% CI = 1.02-5.42, p = 0.046). No events were found in patients with an absence of both OSA and the TT genotype (N = 30). The effect of the SNP was partially (16.2%) mediated by e-selectin levels. CONCLUSION: This is the first study to examine genetic variants as a risk factor for incident CVD in the context of OSA. Although these results are preliminary and in need of replication, it suggests that genetic markers may become useful in helping to guide precision clinical care.

Circulating markers of oxidative stress and risk of incident cardiovascular events in obstructive sleep apnea.

The identification of which patients with obstructive sleep apnea (OSA) are more likely to develop cardiovascular disease (CVD) remains a challenge. OSA causes oxidative stress (OS) which may contribute to CVD pathogenesis. Therefore, OS markers could be useful in risk-stratifying cardiovascular (CV) risk in OSA patients. The purpose of this pilot study was to assess whether three OS marker levels could be associated with incident CVD in suspected OSA patients. Morning plasma levels of 8-isoprostane, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and superoxide dismutase (SOD) were measured in patients with suspected OSA referred for a polysomnogram (PSG). A composite outcome of CV events was defined by linkage with provincial administrative health databases. Cox proportional hazards models were used to assess the relationship between the levels of OS markers and events. 352 patients were included (mean age of 51.4 years, 68% male, median apnea hypopnea index of 16/h). Thirty-one first CV events occurred over an 8-year follow-up. In univariate or fully adjusted models, none of the OS markers were significantly associated with incident CV events (hazard ratio in adjusted models of: 1.25 (95% CI 0.56-2.80, p = 0.59), 1.15 (0.52-2.57, p = 0.73), 0.77 (0.37-1.61, p = 0.48), for 8-OHdG, 8-isoprostane and SOD; however, confidence intervals were wide. In this small preliminary study, oxidative stress markers were not significantly associated with risk of CV events. However, moderate associations between these markers and risk of CV events are possible and should be the focus of future larger studies. Supplementary Information: The online version contains supplementary material available at 10.1007/s41105-022-00399-0.

Circulating levels of cell adhesion molecules and risk of cardiovascular events in obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) patients are at increased risk of cardiovascular disease (CVD). Cell adhesion molecules (CAM) are increased in OSA and CAM are also implicated in the development of CVD. RESEARCH QUESTION: Do CAM (ICAM-1, VCAM-1 and E-selectin) have prognostic value in identifying risk of cardiovascular events in OSA? STUDY DESIGN AND METHODS: Patients with suspected OSA referred for a polysomnogram provided a fasting blood sample. Plasma levels of ICAM-1, VCAM-1 and E-selectin were determined by multiplex Luminex Assay (Milliporesigma ON, Canada). Cardiovascular events were determined by deterministic linkage to provincial health databases. RESULTS: 418 patients were included in the analysis. Mostly male (68.2%), mean age of 50.7 yrs, median AHI 16.5 events/hour, and mean BMI of 31.7 kg/m2. 36 cardiovascular events occurred in 8-yrs of follow up. Higher levels of ICAM-1 were associated with developing CVD (HR = 3.65 95% CI 1.40-9.53, 2nd and 3rd tertiles vs. 1st tertile), including in patients with OSA (HR = 3.1 95% CI 1.16-8.25). E-selectin was significantly associated with cardiovascular events in patients with moderate to severe OSA (HR = 3.31 95% CI 0.94-11.72, 2nd and 3rd tertiles vs. 1st tertile) but not in patients without moderate to severe OSA (HR = 0.67 95% CI 0.19-2.38), p-value for interaction = 0.07. INTERPRETATION: In a suspected OSA cohort, patients with higher levels of ICAM-1 (>816 ng/ml) were significantly more likely to experience a cardiovascular event within 8 years after PSG. In moderate to severe OSA patients, a higher E-selectin (>36.4 ng/ml) was significantly associated with cardiovascular events.

Long-term periodontal changes associated with oral appliance treatment of obstructive sleep apnea.

STUDY OBJECTIVES: To characterize the mandibular anterior teeth crown height as a marker of periodontal changes and bone loss as a side effect of an oral appliance worn for a minimum of 4.5 years. METHODS: This retrospective study conducted in patients with healthy baseline periodontium recruited participants among consecutive sleep apnea patients treated with an oral appliance between 2004 to 2014. Eligible participants were recalled for a follow-up visit at which a periodontal examination was performed and a lateral cephalogram and dental impressions were obtained. Clinical crown height for mandibular anterior teeth and cephalometric variables were measured and compared before and after treatment. A full periodontal evaluation was performed at the follow-up visit. RESULTS: Twenty-one patients enrolled with a mean treatment length of 7.9 ± 3.3 years. For the mandibular anterior teeth, clinical crown height did not change over the evaluated period. At follow-up, all the periodontal assessed variables were within normal limits, with the mean probing depth of 1.4 ± 0.5 mm, recession 0.6 ± 1.1 mm, and clinical attachment loss 0.8 ± 1.0 mm. Compared with baseline, there was a significant proclination of mandibular incisors (mean increase of 5.1 degrees) with the continued use of an oral appliance. Gingival levels were maintained with clinically insignificant changes during the observation period. CONCLUSIONS: Inclination of the mandibular incisors increases significantly with the use of an oral appliance in patients with obstructive sleep apnea. Positional changes in these teeth were not associated with any measured evidence of increase in clinical crown height or gingival recession. CITATION: Heda P, Alalola B, Almeida FR, Kim H, Peres BU, Pliska BT. Long-term periodontal changes associated with oral appliance treatment of obstructive sleep apnea. J Clin Sleep Med. 2021;17(10):2067-2074.

Obstructive Sleep Apnea Severity, Body Mass Index, and Circulating Levels of Cellular Adhesion Molecules.

PURPOSE: To investigate the relationship between obstructive sleep apnea (OSA) severity, body mass index (BMI), and circulating levels of inflammatory adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin). METHODS: A cross-sectional clinical cohort study on all consecutive adults referred to the University of British Columbia (UBC) Sleep Laboratory for a polysomnogram (PSG) for suspected OSA provided a morning blood sample. Samples were analyzed with multiplex immune assay (MilliporeSigma, CA) to assess the levels of adhesion molecules. RESULTS: 488 patients were studied; the majority were male (68%) with a mean age of 50 yrs, mean AHI of 23 events/hour, and mean BMI of 32 kg/m2. In multivariable linear regression models, all three adhesion molecules were significantly associated with BMI (E-selectin p < 0.0001; ICAM-1 p = 0.0007; VCAM-1 p = 0.0003). However, only E-selectin was independently associated with AHI (p = 0.02); there was no significant interaction between AHI and BMI for E-selectin (p = 0.33). CONCLUSIONS: Although all three adhesion molecules were associated with BMI, only E-selectin was independently associated with OSA severity. Future studies are needed to determine the clinical significance of the relationship between E-selectin and OSA.

Obstructive Sleep Apnea and Circulating Biomarkers of Oxidative Stress: A Cross-Sectional Study.

Oxidative stress (OS) drives cardiometabolic diseases. Intermittent hypoxia consistently increases oxidative stress markers. Obstructive sleep apnea (OSA) patients experience intermittent hypoxia and an increased rate of cardiovascular disease, however, the impact of OSA on OS markers is not clear. The objective was to assess relationships between OSA severity and biomarker levels. Patients with suspected OSA referred for a polysomnogram (PSG) provided fasting blood sample. Plasma levels of 8-isoprostane, 8-hydroxydeoxyguanosine (8-OHdG), and superoxide dismutase (SOD) were measured. The relationship between OSA and OS was assessed both before and after controlling for confounders (age, sex, smoking history, history of cardiovascular disease, ethnicity, diabetes, statin usage, body mass index (BMI)). 402 patients were studied (68% male, mean age ± SD = 50.8 ± 11.8 years, apnea-hypopnea index (AHI) = 22.2 ± 21.6 events/hour, BMI = 31.62 ± 6.49 kg/m2). In a multivariable regression, the AHI significantly predicted 8-isoprostane levels (p = 0.0008) together with age and statin usage; AHI was not a predictor of 8-OHdG or SOD. Female sex (p < 0.0001) and no previous history of cardiovascular disease (p = 0.002) were associated with increased antioxidant capacity. Circulating 8-isoprostane levels may be a promising biomarker of the severity of oxidative stress in OSA patients. Prospective studies are needed to determine whether this biomarker is associated with long-term cardiometabolic complications in OSA.

Experimental composites of polyacrilonitrile-electrospun nanofibers containing nanocrystal cellulose.

OBJECTIVE: To test the effects of addition of polyacrilonitrile (PAN) nanofibers and nanocrystal cellulose (NCC)-containing PAN nanofibers on flexural properties of experimental dental composites. METHODS: 11wt% PAN in dimethylformamide (DMF) solution was electrospun at 17.2kVA and 20cm from the collector drum. NCC was added to the solution at 3wt%. Fiber mats were produced in triplicates and tested as-spun. Strips (5cm×0.5cm) were cut from the mat in an orientation parallel and perpendicular to the rotational direction of the collector drum. Tensile tests were performed and ultimate tensile strength (UTS), elastic modulus (E) and elongation at maximum stress (%) were calculated from stress/strain plots. Fiber mats were then infiltrated by resin monomers (50/50 BisGMA/TEGDMA wt%), stacked in a mold (2×15×25) and light-cured. Beams (2×2×25mm) were cut from the slabs and tested in a universal testing machine. Data were analyzed by multiple t-test and one-way ANOVA (α=0.05). RESULTS: Addition of 3% NCC resulted in higher tensile properties of the fibers. Fibers presented anisotropic behavior with higher UTS and E when tested in perpendicular orientation. The incorporation of 3% NCC-PAN nanofibers resulted in significant increase in work of fracture and flexural strength of experimental dental composite beams. SIGNIFICANCE: NCC was found to be a suitable nanoparticle to reinforce experimental dental composites by incorporation via nanofiber. This fundamental study warrants future investigation in the use of electrospun nanofibres as a way to reinforce dental composites.

Circulating biomarkers to identify cardiometabolic complications in patients with Obstructive Sleep Apnea: A systematic review.

Untreated Obstructive sleep apnea (OSA) is associated with an increased risk of cardiometabolic diseases such as diabetes and myocardial infarction. However, it is difficult to predict which patients are at particularly high risk. This systematic review aimed to identify potentially useful circulating biomarkers that could predict cardiometabolic complications in OSA. We searched Cochrane (EBM), EMBASE, Medline, PubMed, and Web of Science databases. Search concepts included: "Obstructive Sleep Apnea", "Biomarkers" and "Risk-Stratification". Manuscripts were included if they studied adults with OSA, circulating (blood) markers, and relationships with clinical outcomes. After screening, 10 were included. Studies addressed cardiovascular disease, type 2 diabetes, end-stage renal disease and metabolic syndrome. In general, levels of inflammatory markers, adhesion molecules, and vascular proteins were associated with the presence of cardiometabolic disease in OSA patients. Although studies regarding prognostic circulating biomarkers in OSA are limited, a number of potentially promising biomarkers were identified in our review. However, more research is needed using prospective cohorts to determine which biomarkers are most robustly associated with and useful in predicting future cardiovascular and metabolic sequelae in OSA patients. Identification of such biomarkers could guide more selective and targeted therapy for OSA in an emerging era of precision-based medicine.

Characterization, distribution, biology and impact on Italian walnut orchards of the invasive North-American leafminer Coptodisca lucifluella (Lepidoptera: Heliozelidae).

The leafminer Coptodisca sp. (Lepidoptera: Heliozelidae), recently recorded for the first time in Europe on Italian black and common walnut trees, is shown to be the North-American Coptodisca lucifluella (Clemens) based on morphological (forewing pattern) and molecular (cytochrome oxidase c subunit I sequence) evidence. The phylogenetic relatedness of three species feeding on Juglandaceae suggests that C. lucifluella has likely shifted, within the same host plant family, from its original North-American hosts Carya spp. to Juglans spp. Over the few years since its detection, it has established in many regions in Italy and has become a widespread and dominant invasive species. The leafminer completes three to four generations per year, with the first adults emerging in April-May and mature larvae of the last generation starting hibernation in September-October. Although a high larval mortality was recorded in field observations (up to 74%), the impact of the pest was substantial with all leaves infested at the end of the last generation in all 3 years tested. The distribution of the leafminer in the canopy was homogeneous. The species is redescribed and illustrated, a lectotype is designated and a new synonymy is established.

Integration of molecular, ecological, morphological and endosymbiont data for species delimitation within the Pnigalio soemius complex (Hymenoptera: Eulophidae).

Integrative taxonomy is a recently developed approach that uses multiple lines of evidence such as molecular, morphological, ecological and geographical data to test species limits, and it stands as one of the most promising approaches to species delimitation in taxonomically difficult groups. The Pnigalio soemius complex (Hymenoptera: Eulophidae) represents an interesting taxonomical and ecological study case, as it is characterized by a lack of informative morphological characters, deep mitochondrial divergence, and is susceptible to infection by parthenogenesis-inducing Rickettsia. We tested the effectiveness of an integrative taxonomy approach in delimiting species within the P. soemius complex. We analysed two molecular markers (COI and ITS2) using different methods, performed multivariate analysis on morphometric data and exploited ecological data such as host-plant system associations, geographical separation, and the prevalence, type and effects of endosymbiont infection. The challenge of resolving different levels of resolution in the data was met by setting up a formal procedure of data integration within and between conflicting independent lines of evidence. An iterative corroboration process of multiple sources of data eventually indicated the existence of several cryptic species that can be treated as stable taxonomic hypotheses. Furthermore, the integrative approach confirmed a trend towards host specificity within the presumed polyphagous P. soemius and suggested that Rickettsia could have played a major role in the reproductive isolation and genetic diversification of at least two species.

A karyological study of the genus Pnigalio Schrank (Hymenoptera: Eulophidae): assessing the taxonomic utility of chromosomes at the species level.

We provide a karyological study of 12 species of the genus Pnigalio in an attempt to evaluate the taxonomic utility of karyotypes at the species level. For all species of Pnigalio examined the number of chromosome was 2n=12. Karyotype formulae presented mainly metacentric and submetacentric chromosomes, although a pair of acrocentrics or subtelocentrics, shorter than biarmed chromosomes, was present in some species. The analysis of karyotypes of Pnigalio showed frequent but not general interspecific variability of the chromosome traits. Although most of the studied species revealed concordance between morphological and karyological characters (centromeric index and relative length), two other categories have been identified: morphologically distinct species without reciprocal differences in karyotype structure, and morphologically similar species that strongly differ in chromosomal characters.

Rickettsia symbionts cause parthenogenetic reproduction in the parasitoid wasp Pnigalio soemius (Hymenoptera: Eulophidae).

Bacteria in the genus Rickettsia are intracellular symbionts of disparate groups of organisms. Some Rickettsia strains infect vertebrate animals and plants, where they cause diseases, but most strains are vertically inherited symbionts of invertebrates. In insects Rickettsia symbionts are known to have diverse effects on hosts ranging from influencing host fitness to manipulating reproduction. Here we provide evidence that a Rickettsia symbiont causes thelytokous parthenogenesis (in which mothers produce only daughters from unfertilized eggs) in a parasitoid wasp, Pnigalio soemius (Hymenoptera: Eulophidae). Feeding antibiotics to thelytokous female wasps resulted in production of progeny that were almost all males. Cloning and sequencing of a fragment of the 16S rRNA gene amplified with universal primers, diagnostic PCR screening of symbiont lineages associated with manipulation of reproduction, and fluorescence in situ hybridization (FISH) revealed that Rickettsia is always associated with thelytokous P. soemius and that no other bacteria that manipulate reproduction are present. Molecular analyses and FISH showed that Rickettsia is distributed in the reproductive tissues and is transovarially transmitted from mothers to offspring. Comparison of antibiotic-treated females and untreated females showed that infection had no cost. Phylogenetic analyses of 16S rRNA and gltA gene sequences placed the symbiont of P. soemius in the bellii group and indicated that there have been two separate origins of the parthenogenesis-inducing phenotype in the genus Rickettsia. A possible route for evolution of induction of parthenogenesis in the two distantly related Rickettsia lineages is discussed.

Phenotypic plasticity of pigmentation and morphometric traits in Pnigalio soemius (Hymenoptera: Eulophidae).

Species of the genus Pnigalio Schrank are ectoparasitoids on several pest insects. Most species are polyphagous parasitoids of lepidopteran and dipteran leafminers. Despite their potential economic importance, information on intraspecific phenotypic variability is insufficient. Pnigalio soemius (Walker) was reared at five different temperatures (10, 15, 20, 25, 30 degrees C) on mature larvae of one of its natural hosts, Cosmopterix pulchrimella Chambers (Lepidoptera: Cosmopterigidae), to investigate the influence of temperature on size, colour and other morphological traits, and to measure the range of variation of several characters. Thermal developmental reaction norms, which represent the effect of temperature during growth and development on the value of some adult traits, were produced. The results confirmed the influence of temperature on numerous characters and that these characters had a larger range of variation than realized previously in the construction of taxonomic keys to species. In particular, the number and position of the costulae on the propodeum and colour of the gaster were affected by rearing temperature.