Highly potent 4-amino-indolo[2,3-c]azepin-3-one-containing somatostatin mimetics with a range of sst receptor selectivities

The synthesis, biological evaluation, and conformational analysis of 4-amino-indolo[2,3-c]azepin-3-one (Aia)-containing SRIF mimetics are reported. Different subtype selectivities are observed depending on the N- and C-terminal substituents of the D-Aia-Lys dipeptide mimetic. An sst(5)-selective analogue with subnanomolar binding affinity was obtained that is the most potent agonist reported to date. A nonselective mimetic with high potency was also identified. This study allows a better definition of the bioactive conformation of the essential D-Trp side chain in the somatostatin pharmacophore.

Adaptive rather than non-adaptive evolution of Mimulus guttatus in its invasive range

Adaptive and non-adaptive evolutionary processes are likely to play important roles in biological invasions but their relative importance has hardly ever been quantified. Moreover, although genetic differences between populations in their native versus invasive ranges may simply reflect different positions along a genetic latitudinal cline, this has rarely been controlled for. To study non-adaptive evolutionary processes in invasion of Mimulus guttatus, we used allozyme analyses on offspring of seven native populations from western North America, and three and four invasive populations from Scotland and New Zealand, respectively. To study quantitative genetic differentiation, we grew 2474 plants representing 17 native populations and the seven invasive populations in a common greenhouse environment under temporarily and permanently wet soil conditions. The absence of allozyme differentiation between the invasive and native range indicates that multiple genotypes had been introduced to Scotland and New Zealand, and suggests that founder effects and genetic drift played small, if any, roles in shaping genetic structure of invasive M. guttatus populations. Plants from the invasive and native range did not differ in phenology, floral traits and sexual and vegetative reproduction, and also not in plastic responses to the watering treatments. However, plants from the invasive range produced twice as many flower-bearing upright side branches than the ones from the native populations. Further, with increasing latitude of collection, vegetative reproduction of our experimental plants increased while sexual reproduction decreased. Plants from the invasive and native range shared these latitudinal clines. Because allozymes showed that the relatedness between native and invasive populations did not depend on latitude, this suggests that plants in the invasive regions have adapted to the local latitude. Overall, our study indicates that quantitative genetic variation of M. guttatus in its two invasive regions is shaped by adaptive evolutionary processes rather than by non-adaptive ones. (C) 2007 Gesellschaft fur Okologie. Published by Elsevier GmbH. All rights reserved.

Prevalence and time course of acute mountain sickness in older children and adolescents after rapid ascent to 3450 meters

OBJECTIVE: Acute mountain sickness is a frequent and debilitating complication of high-altitude exposure, but there is little information on the prevalence and time course of acute mountain sickness in children and adolescents after rapid ascent by mechanical transportation to 3500 m, an altitude at which major tourist destinations are located throughout the world. METHODS: We performed serial assessments of acute mountain sickness (Lake Louise scores) in 48 healthy nonacclimatized children and adolescents (mean +/- SD age: 13.7 +/- 0.3 years; 20 girls and 28 boys), with no previous high-altitude experience, 6, 18, and 42 hours after arrival at the Jungfraujoch high-altitude research station (3450 m), which was reached through a 2.5-hour train ascent. RESULTS: We found that the overall prevalence of acute mountain sickness during the first 3 days at high altitude was 37.5%. Rates were similar for the 2 genders and decreased progressively during the stay (25% at 6 hours, 21% at 18 hours, and 8% at 42 hours). None of the subjects needed to be evacuated to lower altitude. Five subjects needed symptomatic treatment and responded well. CONCLUSION: After rapid ascent to high altitude, the prevalence of acute mountain sickness in children and adolescents was relatively low; the clinical manifestations were benign and resolved rapidly. These findings suggest that, for the majority of healthy nonacclimatized children and adolescents, travel to 3500 m is safe and pharmacologic prophylaxis for acute mountain sickness is not needed.

Range of motion after computed tomography-based simulation of intertrochanteric corrective osteotomy in cases of slipped capital femoral epiphysis: comparison of uniplanar flexion osteotomy and multiplanar flexion, valgisation, and rotational osteotomies

BACKGROUND: Various osteotomy techniques have been developed to correct the deformity caused by slipped capital femoral epiphysis (SCFE) and compared by their clinical outcomes. The aim of the presented study was to compare an intertrochanteric uniplanar flexion osteotomy with a multiplanar osteotomy by their ability to improve postoperative range of motion as measured by simulation of computed tomographic data in patients with SCFE. METHODS: We examined 19 patients with moderate or severe SCFE as classified based on slippage angle. A computer program for the simulation of movement and osteotomy developed in our laboratory was used for study execution. According to a 3-dimensional reconstruction of the computed tomographic data, the physiological range was determined by flexion, abduction, and internal rotation. The multiplanar osteotomy was compared with the uniplanar flexion osteotomy. Both intertrochanteric osteotomy techniques were simulated, and the improvements of the movement range were assessed and compared. RESULTS: The mean slipping and thus correction angles measured were 25 degrees (range, 8-46 degrees) inferior and 54 degrees (range, 32-78 degrees) posterior. After the simulation of multiplanar osteotomy, the virtually measured ranges of motion as determined by bone-to-bone contact were 61 degrees for flexion, 57 degrees for abduction, and 66 degrees for internal rotation. The simulation of the uniplanar flexion osteotomy achieved a flexion of 63 degrees, an abduction of 36 degrees, and an internal rotation of 54 degrees. CONCLUSIONS: Apart from abduction, the improvement in the range of motion by a uniplanar flexion osteotomy is comparable with that of the multiplanar osteotomy. However, the improvement in flexion for the simulation of both techniques is not satisfactory with regard to the requirements of normal everyday life, in contrast to abduction and internal rotation. LEVEL OF EVIDENCE: Level III, Retrospective comparative study.

Femoral morphology due to impingement influences the range of motion in slipped capital femoral epiphysis

Femoroacetabular impingement due to metaphyseal prominence is associated with the slippage in patients with slipped capital femoral epiphysis (SCFE), but it is unclear whether the changes in femoral metaphysis morphology are associated with range of motion (ROM) changes or type of impingement. We asked whether the femoral head-neck junction morphology influences ROM analysis and type of impingement in addition to the slip angle and the acetabular version. We analyzed in 31 patients with SCFE the relationship between the proximal femoral morphology and limitation in ROM due to impingement based on simulated ROM of preoperative CT data. The ROM was analyzed in relation to degree of slippage, femoral metaphysis morphology, acetabular version, and pathomechanical terms of "impaction" and "inclusion." The ROM in the affected hips was comparable to that in the unaffected hips for mild slippage and decreased for slippage of more than 30 degrees. The limitation correlated with changes in the metaphysic morphology and changed acetabular version. Decreased head-neck offset in hips with slip angles between 30 degrees and 50 degrees had restricted ROM to nearly the same degree as in severe SCFE. Therefore, in addition to the slip angle, the femoral metaphysis morphology should be used as criteria for reconstructive surgery.

Long-range correlations in rectal temperature fluctuations of healthy infants during maturation

BACKGROUND: Control of breathing, heart rate, and body temperature are interdependent in infants, where instabilities in thermoregulation can contribute to apneas or even life-threatening events. Identifying abnormalities in thermoregulation is particularly important in the first 6 months of life, where autonomic regulation undergoes critical development. Fluctuations in body temperature have been shown to be sensitive to maturational stage as well as system failure in critically ill patients. We thus aimed to investigate the existence of fractal-like long-range correlations, indicative of temperature control, in night time rectal temperature (T(rec)) patterns in maturing infants. METHODOLOGY/PRINCIPAL FINDINGS: We measured T(rec) fluctuations in infants every 4 weeks from 4 to 20 weeks of age and before and after immunization. Long-range correlations in the temperature series were quantified by the correlation exponent, alpha using detrended fluctuation analysis. The effects of maturation, room temperature, and immunization on the strength of correlation were investigated. We found that T(rec) fluctuations exhibit fractal long-range correlations with a mean (SD) alpha of 1.51 (0.11), indicating that T(rec) is regulated in a highly correlated and hence deterministic manner. A significant increase in alpha with age from 1.42 (0.07) at 4 weeks to 1.58 (0.04) at 20 weeks reflects a change in long-range correlation behavior with maturation towards a smoother and more deterministic temperature regulation, potentially due to the decrease in surface area to body weight ratio in the maturing infant. alpha was not associated with mean room temperature or influenced by immunization CONCLUSIONS: This study shows that the quantification of long-range correlations using alpha derived from detrended fluctuation analysis is an observer-independent tool which can distinguish developmental stages of night time T(rec) pattern in young infants, reflective of maturation of the autonomic system. Detrended fluctuation analysis may prove useful for characterizing thermoregulation in premature and other infants at risk for life-threatening events.

Effect of ascent protocol on acute mountain sickness and success at Muztagh Ata, 7546 m

Bloch, Konrad E., Alexander J. Turk, Marco Maggiorini, Thomas Hess, Tobias Merz, Martina M. Bosch, Daniel Barthelmes, Urs Hefti, Jacqueline Pichler, Oliver Senn, and Otto D. Schoch. Effect of ascent protocol on acute mountain sickness and success at Muztagh Ata, 7546 m. High Alt. Med. Biol. 10:25-32, 2009.-Data on acclimatization during expedition-style climbing to > 5000 m are scant. We evaluated the hypothesis that minor differences in ascent protocol influence acute mountain sickness (AMS) symptoms and mountaineering success in climbers to Muztagh Ata (7546 m), Western China. We performed a randomized, controlled trial during a high altitude medical research expedition to Muztagh Ata. Thirty-four healthy mountaineers (mean age 45 yr, 7 women) were randomized to follow one of two protocols, ascending within 15 or 19 days to the summit of Muztagh Ata at 7546 m, respectively. The main outcome measures, AMS symptom scores and the number of proceeding climbers, were assessed daily. Mean +/- SD AMS-C scores of 16 climbers randomized to slow ascent were 0.06 +/- 0.18, 0.26 +/- 0.08, 0.41 +/- 0.45, 0.53 +/- 0.77 at camps I (5533 m), II (6265 m), III (6865 m), and the summit (7546 m), respectively. Corresponding values in 18 climbers randomized to fast ascent were significantly higher: 0.17 +/- 0.23, 0.43 +/- 0.75, 0.49 +/- 0.36, and 0.69 +/- 0.54 (p < 0.008, vs. slow ascent in regression analysis accounting for weather-related protocol deviation). Climbers randomized to slow ascent were able to ascend according to the protocol without AMS for significantly more days than climbers randomized to fast ascent (p = 0.04, Kaplan-Meier analysis). More climbers randomized to slow ascent were successful in reaching the highest camp at 6865 m without AMS (odds ratio 9.5; 95% confidence interval 1.02 to 89). In climbers ascending to very high altitudes, differences of a few days in acclimatization have a significant impact on symptom severity, the prevalence of AMS, and mountaineering success. ClinicalTrials.gov Identifier NCT00603122.