Initiating transitional care for adolescents with cystic fibrosis at the age of 12 is both feasible and promising.

AIM: Adolescence is a vulnerable period in cystic fibrosis, associated with declining lung function. This study described, implemented and evaluated a transition programme for adolescents. METHODS: We conducted a single centre, nonrandomised and noncontrolled prospective programme at the cystic fibrosis centre at Copenhagen University Hospital Rigshospitalet from 2010 to 2011, assessing patients aged 12-18 at baseline and after 12 months. Changes implemented included staff training on communication, a more youth-friendly feel to the outpatient clinic, the introduction of youth consultations partly alone with the adolescent, and a parents' evening focusing on cystic fibrosis in adolescence. Lung function and body mass index (BMI) were measured monthly and adolescents were assessed for their readiness for transition and quality of life at baseline and 12 months. RESULTS: We found that 40 (98%) of the eligible patients participated and youth consultations were successfully implemented with no dropouts. The readiness checklist score increased significantly over the one-year study period, indicating increased readiness for transfer and self-care. Overall quality of life, lung function and BMI remained stable during the study period. CONCLUSION: A well-structured transition programme for cystic fibrosis patients as young as 12 years of age proved to be both feasible and sustainable.

[Frozen embryo transfer protocol: does spontaneous cycle give good results?]. / Protocoles de replacement d'embryons congelés: le cycle spontané donne-t-il de bons résultats?

OBJECTIVE: Frozen embryos' transfer optimize the pregnancy rates per retrieval. In France, 60% of transfer cycles occur in stimulated cycles. The aim of this study was to evaluate the outcomes of frozen embryo transfers in spontaneous, substituted and stimulated cycle. PATIENTS AND METHODS: This retrospective study includes patients who are 18-43 years old and had a frozen embryo transfer between 1st January 2008 and 31st December 2008. Three transfer protocols have been used: the spontaneous cycle (group 1), substituted cycle (group 2), and stimulated cycle (group 3). The characteristics of couples, embryonic parameters and data transfer cycles, and their outcomes were evaluated. RESULT(S): Among the 333 patients, 132 were included in the first group, 24 in the second group and 177 in the third group. After checking the homogeneity of the three groups, we found pregnancy rates (respectively 20.49 vs 13.04% and 11.32%, P=0.0348), and deliveries (respectively 13.93 vs 8,7 and 6.29%, P=0.0314), significantly higher in spontaneous cycles. DISCUSSION AND CONCLUSION: Currently there is no consensus on the best technique for endometrial preparation for frozen embryo transfer. Our results support transfers in spontaneous cycle for normo-ovulating patients. Natural cycles can achieve good pregnancy rates while minimizing the costs and side effects.

Comparison of absolute benefits of anticancer therapies determined by snapshot and area methods.

BACKGROUND: Reporting of relative risk reduction as the measure of treatment effect in randomized clinical trials (RCTs) may be difficult to understand. Here, we compare two methods for assessing absolute benefits of anticancer therapies. MATERIALS AND METHODS: We searched PubMed for RCTs comparing therapies for breast and colorectal cancers published 1975-2009 (adjuvant setting) and 2000-2010 (metastatic setting). Eligible trials reported statistically significant differences. Kaplan-Meier curves were assessed for absolute differences in time-to-event end points at a single point (snapshot method) and as the area between curves (area method). Pooled absolute benefits determined by both methods were compared by the Pitman-Morgan test. RESULTS: Eighty-three and 39 paired curves were assessed in the adjuvant and metastatic settings, respectively. In trials of adjuvant therapy, absolute benefits were larger and more variable when assessed at different time points by the snapshot compared with the area method (median and ranges for 60-month difference in overall survival: 7.6% [2.5%-28.4%] and 4.5% [1.8%-13.6%]; P = 0.002, respectively). For metastatic disease, both methods were within 0.5 month of each other in 62% of trials. CONCLUSIONS: The area method provides an alternative measure of absolute treatment effect, which uses all of the available data and is less dependent on the shape of survival curves.

Reproducibility of in vivo corneal confocal microscopy as a novel screening test for early diabetic sensorimotor polyneuropathy.

AIM: With the goal of identifying a valid biomarker of early diabetic sensorimotor polyneuropathy, we aimed to identify the most reliable in vivo corneal confocal microscopy (CCM) parameter for detection of abnormality of small nerve fibre morphology. METHODS: Cross-sectional examination of 46 subjects (26 with Type 1 diabetes and 20 healthy volunteers) examined by corneal confocal microscopy for intra- and interobserver reproducibility by the intraclass correlation coefficient method. Corneal nerve fibre density, nerve branch density, nerve fibre length and tortuosity were measured on the same day that subjects underwent clinical and electrophysiological examination. RESULTS: The 26 subjects with Type 1 diabetes had mean age and diabetes duration 42.8 ± 16.9 and 22.7 ± 16.4 years, respectively. Twelve of those subjects (46%) did not meet criteria for diabetic sensorimotor polyneuropathy, while five (19%) had mild, three (12%) had moderate and six (23%) had severe diabetic sensorimotor polyneuropathy. None of the healthy volunteers (mean age 41.4 ± 17.3 years) had polyneuropathy. Re-examination of selected corneal confocal microscopy images or sets of 40 images yielded very good to excellent intraclass correlation coefficients for all parameters. However, only one parameter (corneal nerve fibre length) emerged with consistently very good reproducibility using a clinically relevant 'study-level' protocol of subject re-examination (intra-observer intraclass correlation coefficient 0.72; interobserver intraclass correlation coefficient 0.73). Despite no differences in intraclass correlation coefficient between subgroups, corneal nerve fibre length was significantly lower (14.76 vs. 16.15 mm/mm(2), P = 0.04) in those with diabetes. CONCLUSIONS: Development of corneal confocal microscopy may need to focus on the measurement of corneal nerve fibre length, as it appears to have superior reliability in comparison with other parameters, and as evidence exists for its potential as a clinical biomarker of early diabetic sensorimotor polyneuropathy.

Absolute benefits of medical therapies in phase III clinical trials for breast and colorectal cancer.

BACKGROUND: Phase III randomized clinical trials (RCTs) have become larger and are powered to detect small absolute benefits. Temporal changes in absolute benefits of experimental medical therapies reported in RCTs are unknown. METHODS: We identified all RCTs with sample size > or =200 evaluating experimental medical therapies for breast and colorectal cancer published from 1975 to 2007. We assessed changes over three decades in absolute differences in time-to-event end points between experimental and control arms by (i) the usual method (i.e. at one point) and (ii) as the area between time-to-event curves up to a predefined time. RESULTS: We identified 236 eligible RCTs of which 57% (N = 135) evaluated adjuvant treatments. Experimental treatments became more often compared with active treatments (48% versus 59% versus 81%; P < 0.0001). Median absolute benefits of experimental adjuvant treatments decreased but outcomes in control arms improved with time. For RCTs evaluating metastatic disease, there were no changes in absolute benefit over time but incremental monthly costs of new approved treatments increased with time by 100-fold (P < 0.0001). CONCLUSION: In RCTs of breast and colorectal cancer, new effective adjuvant treatments show decreasing absolute benefit, while new treatments of metastatic disease show unchanging levels of benefit at rapidly escalating costs.

Global drug development in cancer: a cross-sectional study of clinical trial registries.

BACKGROUND: Drug development in cancer is costly and may be directed toward 'profitable' cancers of the more developed regions (MDR) as compared with those of the less developed regions (LDR) of the world. Here, we describe drug development in relation to cancer type and geographic location. MATERIALS AND METHODS: We reviewed phase II and III clinical trials evaluating new cancer drugs, which were registered from January to June 2008. Correlations were sought between the number of clinical trials and incidence, mortality and prevalence of the cancers studied (obtained from GLOBOCAN 2002) and stratified by region of the world. RESULTS: We identified 399 newly registered trials. Most trials (N = 229, 57%) were sponsored by industry. The most common types of cancer studied were breast 73 (18%), lung 57 (14%), prostate 44 (11%) and colorectal 28 (7%). In MDR, incidence, mortality and prevalence correlated significantly (Pearson r = 0.80, 0.73 and 0.63; P < or = 0.01) with the number of all registered clinical trials, whereas in LDR, only prevalence showed significant association (Pearson r = 0.55; P = 0.03) with the number of trials for a given type of cancer. CONCLUSION: Lethal cancers that are common in the LDR (e.g. stomach, liver and esophageal cancers) deserve greater emphasis for drug development.

Aminonaphthoquinone induces oxidative stress in Staphylococcus aureus.

The biological activity of 5-amino-8-hydroxy-1,4-naphthoquinone (ANQ) on Staphylococcus aureus was investigated in comparison with the unsubstituted 1,4-naphthoquinone (NQ). Complete inhibition of microbial growth was observed with ANQ and NQ at 50 and 10 microg/mL, respectively. The antibacterial effect of naphthoquinones decreased in the presence of sodium ascorbate, but the superoxide scavenger 4,5-dihydroxy-1,3-benzene-disulfonic acid (Tiron) was able to protect S. aureus only from the harmful effect of ANQ. Naphthoquinones blocked oxygen uptake and induced cyanide-insensitive oxygen consumption. When combining rotenone or salicylhydroxamic acid with ANQ or NQ, a slight decrease in respiratory activity was observed. Assays in the presence of naphthoquinones induced an increase of lipid peroxidation in S. aureus, as determined by thiobarbituric acid reactive substances. These results showed that 1,4-naphthoquinones effectively act as electron acceptors and induce an increase in reactive oxygen species that are toxic to S. aureus cells.

Mineralisation studies of 14C-labelled metsulfuron-methyl, tribenuron-methyl, chlorsulfuron and thifensulfuron-methyl in one Danish soil and groundwater sediment profile.

Bacterial mineralisation of four sulfonylurea herbicides at 20 microg kg(-1) in a sandy soil from nine different depths in a sandy soil horizon (5-780 cm) was investigated in laboratory studies. Metsulfuron-methyl, chlorsulfuron, and tribenuron-methyl were 14C-labelled in the sulfonamide ring, while thifensulfuron-methyl was labelled in the thiophene ring. The highest mineralised amount in 126 days was observed for metsulfuron-methyl (40%) followed by tribenuron-methyl (25%), and thifensulfuron-methyl (11%). Chlorsulfuron showed low mineralisation in all the soils tested (<4%). Mineralisation of the herbicides metsulfuron-methyl and tribenuron-methyl varied according to soil depth (upper profile: 5-70 cm, and lower profile: 165-780 cm) and were proven faster in soil taken from depths 5-7 and 30-35 cm, and slower in depths 45-50 and 70-75 cm. Mineralisation was absent in the lower profile (165-780 cm). As an indicator of microbial activity bacterial counts were taken at the experimental start; these counts grouped in three levels: highest in the surface layer (5-7 cm), slightly lower in the depths 30-75 cm, and lowest in the lower profile (165-780 cm). Residual concentrations of metsulfuron-methyl correlated to the accumulated amount mineralised, with high residual concentrations in soil showing low mineralisation. Also chlorsulfuron showed high residual concentrations with increasing depth in the upper profile, but the relatively high dissipation at 30-35 cm and lower one at 45-50 cm could not be related with the lack of mineralisation. This shows that hydrolysis occurs, but mineralisation of the chloro-substituted sulfonamide is restricted. Tribenuron-methyl and thifensulfuron-methyl could not be detected due to interference with other compounds.

Preparation and characterization of bio-diesels from various bio-oils.

Methyl, ethyl, 2-propyl and butyl esters were prepared from canola and linseed oils through transesterification using KOH and/ or sodium alkoxides as catalysts. In addition, methyl and ethyl esters were prepared from rapeseed and sunflower oils using the same catalysts. Chemical composition of the esters was determined by HPLC for the class of lipids and by GC for fatty acid compositions. The bio-diesel esters were characterized for their physical and fuel properties including density, viscosity, iodine value, acid value, cloud point, pure point, gross heat of combustion and volatility. Methyl and ethyl esters prepared from a particular vegetable oil had similar viscosities, cloud points and pour points, whereas methyl, ethyl, 2-propyl and butyl esters derived from a particular vegetable oil had similar gross heating values. However, their densities, which were 2 7% higher than those of diesel fuels, statistically decreased in the order of methyl approximately 2-propyl > ethyl > butyl esters. Butyl esters showed reduced cloud points (-6 degrees C to -10 degrees C) and pour points (-13 degrees C to -16 degrees C) similar to those of summer diesel fuel having cloud and pour points of -8 degrees C and -15 degrees C, respectively. The viscosities of bio-diesels (3.3-7.6 x 10(-4) Pa s at 40 degrees C) were much less than those of pure oils (22.4-45.1 x 10(-4) Pa s at 40 degrees C) and were twice those of summer and winter diesel fuels (3.50 and 1.72 x 10(-4) Pa s at 40 degrees C), and their gross heat contents of approximately 40 MJ/kg were 11% less than those of diesel fuels (approximately 45 MJ/kg). For different esters from the same vegetable oil, methyl esters were the most volatile, and the volatility decreased as the alkyl group grew bulkier. However, the bio-diesels were considerably less volatile than the conventional diesel fuels.

The leader's role in building collaborative teams.

The future requires a new way of leading. The team concept has been recognized as playing a principle role in this new order, but teams mistakenly have either been added or overlaid on existing responsibilities and ways of doing business and often have not been as effective as intended. Therefore, there needs to be a fundamental change in the entire concept of organization structure itself, and a paradigm shift in the way we think about teams. Teams must be truly collaborative. The collaborative team structure is presented as the way to successfully adapt to the challenges of the late 1990s and the 21st century.

Dynamic reconstruction of the oropharyngeal swallow using computer based animation.

The oropharyngeal swallow was modeled with computer based animation using data from biplane videofluorographic and dynamic CT images of 10 ml liquid swallows of a volunteer subject. Tracings of oropharyngeal structures from synchronized, magnification adjusted, images of the posterior-anterior, lateral, and cross-sectional planes were aligned in three dimensions with graphics animation software. Twenty oropharyngeal configurations were created at 1/15 second intervals to dynamically illustrate the swallow. These three-dimensional reconfigurations could be sequenced into an animation routine. Software analysis of the model permitted quantification of structural movement and intrapharyngeal volume across time. Such analyses can be used to detail both the efficacy of individual functional elements of the swallow as well as global pump function. It is hoped that modeling the oropharyngeal swallow will be useful to analyze mechanisms of dysphagia and the mechanics of compensatory therapeutic strategies.

The Hep G2 cell line in the study of growth hormone receptor/binding protein.

This study identifies specific, high affinity GH-receptors (GH-R) in human hepatoma Hep G2 cells. The binding characteristics of GH-R in the Hep G2 cells are similar to those of human liver membranes, such as the high specificity for hGH, the binding affinity (Ka = 1.7 +/- 0.5 x 10[9] M[-1]) and the molecular weight of the membrane bound GH-R (apparent 125,000 and 71,000). In addition, lower molecular weight forms (approximately 94,000 and approximately 58,000) were identified as GH-binding protein (GH-BP) in Hep G2 conditioned medium, or following incubation of Hep G2 cells, in the presence of 10 mM N-ethylmaleimide for 90 min at 30 degrees C; the latter are presumed to be shed by a proteolytic cleavage of the GH-R. Exposure of Hep G2 cells to physiologic concentrations of hGH resulted in a concentration-dependent increase in 3H-thymidine incorporation, up to 48.4 +/- 7.9% above control. In summary, the demonstration of specific, high affinity GH-R in Hep G2 cells, as well as shedding of GH-BP, suggest these cells may provide a homologous human system to study the receptor-effector interrelationship of hGH and to further our understanding of hepatocyte production of soluble GH-BP.

Ontogenesis of the sexual dimorphism of growth hormone secretion by perifused rat hemipituitaries.

The aims of the present study were to investigate the sexual dimorphism and the role of sex steroids in GH secretion at the pituitary level, and to evaluate the ontogenesis of these effects. Towards these aims we used an in vitro perifusion system of hemipituitaries under a simulated milieu of hypothalamic factors: two 3-min pulses of GHRH at 3-hour intervals were separated by continuous flow of somatostatin. Rat GH was measured in 2.4-min fractions and analyzed by the pulse analysis program PULSAR. Pulses were similar in prepubertal male and female rats, but sexual dimorphism was evident in adults. In adult males, who had undergone neonatal gonadectomy, GH pulse amplitude and area under the curve (AUC) were lower compared to control. When gonadectomy had been performed at a prepubertal age, the pulse amplitude was still lower, but the AUC was not different from control. The gap between orchiectomy at neonatal and prepubertal age indicates the perinatal imprint, which induces an increase in AUC. Neonatal testosterone treatment of intact female rats had no effect on GH secretion by adult pituitaries. In neonatally gonadectomized female rats, under neonatal testosterone treatment, the pulse amplitude increased. A similar increase was observed after neonatal gonadectomy without testosterone treatment. We conclude that the sexual dimorphism of GH secretion is partially induced at the pituitary level and its response to the hypothalamic hormones. We assume that a neonatal imprint effect of testosterone in the male induces primarily an increase in AUC in response to GHRH. The imprint in females influences the GH pulse amplitude and AUC.

Growth hormone-binding protein in partially hepatectomized rats.

The role of the liver in regulating serum growth hormone-binding protein (GH-BP) was studied. We measured rat serum GH-BP and insulin-like growth factor 1 (IGF-1) 30 min to 96 h after 70% partial hepatectomy (PHP) or sham operation in adult male rats. Serum GH-BP declined sharply from 5.8 +/- 0.1% at baseline to 3.9 +/- 0.5% by 48 h following PHP. By 72 h serum GH-BP at baseline to 3.9 +/- 0.5% by 48 h following PHP. By 72 h serum GH-BP returned to baseline level and remained at that level 96 h postoperatively. In sham-operated female rats, serum GH-BP was about 2-fold higher than in males (10.5 +/- 1.46 versus 5.8 +/- 0.2%), whereas 24 h after hepatectomy a significant drop of about 50% was observed (p < 0.001). Serum IGF-1 decreased within 2-4 h postoperatively in both sham-operated and PHP groups, but thereafter was lower in the PHP rats, up to 48 h after operation, compared to sham-operated rats (p < 0.03). The study shows that the liver has an important role in the determination of serum GH-BP levels. The return to normal GH-BP level, even before the liver regained its full size following hepatectomy, suggests an increase in GH-BP production by the regenerating liver.

Evaluating temperature regulation by field-active ectotherms: the fallacy of the inappropriate question.

We describe a research protocol for evaluating temperature regulation from data on small field-active ectothermic animals, especially lizards. The protocol requires data on body temperatures (Tb) of field-active ectotherms, on available operative temperatures (Te, "null temperatures" for nonregulating animals), and on the thermoregulatory set-point range (preferred body temperatures, Tset). These data are used to estimate several quantitative indexes that collectively summarize temperature regulation: the "precision" of body temperature (variance in Tb, or an equivalent metric), the "accuracy" of body temperature relative to the set-point range (the average difference between Tb and Tset), and the "effectiveness" of thermoregulation (the extent to which body temperatures are closer on the average to the set-point range than are operative temperatures). If additional data on the thermal dependence of performance are available, the impact of thermoregulation on performance (the extent to which performance is enhanced relative to that of nonregulating animals) can also be estimated. A sample analysis of the thermal biology of three Anolis lizards in Puerto Rico demonstrates the utility of the new protocol and its superiority to previous methods of evaluating temperature regulation. We also discuss several ways in which the research protocol can be extended and applied to other organisms.

Organized media for fluorescence analysis of complex samples: comparison of bile salt and conventional detergent micelles in coal liquids.

Accurate quantitative determinations are often difficult to obtain from fluorescence analysis of complex samples due to sample matrix effects and intermolecular interactions between solutes. Organized media can be used to minimize these unwanted processes without physical separation or extraction of the analytes from the sample matrix by isolating the analyte molecules in a uniform microenvironment within the sample. The advantages of bile salt micellar media over conventional detergent micelles are demonstrated for analysis of coal liquids. The bile salt media is shown to increase the sensitivity and dynamic range of fluorescence measurements relative to simple ethanolic solutions, without promoting gound-state and excited-state interactions that occur in the detergent micellar media.

Growth hormone and insulin-like growth factor-I increase macrophage uptake and degradation of low density lipoprotein.

Hyperlipidemia has been reported in adults with hypopituitarism, and human (h) GH therapy has been shown to lower plasma cholesterol in patients with hypercholesterolemia. Macrophage cholesterol accumulation is an early event in atherosclerosis, and these cells have been shown to respond to GH and insulin-like growth factor (IGF-I). The present study was aimed at investigating the activity of GH and IGF-I in macrophages, and used murine macrophages as a model system to investigate the effects of GH and IGF-I on cellular uptake and metabolism of low density lipoprotein (LDL). The J-774 murine macrophage cell line was shown to bind hGH, to respond to hGH by an increase in cell IGF-I content, and to have specific high affinity binding sites for IGF-I. Mouse peritoneal macrophages and the J-774 macrophage cell line respond to hGH with a dose-dependent stimulation of cellular association and degradation of LDL as well as an enhanced cholesterol esterification rate. A similar response was observed after in vitro treatment of the cells with IGF-I. Preliminary results in human monocyte-derived macrophages showed similar results. The dependency of the effect of hGH on locally produced IGF-I was shown by abrogation of the hGH effect after adding anti-IGF-I antibody to the culture medium. It is concluded that murine macrophages possess the machinery to bind GH, produce IGF-I, and bind IGF-I. This machinery is used by macrophages, and apparently by other cells, to execute GH-dependent IGF-I-mediated stimulation of cellular uptake and metabolism of LDL. This may provide the explanation for both the elevated plasma LDL concentration in patients with GH deficiency and the effect of GH therapy to reduce plasma LDL levels.

The distal axis of growth hormone (GH) in nutritional disorders: GH-binding protein, insulin-like growth factor-I (IGF-I), and IGF-I receptors in obesity and anorexia nervosa.

The endocrine abnormalities along the growth hormone (GH) axis in anorexia nervosa (AN) and in obesity include hypothalamic, pituitary, and peripheral elements. The present study was undertaken to evaluate the effects of these nutritional extremes on GH-binding protein (BP) levels and on Insulin-like growth factor-I (IGF-I) receptors on red blood cells (RBC). Nine patients with AN and 20 obese subjects were compared with normal control children, adolescents, and adults. GH-BP was measured by a binding assay with dextran-coated charcoal separation. IGF-I binding was measured on enriched RBC. Serum GH-BP levels were markedly reduced in the AN patients, and highly increased in the obese. Scatchard analyses showed linear plots with unaltered binding affinities (Ka). The binding capacity (Bmax) was significantly lower than normal control in the AN patients and higher in the obese. GH-BP levels correlated positively with the body mass index (BMI). RBC [125I]IGF-I binding was significantly elevated in the AN patients and low in the obese. Scatchard analyses showed curvilinear plots. The high-affinity constants (Ka1) were slightly, but significantly, higher in the AN patients and in the obese compared with control. The binding capacity of the first binder (Bmax1) was lower in obesity than in AN or control. The low-affinity constants (Ka2) were similar in the three groups, and its binding capacity (Bmax2) was similar in the AN patients and the controls, but significantly lower in the obese. [125I]IGF-I binding correlated negatively and significantly with the BMI and with the GH-BP.(ABSTRACT TRUNCATED AT 250 WORDS)