Circadian rhythm of serum cortisol after repeated inhalation of the new topical steroid ciclesonide

The new inhalative glucocorticoid ciclesonide which is activated in lung to a more potent metabolite was hypothesized to have low risk for systemic and local side-effects in man. Therefore, a placebo-controlled, randomized, double-blind, four-period, change-over equivalence study in 12 healthy male volunteers (age 21-28 yr, body weight 62-90 kg) was conducted to assess the influence of three dosage regimens (800 microg in the morning, 800 microg in the evening, 400 microg twice daily for 7 d, metered inhalers) on the circadian time serum cortisol rhythm. RESULTS: Serum cortisol showed the typical circadian rhythm. The geometric mean of the 24-h mesor (AUC((0-24 h))/24 h) was 7.22 microg/dl for placebo, 6.75 microg/dl for the 800 microg ciclesonide morning dose, 7.08 microg/dl for the 800 microg evening dose, and 6.75 microg/dl for 400 microg ciclesonide inhaled twice daily. Because there was also no influence on cortisol amplitude and acrophase (time of maximum), the profiles after ciclesonide were equivalent to the placebo control. The small differences were considered not to be of clinical significance. In conclusion, inhaled ciclesonide in daily doses of 800 microg for 7 d is without clinically relevant effects on the hypothalamic-pituitary-adrenal axis independent of the time of administration.     

Pharmacokinetic evaluation of gepirone immediate-release capsules and gepirone extended-release tablets in healthy volunteers

In an open-label, randomized, crossover study, the pharmacokinetics of gepirone immediate-release (gepirone-IR) and different gepirone extended-release (gepirone-ER, types 1, 2, and 3) formulations were compared. Mean maximum concentration (C(max)) was 6.1 ng/mL for gepirone-IR, which was statistically significantly (p < 0.05) higher than that of two of the ER-formulations (3.7 and 3.6 ng/mL, respectively, for types 2 and 3). The mean time to C(max) (mean T(max)) was 1.3 h for gepirone-IR and ranged from 4.8 to 5.6 h for gepirone-ER. The mean area under the curve of concentration versus time (AUC(30)) was similar and not statistically significantly different between gepirone-IR and ER. For the 1-(2-pyrimidinyl)-piperazine (1-PP) metabolite, C(max) and AUC(30) were statistically significantly (p < 0.05) higher and T(max) was lower for gepirone-IR compared with ER. No significant differences in bioavailability were observed between the IR and the three gepirone-ER formulations, indicating that any of the once-daily gepirone-ER formulations could be substituted for gepirone-IR. This study revealed a reduction in the peak-to-trough fluctuations in plasma gepirone concentrations and maintenance of consistent plasma levels with gepirone-ER.     

The phosphodiesterase 4 inhibitor roflumilast is effective in the treatment of allergic rhinitis

BACKGROUND: The beneficial effects of phosphodiesterase 4 (PDE4) inhibitors in allergic asthma have been shown in previous preclinical and clinical studies. Because allergic rhinitis and asthma share several epidemiologic and pathophysiologic factors, PDE4 inhibitors might also be effective in allergic rhinitis. OBJECTIVE: The main objective of this study was to investigate the efficacy of oral roflumilast (500 microg/day) in allergic rhinitis. METHODS: In a randomized, placebo-controlled, double-blinded, crossover study, 25 subjects (16 male, 9 female; median age, 28 years) with histories of allergic rhinitis but asymptomatic at screening received roflumilast (500 microg once daily) and placebo for 9 days each with a washout period of at least 14 days in between treatment periods. In each of the treatment periods, controlled intranasal allergen provocation with pollen extracts was performed daily beginning the third day of treatment, each time approximately 2 hours after study drug administration. Five and 30 minutes after each allergen provocation, rhinal airflow was measured by means of anterior rhinomanometry and the subjective symptoms obstruction, itching, and rhinorrhea were assessed by means of a standardized visual analog scale. RESULTS: Rhinal airflow improved almost consistently during the 9 days of roflumilast treatment, and it was significantly higher at study day 9 on roflumilast in comparison with placebo, a result also found for itching and rhinorrhea. With respect to the subjective obstruction score, a significant difference in comparison with placebo could be demonstrated within 4 days. CONCLUSION: This study shows that a PDE4 inhibitor, roflumilast, effectively controls symptoms of allergic rhinitis. Thus PDE4 inhibitors might be a future treatment option not only in allergic asthma but also in allergic rhinitis or the combination of the 2 diseases.     

Delay estimation for cortico-peripheral relations

In neurophysiology, time delays between concurrently measured time series are usually estimated from the slope of a straight line fitted to the phase spectrum. We point out that this estimate is valid only in the case in which, one signal is a mere time-delayed copy of the other one. We present a procedure for delay estimation that applies to a much wider class of systems with nontrivial phase spectrum like for example lowpass filters. The procedure is based on the Hilbert transform relation between the phase of a linear system and its log gain. The Hilbert transform relation is nonlocal in frequency space, a fact that limits its applicability to experimental data. We explore these limits, and demonstrate that the method is applicable to neurophysiological time series. We present the successful application of the Hilbert transform behavior method to concurrently recorded epicortical brain activity and peripheral tremor. We point out and explain physiologically unreasonable delay estimates given by the traditional method. Finally, we discuss the assumptions underlying the applicability of the Hilbert transform method in the neuroscience context.     

Clinical Predictors of Sleep Apnea in Patients Undergoing Bariatric Surgery

Background: Sleep apnea is a frequent and unappreciated condition of morbidly obese patients. If unrecognized it could lead to significant postoperative complications. A clinical tool to assess the severity of sleep apnea is not available.We prospectively determined whether the Epworth Sleepiness Scale (ESS) or body mass index (BMI) predict the severity of sleep apnea in morbidly obese patients. Methods: 66 consecutive patients evaluated for bariatric surgery from June to November 1999 were examined and prospectively administered a health questionnaire including the ESS. Patients with an ESS ≥ 6 were referred for polysomnography with calculation of Respiratory Disturbance Index (RDI). Sleep apnea was graded as mild (RDI 6-20), moderate (RDI 21-40) and severe (RDI>40). Clinical variables such as BMI and ESS score were compared using regression analysis. Data are mean ± SEM. Results: 4 men and 23 women (27/66) who scored >6 on the ESS completed a sleep study. Mean ESS was 13 ± 4.5. Sleep apnea was mild in 13 patients, moderate in 7, severe in 6, and absent in 1. Mean age was 43 ± 9.5 years. BMI was 52 ± 10 kg/m². Linear regression analysis did not demonstrate correlation between ESS score and severity of sleep apnea (r²=0.03, p>0.05). Multiple regression analysis demonstrated no correlation between BMI, patient snoring, and RDI score. Conclusions: Sleep apnea is frequent in candidates screened for bariatric surgery. ESS is a useful tool to investigate daytime sleepiness and other manifestations of sleep apnea. However, the ESS does not predict the severity of sleep apnea. Clinical suspicion of sleep apnea should prompt polysomnography.     

Effect of vegetable and carotenoid consumption on aberrant crypt multiplicity, a surrogate end-point marker for colorectal cancer in azoxymethane-induced rats

Epidemiological studies indicate that increased vegetable consumption reduces the risk of colorectal cancer mortality. In the present study we have investigated the effect of consumption of standard diets supplemented with freeze-dried vegetables (peas, spinach, sprouts and broccoli) and carotenoids (all-trans beta-carotene and palm oil carotenoid extract) on surrogate end-point markers for colorectal cancer in an azoxymethane-induced rat model. Mean aberrant crypt multiplicity was reduced (19%) by the pea-supplemented diet only (P < 0.05). The vegetable-induced effect was more apparent in aberrant crypt foci with higher multiplicity. Intervention with diets supplemented with peas, spinach, sprouts and a mix of all vegetables reduced the number of foci with >2 aberrant crypts/focus by 37, 26, 23 and 26%, respectively (P < 0.05). Even more pronounced effects were observed in foci with >3 aberrant crypts/focus, with reductions of approximately 50% in the pea and spinach intervention groups. All-trans beta-carotene and palm oil-derived carotenoids, supplied at similar doses to those expected in the vegetable diets, inhibited ACM only marginally. Aberrant crypt foci formation in groups fed a sprout-supplemented diet prior to or following azoxymethane treatment was similar, indicating that this effect is due to inhibition of promotion rather than initiation of colorectal carcinogenesis. Vegetable and carotenoid consumption did not affect in situ proliferation of colonic crypt cells, as assessed by semi-automated image analysis of bromodeoxyuridine (BrdU)-positive nuclei. BrdU-negative nuclei of colonic crypt cells were reduced slightly in the combined vegetable groups, as compared with the control (P < 0.05). These data: (i) are in line with epidemiological evidence regarding beneficial effects of vegetable consumption on colorectal carcinogenesis; (ii) indicate that consumption of several types of vegetables inhibits early post-initiation events in colorectal carcinogenesis; (iii) suggest that the vegetable-induced effect is more pronounced in advanced lesions; (iv) indicate that the carotenoid content of the vegetables (alpha- and beta-carotene) contributes only marginally to the vegetable-induced effects.     

Community‐Based Practice Experience of Unsuspected Breast Magnetic Resonance Imaging Abnormalities Evaluated With Second‐Look Sonography

Objective. The purpose of this study was to assess the utility and efficacy of second‐look breast sonography in the evaluation of abnormalities identified on presurgical breast magnetic resonance imaging (MRI) examinations. Methods. A retrospective review was performed of 152 presurgical breast MRI examinations having 196 unsuspected abnormalities to identify findings that underwent subsequent breast sonography. Eligible examinations had a suspicious abnormality identified on presurgical MRI and documentation of the location and size of the finding on MRI and subsequent second‐look sonography. Fourteen examinations not meeting the criteria were excluded, with 182 abnormalities remaining. Patient medical records were reviewed. Results. Seventy percent (128 of 182) of breast MRI lesions were visible at second‐look sonography; 30% (54 of 182) were sonographically occult. Ninety‐five percent (121 of 128) of sonographically visible abnormalities underwent breast biopsy. Pathologic examinations of sampled sonographically visible lesions revealed 39 cancers, 9 high‐risk lesions, 72 benign lesions, and 1 lesion not specified at surgery; 23% (9 of 128) of cancers were in the contralateral breast. Fifty‐four lesions were sonographically occult. Needle biopsy was performed for 93% (50 of 54) of occult lesions, revealing 8 cancers, 1 high‐risk lesion, and 41 benign lesions; 3 of the benign lesions did not have sufficient pathologic specimens but were benign at follow‐up. Magnetic resonance imaging guidance was used in 86% (43 of 50) of these biopsies. One contralateral cancer was identified in the sonographically occult subset. Of the 182 lesions that underwent second‐look sonography, 20% (36 of 182) had a change in management. Conclusions. Second‐look sonography has value in the evaluation of abnormalities found on breast MRI. We found enhancements in 70% (128 of 182), yielding 39 cancers.     

“When Looking Back on My Past Life I Regret…”: Retrospective Regret in the Second Half of Life

ABSTRACT

The study investigated the frequency, themes, and attributions for significant regrets in a random probability sample of 3,917 German and Dutch nationals between the ages of 40 and 85 years. It was found that 14% did not have any regrets in spontaneous memory, and that this increased with the age of the respondents. With respect to mentioned regrets, older people, women, and those living in the former East Germany were more likely to recall externally attributed events; younger participants, men, West Germans, and the Dutch recalled more internally attributed events. Largely, memories related to 4 major themes: (a) mistakes, behavior, and bad decisions in general; (b) hard times; (c) social relationships; and (d) missed educational opportunities. The importance of these themes, however, varied according to age, gender, and regional belonging. Differences in the kind of attribution and in the centrality of themes are discussed in terms of lifespan theory, death preparation, and cultural differences.