Petrobasal Vein: A Previously Unrecognized Vein Directly Connecting the Superior Petrosal Sinus with the Emissary Vein of the Foramen Ovale.

BACKGROUND AND PURPOSE: The superior petrosal sinus terminates anteriorly at the cavernous sinus and posteriorly at the transverse sinus. Venous variations directly connecting the superior petrosal sinus and the emissary veins of the foramen ovale are not well-recognized. We present a connecting vein, provisionally named the petrobasal vein. MATERIALS AND METHODS: Biplane cerebral angiography of the bilateral internal carotid arteries and the vertebral artery acquired in 267 patients was retrospectively reviewed by 2 neuroradiologists with special interest in the existence and course of the petrobasal vein. RESULTS: The petrobasal vein was observed to lie anterior-posteriorly on the superior surface of the petrosal bone and connected to the midportion of the superior petrosal sinus and the emissary veins of the foramen ovale in 41 patients (15%) and sides (7.9%); it drained into the pterygoid plexus. The petrobasal vein was observed on VAG in 21 patients, on ICAG alone in 8 patients (9 sides), on both VAG and ICAG in 12 patients, and on ICAG in 1 patient. In the patients in whom the petrobasal vein was visualized on the ICAs, the superficial middle cerebral vein drained into a combination of the pterygoid plexus via the emissary veins of the foramen ovale and the superior petrosal sinus. CONCLUSIONS: The petrobasal vein, an unknown vein directly connecting the superior petrosal sinus and the emissary veins of the foramen ovale and draining into the pterygoid plexus, can occasionally be identified on cerebral angiography as a variant drainage route from the cerebellum and brainstem veins and/or from the superficial middle cerebral vein. The petrobasal vein is thought to be a remnant of the primitive tentorial sinus.

Long-range correlated glucose fluctuations in diabetes.

OBJECTIVES: Our objective is to investigate diabetes-related alteration of glucose control in diurnal fluctuations in normal daily life by detrended fluctuation analysis (DFA). METHODS: The fluctuations of glucose of 12 non-diabetic subjects and 15 diabetic patients were measured using a continuous glucose monitoring system (CGMS) over a period of one day. The glucose data was calculated by the DFA method, which is capable of revealing the presence of long-range correlations in time series with inherent non-stationarity. RESULTS: Compared with the non-diabetic subjects, the mean glucose level and the standard deviation are significantly higher in the diabetic group. The DFA exponent alpha is calculated, and glucose time series are searched for the presence of negatively (0.5 < alpha < 1.5) or positively (1.5 < alpha) correlated fluctuations. A crossover phenomenon, i.e. a change in the level of correlations, is observed in the non-diabetic subjects at about two hours; the net effects of glucose flux/reflux causing temporal changes in glucose concentration are negatively correlated in a "long-range" (> two hours) regime. However, for diabetic patients, the DFA exponent alpha = 1.65 +/- 0.30, and in the same regime positively correlated fluctuations are observed, suggesting that the net effects of the flux and reflux persist for many hours. CONCLUSIONS: Such long-range positive correlation in glucose homeostasis may reflect pathogenic mechanisms of diabetes, i.e., the lack of the tight control in blood glucose regulation. Using modern time series analysis methods such as DFA, continuous evaluation of glucose dynamics could promote better diagnoses and prognoses of diabetes and a better understanding of the fundamental mechanism of glucose dysregulation in diabetes.

Modulation of branched-chain 2-oxo acid dehydrogenase complex activity in rat skeletal muscle by endurance training.

Effects of endurance training and high-fat diet intake on the branched-chain 2-oxo acid dehydrogenase complex in skeletal muscle were examined in rats. The basal activities of the enzyme complex (approximately 4% in active form of the total enzyme) in the muscle of rats under the fed conditions were not different between trained and untrained rats. The basal activity in the muscle was elevated by 24 h starvation in both groups of rats, but the level of the elevation was significantly greater in the trained rats than in the untrained rats. On the other hand, high-fat diet intake did not alter the basal activity of the enzyme complex in the muscle or the profile of activation of the enzyme complex by muscle contractions elicited by the electrical stimulation, suggesting that the fat content in the diet does not affect the enzyme activity in the muscle. Neither training nor diet affected the total enzyme activity or the amount of enzyme protein. Activation by leucine administration of the enzyme complex in the muscle was greater in the trained rats than in the untrained rats, suggesting that the activity state of the enzyme complex is more responsive to regulation by the 2-oxo acid derived from leucine in the muscles of endurance-trained rats.

Regulation by physical training of enzyme activity and gene expression of branched-chain 2-oxo acid dehydrogenase complex in rat skeletal muscle.

We examined the effects of short-term (5 weeks) and long-term (12 weeks) physical training on actual and total activities, protein content and mRNA abundance of branched-chain 2-oxo acid dehydrogenase complex in rat skeletal muscle. The actual and total activities were significantly increased approximately 60% and approximately 40%, respectively, by long-term training. No effects of short-term training on activities were observed. The increase in the total activity corresponded to increased protein content of the E1 alpha and E2 components of the complex. On the other hand, mRNA abundance for E1 alpha and E2 were not affected by the training, but that for E1 beta was slightly, but significantly increased by both short-term and long-term trainings. These divergent alterations of the message levels for the subunits of the complex suggest that posttranslational regulatory mechanisms determine the amount of the complex in skeletal muscle. Since the complex is located in the mitochondrial matrix space, mitochondrial biogenesis in response to the training was examined by determining the content of mitochondrial DNA in the muscle. The mitochondrial DNA was proportionally increased with the total activity as well as the protein content of the complex, suggesting that expression of branched-chain 2-oxo acid dehydrogenase complex in skeletal muscle in response to physical training is associated with mitochondrial biogenesis.

Pathogenic factors responsible for glucose intolerance in patients with NIDDM.

To define the pathogenic factors responsible for glucose intolerance in NIDDM, we estimated insulin secretory capacity, SI, and SG in 11 healthy, nondiabetic subjects and 9 NIDDM patients who had no SI impairment. All subjects studied were nonobese and normotensive. Each underwent a 75-g OGTT and a modified FSIGT: glucose was administered (300 mg/kg body weight), and insulin was infused (20 mU/kg over 5 min) from 20 to 25 min after the administration of glucose. SI and SG were estimated by Bergman's minimal-model method. The insulin response to oral glucose was significantly lower in NIDDM patients than in normal control subjects. First-phase insulin secretion expressed as the integrated area of plasma insulin above the basal level during the first 20 min was much smaller in NIDDM subjects (214 +/- 112 pM.min) than in control subjects (4643 +/- 885 pM.min, P < 0.01). SI was not statistically different in normal control subjects (1.27 +/- 0.18 x 10(-4) min-1.pM-1) versus diabetic patients (1.62 +/- 0.33 x 10(-4) min-1.pM-1). However, SG was significantly lower in diabetic subjects (1.11 +/- 0.17 x 10(-2) min-1) than in control subjects (2.35 +/- 0.26 x 10(-2) min-1, P < 0.01). These results suggest that impaired insulin secretion and decreased SG are the factors responsible for glucose intolerance of Japanese NIDDM patients with normal insulin sensitivity. Because SI and SG are the factors responsible for glucose intolerance of NIDDM patients with insulin resistance, it is conceivable that decreased SG is common in NIDDM patients regardless of their SI index.

Glucose effectiveness in two subtypes within impaired glucose tolerance. A minimal model analysis.

To clarify the event that is involved in the pathogenesis of impaired glucose tolerance (IGT), we studied 15 individuals with IGT and 15 subjects with normal tolerance using the minimal model approach. Our IGT subjects were characterized by normal insulin secretory responses to oral glucose and mild impairments in insulin sensitivity (SI) and glucose effectiveness (SG) at basal and zero insulin. Next, we classified our IGT subjects into two subpopulations: one with normal insulin sensitivity (SI: 0.92 +/- 0.11 x 10(-4) min-1.pmol/l-1 and the other with insulin resistance (SI:0.31 +/- 0.06 x 10(-4)min-1.pmol/l-1, P < 0.05). The populations did not differ with respect to body mass index and fasting plasma glucose level. Basal plasma insulin level was higher in the insulin-resistant group (84.8 +/- 23.3 pmol/l) than in the insulin-sensitive group (48.7 +/- 6.8 pmol/l), but the difference was not statistically significant. The absolute insulin secretory responses to oral glucose were significantly higher in the resistant group (83,205 +/- 17,787 pmol/l x min) than in the sensitive group (24,727 +/- 3,591 pmol/l x min, P < 0.01), whose absolute responses were similar to those of normal control subjects (24,576 +/- 2,767 pmol/l x min). No significant difference was observed in SG between the resistant (0.016 +/- 0.002 min-1) and sensitive (0.013 +/- 0.002 min-1, P > 0.05) type of IGT, but SG was significantly type of IGT, but SG was significantly decreased in both groups compared with normal control subjects (0.023 +/- 0.002 min-1, P < 0.05-0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Endogenous glucose production and glucose effectiveness in type 2 diabetic subjects derived from stable-labeled minimal model approach.

Insulin sensitivity, glucose effectiveness, and endogenous glucose production (EGP) during stable-labeled, frequently sampled insulin-modified intravenous glucose tolerance test (FSIGT) were evaluated by a single-and two-compartment minimal model combined with nonparametric deconvolution in eleven nonobese Japanese type 2 diabetic patients. Four patients were treated with sulfonylureas, and the remaining seven with diet therapy alone. None had diabetic retinopathy and microalbuminuria. Their fasting glucose level was 117+/-7 mg/dl (mean +/- SE), and HbA1c was 6.6+/-0.3%. Age-, sex-, and BMI-matched subjects with normal glucose tolerance served as control subjects. Plasma insulin response to the stimuli and insulin sensitivity indexes (S(I), S(I)*, and S(I)2* were derived from a minimal model and single- and two-compartment-labeled minimal models) were impaired in the type 2 diabetic patients. The combined ability of glucose, per se, to increase its own uptake and suppress EGP (glucose effectiveness [SG]), which was derived from kinetic analysis of plasma glucose by a minimal model, was significantly lower in the type 2 diabetic patients (0.0132+/-0.0015 vs. 0.0203+/-0.0022; P<0.05). However, the ability of glucose, per se, to stimulate glucose uptake, assessed as S(G)* and S(G)2* from the kinetic analysis of labeled glucose by single- and two-compartment minimal model, was not impaired in those patients. EGP of the type 2 diabetic patients as a whole was suppressed to the level similar to that of the control subjects despite a higher plasma glucose level throughout FSIGT. When EGP in the diabetic subjects was analyzed, considering their recent glycemic control, the initial suppression was blunted in the patients with higher HbA1c levels. In conclusion, glucose mass action to stimulate glucose uptake remains near-normal in the lean Japanese type 2 diabetic patients of this study, whereas ability of glucose to suppress EGP is impaired in the patients with recent hyperglycemia. This blunted suppression of EGP might be one of the conspirators for decreased S(G) in subjects with type 2 diabetes.

Effect of mild exercise training on glucose effectiveness in healthy men.

OBJECTIVE: To detect whether mild exercise training improves glucose effectiveness (S(G)), which is the ability of hyperglycemia to promote glucose disposal at basal insulin, in healthy men. RESEARCH DESIGN AND METHODS: Eight healthy men (18-25 years of age) underwent ergometer training at lactate threshold (LT) intensity for 60 min/day for 5 days/week for 6 weeks. An insulin-modified intravenous glucose tolerance test was performed before as well as at 16 h and 1 week after the last training session. S(G) and insulin sensitivity (S(I)) were estimated using a minimal-model approach. RESULTS: After the exercise training, VO(2max) and VO(2) at LT increased by 5 and 34%, respectively (P < 0.05). The mild exercise training improves S(G) measured 16 h after the last training session, from 0.018 +/- 0.002 to 0.024 +/- 0.001 min(-1) (P < 0.05). The elevated S(G) after exercise training tends to be maintained regardless of detraining for 1 week (0.023 +/- 0.002 min(-1), P = 0.09). S(I) measured at 16 h after the last training session significantly increased (pre-exercise training, 13.9 +/- 2.2; 16 h, 18.3 +/- 2.4, x10(-5). min(-1). pmol/l(-1), P < 0.05) and still remained elevated 1 week after stopping the training regimen (18.6 +/- 2.2, x10(-5). min(-1). pmol/l(-1), P < 0.05). CONCLUSIONS: Mild exercise training at LT improves S(G) in healthy men with no change in the body composition. Improving not only S(I) but also S(G) through mild exercise training is thus considered to be an effective method for preventing glucose intolerance.

Remnant-like particle cholesterol, triglycerides, and insulin resistance in nonobese Japanese type 2 diabetic patients.

OBJECTIVE: The aim of the study was to investigate the relationships between remnant-like particle (RLP) cholesterol, triglycerides, and insulin resistance in nonobese Japanese type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A total of 86 nonobese Japanese type 2 diabetic patients (72 men and 14 women, aged 40-83 years, BMI 20.1-26.6 kg/m2) were studied. BMI, HbA1c levels, and fasting concentrations of plasma glucose, serum lipids (RLP cholesterol, total cholesterol, HDL cholesterol, and triglycerides), and serum insulin were measured. Insulin resistance was estimated by the homeostasis model assessment (HOMA-IR). The subjects were divided into two groups according to the value of HOMA-IR. Values >2.5 were indicative of the insulin-resistant state, and values <2.5 were indicative of the insulin-sensitive state. RESULTS: The insulin-resistant group had significantly higher RLP cholesterol and triglyceride levels and lower HDL cholesterol levels compared with the insulin-sensitive group. Univariate regression analysis showed that insulin resistance was positively correlated with BMI (r = 0.254, P = 0.019), HbA1c levels (r = 0.278, P = 0.011), RLP cholesterol levels (r = 0.315, P = 0.004), and triglyceride levels (r = 0.332, P = 0.002) and was negatively correlated with HDL cholesterol levels (r = -0.301, P = 0.006) in our diabetic patients. Multiple regression analysis showed that insulin resistance was independently associated with serum triglyceride levels, which explained 13.5% of the variability of insulin resistance in our nonobese Japanese type 2 diabetic patients. CONCLUSIONS: These results indicate that 1) nonobese Japanese type 2 diabetic patients with insulin resistance are characterized by high RLP cholesterol and triglyceride levels, and low HDL cholesterol levels; and 2) the level of serum triglycerides is an independent predictor of insulin resistance in these patients.

Effect of resistance exercise training on bone formation and resorption in young male subjects assessed by biomarkers of bone metabolism.

We studied the effects of high intensity resistance exercise training on bone metabolism in 17 young adult Oriental males (23-31 years) by measuring sensitive biomarkers of bone formation and resorption. The subjects were assigned to a training group and a sedentary group. The training group followed a weight training program three times per week for 4 months. In the training group, serum osteocalcin concentration and serum bone-specific alkaline phosphatase activity were significantly increased within the first month after the beginning of resistance exercise training, and the elevated levels remained throughout the training period, while there was no significant change in plasma procollagen type-I C-terminal concentration. Urinary deoxypyridinoline excretion was transiently suppressed and returned to the initial value but was never stimulated during the 4 months. These results suggest that the resistance exercise training enhanced bone formation without prior bone resorption. In the sedentary group, there was no significant difference in bone metabolic markers except plasma procollagen type-I C-terminal, which continuously decreased during the experimental period. There were no significant changes in total and regional bone mineral density in either group. In conclusion, (1) resistance exercise training increased markers of bone formation, while it transiently suppressed a marker of bone resorption, and (2) such adaptive changes of bone metabolism to resistance exercise training occurred during the early period of the training, before changes in bone density were observable through densitometry.

High-dose but not low-dose dexamethasone impairs glucose tolerance by inducing compensatory failure of pancreatic beta-cells in normal men.

The diabetogenic effects of glucocorticoids appear to be dose dependent. To determine the effects of different doses of dexamethasone on glucose metabolism, we performed frequently sampled intravenous glucose tolerance tests in 20 healthy young men. Glucose kinetics were analysed by the minimal model. Ten subjects received low-dose dexamethasone (2 mg/day) for 3 days, and the other 10 received high-dose dexamethasone (6 mg/day) for 3 days. The rate of glucose disappearance (KG) did not decrease in the low-dose group (2.46 +/- 0.20 to 2.19 +/- 0.11% min-1, P = 0.35). In contrast, KG in the high-dose group did decrease significantly (2.43 +/- 0.29 to 1.81 +/- 0.11% min-1, P < 0.05). The factor responsible for the decline in KG in the high-dose group was not glucose effectiveness because these values did not change in either group. The insulin sensitivity decreased significantly, by 46% in the low-dose group and 69% in the high-dose group [17.1 +/- 2.7 to 9.2 +/- 1.5 and 18.5 +/- 3.7 to 5.8 +/- 0.9 x 10(-5) min-1 (pmol/L)-1, P < 0.001 and P < 0.01, respectively]. The insulin area (0-20 min) increased significantly, by 104% in the low-dose group and 114% in the high-dose group [3412.6 +/- 609.7 to 6972.7 +/- 1450.1 and 4086.7 +/- 864.5 to 8750.0 +/- 1451.6 (pmol/L) min, P < 0.01 and P < 0.01, respectively]. Insulin sensitivity x insulin area as an estimate of insulin-dependent glucose uptake and insulin's action to suppress hepatic glucose production decreased significantly in the high-dose group (0.588 +/- 0.112 to 0.441 +/- 0.073, P < 0.05), but did not change in the low-dose group (0.436 +/- 0.050 to 0.484 +/- 0.032, P = 0.77). Therefore, the decline in KG in the high-dose group may be associated with the compensatory failure of pancreatic beta-cells against for the insulin resistance.

Troglitazone ameliorates insulin resistance in patients with Werner's syndrome.

Insulin resistance in Werner's syndrome (WS) is probably due to defective signaling distal to the insulin receptor. To analyze the metabolic effects of troglitazone (TRO) in these patients, we performed frequently sampled iv glucose tolerance tests. Glucose kinetics were analyzed by the minimal model. Five patients with WS (mean age, 41.2 yr; body mass index, 17.0 kg/m2) were treated with TRO (400 mg/day) for 4 weeks. Each subject underwent a 75-g OGTT and frequently sampled iv glucose tolerance tests. Treatment reduced the area under the curve of glucose and insulin in the OGTT by 26% and 43%, respectively. Glucose tolerance, as manifested by the glucose disappearance rate improved significantly (1.36 +/- 0.16 to 1.94 +/- 0.30%/min; P < 0.05). Although the first phase insulin secretion was unchanged, insulin sensitivity and glucose effectiveness increased significantly [0.47 +/- 0.11 to 1.38 +/- 0.37 x 10(-4) min/pmol.L (P < 0.05) and 1.72 +/- 0.17 to 2.52 +/- 0.24 x 10(-2) min-1 (P < 0.05), respectively]. However, treatment did not change glucose effectiveness at zero insulin. In patients with WS, TRO ameliorates glucose intolerance mediated by increased insulin sensitivity as well as glucose effectiveness, as assessed by minimal model analysis. TRO may modulate the postreceptor signaling component and be a clinically useful regimen for the treatment of patients with the intracellular insulin signaling defect.

Insulin sensitivity during very-low-calorie diets assessed by minimal modeling.

The time course of plasma glucose, insulin, and C-peptide after intravenous glucose (300 mg/kg body wt) injection was analyzed with minimal model approach in nine normal females and seven obese females. Glucose tolerance, estimated by glucose assimilation coefficient (KG), was positively correlated with glucose effectiveness (SG), but not correlated with peripheral insulin sensitivity (SI) in obese females as well as normal females. These factors were estimated before and after weight loss with 1.8-MJ (420-kcal) very-low-calorie diets (VLCDs) or with 2.5-3.3-MJ (600-800-kcal) low-calorie diets in two obese subjects. KG and glucose effectiveness decreased after acute weight loss with VLCD, although insulin sensitivity increased. Weight loss with low calorie diets resulted in improvement of KG and glucose effectiveness. These results suggest that a significant amount of glucose is taken up through insulin-independent mechanisms during the intravenous glucose tolerance test (ivGTT) in these subjects. This insulin-independent glucose uptake may be an important determinant of the fate of glucose in obese females as well as normal females.

Paradoxical adaptation of mature radius to unilateral use in tennis playing.

The positive effects of physical activity on human bone mass have been well documented in many cross-sectional studies comparing athletes with sedentary controls as well as in longitudinal follow-up. By applying peripheral quantitative computed tomography (pQCT), which has the advantage of measuring volumetric bone mineral density (BMD) and the ability to distinguish among trabecular and cortical components, it was demonstrated that cortical BMD of the dominant arm was not greater than that of the nondominant arm. Cortical drift toward the periosteal direction and an increase in cortical thickness resulted in an improvement of mechanical characteristics of the playing arm's midradius. An improvement in the mechanical properties of young adult bone in response to long-term exercise was therefore related to geometric adaptation, but not to an increase in BMD. The manner in which the recruitment and function of bone cells are coordinated differs between the growing and the nongrowing skeleton. In the former, modeling is the dominant mode, and in the latter it is remodeling. In the present study, the side-to-side difference of 92 middle-aged female tennis players who initiated training after bone had matured was analyzed by pQCT. The side-to-side difference detected suggested a paradoxical adaptation of the mature radius to unilateral use during tennis playing, and that tennis playing after bone had matured did not stimulate cortical drift in the periosteal direction, unlike that seen in young subjects. Unexpectedly, the cross-sectional areas (periosteal and endocortical area) of the radius were smaller in the dominant arm than in the nondominant arm in the middle-aged female players. The findings suggest that unilateral use of the arm after the third decade of life suppresses age-related changes in bone geometry.

Hyperresponsiveness of cough receptors in patients with bronchial asthma.

The hyperresponsiveness of cough receptors was evaluated using the acetic acid inhalation test in healthy adults, patients with bronchial asthma, and children with or without cough. The concentration of acetic acid inducing cough was more than 20% in all 16 healthy adults and 18 children in the control group. There were two groups of asthmatic patients: Those in group 1 showed normal response to more than 20% acetic acid (n = 46), and those in group 2 showed a sensitive reaction to less than 10% (n = 11). Mean age was 9.0 +/- 4.2 years in group 1 and 15.1 +/- 7.6 years in group 2 (statistical significance, P less than .001). Six of 11 asthmatic patients in group 2 were classified as nonallergic asthmatics, whereas only five of 46 patients in group 1 were nonallergic (P less than .01). Bronchoconstriction was not induced in any case, in spite of the production of cough. It is suggested that the hyperresponsiveness of individual cough receptors without the stimulation of irritant receptors be evaluated.

Attenuation of tachykinin-induced airflow obstruction and microvascular leakage in immature airways.

1. To study the effect of maturation on substance P (SP)- and neurokinin A (NKA)-induced airflow obstruction and airway microvascular leakage (MVL), we have measured changes in both lung resistance (RL) and extravasation of Evans blue dye in anaesthetized immature (aged 14 +/- 1 days) and adult guinea-pigs (aged 80 +/- 3 days). 2. RL and its recovery after hyperinflation at 5 min were measured for 6 min after i.v. SP (0.2, 1 and 30 nmol kg-1), NKA (1 and 10 nmol kg-1) or vehicle (0.9% NaCl). After measurement of RL, MVL in trachea, main bronchi and intrapulmonary airways was also examined. 3. The order of potency in inducing airflow obstruction did not change with age (NKA > SP) but immature animals required a larger dose of SP or NKA than adults to cause a significant increase in RL. 4. The order of potency in inducing airway microvascular leakage was SP > NKA in both immature and adult animals. The amount of extravasated dye after SP was significantly less in immature airways, especially in central airways. 5. Phosphoramidon (2.5 mg kg-1), a neutral endopeptidase (NEP) inhibitor, significantly increased RL after 0.2 nmol kg-1 SP only in adult airways. Phosphoramidon enhanced the dye extravasation after 0.2 nmol kg-1 SP in both immature and adult airways with a significantly greater amount of dye in adult animals, suggesting that mechanisms other than changes in NEP activity may be responsible for this age-related difference. 6. RL after hyperinflation following SP was not correlated with the degree of extravasation of Evans blue dye in immature animals, whereas it was closely correlated in adult animals. 7. SP and NKA may be less potent in causing both bronchoconstriction and microvascular leakage in immature airways. 8. Airway oedema caused by microvascular leakage may contribute less in immature airways to airflow obstruction after SP or NKA.

Differential effects of phosphoramidon on neurokinin A- and substance P-induced airflow obstruction and airway microvascular leakage in guinea-pig.

1. The effects of the inhaled neuropeptides, neurokinin A (NKA) and substance P (SP) on lung resistance (RL) and airway microvascular permeability were studied in anaesthetized guinea-pigs. 2. Single doses of inhaled NKA (3 x 10(-5), 1 x 10(-4), 3 x 10(-4) M; 45 breaths) and SP (1 x 10(-4), 3 x 10(-4), 1 x 10(-3); 45 breaths) caused a dose-dependent increase in both RL and airway microvascular leakage, assessed as extravasation of the albumin marker, Evans blue dye. 3. NKA at 1 x 10(-4) and 3 x 10(-4) M resulted in a significantly higher increase in RL than SP at the same doses. 4. Inhaled SP (3 x 10(-4) M; 45 breaths) caused significantly higher Evans blue dye extravasation in main bronchi and proximal intrapulmonary airways compared to the same dose of NKA. 5. Pretreatment with the specific inhibitor of neural endopeptidase (NEP24.11), phosphoramidon, caused an approximately 100 fold leftward shift of the RL responses to inhaled NKA and SP. 6. Phosphoramidon significantly potentiated both NKA- and SP-induced airway microvascular leakage at proximal intrapulmonary airways, but not at any other airway level. 7. Inhibition of NEP24.11 potentiate both the SP- or NKA-induced airflow obstruction to a larger extent than the induced airway microvascular leakage, suggesting that NEP24.11 is more important in the modulation of the airflow obstruction observed after these mediators.

Difference in airway reactivity in children with atopic vs nonatopic asthma.

STUDY OBJECTIVE: To examine the difference in the mechanisms of bronchial hyperresponsiveness (BHR) in nonatopic asthma and in atopic asthma, we studied bronchial reactivity against nonspecific stimuli in children with atopic asthma and nonatopic asthma. DESIGN AND PARTICIPANTS: Fourteen children with nonatopic asthma, 24 children with atopic asthma, and 20 age-matched controls participated in this study. MEASUREMENTS: Inhalation challenge was performed by administering progressively doubling doses of methacholine with a continuous inhalation provocation method. The speed of bronchoconstriction to methacholine (Sm) and the speed of reversal of bronchoconstriction to methacholine after inhalation of a beta2-agonist (r-Sm), which was considered to represent the effect of the beta2-agonist, were calculated from the dose-response curve. RESULTS: The value of Sm was higher in the nonatopic asthma group than in the atopic asthma group and the control group. The value of r-Sm was also higher in the nonatopic asthma group than in the atopic asthma group, but did not differ from that in the control group. CONCLUSION: These results indicate that bronchial reactivity against methacholine and the beta2-agonist was greater in nonatopic asthma than in atopic asthma, and that the mechanism of BHR in children with nonatopic asthma may differ from that in children with atopic asthma.

Relationship between bronchial hyperresponsiveness and development of asthma in wheezy infants.

STUDY OBJECTIVES: To evaluate the relationship between bronchial hyperresponsiveness (BHR) in infants with wheezing and the subsequent development of asthma. INTERVENTION: Bronchial reactivity to inhaled methacholine (BRm) during the infantile period was studied using the transcutaneous partial pressure of oxygen (tcPO(2)) method. Children were followed long-term for the development of asthma. PATIENTS: Fourteen children with bronchiolitis (mean age, 0.7 years) and 48 with wheezy bronchitis (mean age, 2.3 years) were enrolled. For comparison, 40 children with asthma (mean age, 4.6 years) and 27 healthy control subjects without chronic respiratory disease (mean age, 2.7 years) were studied. MEASUREMENTS: Consecutive doses of methacholine were doubled until a 10% decrease in tcPO(2) from baseline was reached. The cumulative dose of methacholine (Dmin) at the inflection point of tcPO(2) (Dmin-PO(2)) was recorded. RESULTS: During > 10 years of follow-up, seven patients with bronchiolitis developed asthma and all patients in the higher BRm set developed asthma, compared with none in the lower BRm set. In the wheezy bronchitis group, Dmin-PO(2) values in the 32 patients who developed asthma were lower than those in patients who had not developed asthma (p < 0.001). CONCLUSIONS: We concluded that there is a tendency for infants with a clinical diagnosis of bronchiolitis or wheezy bronchitis and who show BHR in the infantile period to develop asthma. The presence of increased BHR after infantile respiratory diseases associated with wheezing may be a prelude to the development of childhood asthma.

Roxithromycin reduces the degree of bronchial hyperresponsiveness in children with asthma.

We evaluated the effects of a new semisynthetic macrolide antibiotic, roxithromycin, on the bronchial hyperresponsiveness to histamine in children with asthma. Twelve hospitalized asthmatic children, aged 11 to 15 years (mean age, 12.9 years), were enrolled in this study. They were treated with 150 mg of roxithromycin once a day orally for 8 weeks without any side effects. The PC20 value 4 or 8 weeks after the administration of roxithromycin increased significantly over the initial values (p < 0.05, p < 0.01, respectively). No significant change was observed in serum theophylline concentrations during this study. Serum cortisol level in the morning did not change after the administration of roxithromycin for 4 weeks. These results suggest that administration of roxithromycin may act favorably in the treatment of childhood asthma.