Direct in vitro and in vivo demonstration of muscarinic receptor binding by the novel radioligand, [3H]5-hydroxymethyltolterodine,in the bladder and other tissues of rats

In vitro and in vivo binding sites of [³H]-labeled 5-hydroxymethyltolterodine (5-HMT), a new radioligand for labeling muscarinic receptors in rat tissues were characterized. Specific [³H]5-HMT binding in rat tissues was saturable and of high affinity in each tissue. The dissociation constant (K_d) was significantly lower in bladder and heart than in submaxillary gland. Significant levels of in vivo specific [³H]5-HMT binding by intravenous injection of the radioligand were detected in tissues, except for cerebral cortex. Thus, [³H]5-HMT was shown to specifically label muscarinic receptors in rat tissues, suggesting a useful radioligand for labeling muscarinic receptors with high affinity.     

Cardiac output during exercise: A comparison of four methods

Several techniques assessing cardiac output (Q) during exercise are available. The extent to which the measurements obtained from each respective technique compares to one another, however, is unclear. We quantified Q simultaneously using four methods: the Fick method with blood obtained from the right atrium (Q_Fick‐M), Innocor (inert gas rebreathing; Q_Inn), Physioflow (impedance cardiography; Q_Phys), and Nexfin (pulse contour analysis; Q_Pulse) in 12 male subjects during incremental cycling exercise to exhaustion in normoxia and hypoxia (F_iO₂ = 12%). While all four methods reported a progressive increase in Q with exercise intensity, the slopes of the Q/oxygen uptake (VO₂) relationship differed by up to 50% between methods in both normoxia [4.9 ± 0.3, 3.9 ± 0.2, 6.0 ± 0.4, 4.8 ± 0.2 L/min per L/min (mean ± SE) for Q_Fick‐M, Q_Inn, Q_Phys and Q_Pulse, respectively; P = 0.001] and hypoxia (7.2 ± 0.7, 4.9 ± 0.5, 6.4 ± 0.8 and 5.1 ± 0.4 L/min per L/min; P = 0.04). In hypoxia, the increase in the Q/VO₂ slope was not detected by Nexfin. In normoxia, Q increases by 5–6 L/min per L/min increase in VO₂, which is within the 95% confidence interval of the Q/VO₂ slopes determined by the modified Fick method, Physioflow, and Nexfin apparatus while Innocor provided a lower value, potentially reflecting recirculation of the test gas into the pulmonary circulation. Thus, determination of Q during exercise depends significantly on the applied method.     

Phenotype classification using the combination of lung sound analysis and fractional exhaled nitric oxide for evaluating asthma treatment

Background

We report the utility of combining lung sound analysis and fractional exhaled nitric oxide (FeNO) for phenotype classification of airway inflammation in patients with bronchial asthma.We investigated the usefulness of the combination of the expiration-to-inspiration sound power ratio in the mid-frequency range (E/I MF) of 200–400 Hz and FeNO for comprehensively classifying disease type and evaluating asthma treatment.

Relationship between stimulated prolactin release from GH cells and cyclic AMP degradation and formation

We have studied the relationship between the prolaction (PRL) release induced by thyroliberin (TRH) and theophylline and the formation and inactivation of adenosine 3', 5'-cyclic monophosphate (cyclic AMP) in cultured rat-pituitary cells (GH3 cells). TRH, which stimulated prolactin release, increased cyclic AMP formation and stimulated transiently both the low- and high-Km cyclic phosphodiesterases. The maximal effect on the phosphodiesterase was observed at 30 mM TRH. The stimulatory effect of TRH on the activity of the cyclic AMP phosphodiesterases was duplicated by incubation of the cells with cyclic AMP (2-10 mM). In washed particulate GH3 cell fractions, TRH increased the adenylyl cyclase activity up to 180%. Treatment of GH3 cells with theophylline stimulated the release of PRL and inhibited cyclic AMP degradation probably leading to the measured increase in cellular concentrations of the nucleotide. The effects of TRH and theophylline on cellular cyclic AMP concentrations and on PRL release were additive. There was a positive correlation between PRL release and cellular cyclic AMP concentration (r = 0.97). The elevations observed in cellular cyclic AMP concentration after TRH treatment are due to increased formation which in turn leads to phosphodiesterase activation. Therefore, cyclic AMP formation appears to be an intermediary step in the stimulus-secretion coupling caused by the tripeptide.     

Redefining Diastolic Dysfunction Grading: Combination of E/A ≤0.75 and Deceleration Time >140 ms and E/ε′ ≥10

ObjectivesThis study sought to examine left atrial (LA) mechanics and the prognostic impact of patients with echocardiographic findings of E/A ratio ≤0.75, deceleration time (DcT) of mitral E-wave >140 ms, but E/ε′ ≥10.BackgroundTraditional diastolic dysfunction (DD) grading system could not classify every patient into a specific group. We considered the group of patients with E/A ≤0.75, DcT >140 ms, but E/ε′ ≥10 (proposed new DD grade) as a new group in the DD grading system.MethodsA total of 1,362 consecutive patients were stratified according to the new DD grading system, and the LA volumes, strain, and strain rates were measured by 2-dimensional speckle-tracking analysis. All patients were followed up to determine cardiac death and major adverse cardiac events.ResultsAn E/A ≤0.75, DcT >140 ms, but E/ε′ ≥10 was observed in 227 patients (17%). LA volumes in patients with the new DD grade were between those of the impaired relaxation group and the pseudonormal group. LA strain of the new DD grade was similar to that of the pseudonormal group, whereas LA booster function was preserved as in the impaired relaxation group. During a mean follow-up of 3.0 ± 1.1 years, 25 patients had cardiac death and 61 had major adverse cardiac events. Event-free survival for major adverse cardiac events of the new DD grade was worse than that of the impaired relaxation group but similar to that of the pseudonormal group.ConclusionsThe new DD grade is frequently observed and has a prognosis similar to that of the pseudonormal group but significantly worse than that of the impaired relaxation group. However, LA booster function was maintained at the expense of LA volume enlargement. Thus, the new grade should be a distinct entity for routine DD grading.     

An inactive lifestyle and low physical fitness are associated with functional somatic symptoms in adolescents. The TRAILS study

Objective

An inactive lifestyle has been associated with functional somatic symptoms (FSS), but findings are contradictory. Moreover, mediating factors in this relationship are unclear. We examined whether low physical activity was related to FSS in adolescents, and whether this association was mediated by low physical fitness.

Methods

This study was part of the Dutch longitudinal cohort study TRAILS, in which 1816 adolescents (mean age 16.3 years, SD 0.7) participated during the third (T3) and 1881 (mean age 19.1 years, SD 0.6) during the fourth (T4) assessment waves. Adolescents' exercise and sedentary behavior levels and the number of FSS were assessed by questionnaires at T3 and T4. Physical fitness (VO₂Max) was determined for 687 adolescents by a shuttle run test at T3. The association between physical activity and FSS was examined with bootstrapped linear regression analyses, adjusted for smoking and gender. In addition, bootstrapped mediation analyses were performed.

Results

A lack of exercise (b = 0.05, bootstrap 95%-CI: 0.01 to 0.09) and high sedentary behavior (b = 0.10, bootstrap 95%-CI: 0.06 to 0.14) at T3 were positively associated with FSS at T3. Since no longitudinal effects were found, shared associations were tested instead of mediation. The associations between a lack of exercise and FSS, and sedentary behavior and FSS were shared with physical fitness (b = 0.01, bootstrap 95%-CI: 0.010.02. and b = 0.03, bootstrap 95%-CI: 0.010.05).

Conclusion

An inactive lifestyle is associated with increased FSS in adolescents. Only part of this association is shared with low physical fitness.