The Effects of Environmental Exposure on Epigenetic Modifications in Allergic Diseases.

Allergic diseases are one of the most common chronic conditions and their prevalence is on the rise. Environmental exposure, primarily prenatal and early life influences, affect the risk for the development and specific phenotypes of allergic diseases via epigenetic mechanisms. Exposure to pollutants, microorganisms and parasites, tobacco smoke and certain aspects of diet are known to drive epigenetic changes that are essential for immune regulation (e.g., the shift toward T helper 2-Th2 cell polarization and decrease in regulatory T-cell (Treg) differentiation). DNA methylation and histone modifications can modify immune programming related to either pro-allergic interleukin 4 (IL-4), interleukin 13 (IL-13) or counter-regulatory interferon γ (IFN-γ) production. Differential expression of small non-coding RNAs has also been linked to the risk for allergic diseases and associated with air pollution. Certain exposures and associated epigenetic mechanisms play a role in the susceptibility to allergic conditions and specific clinical manifestations of the disease, while others are thought to have a protective role against the development of allergic diseases, such as maternal and early postnatal microbial diversity, maternal helminth infections and dietary supplementation with polyunsaturated fatty acids and vitamin D. Epigenetic mechanisms are also known to be involved in mediating the response to common treatment in allergic diseases, for example, changes in histone acetylation of proinflammatory genes and in the expression of certain microRNAs are associated with the response to inhaled corticosteroids in asthma. Gaining better insight into the epigenetic regulation of allergic diseases may ultimately lead to significant improvements in the management of these conditions, earlier and more precise diagnostics, optimization of current treatment regimes, and the implementation of novel therapeutic options and prevention strategies in the near future.

Food Allergen Immunotherapy in the Treatment of Patients with IgE-Mediated Food Allergy.

The prevalence of allergic diseases, including food allergy, is increasing, especially in developed countries. Implementation of an elimination diet is not a sufficient therapeutic strategy in patients with food allergy, whose quality of life is significantly impaired. In recent years, new effective therapeutic strategies have been developed, such as the application of oral, sublingual, and epicutaneous immunotherapy. Oral immunotherapy is the most often applied strategy because of its effectiveness and ease of application, with an acceptable safety profile. The effectiveness of oral immunotherapy in patients with egg, cow's milk, and peanut allergy has been proven both in terms of raising of the threshold and the development of tolerance, and in some patients, the development of sustainable unresponsiveness. Although oral immunotherapy is an effective treatment for food allergy, several limitations, including a long duration and a significant rate of reported adverse events, reduces its success. Therefore, new therapeutic options, such as treatment with biologicals, either as combinations with food allergen immunotherapy or as monotherapy with the aim of improving the efficacy and safety of treatment, are being investigated.

Protocol Development of a Personalized Balanced Nutrition Concept for Preschool Children, Primarily Those with Food Allergies, Using an IT Platform.

Children with food allergies are at higher risk for severe anaphylactic reactions and for key nutrient deficiency. In order to address these concerns, enable early detection, and improve the monitoring of children with food allergies, an innovative IT platform will be developed by IT experts (IN2 Ltd. Zagreb, Croatia, part of Constellation Software Inc. (Toronto, ON, Canada)) and Srebrnjak Children's Hospital, Zagreb, Croatia (SCH) for the effective implementation of personalized balanced nutrition in preschool institutions in Croatia. Additionally, the data obtained through this research, including epidemiological data on allergic diseases, clinical data (diagnostic allergy tests and others), anthropometry, and physical activity status, will be used to create a national Allergy registry. Other than being a tool for personalized and balanced nutrition for children, especially those with special dietary requirements (including food allergy and intolerance), the IT platform developed in this study will enable the continuous monitoring of these children as a part of their clinical management plan and earlier detection of food allergies, intolerance, and other conditions, even outside of the healthcare system. This research also aims at optimizing current and developing novel personalized therapeutic regimes, detecting novel early biomarkers in children with food allergies and intolerances, and involving all key stakeholders (caregivers, preschool institutions, etc.) in the shared-care approach in the management of food allergies in children.

Treatment outcome clustering patterns correspond to discrete asthma phenotypes in children.

Despite widely and regularly used therapy asthma in children is not fully controlled. Recognizing the complexity of asthma phenotypes and endotypes imposed the concept of precision medicine in asthma treatment. By applying machine learning algorithms assessed with respect to their accuracy in predicting treatment outcome, we have successfully identified 4 distinct clusters in a pediatric asthma cohort with specific treatment outcome patterns according to changes in lung function (FEV1 and MEF50), airway inflammation (FENO) and disease control likely affected by discrete phenotypes at initial disease presentation, differing in the type and level of inflammation, age of onset, comorbidities, certain genetic and other physiologic traits. The smallest and the largest of the 4 clusters- 1 (N = 58) and 3 (N = 138) had better treatment outcomes compared to clusters 2 and 4 and were characterized by more prominent atopic markers and a predominant allelic (A allele) effect for rs37973 in the GLCCI1 gene previously associated with positive treatment outcomes in asthmatics. These patients also had a relatively later onset of disease (6 + yrs). Clusters 2 (N = 87) and 4 (N = 64) had poorer treatment success, but varied in the type of inflammation (predominantly neutrophilic for cluster 4 and likely mixed-type for cluster 2), comorbidities (obesity for cluster 2), level of systemic inflammation (highest hsCRP for cluster 2) and platelet count (lowest for cluster 4). The results of this study emphasize the issues in asthma management due to the overgeneralized approach to the disease, not taking into account specific disease phenotypes.

Predicting Treatment Outcomes Using Explainable Machine Learning in Children with Asthma.

Asthma in children is a heterogeneous disease manifested by various phenotypes and endotypes. The level of disease control, as well as the effectiveness of anti-inflammatory treatment, is variable and inadequate in a significant portion of patients. By applying machine learning algorithms, we aimed to predict the treatment success in a pediatric asthma cohort and to identify the key variables for understanding the underlying mechanisms. We predicted the treatment outcomes in children with mild to severe asthma (N = 365), according to changes in asthma control, lung function (FEV1 and MEF50) and FENO values after 6 months of controller medication use, using Random Forest and AdaBoost classifiers. The highest prediction power is achieved for control- and, to a lower extent, for FENO-related treatment outcomes, especially in younger children. The most predictive variables for asthma control are related to asthma severity and the total IgE, which were also predictive for FENO-based outcomes. MEF50-related treatment outcomes were better predicted than the FEV1-based response, and one of the best predictive variables for this response was hsCRP, emphasizing the involvement of the distal airways in childhood asthma. Our results suggest that asthma control- and FENO-based outcomes can be more accurately predicted using machine learning than the outcomes according to FEV1 and MEF50. This supports the symptom control-based asthma management approach and its complementary FENO-guided tool in children. T2-high asthma seemed to respond best to the anti-inflammatory treatment. The results of this study in predicting the treatment success will help to enable treatment optimization and to implement the concept of precision medicine in pediatric asthma treatment.

GLCCI1 and STIP1 variants are associated with asthma susceptibility and inhaled corticosteroid response in a Tunisian population.

Objective: Pharmacogenetic studies have recognized specific genes that highly correlate with response to inhaled corticosteroids (ICS) treatment in asthma patients. Among the genes identified, we selected glucocorticoid-induced transcript 1 (GLCCI1) and stress-induced phosphoprotein 1 (STIP1) to evaluate the impact of these gene polymorphisms on ICS treatment response in Tunisian asthmatics.Methods: We analyzed four single nucleotide polymorphisms (SNPs): two in GLCCI1 (rs37972 and rs37973), and two in STIP1 (rs2236647 and rs2236648), which are genes associated with susceptibility to asthma and response to ICS in a Tunisian cohort. The SNPs were genotyped using reverse transcriptase polymerase chain reaction (RT-PCR) techniques.Results: This case-control study consisted of 230 adult asthmatic patients and 236 healthy subjects. Seventy-five asthmatics were selected and followed through 12 weeks of routine treatment. The T allele rs2236648 in STIP1 was associated with allergic asthma (OR = 0.38, 95%CI = 0.20-0.69, p = 0.001). The rs37972 and rs37973 of GLCCI1 were associated with a higher risk of asthma (p < 0.001). The T allele rs37972 and G allele rs37973 were correlated with a strong risk for developing severe asthma (p < 0.001). Asthma patients carrying the rs37973 GG genotype had less improvement in the forced expiratory volume in one second (FEV1) than those with the AA or AG genotypes after 12 weeks of treatment (p < 0.001). Also, the G allele of rs37973 was associated with worse response to ICS after 12 weeks of treatment (p < 0.001).Conclusion: The rs37972 and rs37973 polymorphisms can serve as potential asthma risk biomarkers in a Tunisian population.

Association of bacterial load in drinking water and allergic diseases in childhood.

BACKGROUND: Treatment of drinking water may decrease microbial exposure. OBJECTIVE: To investigate whether bacterial load in drinking water is associated with altered risk of allergic diseases. METHODS: We recruited 1,110 schoolchildren aged 6-16 years between 2011 and 2013 in Pozega-Slavonia County in Croatia, where we capitalized on a natural experiment whereby individuals receive drinking water through public mains supply or individual wells. We obtained data on microbial content of drinking water for all participants; 585 children were randomly selected for more detailed assessments, including skin prick testing. Since water supply was highly correlated with rural residence, we compared clinical outcomes across four groups (Rural/Individual, Rural/Public, Urban/Individual and Urban/Public). For each child, we derived quantitative index of microbial exposure (bacterial load in the drinking water measured during the child's first year of life). RESULTS: Cumulative bacterial load in drinking water was higher (median [IQR]: 6390 [4190-9550] vs 0 [0-0]; P < .0001), and lifetime prevalence of allergic diseases was significantly lower among children with individual supply (5.5% vs 2.3%, P = .01; 14.4% vs 6.7%, P < .001; 25.2% vs 15.1%, P < .001; asthma, atopic dermatitis [AD] and rhinitis, respectively). Compared with the reference group (Urban/Public), there was a significant reduction in the risk of ever asthma, AD and rhinitis amongst rural children with individual supply: OR [95% CI]: 0.14 [0.03,0.67], P = .013; 0.20 [0.09,0.43], P < .001; 0.17 [0.10,0.32], P < .001. Protection was also observed in the Rural/Public group, but the effect was consistently highest among Rural/Individual children. In the quantitative analysis, the risk of allergic diseases decreased significantly with increasing bacterial load in drinking water in the first year of life (0.79 [0.70,0.88], P < .001; 0.90 [0.83,0.99], P = .025; 0.80 [0.74,0.86], P < .001; current wheeze, AD and rhinitis). CONCLUSIONS AND CLINICAL RELEVANCE: High commensal bacterial content in drinking water may protect against allergic diseases.

Respiratory and allergic disorders in children with severe and partial immunoglobulin A immunodeficiency.

BACKGROUND: Immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency. Although most people with selective IgAD (sIgAD) are asymptomatic, many patients often suffer from recurrent respiratory infections and different allergic disorders. Our aim was to investigate connection between subtypes of sIgAD and incidence of respiratory and allergic disorders, as well as connection with lung function changes in children. METHODS: Children with IgAD where divided into two groups; severe IgAD in patients was defined as serum IgA level <7 mg/dL, while partial IgA deficiency diagnosis was made when serum IgA levels was higher than 7 mg/dL but at least two standard deviations (SD) below mean normal concentrations for their age. All patients were evaluated by their clinical and laboratory investigation parameters and compared to control group of children. RESULTS: Group of children with IgAD, severe as well as partial, showed higher prevalence of allergic diseases and total number of infections, compared to controls. There was a statistically significant difference in lung function for peak expiratory flow (PEF), the maximal expiratory flow at 50% of the forced vital capacity (MEF50) and fraction of exhaled nitric oxide (FENO) between group of patients with severe as well as partial IgAD and control group, where children with IgAD showed reduced lung function. CONCLUSIONS: Children with sIgAD are at increased risk for higher number of respiratory infections and developing allergic diseases, resulting in significantly lower pulmonary function which is related with the severity of sIgAD.

Examination of a New Delivery Approach for Oral Cannabidiol in Healthy Subjects: A Randomized, Double-Blinded, Placebo-Controlled Pharmacokinetics Study.

INTRODUCTION: Therapeutic effects of cannabidiol (CBD) in specialized populations continue to emerge. Despite supra-physiological dosing being shown to be tolerable in various pathologies, optimization of CBD absorption has obvious benefits for general health and recreational usage. Our objectives were to: (1) to investigate a joint pharmacokinetic-physiological time course of multiple recreational-equivalent (< 100 mg) dosages of oral CBD in young healthy adults and (2) evaluate a newly developed technology (TurboCBD™) for the enhanced delivery of CBD. METHODS: In a double-blinded, placebo-controlled, cross-over design, 12 participants received placebo, generic 45 or 90 mg of CBD, or TurboCBD™ delivery technology capsules on five separate occasions. RESULTS: Although there were no differences in the 45 mg conditions, circulating CBD levels were higher with the TurboCBD™ 90 mg group at both 90 (+ 86%) and 120 (+ 65%) min compared with the 90 mg control (p < 0.05). Total area under the curve tended to be higher with TurboCBD™ 90 mg compared with 90 mg (10,865 ± 6322 ng ml-1 vs. 7114 ± 2978 ng ml-1; p = 0.088). Only the TurboCBD™ 90 mg dose was elevated greater than placebo at 30 min (p = 0.017) and remained elevated at 4 h (p = 0.002). CONCLUSION: Consistent with higher bioavailability, TurboCBD™ 90 mg at the peak CBD concentration was associated with an increase in cerebral perfusion and slight reduction in blood pressure compared with baseline and the 90 mg control. Further studies are needed to establish the mechanisms of action of this technology and to explore the therapeutic potential of acute and chronic dosing on more at-risk populations. FUNDING: Lexaria Bioscience Corp. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03295903.

Ragweed pollen and allergic symptoms in children: Results from a three-year longitudinal study.

Common ragweed is a highly allergenic invasive species in Europe, expected to become widespread under climate change. Allergy to ragweed manifests as eye, nasal and lung symptoms, and children may retain these throughout life. The dose-response relationship between symptoms and pollen concentrations is unclear. We undertook a longitudinal study, assessing the association between ragweed pollen concentration and allergic eye, nasal and lung symptoms in children living under a range of ragweed pollen concentrations in Croatia. Over three years, 85 children completed daily diaries, detailing allergic symptoms alongside daily location, activities and medication, resulting in 10,130 individual daily entries. The daily ragweed pollen concentration for the children's locations was obtained, alongside daily weather and air pollution. Parents completed a home/lifestyle/medical questionnaire. Generalised Additive Mixed Models established the relationship between pollen concentrations and symptoms, alongside other covariates. Eye symptoms were associated with mean daily pollen concentration over four days (day of symptoms plus 3 previous days); 61 grains/m3/day (95%CI: 45, 100) was the threshold at which 50% of children reported symptoms. Nasal symptoms were associated with mean daily pollen concentration over 12 days (day of symptoms plus 11 previous days); the threshold for 50% of children reporting symptoms was 40 grains/m3/day (95%CI: 24, 87). Lung symptoms showed a relationship with mean daily pollen concentration over 19 days (day of symptoms plus 18 previous days), with a threshold of 71 grains/m3/day (95%CI: 59, 88). Taking medication on the day of symptoms showed higher odds, suggesting responsive behaviour. Taking medication on the day prior to symptoms showed lower odds of reporting, indicating preventative behaviour. Different symptoms in children demonstrate varying dose-response relationships with ragweed pollen concentrations. Each symptom type responded to pollen exposure over different time periods. Using medication prior to symptoms can reduce symptom presence. These findings can be used to better manage paediatric ragweed allergy symptoms.

Modifiable Risk Factors for Common Ragweed (Ambrosia artemisiifolia) Allergy and Disease in Children: A Case-Control Study.

Ragweed allergy is a major public health concern. Within Europe, ragweed is an introduced species and research has indicated that the amounts of ragweed pollen are likely to increase over Europe due to climate change, with corresponding increases in ragweed allergy. To address this threat, improving our understanding of predisposing factors for allergic sensitisation to ragweed and disease is necessary, specifically focusing upon factors that are potentially modifiable (i.e., environmental). In this study, a total of 4013 children aged 2⁻13 years were recruited across Croatia to undergo skin prick tests to determine sensitisation to ragweed and other aeroallergens. A parental questionnaire collected home environment, lifestyle, family and personal medical history, and socioeconomic information. Environmental variables were obtained using Geographical Information Systems and data from nearby pollen, weather, and air pollution stations. Logistic regression was performed (clustered on school) focusing on risk factors for allergic sensitisation and disease. Ragweed sensitisation was strongly associated with ragweed pollen at levels over 5000 grains m⁻3 year−1 and, above these levels, the risk of sensitisation was 12⁻16 times greater than in low pollen areas with about 400 grains m⁻3 year−1. Genetic factors were strongly associated with sensitisation but nearly all potentially modifiable factors were insignificant. This included measures of local land use and proximity to potential sources of ragweed pollen. Rural residence was protective (odds ratio (OR) 0.73, 95% confidence interval (CI) 0.55⁻0.98), but the factors underlying this association were unclear. Being sensitised to ragweed doubled (OR 2.17, 95% CI 1.59⁻2.96) the risk of rhinoconjunctivitis. No other potentially modifiable risk factors were associated with rhinoconjunctivitis. Ragweed sensitisation was strongly associated with ragweed pollen, and sensitisation was significantly associated with rhinoconjunctivitis. Apart from ragweed pollen levels, few other potentially modifiable factors were significantly associated with ragweed sensitisation. Hence, strategies to lower the risk of sensitisation should focus upon ragweed control.

Expression of Mitochondrial Respiratory Chain Complexes in the Vaginal Wall in Postmenopausal Women with Pelvic Organ Prolapse.

BACKGROUND/AIMS: Pelvic organ prolapse (POP) is a common disease affecting adult women. It is a result of the vaginal wall disorder as well as damage of the supportive structures contributing to the integrity of the pelvic floor. Mitochondrial disorders may have an important role in the vaginal wall degeneration leading to POP. The goal of this research is to examine if POP is associated with an altered expression of mitochondrial respiratory chain complexes. METHODS: Samples of vaginal tissue were collected from 16 postmenopausal women: 10 had POP and 6 had other forms of benign gynecological disease. Using western blot, samples were analyzed to assess the expression of mitochondrial proteins including citrate synthase (CS), individual complexes of the mitochondrial respiratory chain and alpha smooth muscle actin (SMA). RESULTS: A significantly reduced expression of SMA and complex II in vaginal tissue of women with POP was found, compared to the control group (p < 0.05), with a tendency for a reduced expression of CS (p = 0.06) and other complexes in the POP group. CONCLUSIONS: Our results indicate that there is a decreased quantity of the smooth muscle and a decreased expression of mitochondrial markers in the vaginal wall of women with prolapse suggesting their possible role in the pathogenesis of POP.

2D speckle tracking echocardiography of the right ventricle free wall in SCUBA divers after single open sea dive.

The presence of circulating gas bubbles and their influence on pulmonary and right heart hemodynamics was reported after uncomplicated self-contained underwater breathing apparatus (SCUBA) dive(s). Improvements in cardiac imaging have recently focused great attention on the right ventricle (RV). The aim of our study was to evaluate possible effects of a single air SCUBA dive on RV function using 2D speckle tracking echocardiography in healthy divers after single open sea dive to 18 meters of seawater, followed by bottom stay of 47 minutes with a direct ascent to the surface. Twelve experienced male divers (age 39.5 ± 10.5 years) participated in the study. Echocardiographic assessment of the right ventricular function (free wall 2 D strain, tricuspid annular planes systolic excursion [TAPSE], lateral tricuspid annular peak systolic velocity [RV s`] and fractional area change [FAC]) was performed directly prior to and 30, 60, 90 and 120 minutes after surfacing. Two-dimensional strain of all three segments of free right ventricular wall showed a significant increase in longitudinal shortening in post-dive period for maximally 26% (basal), 15.4% (mid) and 16.3% (apical) as well as TAPSE (11.6%), RV FAC (19.2%), RV S` (12.7%) suggesting a rise in systolic function of right heart. Mean pulmonary arterial pressure (mean PAP) increased post-dive from 13.3 mmHg to maximally 23.5 mmHg (P = .002), indicating increased RV afterload. Our results demonstrated that single dive with significant bubble load lead to increase in systolic function and longitudinal strain of the right heart in parallel with increase in mean PAP.

A review of clinical efficacy, safety, new developments and adherence to allergen-specific immunotherapy in patients with allergic rhinitis caused by allergy to ragweed pollen (Ambrosia artemisiifolia).

Allergic rhinitis is a common health problem in both children and adults. The number of patients allergic to ragweed (Ambrosia artemisiifolia) is on the rise throughout Europe, having a significant negative impact on the patients' and their family's quality of life. Allergen-specific immunotherapy (AIT) has disease-modifying effects and can induce immune tolerance to allergens. Both subcutaneous immunotherapy and sublingual immunotherapy with ragweed extracts/preparations have clear positive clinical efficacy, especially over pharmacological treatment, even years after the treatment has ended. AIT also has very good safety profiles with extremely rare side effects, and the extracts/preparations used in AIT are commonly well tolerated by patients. However, patient adherence to treatment with AIT seems to be quite low, mostly due to the fact that treatment with AIT is relatively time-demanding and, moreover, due to patients not receiving adequate information and education about the treatment before it starts. AIT is undergoing innovations and improvements in clinical efficacy, safety and patient adherence, especially with new approaches using new adjuvants, recombinant or modified allergens, synthetic peptides, novel routes of administration (epidermal or intralymphatic), and new protocols, which might make AIT more acceptable for a wider range of patients and novel indications. Patient education and support (eg, recall systems) is one of the most important goals for AIT in the future, to further enhance treatment success.

Effects of allergic diseases and age on the composition of serum IgG glycome in children.

It is speculated that immunoglobulin G (IgG) plays a regulatory role in allergic reactions. The glycans on the Fc region are known to affect IgG effector functions, thereby possibly having a role in IgG modulation of allergic response. This is the first study investigating patients' IgG glycosylation profile in allergic diseases. Subclass specific IgG glycosylation profile was analyzed in two cohorts of allergen sensitized and non-sensitized 3- to 11-year-old children (conducted at University of Aberdeen, UK and Children's Hospital Srebrnjak, Zagreb, Croatia) with 893 subjects in total. IgG was isolated from serum/plasma by affinity chromatography on Protein G. IgG tryptic glycopeptides were analyzed by liquid chromatography electrospray ionization mass spectrometry. In the Zagreb cohort IgG glycome composition changed with age across all IgG subclasses. In both cohorts, IgG glycome composition did not differ in allergen sensitized subjects, nor children sensitized to individual allergens, single allergen mean wheal diameter or positive wheal sum values. In the Zagreb study the results were also replicated for high total serum IgE and in children with self-reported manifest allergic disease. In conclusion, our findings demonstrate no association between serum IgG glycome composition and allergic diseases in children.

The effects of nitroglycerin, norepinephrine and aminophylline on intrapulmonary arteriovenous anastomoses in healthy humans at rest.

We have investigated the effects of the intravenous infusion of nitroglycerin (NTG), norepinephrine (NE) and aminophylline (AMP) on the opening and recruitment of intrapulmonary arteriovenous anastomoses (IPAVA) in healthy humans at rest. In ten volunteers saline contrast echocardiography was performed during administration of two doses of the NTG (3µgkg(-1)min(-1) and 6µgkg(-1)min(-1)) and NE (0.1µgkg(-1)min(-1) and 0.25µgkg(-1)min(-1)) as well as 30min following the administration of AMP at rate of 6mgkg(-1). Echocardiography was used to assign bubble scores (0-5) based on the number and spatial distribution of bubbles in the left ventricle. Doppler ultrasound was used to estimate pulmonary artery systolic pressure. Using a Finometer the following hemodynamic parameters were assessed: heart rate, stroke volume, cardiac output, total peripheral resistance as well as systolic, diastolic and mean arterial pressure. The most important finding from the current study was that nitroglycerin, norepinephrine and aminophylline in the applied doses were not found to promote IPAVA opening in healthy humans at rest.

Autonomic and cardiovascular responses to chemoreflex stress in apnoea divers.

Sleep apnoea, with repeated periods of hypoxia, results in cardiovascular morbidity and concomitant autonomic dysregulation. Trained apnoea divers also perform prolonged apnoeas accompanied by large lung volumes, large reductions in cardiac output and severe hypoxia and hypercapnia. We tested the hypothesis that apnoea training would be associated with decreased cardiovagal and sympathetic baroreflex gains and reduced respiratory modulation of muscle sympathetic nerve activity (MSNA; microneurography). Six trained divers and six controls were studied at rest and during asphyxic rebreathing. Despite an elevated resting heart rate (70+/-14 vs. 56+/-10 bpm; p=0.038), divers had a similar cardiovagal baroreflex gain (-1.22+/-0.47 beats/mmHg) as controls (-1.29+/-0.61; NS). Similarly, though MSNA burst frequency was slightly higher in divers at rest (16+/-4 bursts/min vs. 10+/-5 bursts/min, p=0.03) there was no difference in baseline burst incidence, sympathetic baroreflex gain (-3.8+/-2.1%/mmHg vs. -4.7+/-1.7%/mmHg) or respiratory modulation of MSNA between groups. Resting total peripheral resistance (11.9+/-2.6 vs. 12.3+/-2.2 mmHg/L/min) and pulse wave velocity (5.82+/-0.55 vs. 6.10+/-0.51 m/s) also were similar between divers and controls, respectively. Further, the sympathetic response to asphyxic rebreathing was not different between controls and divers (-1.70+/-1.07 vs. -1.74+/-0.84 a.u./% desaturation). Thus, these data suggest that, unlike patients with sleep apnoea, apnoea training in otherwise healthy individuals does not produce detectable autonomic dysregulation or maladaption.

Peripheral chemoreflex sensitivity and sympathetic nerve activity are normal in apnea divers during training season.

Apnea divers are exposed to repeated massive arterial oxygen desaturation, which could perturb chemoreflexes. An earlier study suggested that peripheral chemoreflex regulation of sympathetic vasomotor tone and ventilation may have recovered 4 or more weeks into the off season. Therefore, we tested the hypothesis that peripheral chemoreflex regulation of ventilation and sympathetic vasomotor tone is present during the training season. We determined ventilation, heart rate, blood pressure, cardiac stroke volume, and muscle sympathetic nerve activity (MSNA) during isocapnic hypoxia in 10 breath hold divers and 11 matched control subjects. The study was carried out at the end of the season of intense apnea trainings. Baseline MSNA frequency was 30+/-4bursts/min in control subjects and 25+/-4bursts/min in breath hold divers (P=0.053). During hypoxia burst frequency and total sympathetic activity increased similarly in both groups. Sympathetic activity normalized during the 30-minute recovery. Hypoxia-induced stimulation of minute ventilation was similar in both groups, although in divers it was maintained by higher tidal volumes and lower breathing frequency compared with control subjects. In both groups, hypoxia increased heart rate and cardiac output whereas total peripheral resistance decreased. Blood pressure remained unchanged. We conclude that peripheral chemoreflex regulation of ventilation and sympathetic vasomotor tone is paradoxically preserved in apnea divers, both, during the off and during the training season. The observation suggests that repeated arterial oxygen desaturation may not be sufficient explaining sympathetic reflex abnormalities similar to those in obstructive sleep apnea patients.