Near-infrared fluorescence cholangiography assisted laparoscopic cholecystectomy (FALCON): an international multicentre randomized controlled trial.

AIM: To assess the added value of Near InfraRed Fluorescence (NIRF) imaging during laparoscopic cholecystectomy. METHODS: This international multicentre randomized controlled trial included participants with an indication for elective laparoscopic cholecystectomy. Participants were randomised into a NIRF imaging assisted laparoscopic cholecystectomy (NIRF-LC) group and a conventional laparoscopic cholecystectomy (CLC) group. Primary end point was time to 'Critical View of Safety' (CVS). The follow-up period of this study was 90 postoperative days. An expert panel analysed the video recordings after surgery to confirm designated surgical time points. RESULTS: A total of 294 patients were included, of which 143 were randomized in the NIRF-LC and 151 in the CLC group. Baseline characteristics were equally distributed. Time to CVS was on average 19 min and 14 s for the NIRF-LC group and 23 min and 9 s for the CLC group (p 0.032). Time to identification of the CD was 6 min and 47 s and 13 min for NIRF-LC and CLC respectively (p < 0.001). Transition of the CD in the gallbladder was identified after an average of 9 min and 39 s with NIRF-LC, compared to 18 min and 7 s with CLC (p < 0.001). No difference in postoperative length of hospital stay nor occurrence of postoperative complications was found. ICG related complications were limited to one patient who developed a rash after injection of ICG. CONCLUSION: Use of NIRF imaging in laparoscopic cholecystectomy provides earlier identification of relevant extrahepatic biliary anatomy: earlier achievement of CVS, cystic duct visualisation and visualisation of both cystic duct and cystic artery transition into the gallbladder.

Pitfalls and clinical recommendations for the primary lumbar hernia based on a systematic review of the literature.

PURPOSE: The lumbar abdominal wall hernia is a rare hernia in which abdominal contents protrude through a defect in the dorsal abdominal wall, which can be of iatrogenic, congenital, or traumatic origin. Two anatomical locations are known: the superior and the inferior lumbar triangle. The aim of this systematic review is to provide a clear overview of the existing literature and make practical clinical recommendations for proper diagnosis and treatment of the primary lumbar hernia. METHODS: The systematic review was conducted according to the PRISMA guidelines. A systematic search in PubMed, MEDLINE, and EMBASE was performed, and all studies reporting on primary lumbar hernias were included. No exclusion based on study design was performed. Data regarding incarceration, recurrence, complications, and surgical management were extracted. RESULTS: Out of 670 eligible articles, 14 were included and additional single case reports were analysed separately. The average quality of the included articles was 4.7 on the MINORS index (0-16). Risk factors are related to increased intra-abdominal pressure. CT scanning should be performed during pre-operative workup. Available evidence favours laparoscopic mesh reinforcement, saving open repair for larger defects. Incarceration was observed in 30.8% of the cases and 2.0% had a recurrence after surgical repair. Hematomas and seromas are common complications, but surgical site infections are relatively rare. CONCLUSION: The high risks of incarceration in lumbar hernias demand a relatively fast elective repair. The use of a mesh is recommended, but the surgical approach should be tailored to individual patient characteristics and risk factors.

Evaluation of a novel dye for near-infrared fluorescence delineation of the ureters during laparoscopy.

BACKGROUND: Iatrogenic ureteric injury remains a risk in laparoscopic pelvic procedures. Near-infrared fluorescence (NIRF) imaging is a promising new technique for enhanced intraoperative visualization of anatomical structures that could improve the safety of laparoscopic surgery. A new dye, IRDye® 800-BK, has been developed for intraoperative visualization of the ureters using NIRF. The present study was a first evaluation of the performance of IRDye® 800-BK for ureteric imaging during NIRF laparoscopy. METHODS: This study consisted of three parts: real-time in vivo NIRF imaging using IRDye® 800-BK in pigs during laparoscopic surgery, ex vivo NIRF imaging of freshly explanted pig ureters and ex vivo NIRF imaging of explanted human ureters. RESULTS: In all animals, both left and right ureters were visualized throughout the laparoscopic procedure for 120 min, with the best results at a dose of 0·15 mg dye per kg bodyweight. NIRF imaging was successful in all human and porcine ureters studied, with a range of dye concentrations. CONCLUSION: NIRF imaging of the ureters using IRDye® 800-BK was used successfully both in vivo in a porcine model, and ex vivo in porcine and human ureters.

A claims-based Markov model for Crohn's disease.

BACKGROUND: Crohn's disease is a chronic condition that often presents in early adulthood. AIM: To evaluate health care costs and costs per quality-adjusted life year (QALY) for Crohn's disease. METHODS: A Markov model was developed using administrative claims data for patients aged > or = 18 years with > or = 3 years of continuous enrolment from 2000 to 2008 and > or =2 Crohn's disease claims. Disease states (remission, mild-moderate, moderate-severe, and severe-fulminant) were defined using the American College of Gastroenterology treatment guidelines criteria. Transition probabilities were calculated from consecutive 6-month periods. Costs were determined from paid claims and QALY utilities were obtained from the literature. The model assumed a 30-year-old patient at the time of entry into the model. RESULTS: There were 40 063 patients identified, with a total of 420 773 cycles [remission (197 111; 46.8%), mild-moderate (44 024; 10.5%), moderate-severe (132 695; 31.5%), severe-fulminant (46 925; 11.2%)]. The costs/QALY for remission, mild-moderate, moderate-severe, and severe-fulminant disease states respectively were $2896, $8428, $11 518 and $69 277 for males and $2896, $8426, $22 633 and $69 412 for females. CONCLUSIONS: Overall, health care costs for patients with Crohn's disease increased with disease severity. Although the probabilities of transitioning from other health states to the severe-fulminant disease state were low, the cost/QALY was high.

Benefits of high altitude allergen avoidance in atopic adolescents with moderate to severe asthma, over and above treatment with high dose inhaled steroids.

Some patients with severe asthma cannot be controlled with high doses of inhaled steroids (ICS), which may be related to ongoing environmental allergen exposure. We investigated whether 10 weeks of high altitude allergen avoidance leads to sustained benefits regarding clinical and inflammatory markers of disease control in adolescents with persistent asthma despite treatment with high dose ICS. Eighteen atopic asthmatic adolescents (12-18 yr, 500-2000 microg ICS daily) with established house dust mite allergy, participated in a parallel-group study. Quality of life (PAQL), lung function, bronchial hyperresponsiveness (BHR) to adenosine and histamine, induced sputum and urine samples were collected repeatedly from 10 patients during a 10-week admission period to the Swiss Alps (alt. 1560 m) and at 6 weeks after return to sea level. Results were compared with those in eight patients, studied in their home environment at sea level for a similar time period. Throughout the study, asthma medication remained unchanged in both groups. During admission to high altitude, PAQL, lung function, BHR to adenosine and histamine, and urinary levels of eosinophil protein X (U-EPX), leukotriene E4 (U-LTE4) and 9alpha11beta prostaglandin F2 (U-9alpha11beta PGF2) improved significantly (P < 0.05), with a similar tendency for sputum eosinophils (P < 0.07). Furthermore, the changes in PAQL and BHR to adenosine and histamine were greater in the altitude than in the control group (P < 0.05). At 6 weeks after renewed allergen exposure at sea level, the improvements in PAQL (P < 0.05), BHR to adenosine (P < 0.07) and histamine (P < 0.05), as well as U-EPX (P < 0.05) and U-LTE4 (P < 0.05) were maintained. A short period of high altitude allergen avoidance, on top of regular treatment with ICS and long-acting beta2-agonists, results in improvement of asthma, as assessed by clinical and inflammatory markers of disease severity. These findings indicate that short-term, rigorous allergen avoidance can improve the long-term control of severe asthma over and above what can be achieved even by high doses of inhaled steroids.

Mirtazapine effects on alertness and sleep in patients as recorded by interactive telecommunication during treatment with different dosing regimens.

This double-blind study compared mirtazapine's effects on alertness and sleep between parallel groups treated for 2 weeks according to a fixed regimen of 30 mg at bedtime (N = 69) and one that increased in dose from 15 to 30 mg at bedtime after the first week (N = 71). These patients with depression used an interactive telephone/computer system for daily alertness and sleep recordings on self-rating scales before and during treatment. Efficacy (17-item Hamilton Rating Scale for Depression [HAM-D], Clinical Global Impression Scale [CGI]) and safety assessments were made by participating psychiatrists. Both groups' alertness ratings were subnormal at baseline and even lower after the first dose. The ratings recovered after the second dose and increased progressively to levels 18% higher than those at baseline by the end of treatment. Patients receiving the fixed dose reported earlier sleep onset and longer duration. Similar mean changes in HAM-D scores (approximately -40%) and frequencies of CGI responders (>50%) occurred in both groups. The regimens were equally well tolerated. Somnolence, the most frequent side effect, was reported by only 10% of each group during the first week and by fewer patients during the second. Mirtazapine in fixed and ascending nocturnal dosing regimens was found to facilitate sleep, but it does not generally reduce daytime alertness. The fixed regimen seems preferable because of its greater effects on sleep.

Induced sputum in adolescents with severe stable asthma. Safety and the relationship of cell counts and eosinophil cationic protein to clinical severity.

This study examined the safety of sputum induction and the relation between sputum cell counts and clinical parameters in adolescents with severe persistent asthma. Within 5 days, induced sputum and reversibility in forced expiratory volume in one second (FEV1), quality of life, provocative concentration causing a 20% fall in FEV1 (PC20) of adenosine monophosphate and histamine, exercise-induced bronchoconstriction, overall asthma severity index, and blood eosinophils were collected in 20 atopic adolescents with moderate-to-severe persistent asthma (12-18 yrs of age, FEV1 65-110% of predicted, on 500-2,000 microg inhaled steroids daily). FEV1 was reversible by 13.3-2.3% pred. After sputum induction, FEV1 was still increased by 9.0+/-2.6% pred as compared to the pre-salbutamol baseline. Sputum contained, median (range): 12.4 (0.4-59.5)% squamous cells, 47.3 (6.8-84.0)% macrophages, 39.0 (4.6-84.8)% neutrophils, 4.8 (1.0-12.4)% lymphocytes, 0.4 (0-10.8)% eosinophils and 3.6 (0-23.4)% bronchial epithelial cells. Sputum eosinophils showed a trend towards a significant association with the overall asthma severity index (r=0.46, p=0.06) and correlated inversely with baseline FEV1 (r=-0.51, p=0.03). In conclusion, sputum can be induced safely in adolescents with moderate-to-severe persistent asthma, if pretreated with beta2-agonists. Despite relatively low sputum eosinophil counts in these patients on inhaled steroids, the association of eosinophil numbers with baseline forced expiratory volume in one second and asthma severity index favours a role of induced sputum in monitoring adolescents with severe asthma.

New iodinated progestins as potential ligands for progesterone receptor imaging in breast cancer. Part 1: Synthesis and in vitro pharmacological characterization.

Five putative iodinated progesterone receptor (PR) binding ligands were synthesized and evaluated as potential imaging agents for PR-positive human breast tumours. Two compounds (E- and Z-17-hydroxy-21-iodo-19-nor-17alpha-pregna-4,20-dien-3-one; E- and Z-IPG1) were previously described, but are re-evaluated. The other three were novel compounds: two nortestosterone analogues derived from ORG 3236 (E- and Z-13-ethyl-17-hydroxy-21-iodo-11-methylene-18,19-dinor-17alpha-pre gna-4,20-diene-3-one; E- and Z-IPG2) and one norprogesterone analogue derived from ORG 2058 (21-[4-iodophenoxy]-16alpha-ethyl-19-norpregn-4-ene-3, 20-dione; IPG3). The E-iodovinyl nortestosterone compounds were obtained by a new route of synthesis. Competitive binding studies were performed to determine their binding affinities for the PR in three types of tissue (human MCF-7 breast tumour cells and rat uterine and mammary tumour tissue) and for the androgen receptor (AR) in human MCF-7 breast tumour cells, as well as for the sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG) in human plasma. All four 17alpha-iodovinyl nortestosterone derivatives displayed high binding affinity for the human PR, that of Z-IPG1 and E- and Z-IPG2 being even higher than that of ORG2058. Their affinities for the rat PR were somewhat lower, especially those of both E-isomers. The affinity of IPG3 was lower for both the human and rat PR. The nortestosterone derivatives also showed AR binding, the relative binding affinities ranging from 4.3 to 17.0% as compared with 5alphaDHT. Additionally, neither of these steroids displayed any significant binding to either SHBG or CBG in human plasma. We conclude that the in vitro binding properties of all four 17alpha-iodovinyl nortestosterone derivatives warrant evaluation of the distribution characteristics of their 123I-labelled analogues to determine their usefulness as PR imaging agents.

New iodinated progestins as potential ligands for progesterone receptor imaging in breast cancer. Part 2: In vivo pharmacological characterization.

On the basis of the observed high selective binding to both the human and rat progesterone receptor (PR) in vitro, three 17alpha-iodovinyl-substituted nortestosterone derivatives, i.e., the Z-isomer of 17alpha-iodovinyl-19-nortestosterone (Z-IVNT; Z-IPG1) and both the stereoisomers of 17alpha-iodovinyl-18-methyl-11-methylene-19-nortestosterone (E- and Z-IPG2), were selected for radio-iodination and subsequently evaluated as potential radioligands for PR imaging in human breast cancer. Their target tissue uptake, retention, and uptake selectivity were studied in female rats. The distribution studies revealed that PR-mediated uptake in the uterus and ovaries could only be demonstrated for Z-[123I]IPG2. The target tissue uptake selectivity was, however, low, with the highest uterus-to-nontarget tissue uptake ratios observed at 2-4 h postinjection (p.i.), being 4.4, 1.8, and 7.4 for the uterus-to-blood, -fat, and -muscle ratio, respectively. For Z-[123I]IPG2, distribution was also studied in dimethylbenzanthracene (DMBA)-induced mammary tumour-bearing rats and in normal rabbits. Mammary tumour uptake of Z-[123I]IPG2 in the mammary tumour-bearing rat was also found to be PR-specific. In rabbits, higher selective target tissue uptake of Z-[123I]IPG2 was observed than in rats, resulting in uterus-to-blood, -fat, and -muscle ratios of 6.6, 2.2, and 21.3 at 2-4 h p.i., respectively. In conclusion, Z-[123I]IPG2, which displayed high binding affinity for both the human and rat PR in vitro, showed specific PR-mediated target tissue uptake in rats and rabbits in vivo, the uptake selectivity being highest in the latter. Because the binding characteristics appeared to vary between species, a pilot study in breast cancer patients may be needed to decide whether Z-[123I]IPG2 can be of potential use as PR imaging agent in breast cancer.

Synthesis, estrogen receptor binding, and tissue distribution of a new iodovinylestradiol derivative (17alpha,20E)-21-[123I]Iodo-11beta-nitrato-19-norp regna-1,3,5 (10),20-tetraene-3,17-diol (E-[123I]NIVE).

We have synthesized and evaluated E-11beta-nitrato-17alpha-iodovinylestradiol (E-NIVE; E-3c) and its 123I-labelled form, as a new potential radioligand for imaging of estrogen receptor (ER)-positive human breast tumors. E-[123I]NIVE was prepared by stereospecific iododestannylation of the E-tri-n-butylstannylvinyl precursor (E-2c), obtained from reaction of 11beta-nitrato-estrone (8) with E-tributylstannylvinyllithium. In competitive binding studies, E-NIVE proved to have high binding affinity for both the rat and the human ER (Ki 280-730 pM), without significant binding to human sex hormone binding globulin. Distribution studies in normal and mammary tumor-bearing rats showed specific ER-mediated uptake of E-[123I]NIVE in the estrogen target tissues, i.e., uterus, ovaries, pituitary, and hypothalamus, but not in the mammary tumors. Selective retention in these target tissues, including tumor tissue, resulted in significant increases over time for the target tissue-to-muscle uptake ratios, but not for the target tissue-to-fat uptake ratios. The tumor-to-fat uptake ratio even appeared constantly below 1. In the primary estrogen target tissues, E-[123I]NIVE displayed high specific ER-mediated uptake and retention, which resulted in moderate target-to-nontarget tissue uptake ratios. In contrast, in tumor tissue, E-[123I]NIVE uptake appeared to be rather low and not ER-specific. As a consequence, E-[123I]NIVE appears to be a less favorable radioligand for ER imaging in breast cancer than the previously studied stereoisomers of 11beta-methoxy-17alpha-[123I]iodovinylestradiol (E- and Z-[123I]MIVE; [123I]E- and [123I]Z-3b).

The interrelationship between income, health and employment status.

BACKGROUND: The aim of the study was to test the hypothesis that the relatively strong association between income and health compared to that between education/occupation and health, can partly be interpreted in terms of an association between employment status and health. METHODS: Health indicators used were the prevalence of one or more chronic conditions, and perceived general health. Data were generated from a postal survey, part of the baseline data collection of a Dutch prospective cohort study on socioeconomic inequalities in health. RESULTS: After controlling for differences in other socioeconomic indicators, the association between income and health was found to be stronger than that between occupation or education and health. Most of the difference in strength was found to be due to employment status, especially among men. Controlling for employment status, and controlling for the distribution of those with a long-term work disability in particular, reduced the risks of lower income groups, whereas the risks of lower educational and occupational groups hardly changed. CONCLUSIONS: These results suggest that the relatively strong association between income and health can for a large part be interpreted in terms of an interrelationship between employment status, income and health. More specifically, it is largely due to the concentration of the long-term disabled in lower income groups. This indicates the importance of the selection mechanism, as these groups are excluded from paid employment because of their health status, leading to a lowering of income. However, income was still found to be related to perceived general health after controlling for employment status especially among women. This suggests that an explanation in terms of an effect of material factors on health may also be important.

Socio-economic differences in general practitioner and outpatient specialist care in The Netherlands: a matter of health insurance?

Equal treatment for equal needs, irrespective of socio-economic position, is a major issue in many countries. Although in the Netherlands differences in utilization of health care between population groups are less pronounced than in most other countries, some differences by socio-economic position do exist. Controlling for health status, individuals with a high socio-economic status have a higher probability of outpatient contacts with a specialist, but a lower probability of general practitioner contacts, compared with those with a low socioeconomic status. In this cross-sectional study, we studied whether socio-economic differences in GP and outpatient specialist care utilization that exist after health status is taken into account could be explained by different aspects of health insurance. The study population, in which people with asthma and chronic obstructive pulmonary disease (COPD), diabetes mellitus, severe back complaints, and heart diseases are overrepresented, consists of 2867 respondents. Multivariate analyses show that the socio-economic differences in outpatient specialist contacts cannot be explained by differences in health insurance, whereas differences in general practitioner contacts can partially be explained by the fact that individuals with higher socio-economic status more often have a private (instead of public) insurance. This is not owing to differences in deductible or insurance coverage between public and private insurance, but is more likely to be caused by differences in regulatory aspects between these two insurance schemes (such as the stronger gate-keeper role of the general practitioner in the public insurance scheme.

Development of radioligands for the imaging of cardiac beta-adrenoceptors using SPECT. Part I: Asymmetric synthesis and structural characterization of five new iodine-containing beta-adrenoceptor antagonist derivatives.

The asymmetric synthesis of a series of iodinated beta-adrenoceptor ligands is described. One ligand, (S)-(-)-[1-(2-iodophenoxy)]-3'-(tert-butylamino)-2'-propanol (CYBL3), is based on the beta-adrenoceptor antagonist penbutolol. The other ligands are N-iodovinyl and N-iodoaryl analogues of the beta-adrenoceptor antagonist CGP12177. These have been synthesized from 2-amino-3-nitrophenol. Furthermore, radioiodinated [123I]CYBL3 and [123I](2'S,2"E)-[4-(3'-(1",1"-dimethyl-3"-iodo-2" propenylamino)-2'-hydroxy propoxy)]-benzimidazol-2-one have been prepared by radiolabelling the corresponding trialkyltin precursors using [123I]-NaI in the presence of hydrogen peroxide.

Development of radioligands for the imaging of cardiac beta-adrenoceptors using SPECT. Part II: Pharmacological characterization in vitro and in vivo of new 123I-labeled beta-adrenoceptor antagonists.

Cardiac beta-adrenoceptors are assumed to play a key role in chronic heart failure. Although several radioligands labeled with 11C or 18F have been synthesized for imaging purposes with positron emission tomography (PET), so far no optimal ligands are available to image cardiac beta-adrenoceptors using single photon emission tomography (SPECT). In the present study, we characterized four new synthesized analogues of the nonselective beta-adrenoceptor antagonist 4-(3-t-butylamino-2-hydroxypropoxy)-benzimidazol-2-one (CGP12177) and one analogue of the nonselective beta-adrenoceptor antagonist penbutolol. Using classical in vitro displacement studies with left ventricular tissue of New Zealand White rabbits and [125I]iodocyanopindolol as a radioligand, binding affinity to the receptor was determined. From the four analogues, only (2'S,2"E)- [4-(3'-(1",1"-dimethyl-3"-Iodo-2" propenylamino)-2'-hydroxypropoxy)]-benzimidazol-2-one proved to have a high affinity, with Ki = 1.25 +/- 0.09 nM, n = 3. The other analogues showed relatively low affinity, with Ki-values > 1 nM. The analogue of penbutolol ((S)-(-)-[1-(2-Iodophenoxy)]-3'-(tert-butylamino)-2'-propanol) also showed a Ki value of 0.64 +/- 0.26 nM, n = 3. Subsequently, (2'S,2"E)-[4-(3'-(1",1"-dimethyl-3"-Iodo-2" propenylamino)-2'-hydroxypropoxy)]-benzimidazol-2-one and (S)-(-)-[1-(2-Iodophenoxy)]-3'-(tert-butylamino)-2'-propanol were radioactively labeled with 123I to study their biodistribution in New Zealand White rabbits and to determine specific binding. Significant uptake was observed in both lungs and left ventricles. However, both compounds showed high nonspecific binding in vivo because uptake of the radioligand could not be inhibited by preinjection of different (selective- and nonselective-adrenoceptor antagonists and hydrophilic and lipophilic antagonists) antagonists. In conclusion, although two analogues showed reasonable affinity in vitro for the receptor, their binding in vivo proved to be largely nonspecific, suggesting that these two compounds are unsuitable for imaging purposes. However, because marked differences in affinity for the receptor were observed with only little structural changes between compounds, the present results offer future perspectives for the synthesis of a more specific radioligand.

Differences in the effect of allergen avoidance on bronchial hyperresponsiveness as measured by methacholine, adenosine 5'-monophosphate, and exercise in asthmatic children.

Asthma is now considered as an inflammatory airway disease. There is evidence that allergen avoidance reduces clinical symptoms in atopic asthma. We investigated the effect of a month's stay in the hypoallergenic environment of Davos, Switzerland (1560 m) which is relatively free of house dust mite (HDM) on changes in bronchial hyperresponsiveness (BHR), using the challenge tests of adenosine 5'-monophosphate (AMP), exercise and methacholine to test for BHR. Thirteen asthmatic children with an allergy to HDM participated in the study. We measured BHR on admission to the Davos Asthma Center and after 1 month in the house dust-free environment. The medications used by the patients at the time of admission were kept unchanged during this month. No significant difference in BHR was found to methacholine challenge after a 1-month stay at high altitude (P > 0.05). By contrast, the response to AMP was significantly different as indicated by displacement of the dose-response curve to the right by 2.15 doubling concentrations (P = 0.005). We also observed a significant difference in response to exercise (P = 0.03). These results indicate that a month's stay in a hypoallergenic environment caused a reduction in BHR to AMP and exercise, but not to methacholine. In addition, the results support the concept of differences in trigger mechanisms for BHR, and that responses to a methacholine challenge are not the same as responses to an exercise challenge. The observed reduction in BHR in asthmatic children to the indirect bronchial stimuli of AMP and exercise suggest reduced airway inflammation following avoidance of house dust aeroallergens. AMP and exercise challenges may therefore be better indicators of asthmatic airway inflammation than the direct stimulus of methacholine.

Synthesis and in vitro and in vivo characteristics of an iodinated analogue of the beta-adrenoceptor antagonist carazolol.

A new (radio)iodinated, beta-adrenoceptor ligand, (S)-(-)-4-[3-[(1,1-dimethyl-3-iodo-(2E)-propenyl)-amino]-2- hydroxypropoxy]carbazole (CYBL8E, 1), was prepared. 1 is an iodinated analogue of the high-affinity beta-adrenoceptor antagonist carazolol (2). The asymmetric synthesis was achieved in four steps starting from 4-hydroxycarbazole. The iodine-123-labeled form was obtained by an iododestannylation reaction with [123I]NaI in the presence of H2O2. Using classical in vitro displacement experiments with membrane fractions of cardiac left ventricular muscle, 1 proved to have a high affinity for the receptor (Ki = 0.31 +/- 0.03). Biodistribution studies performed in New Zealand white rabbits demonstrated the specificity of the binding in vivo to the receptor. Uptake of [123I]1 was reduced significantly in both atrial muscle, left ventricular muscle, frontal cortex, cerebellum, and striatum, by the pretreatment of the animals with different beta-adrenoceptor antagonists. In conclusion, 1 is a potent nonselective beta-adrenoceptor antagonist, which binds specifically to the beta-adrenoceptor in vivo, and is therefore a promising radioligand for the imaging of beta-adrenoceptors using single photon emission computerized tomography.

Socioeconomic differences in the utilization of health services in a Dutch population: the contribution of health status.

The main question addressed here is to what extent socioeconomic differences in the utilization of health services in the Netherlands can be explained by health status. Our aim is to assess whether the health services has achieved equal assess for equal needs, and which health status measures best control for need. Cross-sectional survey data from 2867 respondents with respect to utilization of six different types of health services are used for analysis. Socioeconomic differences in utilization were present for all services after we controlled for age, sex and marital status. By controlling for health status, differences changed markedly for all health services analyzed. Differences in general practitioner contacts diminished but did not disappear (adjusted odds ratio primary education/university 2.22). The pattern of excess contacts with specialist physicians reverses (adjusted odds ratio 0.74). This is also true for the physiotherapist. The pattern of hospitalizations is unclear. Use of over-the-counter medicines is little affected by control for health status. Adjusted differences in use of prescription medicines become small. Control for health status is best achieved with a set of health measures covering several dimensions of health. Whether low relative utilization among those with low education reflects limited access, or whether higher use of other services is compensatory is hard to decide on the basis of the study. Monitoring access to health care is important for all sorts of systems, including those which are believed to be equitable.

Effect of allergen avoidance at high altitude on direct and indirect bronchial hyperresponsiveness and markers of inflammation in children with allergic asthma.

BACKGROUND: Improvement of allergic asthma is seen at high altitude partly because of low concentrations of allergen, especially house dust mite. To investigate the effect of a hypoallergenic environment (Davos, 1560 m) on airways inflammation, the changes in bronchial hyperresponsiveness measured with methacholine and adenosine 5'-monophosphate (AMP), blood eosinophils, eosinophil cationic protein (ECP), and serum IgE were studied. METHODS: In 16 allergic asthmatic children tests were performed on admission and after one month. Medication was kept unchanged during the month of investigation and the patients performed peak expiratory flow (PEF) measurements twice daily. RESULTS: After one month at high altitude a considerable improvement was seen in the provocative concentration of AMP causing a 20% fall in forced expiratory volume in one second (PC20 AMP), but not with methacholine. There was also a reduction in total blood eosinophils and ECP. No change in serum IgE was observed. Peak flow variability decreased. CONCLUSIONS: After one month at high altitude a reduction in airways inflammation occurs. The results indicate that AMP responsiveness is a more accurate marker of disease activity in relation to inflammation in asthma than methacholine. The benefits of allergen avoidance at high altitude have important clinical implications for children with allergic asthma.

Pharmacologic characterization in vitro and in vivo of iodine 123-labeled derivatives of the beta-adrenoceptor antagonist CGP12177, designed for the imaging of cardiac beta-receptors.

BACKGROUND: Potential new radioligands for the noninvasive imaging of cardiac beta-adrenoceptors with single-photon emission computed tomography were investigated. METHODS AND RESULTS: Two iodinated derivatives of CGP12177 para (S-CYBL2B) and ortho (CYBL2A) substituted CGP12177 and an iodinated form of nadolol (CYBL1) were synthesized. Their affinity was tested in vitro (left ventricular homogenates). The biodistribution of [123I]S-CYBL2B was evaluated in rabbits. Specific binding was assessed by pretreatment of the animals with 0.1 mumol propranolol. The inhibition constant values (in nanomolars, means +/- SEM; n = 3 to 5) were determined at 1.17 +/- 0.42, 28800 +/- 9260, 11.1 +/- 2.1, 53.0 +/- 19.9, and 1790 +/- 700 for CGP12177, CYBL2A, S-CYBL2B, nadolol, and CYBL1. Myocardial uptake of [123I]S-CYBL2B was not inhibited by pretreatment of the animals with propranolol, but uptake by lung tissue could be blocked by propranolol (0.63% +/- 0.09% vs 0.33% +/- 0.02% % injected dose/g x kg; p < 0.05). In isolated right atria, preincubation with S-CYBL2B induced a parallel rightward shift of the concentration-response curve with isoprenaline. CONCLUSIONS: S-CYBL2B shows high affinity for cardiac beta-adrenoceptors, but binding proved nonspecific in vivo, whereas binding in lung tissue was specific. These results suggest that S-CYBL2B is probably not a suitable radioligand for receptor imaging.

Vertical temperature profiles at bird level in broiler houses.

1. The temperature in the close vicinity of commercial broilers was studied in relation to the setpoint temperature throughout the rearing period. 2. Mean temperature in the immediate environment of the chicks was 2.0 degrees C lower than the setpoint of 1 d of age. During the first week this initial temperature difference gradually rose to l.7 degrees C above setpoint. At 18 d of age a further rise to a mean difference of 4.0 degrees C above setpoint was measured. The difference then remained constant from 32 d of age until the end of the fattening period. 3. It was concluded that the chickens were actually brooded at 30 degrees C. During the rearing period the ambient temperature in the close vicinity of the broilers gradually declined to 26 degrees C. 4. During the finishing period, ambient temperature around the broilers was far above the value recommended for optimal food intake and growth. 5. These results are discussed in relation to heat generation and heat fluxes in the broiler houses.