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Aims: Tobacco-smoking behaviours of young people between the age of 18 and 25 years are less understood than those of middle-aged people. The aim of this study is to contribute to improved knowledge of some of the factors that are associated with smoking and cessation among young people., Methods: We use the most recently available public health survey data from the southern region of Skåne in Sweden to analyze these factors. The survey is a cross-sectional study with a total sample size of 28,198 individuals with 2801 in the age category of interest. We apply statistical measures of association between smoking and gender and also model the relationship between smoking and smoking cessation and the role of a set of sociodemographic determinants by means of logistic regression to estimate odds ratios., Results: The findings include significant differences between the younger age group and the older group with respect to the odds of smoking and method of cessation. We also find differences between young women and men with regard to smoking prevalence, intensity and cessation methods. In particular, young women attempt to quit smoking by means of unassisted methods to a significantly higher extent than do young men., Conclusions: There are significant differences between young people and older individuals with respect to a range of smoking behaviours. There are also strong gender effects within the group of young people. Policy development and anti-smoking interventions need to take such differences into consideration for improved effectiveness.

Context: Hypothalamic damage caused by craniopharyngioma (CP) is associated with poor functional outcome., Objective: To assess cognitive function and quality of life in childhood-onset CP on hormonal replacement, including GH treatment., Design: A cross-sectional study with a median follow-up time of 20 years (1-40)., Setting: Patients were recruited from the South Medical Region of Sweden., Participants: The study included 42 patients (20 women) surgically treated for a childhood-onset CP between 1958 and 2000. Patients were aged ≥17 years. Equally many controls, matched for age, sex, residence, and smoking habits, were included. Tumor growth into the third ventricle was found in 25 patients., Main Outcome Measures: All subjects were examined with a battery of cognitive tests and the following questionnaires: Symptom Checklist-90, the Interview Schedule for Social Interaction, and the Social Network concept., Results: The CP patients had lower cognitive performance, reaching statistical significance in 12 of 20 test variables, including executive function and memory. Comparison of patients with tumor growth into the third ventricle to controls revealed a significant lower mean total score (P = .006). A significant negative correlation was recorded between mean z-score of cognitive performance and years since operation (r = -0.407; P = .014). No statistically significant group differences were observed across any of the 9 Symptom Checklist-90 subscales., Conclusions: Adults with childhood-onset CP, on hormone replacement, including GH treatment, have memory defects, disturbed attention, and impaired processing speed. Patients with hypothalamic involvement are more affected. Patients rated their quality of life as good as their matched controls.

Context: The psychosocial health and working capacity in hypopituitary patients receiving long-term growth hormone (GH) therapy are unknown., Objective: Psychosocial health and levels of employment were compared between GH deficient (GHD) patients on long-term replacement and the general population., Design and Participants: In a Swedish nationwide study, 851 GHD patients [101 childhood onset (CO) and 750 adult onset (AO)] and 2622 population controls answered a questionnaire regarding current living, employment and educational level, alcohol consumption and smoking habits. The median time on GH therapy for both men and women with CO GHD was 9 years and for AO GHD 6 years, respectively., Results: As compared to the controls, the GHD patients were less often working full time, more often on sick leave/disability pension, and to a larger extent alcohol abstainers and never smokers (all; P<0.05). Predominantly CO GHD women and men, but to some extent also AO GHD women and men, lived less frequently with a partner and more often with their parents. Particularly AO GHD craniopharyngioma women used more antidepressants, while AO GHD men with a craniopharyngioma used more analgesics., Conclusions: A working capacity to the level of the general population was not achieved among hypopituitary patients, although receiving long-term GH therapy. Patients were less likely to use alcohol and tobacco. The CO GHD population lived a less independent life., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Increased levels of prolactin often coincide with an increased risk for thromboembolic events, but it is unclear whether a direct causal relation exists. Our aim was to examine the effect of prolactin on platelet function. In addition to using recombinant prolactin for experiments in vitro, we analyzed platelet function by flow cytometry in a group of 13 females with hyperprolactinaemia and 18 healthy female controls. Platelet activation was measured by P-selectin expression and by the amount of platelet-bound fibrinogen after stimulation with adenosine di phosphate (ADP), collagen-related peptide and the protease activated receptor (thrombin receptor) (PAR)-activating peptides PAR4-AP and PAR1-AP. Free oscillation rheometry was used to measure clotting time in whole blood. No significant effect on platelet activation or clotting time could be seen in in vitro experiments by adding recombinant prolactin. However, significantly lower P-selectin expression was found in the hyperprolactinemic group when platelets were activated by ADP (5 and 10 μM) or PAR4-AP. The expression of fibrinogen did not differ between the two groups for any of the activators used. For all samples, inverse significant correlations between P-selectin expression and prolactin concentration were found for both 5 μM ADP (r = - 0.61, p < 0.01), 10 μM ADP (r = - 0.62, p < 0.001) and PAR4-AP (r = - 0.69, p < 0.001). Thrombin cleavage of recombinant prolactin resulting in a 16 kDa C-terminal fragment did not alter the P-selectin expression upon activation. We found an indirect inhibitory effect of prolactin on platelets in hyperprolactinemic patients, suggesting that prolactin might have a protective role in thromboembolic disease.

Introduction: Pulmonary carcinoids associated with ectopic adrenocorticotropic hormone secretion have a good prognosis if histological examination shows typical pulmonary carcinoid and low proliferation, whereas a poor outcome is linked to atypical pulmonary carcinoid and high proliferation. Here we describe the diagnostic challenges to find the tumor in Cushing's syndrome secondary to ectopic adrenocorticotropic hormone secretion in two cases with an atypical and a typical pulmonary carcinoid, respectively., Case Presentation: A 63-year-old Caucasian woman presented with aggressive clinical features related to Cushing's syndrome, having very high levels of urinary cortisol and circulating adrenocorticotropic hormone and cortisol. Magnetic resonance imaging showed no pituitary tumor, and bilateral inferior petrosal sinus sampling revealed no central peripheral ratio of adrenocorticotropic hormone. Computed tomography and 111Indium-pentetreoide somatostatin receptor scintigraphy could not visualize any ectopic tumor. The patient was referred for an 11C-5-hydroxytryptophan positron emission tomography, and a small 8mm nodule in her left lung was found. The tumor was removed via a lateral thoracic incision and wedge excision. The histological examination showed an atypical carcinoid with Ki-67 index of 9 to 10%, and an additional lobectomy was performed.The second patient, a 22-year-old Caucasian man, also presented with aggressive Cushing's syndrome, with very high urinary cortisol levels and increased circulating cortisol as well as adrenocorticotropic hormone levels. A magnetic resonance imaging scan of the pituitary showed no tumor, whereas a 12×9×14mm tumor was detected in the right lung on the primary computed tomography scan and no further investigation was performed. The tumor was removed via a lateral thoracic incision and wedge excision. A typical carcinoid with Ki-67 index of 1 to 2% was found and no further surgery was performed.After surgical removal, the biochemical disturbances resolved and significant clinical improvement were achieved in both patients after 24 months of follow up., Conclusions: Diagnostic evaluation time is limited due to the aggressive course in ectopic adrenocorticotropic hormone-dependent Cushing's syndrome. We suggest that 11C-5-hydroxytryptophan positron emission tomography could be considered early as a secondary diagnostic tool when primary computed tomography and/or magnetic resonance imaging scans fail to show any tumor.

Context: Current guidelines on how to divide the daily cortisol substitution dose in patients with primary adrenal insufficiency (PAI) are controversial and mainly based on empirical data., Objective: To assess how an equal dose of hydrocortisone (HC) given either four times daily or twice daily influence diurnal profiles of cortisol and ACTH, patient preferences and health-related quality of life (HRQoL)., Design: Double blind, crossover., Methods: Fifteen patients with PAI (six women) were included. Capsules of HC or placebo were given at 07:00, 12:00, 16:00 and 22:00 h in 4-week treatment periods: either one period with four doses (10 + 10 + 5 + 5 mg) or one period with two doses (20 + 0 + 10 + 0 mg). Diurnal profiles of cortisol and ACTH were collected, and area under the curve (AUC) was calculated. Questionnaires were used to evaluate patient preferences and HRQoL., Results: The four-dose regimen gave a higher serum cortisol before tablet intake in the morning (P = 0·027) and a higher 24-h cortisol(AUC) (P < 0·0001) compared with the two-dose period. In contrast, a lower median plasma ACTH in the morning before tablet intake (P = 0·003) and a lower 24-h ln(ACTH(AUC) ) were found during the four-dose period. The patients preferred the four-dose regimen (P = 0·03), and the HRQoL scores tended to be higher (high score indicates better HRQoL) for the four-dose period. In summary, a four-dose regimen gives increased availability of cortisol and an enhanced effect with a less elevated ACTH in the morning in comparison with a two-dose regimen but the effect on HRQoL remains inconclusive., (© 2012 Blackwell Publishing Ltd.)

Context: Data on bone mineral density (BMD) are lacking in adults with childhood onset (CO)-craniopharyngioma (CP) with hypothalamic damage from the tumor. In patients with CO GH deficiency, BMD increases during GH treatment., Objective: The aims were to evaluate BMD in adults with CO-CPs on complete hormone replacement, including long-term GH and to evaluate the impact of hypothalamic damage on these measures., Design and Participants: BMD (dual-energy X-ray absorptiometry), markers of bone turn over, physical activity and calcium intake were assessed in 39 CO-CP adults (20 women), with a median age of 28 (17-57) years, in comparison with matched population controls., Results: Late puberty induction was recorded in both genders, but reduced androgen levels in females only. Only CP women had lower BMD (P=0.03) at L2-L4, and reduced Z-scores at femoral neck (P=0.004) and L2-L4 (P=0.004). Both genders had increased serum leptin levels (P=0.001), which significantly correlated negatively with BMD at L2-L4 (P=0.003; r=-0.5) and 45% of CP women had Z-score levels ≤-2.0 s.d. Furthermore, 75% of those with a Z-score ≤-2.0 s.d. had hypothalamic involvement by the tumor. Calcium intake (P=0.008) and physical activity (P=0.007) levels were reduced in CP men only. Levels of ostecalcin and crossLaps were increased in CP men only., Conclusions: Despite continuous GH therapy, low BMD was recorded in CO-CP females. Insufficient estrogen and androgen supplementation during adolescence was the main cause, but hypothalamic involvement with consequent leptin resistance was also strongly associated with low BMD in both genders.

Context: Obesity is a frequent manifestation of hypothalamic damage from a craniopharyngioma (CP). It is not yet clarified whether the obesity is due to alterations in energy expenditure, i.e. basal metabolic rate (BMR) and physical activity, or to increased energy intake (EI)., Objective: The aim was to investigate whether energy expenditure and EI differed between childhood onset CP patients and matched population controls and whether these measures were related to hypothalamic damage, as tumor growth into the third ventricle (TGTV)., Design and Methods: Forty-two CP patients (20 women) aged 28 yr (range, 17-57 yr) operated between 1958 and 2000 in the South Medical Region of Sweden (population, 2.5 million) were studied. Body composition, satiety hormones, BMR (indirect calorimetry), physical activity, EI, and attitudes toward eating were assessed. Comparisons were made with matched controls and between patients with (n=25) and without (n=17) TGTV., Results: After adjustment, patients had lower BMR compared to controls (-90 kcal/24 h; P=0.02) and also had lower EI (1778 vs. 2094 kcal/24 h; P=0.008), and the EI/BMR ratio was significantly lower in TGTV patients. Similar dietary macronutrient composition was found, and only significantly higher scales in restricting food intake were recorded in patients. Ghrelin levels were significantly lower in patients, whereas serum insulin and leptin levels were higher (P<0.001), and both ghrelin and insulin correlated significantly to tumor growth. Lower levels of physical activity (P<0.01) were recorded in patients., Conclusions: The major mechanisms that reinforced obesity were hypothalamic damage causing disrupted or impaired sensitivity to feeding-related signals for leptin, insulin, and ghrelin, and reductions in both BMR and physical activity.

Context: Craniopharyngioma patients without GH therapy are at an increased cardiovascular disease (CVD) risk and particularly concerning women. No previous study on long-term GH therapy in adults with childhood onset (CO) craniopharyngioma was identified., Objective: To investigate CVD risk in adults with CO craniopharyngioma on complete hormone replacement, including long-term GH therapy, and to investigate the impact of disease-related factors on CVD risk., Design and Participants: In a cross-sectional study of operated CO craniopharyngiomas (1958-2000) from a defined area of Sweden (2.5 million), we enrolled 42 patients (20 women) with a median age of 28 years (range 17-57) and assessed CVD risk of 20 (4-40) years after first operation. Comparisons were made with matched controls and between patients with tumor growth into the third ventricle (TGTV) versus non-TGTV. GH therapy was 10-12 years in women and men. Results In comparison with controls, both male and female patients had increased body mass index, fat mass, insulin, and leptin levels. Overall, while not significantly increased in male patients, 55-60% of female patients had a medium-high CVD risk, compared with 10-20% in controls. An increased CVD risk (all P<0.05) and higher levels of fat mass and insulin were recorded in the TGTV group versus the non-TGTV group. Late puberty induction and lack of androgens were shown in female patients., Conclusions: Adult patients with CO craniopharyngioma, especially those with TGTV, have persistently increased CVD risk. Conventional hormone substitution, including GH, is insufficient to normalize CVD risk, suggesting an important role for irreversible hypothalamic dysfunction.

Background: Vietnam introduced the Health Care Fund for the Poor in 2002 to increase access to health care and reduce the financial burden of health expenditure faced by the poor and ethnic minorities. It is often argued that effects of financing reforms take a long time to materialize. This study evaluates the short-term impact of the program to determine if pro-poor financing programs can achieve immediate effects on health care utilization and out-of-pocket expenditure., Method: Considering that the program is a non-random policy initiative rolled out nationally, we apply propensity score matching with both single differences and double differences to data from the Vietnam Household Living Standards Surveys 2002 (pre-program data) and 2004 (first post-program data)., Results: We find a small, positive impact on overall health care utilization. We find evidence of two substitution effects: from private to public providers and from primary to secondary and tertiary level care. Finally, we find a strong negative impact on out-of-pocket health expenditure., Conclusion: The results indicate that the Health Care Fund for the Poor is meeting its objectives of increasing utilization and reducing out-of-pocket expenditure for the program's target population, despite numerous administrative problems resulting in delayed and only partial implementation in most provinces. The main lessons for low and middle-income countries from Vietnam's early experiences with the Health Care Fund for the Poor are that it managed to achieve positive outcomes in a short time-period, the need to ensure adequate and sustained funding for targeted programs, including marginal administrative costs, develop effective targeting mechanisms and systems for informing beneficiaries and providers about the program, respond to the increased demand for health care generated by the program, address indirect costs of health care utilization, and establish and maintain routine and systematic monitoring and evaluation mechanisms.

For women and children, especially those who are poor and disadvantaged, to benefit from primary health care, they need to access and use cost-effective interventions for maternal, newborn, and child health. The challenge facing weak health systems is how to deliver such packages. Experiences from countries such as Iran, Malaysia, Sri Lanka, and China, and from projects in countries like Tanzania and India, show that outcomes in maternal, newborn, and child health can be improved through integrated packages of cost-effective health-care interventions that are implemented incrementally in accordance with the capacity of health systems. Such packages should include community-based interventions that act in combination with social protection and intersectoral action in education, infrastructure, and poverty reduction. Interventions need to be planned and implemented at the district level, which requires strengthening of district planning and management skills. Furthermore, districts need to be supported by national strategies and policies, and, in the case of the least developed countries, also by international donors and other partners. If packages for maternal, newborn and child health care can be integrated within a gradually strengthened primary health-care system, continuity of care will be improved, including access to basic referral care before and during pregnancy, birth, the postpartum period, and throughout childhood.

Unlabelled: Fracture risk in GHD patients is not definitely established. Studying fracture incidence in 832 patients on GH therapy and 2581 matched population controls, we recorded a doubled fracture risk in CO GHD women, but a significantly lower fracture risk in AO GHD men., Introduction: The objective of this study was to evaluate fracture incidence in patients with confirmed growth hormone deficiency (GHD) on replacement therapy (including growth hormone [GH]) compared with population controls, while also taking potential confounders and effect modifiers into account., Materials and Methods: Eight hundred thirty-two patients with GHD and 2581 matched population controls answered a questionnaire about fractures and other background information. Incidence rate ratio (IRR) and 95% CI for first fracture were estimated. The median time on GH therapy for childhood onset (CO) GHD men and women was 15 and 12 yr, respectively, and 6 and 5 yr for adult onset (AO) GHD men and women, respectively., Results: A more than doubled risk (IRR, 2.29; 95% CI, 1.23-4.28) for nonosteoporotic fractures was recorded in women with CO GHD, whereas no risk increase was observed among CO GHD men (IRR, 0.61) and AO GHD women (IRR, 1.08). A significantly decreased incidence of fractures (IRR, 0.54; 95% CI, 0.34-0.86) was recorded in AO GHD men., Conclusions: Increased fracture risk in CO GHD women can most likely be explained by interaction between oral estrogen and the GH-IGF-I axis. The adequate substitution rate of testosterone (90%) and GH (94%) may have resulted in significantly lower fracture risk in AO GHD men.

Objectives: The purpose of the study is to quantitatively analyze the role of health insurance in the determinants of catastrophic health payments in a low-income country setting., Methods: The study uses the most recent publicly available household level data from Zambia collected in 1998 containing detailed information on health care utilization and spending and on other key individual, household, and community factors. An econometric model is estimated by means of multivariate regression., Results: The main results are counterintuitive in that health insurance is not found to provide financial protection against the risk of catastrophic payments; indeed, insurance is found to increase this risk., Conclusions: Reasons for the findings are discussed using additional available information focusing on the amount of care per illness episode and the type of care provided. The key conclusion is that the true impact of health insurance is an empirical issue depending on several key context factors, including quality assurance and service provision oversight.

Context: The impact of long-term GH replacement on cerebrovascular and cardiovascular diseases and diabetes mellitus in hypopituitary patients is unknown., Objective: The incidence of nonfatal stroke and cardiac events, and prevalence of type 2 diabetes mellitus (T2D) and cardioprotective medication were compared between cohorts of GH-deficient (GHD) patients and population controls., Design and Participants: The incidence of nonfatal stroke and cardiac events was estimated retrospectively from questionnaires in 750 GHD patients and 2314 matched population controls. A prevalence of T2D and cardioprotective medication was recorded at the distribution of questionnaires. Time since first pituitary deficiency to start of GH therapy was 4 and 2 yr, and time on GH therapy was 6 yr for GHD women and men, respectively., Results: Lifelong incidence of nonfatal stroke was tripled in GHD women and doubled in GHD men, but a decline was seen in both genders during periods after first pituitary hormone deficiency and GHD, during which most patients had GH therapy. The lifelong incidence of nonfatal cardiac events declined in GHD men during first pituitary hormone deficiency and GHD periods. GHD women had a higher prevalence of T2D and lipid-lowering medication, whereas GHD men had a higher prevalence of antihypertensive medication., Conclusions: The declined risks of nonfatal stroke in both genders and of nonfatal cardiac events in GHD men during periods on GH replacement may be caused by prescription of cardioprotective drugs and 6-yr GH replacement. GHD women had an increased prevalence of T2D, partly attributed to higher body mass index and lower physical activity.

Background: In human blood, there are several molecular variants of prolactin with different biological effects. There is a need for new methods to detect and quantify these variants in order to fully understand the pathophysiological role of prolactin., Methods: A method based on ultrafiltration was optimized, validated and compared to PEG precipitation. Serum samples from 84 patients were analyzed before and after pre treatment on two immunoassays, Elecsys (Roche) and Access (Beckman). Protein G precipitation was used to confirm presence of macroprolactin., Results: The recovery of prolactin after ultrafiltration was lower than after PEG precipitation. A limit of 40% recovery after PEG precipitation corresponded to 27% recovery after ultrafiltration. Using these limits there were total agreement regarding detection of macroprolactin (r(s)=0.96). In contrast, recovery of prolactin in samples without macroprolactin showed a considerable disagreement between ultrafiltration and PEG precipitation (r(s)=0.48). Within-run CV was 4% for the ultrafiltration method. The correlation coefficient (r) between the immunoassays was 0.96 after ultrafiltration., Conclusions: Ultrafiltration can be used to compare different prolactin immunoassays and to detect macroprolactin in assays with interference from PEG. For samples without macroprolactin ultrafiltration may give additional information reflecting individual variations of other molecular variants of prolactin.

We studied the effects of individualised growth hormone (GH) substitution, aiming at normal insulin-like growth factor I (IGF-I) levels, on biomechanical output and surface electromyogram (EMG) of isokinetic muscle strength and endurance performance in 18 hypopituitary adults and compared with 17 matched healthy controls. The muscle function tests consisted of isokinetic contractions of the right knee extensors, from which torque and EMG were recorded. Three patients were excluded from the final analysis of the muscle function tests due to technical errors and one control subject moved from the area during the study. We found that GH-deficient adults without GH substitution were weaker and had less endurance than healthy control subjects. At the group level, plasma levels of IGF-I were normalised but generally no significant effects upon biomechanical output and EMG were found after dose titration and 6 months of a constant GH dose. However, subjects with the largest changes in IGF-I had significantly better biomechanical output and EMG compared to those with small changes in IGF-I. This finding may indicate that the net increase in IGF-I levels is critical for improvements in biomechanical output, EMG and perception of fatigue to occur.

Objective: To study the effects of individualized recombinant GH substitution, aiming at normal circulating IGF-I levels, in GH-deficient adults on blood pressure, the renin-angiotensin-aldosterone system (RAAS), natriuretic peptides and urine free cortisol., Study Design: Open study with control group. The patients were titrated in dose steps of 0.17 mg GH/day every 6-8 weeks until an IGF-I level around the mean + 1 SD was attained (T(max)). After another month the dose was reduced by 0.17 mg (minimum dose 0.17 mg/day) to produce IGF-I levels at or slightly below the age-related mean (T(end)), and this maintenance dose was held constant for 6 months., Subjects: Eighteen patients (11 males and seven females) with GH deficiency participated. For comparison we also prospectively evaluated 17 matched control subjects., Measurements: Blood pressure and heart rate, circulating levels of IGF-I, plasma renin activity (PRA), immunoreactive active renin (IRR), angiotensin II, aldosterone, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and 24-h urine aldosterone and urine free cortisol levels., Results: Blood pressure was unchanged by GH substitution but heart rate increased significantly (P < 0.03). PRA was elevated on the highest GH dose (T(max)) compared to baseline (P < 0.01), but returned to baseline and levels of controls at (T(end)). Four patients developed transient oedema and tended to have higher PRA levels than the rest of the subjects (P = 0.09). The circulating levels of IRR, angiotensin II, aldosterone, BNP and 24-h urine aldosterone and urine free cortisol levels were unchanged by GH substitution, and did not differ from the levels in the control subjects. Baseline ANP levels in the patients were lower than in the controls (P < 0.01), but increased after GH substitution (P < 0.01) to levels found in with the controls., Conclusions: We found no major changes of the variables in the circulating renin-angiotensin-aldosterone system and a normalization of atrial natriuretic peptide when an individualized dose of GH was titrated to near-normal IGF-I levels.

Population-based reference values for IGF-I and IGF-binding protein-1 (IGFBP-1) have been established. One hundred and one women and the same number of men, 20-70 years old, were randomly selected from the population registry in the community of Linköping. Participation rate was 67%. Venous blood was drawn in the fasting state. Serum IGF-I was measured by RIA after acid-ethanol extraction and IGFBP-1 was determined by ELISA. IGF-I levels did not differ between genders and the decline with age was similar in men and women (men: Y = 366-3.28 x age (years), r = -0.61, P < 0.0001; women: Y = 386-3.49 x age, r = -0.57, P < 0.0001, P = 0.4 for difference in slope). There were negative correlations between IGF-I and plasma lipids and blood pressure in both genders, but none was independent of age. Serum angiotensin-converting enzyme activity correlated positively with IGF-I in men independently from age (r = 0.21, P = 0.01). The distribution of IGFBP-1 was positively skewed and it was higher in women than in men (5.9 +/- 4.8 micrograms/l and 4.0 +/- 3.3 micrograms/l respectively; Mann-Whitney, P = 0.002). In men and in the women not taking oestrogen, IGFBP-1 correlated positively with age (Spearman rank correlation (Spearman: men: r = 0.32, P = 0.002; women: r = 0.24, P = 0.03). C-peptide correlated negatively (Spearman: men: r = -0.38, P = 0.002; women: r = -0.49, P < 0.000) and sex hormone binding globulin positively with IGFBP-1 (Spearman: men: r = 0.50, P < 0.0001; women: r = 0.55, P < 0.0001). IGF-I declined with age while IGFBP-1, which is considered to modulate the free bioactive fraction of IGF-I, increased. This suggests that IGF-I activity might be even lower in elderly subjects than is accounted for by the low total IGF-I.

50 patients undergoing elective total hip replacement under epidural anesthesia and dextran infusion were given two doses of the vasopressin analogue desmopressin 0.3 micrograms/kg BW or placebo in a double-blinded randomized prospective study. Intraoperative blood loss and drainage loss did not differ significantly between groups, but desmopressin reduced the mean total blood loss (calculated from hemoglobin decrease and blood transfusions) by 310 mL (P less than 0.05).

Twelve patients undergoing total hip replacement, with regional anaesthesia and with dextran infusion for plasma expansion and thromboprophylaxis, were given the vasopressin analogue desmopressin (DDAVP) or placebo in a randomized, double-blind prospective study. In controls (n = 6) we found a prolongation of the bleeding time, low factor VIII (FVIII) and von Willebrand factor (vWF) and a decrease in antithrombin III to levels known to be at risk for venous thrombosis. Desmopressin shortened postoperative bleeding time, gave an early FVIII/vWF complex increase, prevented antithrombin III from falling to critically low values and appeared to activate the fibrinolytic system, both by tPA increase and PAI-1 decrease. Thus in the controls we found changes in both coagulation and fibrinolysis indicating a haemorrhagic diathesis as well as a risk for thromboembolism. Desmopressin induced factor changes that possibly reduce both risks.

Albumin can be immobilized in microparticles of poly-acrylamide in such a way that its ligand-binding properties are retained. With radiolabeled salicylic acid, warfarin, and tryptophan, the same characteristics are obtained for binding to albumin in the microparticles as in free solution. The particles can be used conveniently to determine association constants and the number of binding sites directly. The association constant of a competitive displacer can be determined indirectly as well, as shown with diazepam-salicylic acid and tryptophan-salicylic acid.

Proteins can be immobilized in spherical microparticles of polyacrylamide gel (having a diameter of about 1 microgram) by an emulsion--polymerization technique. Higher cross-linked gels have a structure consisting of relatively large pores. This structure is advantageous when dealing with biologically active proteins acting on molecules dissolved in the surrounding medium. A rapid equilibrium is established between the interior of the particles and the medium, and rate-limiting diffusion is not observed. A suspension of carbonic anhydrase immobilized in microparticles will thus have kinetic properties very much like the free enzyme. In addition to the entrapment of the protein molecules in the three-dimensional network formed by the polyacrylamide threads, protein molecules are also fixed in the cross-linked threads of polyacrylamide. This fixation is probably responsible for the improved stability of the protein molecules against heat denaturation. Not even autoclaving at 110 degrees for 30 min denatured the immobilized enzyme completely (more than 25% of the enzyme activity was left). The higher resistance of molecules in microparticles against proteolytic degradation also is documented.

Membrane-coated tablets were developed to provide a dosage form which exhibits zero-order kinetics. The delivery system consisted of a soluble tablet core surrounded by a porous membrane which controls the diffusion rate. In the system studied, the diffusion rate of potassium chloride was found to be more constant than with other controlled-release products and independent of pH changes within the physiological range. The release profile of a drug can be varied by changing the composition of the membrane. Substantial amounts of the active substance can be loaded into membrane-coated tablets. The membrane protects the gastric mucosa from direct contact with the undissolved active substance. This delivery system has a potential for use with all water-soluble agents where a controlled release is desirable.

Macromolecules can easily be incorporated in microparticles of polyacrylamide by copolymerization with acrylamide in a water-in-oil emulsion. The microparticles preferably arount 1-3 mum in diameter, will have a macroporous structure formed by the polymeric network. The amount of incorporation of the macromolecules will depend on the structure of the network, which, in turn, will depend on the total amount of monomer (T) and the relative amount of cross-linking agent (C) in the monomeric solution. Two mechanisms are responsible for the incorporation; all macromolecules are, independently of the size, fixed in the threads of polyacrylamide and large ones are entrapped within the network formed by the threads. The amount entrapped will depend on the size of the macromolecule and the mean pore radius of the gel. In microparticles with a total concentration of monomers of 8% and a cross-linking of 25% (T-C=8-25) the biological properties of incorporated macromolecules are retained, due to the macroporous structure, as found in binding studies with albumin. The density of the particles will also depend on C and T and, to some extent, on the protein concentration. Due to the fixation in the polyacrylamide threads, some of the incorporated macromolecules will be exposed on the surface, allowing them to react with, for instance, cells, which cannot penetrate the particles. The optimal conditions for the incorporation of macromolecules in the microparticles are investigated.

Reluctance about the identification marking of dentures has been the result of high costs and technical marking problems. The ID band system described here is inexpensive, fast, and requires no expensive special equipment. Embedding the band in a suitable part of the denture provides fully legible, radiopaque, lasting evidence of the denture wearer's identity. Since 1981, all dentures made in Sweden have been legally required to be marked.

The bioavailability and pharmacokinetics of salicylic acid (SA) were studied after single and multiple doses of a new slow-release formulation, based on porous membrane diffusion of sodium salicylate (NaSA). A solution of NaSA and an enteric-coated tablet of NaSA were used for comparison. Dissolution rate studies were carried out at various pH values, and both solid formulations showed pH-dependent release rates. The enteric-coated tablet released its content rapidly at intestinal pH but slowly and irregularly at gastric pH. The dissolution from the controlled-release formulation at intestinal pH was completed after 6h and the drug was delivered at a constant rate. At gastric pH the release rate was lower but complete release was obtained within 24h. The novel formulation appeared to offer complete bioavailability of SA and an even and sustained release of SA, allowing twice-daily medication without increased fluctuations in SA concentrations.

Macromolecules were immobilized by an emulsion polymerization technique in biodegradable microspheres of polyacryldextran, prepared by copolymerizing bisacrylamide with acryldextran. Such particles can be characterized by D-T-C expressions, where D denotes the concentration of derivatized dextran, T is the total concentration of acrylic compounds in the monomeric solution, and C denotes the fraction of cross-linker. In microparticles based on dextran T40 with a D-T-C of 11-1-75, the yield of immobilized protein was greater than in polyacrylamide particles. The properties of the immobilized proteins, e.g., Km and Vmax, were retained. The heat stability of the proteins was improved so that 5--10% of carbonic anhydrase still was active after 30 min at 100 degrees. However, the leakage of proteins from the polyacryldextran particles was greater than from polyacrylamide particles.

A clinically isolated strain of Escherichia coli, resistant to more than 1000 mg/l of trimethoprim, expressed chromosomal dihydrofolate reductase to a level 200-fold higher than that of drug sensitive E. coli K-12 strains, and this high cellular enzyme activity was found to increase further when the cells were cultured in the presence of trimethoprim. The induced increase in enzyme activity was dependent on the drug concentration. The increase was six-fold at 100 mg/l of trimethoprim. The aberrantly regulated dihydrofolate reductase gene mediating trimethoprim resistance could be transduced into E. coli K-12 or moved by recombination into an F' factor and then transferred into trans position in relation to the corresponding chromosomal gene. In either of these positions, the synthesis of dihydrofolate reductase could be induced to increase by adding trimethoprim to the culture medium. The observed induction was dependent on protein synthesis, since it could be abolished by chloramphenicol. No other folic acid analogue was found to induce increased expression of the dihydrofolate reductase gene. Also thymine starvation had no effect. Two further clinical isolates of E. coli, highly resistant to trimethoprim, were shown to produce drug resistant, plasmid-mediated dihydrofolate reductases, which were distinct from the earlier known enzyme types I and II.