The effect of lipoic acid and vitamin E therapies in individuals with the metabolic syndrome.

The metabolic syndrome is associated with abnormal glucose and lipid metabolism, insulin resistance, increased oxidative stress and pro-inflammatory activity that increase the risk of type 2 diabetes and cardiovascular disease. The aim of this study was to investigate the effect of treatment with the antioxidant α-lipoic acid (ALA) with or without vitamin E supplementation, on markers of insulin resistance and systemic inflammation and plasma nonesterified fatty acid (NEFA) concentrations in individuals with the metabolic syndrome. In a randomized, double-blind, placebo-controlled trial, subjects with the metabolic syndrome received ALA (600 mg/day, n = 34), vitamin E (100 IU/day, n = 36), both ALA and vitamin E (n = 41), or matching placebo (n = 40) for 1 year. Fasting circulating concentrations of glucose and insulin were measure every 3 months and NEFA, markers of inflammation, adiponectin and vitamin E were measured at 6 monthly intervals. Plasma NEFA concentrations decreased [-10 (-18, 0)%] at a marginal level of significance (p = 0.05) in those who received ALA alone compared with placebo and decreased [-8 (-14, -1)% (95% CI)] significantly (P = 0.02) in participants who were randomised to ALA with and without vitamin E compared with those who did not receive ALA. Fasting glucose, insulin, homeostatic model assessment of insulin resistance, adiponectin, and markers of inflammation did not change significantly during the study. These data suggest that prolonged treatment with ALA may modestly reduce plasma NEFA concentrations but does not alter insulin or glucose levels in individuals with the metabolic syndrome.

Second-hand smoke exposure in cars and respiratory health effects in children.

We examined potential associations of ever asthma, and symptoms of wheeze (past 12 months), hay fever, eczema and bronchitis (cough with phlegm) among school children exposed to second-hand smoke (SHS) in cars, using a modified Irish International Study of Asthma and Allergies in Childhood (ISAAC) protocol. 2,809 children of 13-14 yrs old and who selected randomly from post-primary schools throughout Ireland completed the 2007 ISAAC self-administered questionnaire. Adjusted OR (adjusted for sex, active smoking status of children interviewed and their SHS exposure at home) were estimated for the associations studied, using multivariable logistic regression techniques. Overall, 14.8% (13.9% in young males, 15.4% in young females) of Irish children aged 13-14 yrs old were exposed to SHS in cars. Although there was a tendency towards increased likelihood of both respiratory and allergic symptoms with SHS exposure in cars, wheeze and hay fever symptoms were significantly higher (adjusted OR 1.35 (95% CI 1.08-1.70) and 1.30 (1.01-1.67), respectively), while bronchitis symptoms and asthma were not significant (1.33 (0.92-1.95) and 1.07 (0.81-1.42), respectively). Approximately one in seven Irish schoolchildren are exposed to SHS in cars and could have adverse respiratory health effects. Further studies are imperative to explore such associations across different population settings.

WITHDRAWN: GLP-1 Has an Anti-Inflammatory Effect on Adipose Tissue Expression of Cytokines, Chemokines, and Receptors in Obese Women.

The above-named article by Manning PJ, Dixit P, Satthenapalli VR, Katare R, and Sutherland WHF (J Clin Endocrinol Metab. [published online ahead of print 21 May 2019]; doi: 10.1210/jc.2018-00197) has been withdrawn by the authors. The authors report, "The reason for this decision is that the statistical methodology we used did not adequately limit the impact of outlier data points on our findings. This was evident after reanalysis of the data using a different method." doi: 10.1210/jc.2019-01393.

Rising prevalence of asthma but declining wheeze in teenagers (1995-2003): ISAAC protocol.

The results of the initial International Study of Asthma and Allergies in Childhood (ISAAC) undertaken in the mid 1990s demonstrated a substantial increase in asthma and wheeze symptoms prevalence in Irish teenagers aged 13-14 years from the 1980s. International research suggests that asthma has increased further in some countries and this study was undertaken to determine whether an upward trend in childhood asthma prevalence has continued in the Republic of Ireland in recent years. We therefore conducted two further national cross sectional studies in the same previously surveyed childhood population throughout the Republic of Ireland, one in 1998 (n=2580) and the other in 2002-3 (n=3089). We report here on rising prevalence trends of asthma (42.1% relative increase) but falling wheeze (10.4% relative reduction) prevalence in these teenage children in 2002-3.

The effect of hormone replacement therapy on cardiovascular risk factors in type 2 diabetes: a randomized controlled trial.

BACKGROUND: Postmenopausal women with diabetes are at high risk for cardiovascular disease, compared with their nondiabetic counterparts. Combined continuous hormone replacement therapy (HRT) is associated with improvements in serum lipoprotein levels in nondiabetic women; however, the effect in women with diabetes has not been determined. We evaluated the effect of combined continuous HRT on lipoprotein and coagulation factor concentrations and glycemic control in postmenopausal women with type 2 diabetes mellitus. METHODS: In a randomized controlled crossover study, 61 subjects received combined continuous HRT or placebo. Each treatment phase was of 6 months' duration, with an 8-week washout phase between treatment phases. RESULTS: Total cholesterol concentration decreased by 7% (95% confidence interval [CI], 4%-11%) during HRT. For low-density lipoprotein concentration, the mean decrease with HRT was 12% (95% CI, 6%-17%). Apolipoprotein B levels decreased in keeping with the reduction in low-density lipoprotein cholesterol concentrations. There were no significant changes in concentrations of high-density lipoprotein, its subfractions, or triglycerides. Lipoprotein(a) and fibrinogen concentrations were reduced by 21% (95% CI, 10%-31%) and 8% (95% CI, 2%-13%), respectively, with HRT. Fructosamine concentrations declined by 5% (95% CI, 2%-9%) during HRT. CONCLUSIONS: In postmenopausal women with type 2 diabetes mellitus, combined continuous HRT has beneficial effects on lipoprotein concentrations and improves some markers of coagulation and glycemic control.

More broken bones: a 4-year double cohort study of young girls with and without distal forearm fractures.

Predictors of childhood fractures have not been investigated previously. This study was undertaken to determine whether a previous history of forearm fracture, low bone mineral density (BMD; both areal bone mineral density [aBMD, g/cm2] and volumetric bone mineral apparent density [BMAD, g/cm3]), or anthropometry, influence fracture risk in young girls. At baseline, two cohorts of girls, aged 3-15 years, were evaluated: 100 had recently broken a forearm (group 1) and 100 were fracture free (group 2). Four years later we restudied 170 of these girls (82 from group 1 and 88 from group 2). We now report the relationships of previous fracture history, baseline BMD (measured by dual-energy X-ray absorptiometry), baseline weight, and height to risk of new fracture. More new fractures occurred in group 1 (37 fractures in 24 girls) than in group 2 (8 fractures in 7 girls; p = 0.0007). The independent predictors for occurrence of a new fracture at any skeletal site in a multivariate model adjusting for age, weight, total body aBMD, and fracture history were previous fracture (hazard ratio [HR], 3.28; 95% CI, 1.41-7.64); age (HR per 1-year increase, 0.91; 95% CI, 0.84-0.99); total body aBMD (HR per 1 SD decrease, 1.92; 95% CI, 1.31-2.81); and body weight (HR per 1 SD increase, 1.49; 95% CI, 1.06-2.08). Girls with two risk factors together had substantially greater fracture risk: previous fracture and low spinal BMAD (HR, 9.4; 95% CI, 2.8-32.0), previous fracture and high body weight (HR, 10.2; 95% CI, 2.8-37.6), or previous fracture and low total body aBMD (HR, 13.0; 95% CI, 3.9-43.1). We conclude that previous forearm fracture, low total body aBMD, low spinal BMAD, and high body weight each increase risk of new fractures within 4 years in young girls. Interventions to reduce the risk of fractures, particularly forearm fractures, in girls warrant further study.

Effect of magnitude of airway responsiveness and therapy with inhaled corticosteroid on histamine tachyphylaxis in asthma.

Histamine challenge testing is used to measure airway responsiveness in asthma. Histamine tachyphylaxis has been demonstrated after repeated challenges in mild asthmatics not using inhaled corticosteroid. Other studies, using subjects with variable severity of asthma, have not demonstrated histamine tachyphylaxis. Forty patients with stable asthma were studied and stratified according to severity of airway hyperresponsiveness and use of inhaled corticosteroid, to examine the effects of these factors on histamine tachyphylaxis. Airway responsiveness was measured as the histamine provocative concentration causing a 20 percent fall in FEV1 (PC20). Twenty subjects had mildly increased airway hyperresponsiveness (PC20 > 1 mg/ml), of whom 10 were using inhaled corticosteroid. Twenty subjects had moderate to severely increased airway hyperresponsiveness (PC20 < 1 mg/ml), of whom 10 were using inhaled corticosteroid. On each of two study days, 1 week apart, two histamine challenges were performed 1 h apart. Histamine tachyphylaxis was found for the entire group on both study days. The geometric mean PC20 increased from 1.0 mg/ml (percent SEM 1.2) to 1.3 mg/ml (percent SEM 1.2) 1 h later on day 1 (p < 0.0005), and 1.1 mg/ml (percent SEM 1.2) to 1.3 mg/ml (percent SEM 1.2) 1 h later on day 2 p < 0.05). Subgroup analysis demonstrated that tachyphylaxis only occurred consistently in subjects with mildly increased airway hyperresponsiveness not receiving inhaled corticosteroid. In this group, the PC20 increased from 2.2 mg/ml (percent SEM 1.2) to 3.2 mg/ml (percent SEM 1.2) on day 1 (p < 0.001), and from 2.5 mg/ml (percent SEM 1.3) to 3.4 mg/ml (percent SEM 1.2) on day 2 (p < 0.05). This study confirms that histamine tachyphylaxis occurs in asthmatics, but is consistently present only in mild, noncorticosteroid-dependent asthmatics.

Hormone-replacement therapy increases serum paraoxonase arylesterase activity in diabetic postmenopausal women.

The paraoxonase (PON1) enzyme is associated with high-density lipoproteins (HDL) in the blood and is low in patients with type 2 diabetes. Hormone-replacement therapy (HRT) can increase HDL cholesterol levels, but its effect on serum PON1 arylesterase activity is uncertain. The aim of the present study was to determine the effect of 6 months' HRT with conjugated equine estrogen and medroxyprogesterone acetate on serum PON1 arylesterase activity in postmenopausal women with type 2 diabetes. Serum PON1 activity was measured immediately before and at the end of the second arm of a randomized, placebo-controlled, crossover with washout study originally designed to test the effect of HRT on plasma lipids in diabetic postmenopausal women. Baseline serum PON1 arylesterase activity was significantly (P <.001) lower in the postmenopausal diabetic women (149 +/- 38 micromol/mL/min; n = 47) than values in healthy postmenopausal women (173 +/- 32 micromol/mL/min; n = 51). Serum PON1 activity increased (10%) significantly (P =.009) in diabetic women treated with HRT compared with placebo. A significant (P =.02) interaction between baseline PON1 activity and treatment indicated a greater increase in PON1 activity during HRT in women with lower baseline activities. At baseline, serum PON1 arylesterase activity was correlated significantly with plasma HDL cholesterol levels in diabetic women (r = 0.333, P =.01, n = 47), and the increase in serum PON1 activity was correlated significantly with the change in plasma HDL cholesterol during HRT (r = 0.659, P =.0001, n = 28). These data suggest that serum PON1 activity is abnormally low in postmenopausal women with type 2 diabetes and increases during HRT, particularly in women with lower baseline levels and in those who show a concomitant increase in HDL cholesterol.

Tachyphylaxis to inhaled histamine in asthmatic subjects.

The bronchoconstriction induced by repeated histamine inhalation tests was studied in eight mild stable asthmatic subjects to determine whether histamine tachyphylaxis occurs in asthmatics. We also studied the specificity of histamine tachyphylaxis by examining for tachyphylaxis in response to inhaled acetylcholine in these subjects. We subsequently investigated whether indomethacin pretreatment inhibited histamine tachyphylaxis. Tachyphylaxis in response to inhaled histamine occurred in all subjects. The mean histamine provocative concentration causing a 20% fall in the forced expiratory volume in 1 s (PC20) increased from 3.04 +/- 1.9 (%SD), to 4.88 +/- 1.9, and to 6.53 +/- 2.2 mg/ml (P less than 0.0005) with successive inhalation tests. Tachyphylaxis was still present at 3 h (P less than 0.01), but not in all subjects at 6 h (P greater than 0.05). Tachyphylaxis, however, did not occur in response to inhaled acetylcholine. In addition, indomethacin pretreatment prevented histamine tachyphylaxis. Thus this study demonstrates that there is a histamine-specific mechanism that can partially protect the airways against repeated bronchoconstriction caused by histamine. This effect may occur through the release of inhibitory prostaglandins in the airway after histamine stimulation. Also when histamine inhalation tests are repeated on the same day, the tests should be separated by greater than 6 h to avoid tachyphylaxis.

Role of the parasympathetic nervous system in airway hyperresponsiveness after ozone inhalation.

Airway hyperresponsiveness develops in dogs after ozone inhalation. This study examined the role of the parasympathetic nervous system in ozone-induced airway hyperresponsiveness in dogs. Dose-response curves to acetylcholine (n = 8) and histamine (n = 4) were measured before and after exposure to ozone (3 ppm for 30 min). The provocative concentration of each agonist was measured on two randomly assigned days separated by at least 1 wk. On one day a control experiment was performed, and on the other day the dogs were pretreated with the ganglionic blocker hexamethonium bromide in doses that block ganglionic transmission. The acetylcholine provocative concentration decreased on the control day from 5.5 mg/ml (%SE 1.8) before ozone to 0.5 mg/ml (%SE 2.0) after ozone (P less than 0.0001). After pretreatment with hexamethonium the acetylcholine provocative concentration decreased from 9.0 mg/ml (%SE 1.8) before ozone to 1.0 mg/ml (%SE 2.0) after ozone (P = 0.002). The results were similar when histamine was used as the agonist. Therefore, ganglionic blockade does not prevent airway hyperresponsiveness after ozone inhalation, and a parasympathetic reflex mechanism is not responsible for airway hyperresponsiveness after ozone inhalation in dogs.

Tachyphylaxis to inhaled methacholine in normal but not asthmatic subjects.

Methacholine inhalation tests measure airway responsiveness in asthmatic and normal subjects. Tachyphylaxis occurs with repeated methacholine inhalations in normal subjects. The purpose of this study was to examine the time course and mechanisms of methacholine tachyphylaxis in normal subjects and to determine whether this occurs in mildly asthmatic subjects. Fifteen normal and nine asthmatic subjects were studied on 2 study days, at least 48 h apart. Each day, two inhalation tests were carried out. On one day, subjects performed two methacholine inhalation tests 3 h later by a methacholine test. Results were expressed as the provocation concentration causing a 20% fall in forced expiratory volume in 1 s (FEV1), (PC20). All normal subjects developed methacholine tachyphylaxis. The mean PC20 increased from 47.3 mg/ml (%SE 1.34) to 115.6 (%SE 1.51) (P less than 0.0001) in a 3-h interval. This increase lasted for greater than or equal to 6 h (P = 0.012). Asthmatic subjects did not develop methacholine tachyphylaxis. Their mean methacholine PC20s were 1.6 mg/ml (%SE 1.4) and 1.5 (%SE 1.4) (P = 0.75) 3 h later. In two other series of experiments, normal subjects were pretreated with the cyclooxygenase inhibitors indomethacin (100 mg/day) or flurbiprofen (150 mg/day) or a placebo for 3 days before two methacholine tests 3 h apart. Both indomethacin and flurbiprofen significantly inhibited the development of methacholine tachyphylaxis. These results confirm that methacholine tachyphylaxis occurs in normal subjects, lasts greater than or equal to 6 h, and may occur through the release of inhibitory prostaglandins. By contrast, methacholine tachyphylaxis does not occur in asthmatic subjects.

The inhibitory influence of tracheal mucosa mounted in close proximity to canine trachealis.

Reduced smooth muscle contractile responses to agonists occur in the presence of epithelium, perhaps due to the release of an epithelium-derived relaxing factor (EpDRF). It is not clear whether the release of EpDRF requires the direct attachment of the epithelium to the smooth muscle. In the present study, using isolated canine tracheal smooth muscle strips, we examined whether the inhibitory effects of airway mucosa require the attachment of the mucosa to smooth muscle. The smooth muscle contractile responses to acetylcholine and histamine were reduced in the presence of airway mucosa, whether the mucosa was attached or in close proximity. The inhibitory effect mediated by the airway mucosa therefore is not dependent on mucosal attachment to smooth muscle. This phenomenon appears to be due to the release of a soluble, short-acting mediator from the airway mucosa.

Thyroid gland and arterial lesions of Beagles with familial hypothyroidism and hyperlipoproteinemia.

Primary hypothyroidism with marked hyperlipoproteinemia and modest to severe atherosclerosis was described in a family of Beagles. The disease was familial and probably hereditary, but the mode of inheritance was unknown. Signs of the disease occurred as early as 1.5 years of age and as late as 5 years of age. The onset of the disease was heralded by reduced concentrations of serum thyroxine, increased binding capacity of thyroxine-binding globulin, and reduced response to injected thyroxine-stimulating hormone. Thereafter, serum lipids, particularly serum cholesterol, increased markedly even though the dogs consumed a diet low in fats and cholesterol. Thyroxine administration resulted in a precipitous decline in serum cholesterol concentrations. Microscopic changes in the thyroid glands included neoplastic transformation, adenomatous hyperplasia, lymphocytic thyroiditis, and atrophy. Moderate to severe atherosclerosis occurred mainly in the coronary and renal arteries. Atherosclerotic arteries were stenotic but patent, and there was no evidence of prior occlusion or thrombosis.

Serologic survey for Actinobacillus capsulatus in free-ranging snowshoe hares (Lepus americanus) from Alaska and Alberta.

A plate agglutination method was developed to test sera from free-ranging snowshoe hares (Lepus americanus) captured in Alaska (USA) or Alberta (Canada) for antibody against Actinobacillus capsulatus. Antiserum against A. capsulatus was prepared in a domestic rabbit. A concentrated suspension of formalin-killed A. capsulatus was prepared for use as an antigen. Serum antibody prevalence for hares was 98 of 239 (41%) in Alaska and 51 of 111 (46%) in Alberta. Prevalence in Alaska peaked in 1981 corresponding to a peak in hare population density. Seasonal prevalence peaked in May in Alaska. Prevalence at one capture site in Alaska was significantly higher than at four other sites. There was no difference in sex-specific prevalence for either Alaska or Alberta.

Asthma, hay fever and eczema in Irish teenagers (ISAAC protocol).

The national prevalence of asthma, hay fever and eczema, employing the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire, was determined during 1995 in 3148 Junior Certificate secondary school children aged 13-14 years throughout the Republic of Ireland. The prevalence values for asthma, hay fever and eczema were 15.2%, 24.8% and 9.4% respectively. Although 5.4% reported having both asthma and hay fever, combinations of the other allergic conditions were less than 2%. Sex difference in prevalence rates for the various conditions occurred with asthma prevalence being higher for males, eczema in females, but hay fever was almost equally reported between males and females. This data documents the prevalence of teenage asthma with associated allergic conditions in the Republic of Ireland and will allow for present and future comparisons of these conditions with other countries world-wide using the ISAAC protocol.

Effects of an oral hygiene punishment procedure on chronic rumination and collateral behaviors in monozygous twins.

This study investigated the suppressive effects of an oral hygiene punishment procedure on the ruminative behavior of profoundly retarded monozygous twins. Rumination, fingers in mouth/tongue out, appropriate behavior, and stereotyped behavior were measured before and during treatment with oral hygiene. Treatment was introduced for each meal in succession across the twins in a multiple-baseline design. Results showed that the rate of rumination of both twins was dramatically reduced to very low levels and stereotyped behavior increased spontaneously with the introduction of oral hygiene. Maintenance data showed that response reduction was maintained over a six-month period and, when compared to baseline levels, increased rates of socially appropriate behavior were evident in both children.

Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2016 revision

BACKGROUND: Allergic rhinitis (AR) affects 10% to 40% of the population. It reduces quality of life and school and work performance and is a frequent reason for office visits in general practice. Medical costs are large, but avoidable costs associated with lost work productivity are even larger than those incurred by asthma. New evidence has accumulated since the last revision of the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines in 2010, prompting its update. OBJECTIVE: We sought to provide a targeted update of the ARIA guidelines. METHODS: The ARIA guideline panel identified new clinical questions and selected questions requiring an update. We performed systematic reviews of health effects and the evidence about patients' values and preferences and resource requirements (up to June 2016). We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence-to-decision frameworks to develop recommendations. RESULTS: The 2016 revision of the ARIA guidelines provides both updated and new recommendations about the pharmacologic treatment of AR. Specifically, it addresses the relative merits of using oral H1-antihistamines, intranasal H1-antihistamines, intranasal corticosteroids, and leukotriene receptor antagonists either alone or in combination. The ARIA guideline panel provides specific recommendations for the choice of treatment and the rationale for the choice and discusses specific considerations that clinicians and patients might want to review to choose the management most appropriate for an individual patient. CONCLUSIONS: Appropriate treatment of AR might improve patients' quality of life and school and work productivity. ARIA recommendations support patients, their caregivers, and health care providers in choosing the optimal treatment.

Active smoking and second-hand-smoke exposure at home among Irish children, 1995-2007.

OBJECTIVE: This study hypothesised a continual decline in current smoking prevalence over four calendar years (1995, 1998, 2002/03 and 2007) and no significant increase in second-hand-smoke (SHS) exposure levels at home after the workplace smoking ban of March 2004 (2007 versus 2002/03 survey) among Irish school children. METHODS: A modified ISAAC (International Study of Asthma and Allergies in Childhood) protocol was used. Children aged 13-14 years from randomly selected representative post-primary schools were studied: 2670 in 1995, 2273 in 1998, 2892 in 2002-2003, and 2805 in 2007. ISAAC is a cross-sectional self-administered questionnaire survey. Smoking history was self-reported. beta Coefficients (slopes) of smoking rates across the four surveys were computed. Odds ratios for smoking rates were also computed using the baseline year (1995) as the reference period. All analyses were performed using SAS software (v 9.1). RESULTS: There were significant reductions in active smoking rates between 1995 and 2007 (from 19.9% to 10.6%, respectively) resulting in 3.3% survey-to-survey reductions, with a significantly greater survey-to-survey decline among girls compared to boys (3.8% vs 2.7%, respectively). 45% of children were exposed to SHS at home in 2007. There was a statistically non-significant 2% overall decline in SHS exposure levels at home in 2007 relative to 2002/03, which was more pronounced in girls. CONCLUSIONS: The continual reduction in active smoking prevalence in children is welcome. That there was no significant increase in SHS exposure at home after the nationwide workplace smoking ban suggests that the ban did not increase smoking inside homes.