Platelet and monocyte activation by hyperglycemia and hyperinsulinemia in healthy subjects

Type 2 diabetes mellitus (T2DM) patients have hyperglycemia and hyperinsulinemia and increased risk of atherosclerosis and acute vascular complications. We have reported elevated circulating tissue factor procoagulant activity (TF-PCA) during hyperglycemia (HG) and hyperinsulinemia (HI) in normal subjects. To evaluate the effect of hyperglycemia and hyperinsulinemia on blood cell activation, we assessed platelet CD40L and P-selectin, monocyte tissue factor (TF), and the formation of monocyte-platelet and neutrophil-platelet aggregates. These were assessed in the resting state and following activation with ADP and thrombin (SFLLRN). Healthy individuals were subjected to 24 h of hyperglycemia and hyperinsulinemia, selective hyperglycemia, selective hyperinsulinemia, or normal glucose and insulin. Platelet CD40L expression increased with high glucose/high insulin, selective hyperglycemia and selective hyperinsulinemia. Monocyte-platelet aggregates increased with high glucose/high insulin. Monocyte TF expression increased with high glucose/high insulin and with selective hyperinsulinemia. Upon stimulation with ADP and SFLLRN, monocyte-platelet and neutrophil-platelet aggregates, platelet CD40L and P-selectin, and monocyte TF increased compared to the resting state but was not different between 0 and 24 h, indicating that the responsiveness to those agonists was not altered.Conclusions: Hyperglycemia-hyperinsulinemia in healthy individuals induced platelet activation and monocyte TF expression promoting a procoagulant and proinflammatory state that may contribute to acute vascular events and atherogenesis. Platelet responsiveness to activation with ADP or SFLLRN appears not to be altered by hyperglycemia-hyperinsulinemia.     

Inspiratory muscle function in asthmatic and healthy subjects: influence of age,nutrition and physical activity

Objective: To compare inspiratory muscle function (strength and endurance) between asthmatics and healthy controls, and the influence of age, nutritional status and physical activity on them. Methods: This is a cross-sectional study. Asthmatic and healthy subjects, aged 6 to 18 years old, recruited from two public schools in Southern Brazil were included in the study. Asthmatic subjects were selected using the criteria presented by the International Study on Asthma and Allergies in Children and control subjects based on the absence of respiratory symptoms. Anthropometric data was measured, body mass index calculated and subjects classified as normal weight, overweight or obese. Physical activity levels, maximum inspiratory pressure (MIP) and inspiratory muscle endurance (IME) were also evaluated. Results: A total of 314 participants were included, separated into control group (181) and asthmatics (133), with a total mean age of 11 years. When both groups were compared, there were no significant differences in both MIP and IME. However, when groups were analyzed subdivided in children and adolescents, IME was significantly reduced (p = 0.003) in asthmatic adolescents. Indeed, when groups were also stratified considering the nutritional status, IME showed a reduction in asthmatic adolescents with overweight (p = 0.042) and obesity (p = 0.041) when compared to healthy controls. No effects of physical activity levels between groups were found. Conclusions: Results demonstrate a reduction in the IME in asthmatic adolescents with overweight and obesity, indicating an association between asthma, nutritional status and respiratory muscle function.     

Subsensitization of beta-adrenoceptors in airways and lymphocytes of healthy and asthmatic subjects

Subsensitization of beta-adrenoceptors in airways and lymphocytes developing during 4 to 5 wk of orally administered terbutaline (a long-acting beta 2 selective bronchodilator) was compared in 10 healthy subjects and 11 subjects with mild asthma. The following results were obtained. Normal subjects developed a significant reduction in acute bronchodilator responsiveness to inhaled isoproterenol but not to subcutaneously administered terbutaline. The subjects with asthma failed to develop any alteration in responsiveness to either inhaled isoproterenol or subcutaneously administered terbutaline. None of 5 normal or 4 asthmatic subjects studied demonstrated any significant change in sensitivity to histamine-induced bronchospasm or any significant decrease in the acute protective effect of subcutaneously administered terbutaline against histamine-induced bronchospasm. Marked and significant decreases occurred in the density of lymphocyte beta-receptor sites in both groups. Maximal isoproterenol-stimulated cyclic AMP responses in lymphocytes from normal subjects were reduced, but in asthmatics, in whom the baseline values were lower to begin with, a similar decrease was not observed. In most instances, the number of receptor sites returned to normal within 2 wk after cessation of terbutaline. A single dose of methylprednisolone caused a return to normal values within 16 h. We conclude that chronic therapy with an oral beta 2-adrenostimulant, although producing striking and significant down-regulation of beta-adrenergic receptors of peripheral lymphocytes, does not lead to physiologically detectable beta-adrenoceptor subsensitivity in the airways of asthmatics or to consistent subsensitivity in the airways of healthy persons.     

The synthetic peptide from HIV increases functional activity of granulocytes in healthy subjects

The influence of HIV lysate and eight synthetic peptides which are fragments of HIV proteins on the functional activity of polymorphonuclear neutrophils (PMN) was tested in 12 healthy subjects. PMN activity in nitroblue tetrazolium reduction (NBT test) and PMN chemiluminescence (CL) was studied. Only one peptide was found to result in a significant increase in NBT test on the whole blood. This was the oligopeptide (G-97) from the CD4-binding site of HIV-1 gp120. The increase of CL response of PMN in the presence of G-97 was revealed after only 15 min preincubation. The same effect in the presence of sera from healthy or infected patients at the persistent generalized lymphadenopathy stage was achieved by increasing the time of preincubation to 30 min. G-97 did not influence the proliferative activity of lymphocytes.     

Effect of ozone on bronchial mucosal inflammation in asthmatic and healthy subjects

Epidemiological studies suggestthat asthmatics are more affected by ozone than healthy people. This study tested three hypotheses (1) that short-term exposure to ozone induces inflammatory cell increases and up-regulation of vascular adhesion molecules in airway lavages and bronchial tissue 6 h after ozone exposure in healthy subjects; (2) these responses are exaggerated in subjects with mild allergic asthma; (3) ozone exacerbates pre-existent allergic airways inflammation. We exposed 15 mild asthmatic and 15 healthy subjects to 0.2 ppm of ozone or filtered air for 2 h on two separate occasions. Airway lavages and bronchial biopsies were obtained 6 h post-challenge. We found that ozone induced similar increases in bronchial wash neutrophils in both groups, although the neutrophil increase in the asthmatic group was on top of an elevated baseline. In healthy subjects, ozone exposure increased the expression of the vascular endothelial adhesion molecules P-selectin and ICAM- 1, as well as increasing tissue neutrophil and mast cell numbers. The asthmatics showed allergic airways inflammation at baseline but ozone did not aggravate this at the investigated time point. At 6 h post-ozone-exposure, we found no evidence that mild asthmatics were more responsive than healthy to ozone in terms of exaggerated neutrophil recruitment or exacerbation of pre-existing allergic inflammation. Further work is needed to assess the possibility of a difference in time kinetics between healthy and asthmatic subjects in their response to ozone.     

Effect of milk ingestion on pulmonary function in healthy and asthmatic subjects

Since Maimonides, it has been common in folk medicine to proscribe milk for asthmatics because its putative stimulation of mucus production can exacerbate asthma symptoms. A literature review, however, failed to reveal any data supporting this notion. We, therefore, compared the effects of ingesting 16 oz. of whole milk (16 g lipid), skim milk (2 g lipid), and water (each on a separate day) on: (1) forced expiratory volume in 1 second (FEV1), (2) forced expiratory flow at 50% of vital capacity (V50), and (3) pulmonary diffusing capacity (DLCO) in 11 asthmatic and 10 nonasthmatic subjects. Measurements were taken at 30 minute intervals for 3 hours. The two milk types did not significantly change FEV1 or V50 in either group, indicating that the amount ingested did not change airway resistance sufficiently to alter airflow parameters. In the asthmatic group, however, DLCO decreased progressively over the 3 hours by 6.8 +/- 1.4% (mean +/- SE) per hour after whole milk (maximum reduction = 21 +/- 1.4%) but not after water or skim milk. In the nonasthmatic group, no significant effects were observed on DLCO after any of the liquids. These data suggest that milk lipids can disturb gas exchange in asthmatic patients.     

Systemic and bronchial inflammation following LPS inhalation in asthmatic and healthy subjects

BACKGROUND: Inhaled endotoxin is known to induce airway inflammation, causing bronchial hyperreactivity. OBJECTIVE: We characterized the response to lipopolysaccharide-inhalation by measuring exhaled nitric oxide (eNO) and inflammatory mediators. PATIENTS AND METHODS: A total of 43 adult volunteers (13 asthmatics, 30 healthy controls) inhaled stepwise LPS every 30 min up to a cumulative dose of 100 microg (2.5, 10.5, 42, 45 microg). After each provocation and up to 24 h later, FEV(1) was determined; the procedure was stopped when FEV(1) declined more than 12.5%. We measured eNO, leucocytes, eosinophils, polymorphonuclear neutrophils (PMNs), C-reactive protein (CrP), lipopolysaccharide binding protein (LBP), eosinophilic cationic protein (ECP), leucotriene B4 (LTB4), thromboxane B2 (TXB2), and body temperature. RESULTS: Initial eNO values were higher in asthmatics (P < 0.01), but only increased in an asthmatic subgroup. Marked differences were observed in the systemic response to LPS inhalation. Significant increases were found for CrP, LBP, and PMNs. There was no correlation between FEV(1) decrease and basal eNO levels. CONCLUSIONS: Inhalation of endotoxin was followed by clinical and laboratory signs of systemic inflammation, with asthmatics responding to the challenge similar as healthy subjects. Bronchial eNO increased only temporarily in asthmatics.     

Changes in serum K+ in healthy and in asthmatic subjects during exercise

Adrenergic mechanisms modulate exercise-induced changes in blood serum K+ concentration ([K+]). Impairment of these same mechanisms may be associated with bronchial hyper-reactivity. If this is accurate, asthmatic subjects should show disturbed K+ regulation during exercise. We measured [K+] and FEV1 in 13 healthy control and in 13 asthmatic subjects pre-exercise, at peak exercise (within 1 min of stopping exercise), and 10 min postexercise. This was done on 2 separate days, one with and one without bronchodilator (BD) pretreatment. Both groups were equally fit, exercising to the same O2 consumption and heart rate. Resting [K+] was normal for both groups (two-day averages were 4.00 +/- 0.07 and 4.09 +/- 0.07 mmol/L, mean +/- SEM, in control and asthmatic subjects, respectively). Without BD pretreatment, at peak exercise, [K+] in control subjects rose by 0.56 +/- 0.08 compared with 0.96 +/- 0.09 in asthmatics (p less than 0.01). After exercise, [K+] returned to baseline (4.12 +/- 0.08) in control subjects but remained elevated in asthmatics (4.60 +/- 0.12, p less than 0.01). Although FEV1 was unchanged in control subjects, in asthmatics it fell after exercise (p less than 0.01). With BD pretreatment: peak exercise [K+] increased by 0.55 +/- 0.09 in control subjects, and by 0.49 +/- 0.01 in asthmatics (p less than 0.01). By 10 min postexercise, it returned to baseline in both groups (4.15 +/- 0.11 for control subjects and 4.32 +/- 0.07 for asthmatics). The asthma group's fall in FEV1 was also abolished. These data indicate that postexercise K+ remains elevated in asthmatics, supporting the suggestion that their adrenergic function is impaired.     

Bronchial effects of aerosolized delta 9-tetrahydrocannabinol in healthy and asthmatic subjects.

Effects on airway dynamics, heart rate, and the central nervous system of various doses of delta9-tetrahydrocannabinol administered in a random, double blind fashion using a Freon-propelled, metered-dose nebulizer were evaluated in 11 healthy men and 5 asthmatic subjects. Effects of aerosolized delta9-tetrahydrocannabinol were compared with aerosolized placebo and isoproterenol and with 20 mg of oral and smoked delta9-tetrahydrocannabinol. In the normal subjects, after 5 to 20 mg of aerosolized delta9-tetrahydrocannabinol, specific airway conductance increased immediately, reached a maximum (33 to 41 per cent increase) after 1 to 2 hours, and remained significantly greater than placebo values for 2 to 3 hours. The bronchodilator effect of aerosolized delta9-tetrahydrocannabinol was less than that of isoproterenol after 5 min, but significantly greater than that of isoproterenol after 1 to 3 hours. The magnitude of bronchodilatation after all doses of aerosolized delta9-tetrahydrocannabinol was comparable, but 5 mg of delta9-tetrahydrocannabinol caused a significantly smaller increase in heart rate and level of intoxication than the 20-mg dose. Smoked delta9-tetrahydrocannabinol produced greater cardiac and intoxicating effects than either aerosolized or oral delta9-tetrahydrocannabinol. Side effects of aerosolized delta9-tetrahydrocannabinol included slight cough and/or chest discomfort in 3 of the 11 normal subjects. Aerosolized delta9-tetrahydrocannabinol caused significant bronchodilatation in 3 of 5 asthmatic subjects, but caused moderate to severe bronchoconstriction associated with cough and chest discomfort in the other 2. These findings indicate that aerosolized delat9-tetrahydrocannabinol, although capable of causing significant bronchodilatation with minimal systemic side effects, has a local irritating effect on the airways, which may make it unsuitable for therapeutic use.     

A comparison of monocyte oxidative responses in leprosy patients and healthy subjects as influenced by mycobacterial lipid pretreatment

Superoxide anion (O2-) release by monocytes from leprosy patients in a paired study was lower than that released by monocytes from healthy controls. Pretreatment of healthy control monocytes with phenolic glycolipid-I (PGL-I) of Mycobacterium leprae resulted in the release of less O2- than released by buffer-treated cells or cells pretreated with structurally similar lipids. However, pretreatment of patient monocytes with PGL-I did not affect the O2- generation, perhaps because the cells already had a lower capacity to produce O2-. Upon further examination of the data from the patient population, monocytes from lepromatous patients released significantly less O2- than cells from normal controls, while tuberculoid patient cells released O2- in amounts similar to that generated by cells from normal controls. In addition, monocytes from patients with a high bacterial index had a lower capacity to generate O2- when compared to cells from healthy individuals.     

Quality of bronchial biopsies for morphology study and cell sampling: A comparison of asthmatic and healthy subjects

BACKGROUND:

Bronchial biopsies are widely used for histopathological, primary cell culture and genetic studies, but very few reports have evaluated their quality.

OBJECTIVES AND METHODS:

The present project evaluated the quality (using a scoring system) and the general morphology of a pool of six bronchial biopsy specimens taken from three different sampling sites (the lobar, segmental and subsegmental carinae) in 27 subjects (13 asthmatic subjects and 14 healthy controls). The present study also assessed quantitative measurements of structural changes related to asthma.

RESULTS:

In total, 94.4% of the biopsy attempts had enough tissue to be processed. From these, 61.7% were scored with a good to excellent quality, while 76.5% presented smooth muscle bundles and 40.5% had an intact epithelium wall. The data also confirmed the structural changes observed in asthma, such as increased apparent thickening of the basement membrane, reduced amounts of smooth muscle for healthy controls and decreased percentage of intact epithelium for asthmatic subjects.

CONCLUSION:

A pool of six bronchial biopsy specimens can provide tissue of excellent quality in both asthmatic and healthy subjects and, consequently, a valuable sample for morphological analysis of mucosal structures.     

Electrodermal activity in hypothyroid patients and healthy subjects.

The involvement of the central nervous system either in hypothyroidism or in hyperthyroidim has previously been shown on the basis of visual, auditory, somatosensory, and central motor evoked potential studies by some investigators. In to our previous study, we found that abnormal electrodermal activity in nonmedicated hyperthyroid patients was not associated with psychiatric symptoms. In this study, our purpose was to investigate whether hypothyroidism results in electrodermal abnormalities in the absence of measurable psychiatric symptoms. Electrodermal activity was recorded with a skin conductance unit connected to a personal computer. Basal levels of electrodermal activity and responsiveness to repeated acoustic stimulation were studied in 14 nonmedicated hypothyroid patients and 14 healthy controls. Psychiatric rating scores indicated that patients and healthy controls had normal levels of anxiety and depression. Hypothyroid patients had lower skin conductance levels, lower fluctation rates and prolonged onset latencies compared with controls. None of the hypothyroid patients had amplitude changes. In conclusion, hypothyroid patients may have abnormal electrodermal activity that is related to the change of hypothalamic-pituitary-thyroid axis function, without associated psychiatric symptoms.     

Acute bronchoconstriction is not a stimulus for sympatho-adrenal activation in asthmatic or healthy subjects

Bronchoconstriction has been found to cause little sympathoadrenal activation in asthmatic patients. It has been questioned whether this is due to blunted sympatho-adrenal reactivity in asthmatics or if bronchoconstriction is a stimulus for sympatho-adrenal activation at all. We therefore compared sympatho-adrenal responses in eight asthmatic patients and 12 healthy subjects by measurements of plasma adrenaline and noradrenaline concentrations before, during and after methacholine-induced bronchoconstriction. Significant bronchoconstriction was obtained in eight of the healthy subjects and in all of the asthmatics. Considerably higher concentrations of methacholine were required to evoke bronchoconstriction in the healthy subjects but the relative magnitudes of bronchoconstriction were similar in the two groups: peak expiratory flow (PEF) decreased by approximately 24 and approximately 28% and specific airway conductance (sGaw) decreased by approximately 68 and approximately 70% in asthmatics and controls, respectively). Methacholine-induced bronchoconstriction did not alter plasma catecholamine levels significantly in either group. In addition, plasma concentrations of catecholamines and neuropeptide Y-like immunoreactivity (NPY-LI) were measured before and during bronchoconstriction induced by histamine or allergen in 8 and 5 asthmatic subjects, respectively. Plasma noradrenaline, adrenaline and NPY-LI remained unchanged up to 30 min after bronchoconstriction induced by histamine or allergen. We, therefore, conclude that bronchoconstriction is not a stimulus for sympatho-adrenal activation and that the lack of an adrenaline response to bronchoconstriction is not likely to be related to NPY release.     

Serum periostin is associated with body mass index and allergic rhinitis in healthy and asthmatic subjects

Background

Many studies have attempted to clarify the factors associated with serum periostin levels in asthmatic patients. However, these results were based on studies of subjects mainly characterized by high eosinophil counts, which may present as an obstacle for clarification in the identification of other factors associated with serum periostin levels. The aim of this study was to determine the factors associated with serum periostin levels in healthy subjects. We also assessed some factors in asthmatic subjects to confirm their extrapolation for management of asthma.

Androgens regulate phosphodiesterase type 5 expression and functional activity in corpora cavernosa

By real-time RT-PCR and Western blot analysis, we found that phosphodiesterase type 5 (PDE5) mRNA and protein abundance was several fold higher in human male than in female reproductive tracts. The highest mRNA level (>1 x 10(7) molecules/microg total RNA) was detected in human corpora cavernosa (CC), where PDE5 protein was immunolocalized in both muscular and endothelial compartment. The possible role of androgens in regulating PDE5 expression was studied using a previously established rabbit model of hypogonadotropic hypogonadism. In this model, hypogonadism reduced, and testosterone (T) supplementation restored, CC PDE5 gene and protein expression. In addition, T supplementation completely rescued and even enhanced cyclic GMP conversion to metabolites, without changing IC(50) for sildenafil (IC(50) = 2.16 +/- 0.62 nm). In control CC strips, sildenafil dose-dependently increased relaxation induced by electrical field stimulation, with EC(50) = 3.42 +/- 1.7 nm. Hypogonadism reduced, and T increased, sildenafil effect on electrical field stimulation, again without changing their relative EC(50) values. CC sensitivity to the NO-donor NCX4040 was greater in hypogonadal rabbit strips than in control or T-treated counterparts. Moreover, sildenafil enhanced NCX4040 effect in eugonadal rabbit strips but not in hypogonadal ones. This suggests that androgens up-regulate PDE5 in rabbit penis. We also measured PDE5 gene expression and metabolic activity in human CC from male-to-female transsexual individuals, chronically treated with estrogens and cyproterone acetate. Comparing the observed values vs. eugonadal controls, PDE5 mRNA, protein, and functional activity were significantly reduced. In conclusion, we demonstrated, for the first time, that androgens positively regulate PDE5, thus providing a possible explanation about the highest abundance of this enzyme in male genital tract.     

蒙特利尔认知评估量表在健康体检人群中的应用

目的研究蒙特利尔认知评估量表(MoCA)在健康体检人群中的分布特征。方法选择1350例健康体检者,采用北京版MoCA对受试者进行认知功能测评。最终777例进入分析,按年龄分为:<65岁组175例,65⁶9岁组200例,7069岁组200例,70⁷4岁组145例,7574岁组145例,75⁷9岁组124例,≥80岁组133例;按受教育年限分为:≤12年组153例和1379岁组124例,≥80岁组133例;按受教育年限分为:≤12年组153例和13²0年组624例。结果不同年龄组、不同受教育年限组MoCA总分比较,差异有统计学意义(P<0.01)。多元线性回归方程显示,年龄与MoCA总分呈负相关(β=-0.639,P=0.000),受教育年限与MoCA总分呈正相关(β=0.741,P=0.000)。以均数-1.5倍标准差为轻度认知障碍筛查的参考值,筛查值范围分别为:<65岁组≤25分,6520年组624例。结果不同年龄组、不同受教育年限组MoCA总分比较,差异有统计学意义(P<0.01)。多元线性回归方程显示,年龄与MoCA总分呈负相关(β=-0.639,P=0.000),受教育年限与MoCA总分呈正相关(β=0.741,P=0.000)。以均数-1.5倍标准差为轻度认知障碍筛查的参考值,筛查值范围分别为:<65岁组≤25分,65⁶9岁组≤24分,7069岁组≤24分,70⁷4岁组≤24分,7574岁组≤24分,75⁷9岁组≤23分,≥80岁组≤19分;≤12年组≤20分,1379岁组≤23分,≥80岁组≤19分;≤12年组≤20分,13²0年组≤24分。结论在健康体检人群中,用MoCA进行认知功能障碍患者的筛查界值不同,尤其在低文化程度和高龄人群更需注意。     

Circadian characteristics of urinary leukotriene E(4) in healthy subjects and nocturnal asthmatic patients.

STUDY OBJECTIVES: Circadian rhythmicity of cysteinyl leukotrienes (LTs) and thromboxane (TX)-A(2) in healthy subjects and nocturnal asthmatic patients remains a subject of controversy. The aim of this study was to investigate the contribution of these mediators to the pathogenesis of nocturnal asthma. METHODS: We measured peak expiratory flow rate, urinary concentration of LTE(4), 11-dehydro-TXB(2), and creatinine eight times every 3 h in three groups: healthy control subjects (n = 5, group A), nocturnal asthmatic patients (n = 9, group B), and nonnocturnal asthmatic subjects (n = 9, group C). To evaluate the reproducibility of the measurement of urinary LTE(4), we measured urinary LTE(4) in group A for 3 separate days. RESULTS: The urinary LTE(4) concentrations from 3 to 6 AM were significantly (p < 0.05) higher than from 3 to 6 PM in both group A and group B, but not in group C. The mean levels of LTE(4) in group B and group C were significantly higher (p < 0.05) than those in group A. In group B, another small peak was observed from 6 to 9 PM. No significant day-to-day variation was observed in group A. Urinary 11-dehydro-TXB(2) values from 3 to 6 AM were significantly (p < 0.001) higher than those levels from 3 to 6 PM in all groups, and the mean levels in group B and group C were significantly higher than those in group A (p < 0.05). CONCLUSIONS: Circadian rhythmicity of urinary LTE(4) with a morning peak was found in healthy control subjects and nocturnal asthmatic subjects, but not in nonnocturnal asthmatic patients. It was suggested that cysteinyl LTs rather than TXA(2) might contribute to the nocturnal worsening of asthma.