Efficacy and safety of very early medical termination of pregnancy: a cohort study.

OBJECTIVE: To assess the efficacy and safety of medical termination of pregnancy (MTOP) when no intrauterine pregnancy (IUP) is confirmed on ultrasound. DESIGN: Retrospective case-note review. SETTING: Two gynaecological clinics in Vienna, Austria, and Gothenburg, Sweden. POPULATION: All women with gestations of ≤49 days undergoing an MTOP during 2004-14 (Vienna) and 2012-15 (Gothenburg). METHODS: Two study cohorts were created: women with and women without a confirmed IUP. An IUP was defined as the intrauterine location of a yolk sac or fetal structure visible by ultrasound. Women with an IUP were selected randomly and included in the IUP cohort. MAIN OUTCOME MEASURES: Efficacy of MTOP, defined as no continuing pregnancy and with no need of surgery for incomplete TOP. RESULTS: After excluding 11 women diagnosed with an extra-uterine or molar pregnancy, 2643 cases were included in the final analysis; 1120 (98.2%) had a successful TOP in the no-IUP group, compared with 1458 (97.1%) in the IUP group, with a risk difference of 1.09% (95% confidence interval, 95% CI, -0.14, 2.32%; P = 0.077). Significantly more women with confirmed IUP were diagnosed with incomplete TOP, and were treated with either surgery or additional medical treatment of misoprostol [64 (4.3%) versus 21 (1.8%); risk difference -2.42%; 95% CI -3.9, -1.1%; P < 0.001]. CONCLUSIONS: There was no difference between the groups in efficacy of MTOP, whereas early treatment resulted in significantly fewer interventions for incomplete TOP. The risk of ectopic pregnancy needs to be considered if treatment is initiated before an IUP is confirmed, but with structured clinical protocols the possibility of the early detection of an ectopic pregnancy in an asymptomatic phase may increase. TWEETABLE ABSTRACT: MTOP before confirmed intrauterine pregnancy is as effective as at later gestation with less incomplete TOP.

Follow-up study of patients treated with olanzapine pamoate in France in real-life treatment situation.

OBJECTIVE: To characterize patients treated with olanzapine pamoate in French centers and investigate the conditions of use of olanzapine pamoate in real-life treatment situation. METHODS: Data came from French sites participating in an international post-authorization safety study. In this observational study, patients diagnosed with schizophrenia were receiving commercially available olanzapine pamoate, in accordance with their physician's usual standard of care. Data were collected during routine visits within the standard course of patient care. RESULTS: One hundred and thirty eight patients (male, 73.9%; mean age, 39.4 years; mean duration of disease, 12.7years) received olanzapine pamoate and were included in the study by 32 investigative psychiatrists distributed across 20 different sites (psychiatric hospitals). During the period of analysis, a total of 2975 injections of olanzapine pamoate was administered to the patients. The mean duration of olanzapine pamoate exposure was 475 days (1.3years). During follow-up, 13.8% of all patients had at least one psychiatric hospitalization, 15.9% had at least one same-day psychiatric hospitalization (information documented for 116patients), and 44.2% received at least one concomitant drug. Three cases of post-injection delirium/sedation syndrome were reported during the analysis period. Treatment emergent adverse events (incidence, 20.3%) were in line with the known profile of olanzapine. CONCLUSION: Patients were administered olanzapine pamoate and monitored in compliance with label recommendations. The safety profile assessment of olanzapine pamoate in actual conditions was consistent with that described in clinical studies.

Changes in energy during treatment of depression: an analysis of duloxetine in double-blind placebo-controlled trials.

AIMS: The aim of this study was to assess how quickly and effectively duloxetine improves energy compared with placebo in patients with major depressive disorder (MDD). METHODS: Data from 10 randomised, double-blind, placebo-controlled clinical trials examining duloxetine (40-60 mg/day) vs. placebo in patients diagnosed with MDD were analysed. Change from baseline at Week 1 through Week 8 in Hamilton Depression Rating Scale (HAM-D) retardation subscale score (Item 1 - depressed mood, Item 7 - work and activities, Item 8 - retardation and Item 14 - genital symptoms) was assessed with mixed model repeated measures analysis. Positive predictive values and negative predictive values were calculated for predictor analysis. RESULTS: Patients treated with duloxetine (N = 1522) experienced statistically significantly (p ≤ 0.05) greater reductions in HAM-D retardation subscale scores vs. placebo (N = 1180) starting at Week 1 throughout Week 8 of treatment. Of the patients with early energy improvement (≥ 20% reduction in HAM-D retardation subscale scores) at Week 1, 48% achieved remission (HAM-D total score ≤ 7) at Week 8; 48% and 46% of patients who experienced early energy improvement at Weeks 2 and 4, respectively, achieved remission at Week 8. DISCUSSION: We demonstrated that treatment with duloxetine, quickly and with increasing magnitude over treatment time, improves low energy symptoms. As early as 1 week after starting treatment with duloxetine, improvement of low energy may serve as a predictor of remission at end-point. CONCLUSIONS: Treatment with duloxetine improves energy in patients with MDD and early response in retardation may serve as a modest predictor of remission at end-point. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov. Study Identifiers: NCT00036335; NCT00073411; NCT00406848 and NCT00536471. Studies HMAQa, HMAQb, HMATa, HMATb, HMBHa and HMBHb predate the registration requirement. DATA POSTING: ClinicalTrials.gov. Study Identifiers: NCT00406848; NCT00536471.

Intra-peritoneal microdialysis and intra-abdominal pressure after endovascular repair of ruptured aortic aneurysms.

OBJECTIVES: This study aims to evaluate intra-peritoneal (ip) microdialysis after endovascular aortic repair (EVAR) of ruptured abdominal aortic aneurysm (rAAA) in patients developing intra-abdominal hypertension (IAH), requiring abdominal decompression. DESIGN: Prospective study. MATERIAL AND METHODS: A total of 16 patients with rAAA treated with an emergency EVAR were followed up hourly for intra-abdominal pressure (IAP), urine production and ip lactate, pyruvate, glycerol and glucose by microdialysis, analysed only at the end of the study. Abdominal decompression was performed on clinical criteria, and decompressed (D) and non-decompressed (ND) patients were compared. RESULTS: The ip lactate/pyruvate (l/p) ratio was higher in the D group than in the ND group during the first five postoperative hours (mean 20 vs. 12), p = 0.005 and at 1 h prior to decompression compared to the fifth hour in the ND group (24 vs. 13), p = 0.016. Glycerol levels were higher in the D group during the first postoperative hours (mean 274.6 vs. 121.7 µM), p = 0.022. The IAP was higher only at 1 h prior to decompression in the D group compared to the ND group at the fifth hour (mean 19 vs. 14 mmHg). CONCLUSIONS: Ip l/p ratio and glycerol levels are elevated immediately postoperatively in patients developing IAH leading to organ failure and subsequent abdominal decompression.

A meta-analysis of the efficacy of wound catheters for post-operative pain management.

Local anesthetics (LA) are injected via catheters placed in surgical wounds for post-operative analgesia. The primary aim of this systematic review was to assess whether LA reduce pain intensity when injected via wound catheters. A literature search was performed from Medline via PubMed, EMBASE and the Cochrane database from 1966 until November 2009. The search strategy included the following key words: pain, postoperative, catheters and local anesthetics. Two co-authors independently read every article that was initially included and extracted data into a pre-defined study record form. A total of 753 studies primarily fit the search criteria and 163 were initially extracted. Of these, 32 studies were included in the meta-analysis. Wound catheters provided no significant analgesia at rest or on activity, except in patients undergoing gynecological and obstetric surgery at 48 h (P=0.03). The overall morphine consumption was lower (≈13 mg) during 0-24 h (P<0.001) in these patients. No significant differences in side effects were found, except for a lower risk of wound breakdown (P=0.048) and a shorter length of hospital stay (P=0.04) in patients receiving LA. A statistically significant heterogeneity was seen between the studies in most end-points. LA injected via wound catheters did not reduce pain intensity, except at 48 h in a subgroup of patients undergoing obstetric and gynecological surgery. Rescue analgesic consumption was also lower in this group at 0-24 h. The magnitude of these effects was small and compounded by pronounced heterogeneity.

Increased activity of L-type Ca2+ channels exposed to serum from patients with type I diabetes.

Type I diabetes [insulin-dependent diabetes mellitus (IDDM)] is an autoimmune disease associated with the destruction of pancreatic beta cells. Serum from patients with IDDM increased L-type calcium channel activity of insulin-producing cells and of GH3 cells derived from a pituitary tumor. The subsequent increase in the concentration of free cytoplasmic Ca2+ ([Ca2+]i) was associated with DNA fragmentation typical of programmed cell death or apoptosis. These effects of the serum were prevented by adding a blocker of voltage-activated L-type Ca2+ channels. When the serum was depleted of immunoglobulin M (IgM), it no longer affected [Ca2+]i. An IgM-mediated increase in Ca2+ influx may thus be part of the autoimmune reaction associated with IDDM and contribute to the destruction of beta cells in vivo.

Type 1 diabetic serum interferes with pancreatic beta-cell Ca2+-handling.

The aim of this study was to clarify the frequency of patients with type 1 diabetes that have serum that increases pancreatic beta-cell cytoplasmic free Ca(2+) concentration, [Ca(2+)](i), and if such an effect is also present in serum from first-degree relatives. We also studied a possible link between the serum effect and ethnic background as well as presence of autoantibodies. Sera obtained from three different countries were investigated as follows: 82 Swedish Caucasians with newly diagnosed type 1 diabetes, 56 Americans with different duration of type 1 diabetes, 117 American first-degree relatives of type 1 diabetic patients with a mixed ethnic background and 31 Caucasian Finnish children with newly diagnosed type 1 diabetes. Changes in [Ca(2+)](i) , upon depolarization, were measured in beta-cells incubated overnight with sera from type 1 diabetic patients, first-degree relatives or healthy controls. Our data show that there is a group constituting approximately 30% of type 1 diabetic patients of different gender, age, ethnic background and duration of the disease, as well as first-degree relatives of type 1 diabetic patients, that have sera that interfere with pancreatic beta-cell Ca(2+)-handling. This effect on beta-cell [Ca(2+)](i) could not be correlated to the presence of autoantibodies. In a defined subgroup of patients with type 1 diabetes and first-degree relatives a defect Ca(2+)-handling may aggravate development of beta-cell destruction.

Role of apoptosis in pancreatic beta-cell death in diabetes.

Apoptosis is a physiological form of cell death that occurs during normal development, and critical mediators of this process include caspases, reactive oxygen species, and Ca2+. Excessive apoptosis of the pancreatic beta-cell has been associated with diabetes. Consequently, apoptosis research has focused on how infiltrating macrophages or cytotoxic T-cells might kill pancreatic beta-cells using cytokines or death receptor triggering. Meanwhile, the intracellular events in the target beta-cell have been largely ignored. Elucidation of such targets might help develop improved treatment strategies for diabetes. This article will outline recent developments in apoptosis research, with emphasis on mechanisms that may be relevant to beta-cell death in type 1 and type 2 diabetes. Several of the models proposed in beta-cell killing converge on Ca2+ signaling, indicating that the pancreatic beta-cell may be an ideal system in which to carefully dissect the role of Ca2+ during apoptosis.

Effects of serum from patients with type 1 diabetes on primary cerebellar granule cells.

Type 1 diabetes is an autoimmune disease of unknown etiology. Our previous work has shown that a factor present in serum from type 1 diabetic patients causes increased Ca2+ channel activity and apoptotic DNA fragmentation in pancreatic beta-cells. Here we examined the effects of type 1 diabetic serum on primary cerebellar granule cells (CGCs). In CGCs, exposure to type 1 diabetic serum did not cause increased apoptosis or changes in Ca2+ channel activity. However, patient serum did cause modulation of Ca2+ signals in a cell type with triangular soma that exhibited low voltage-gated Ca2+ currents. This cell was present primarily in cultures exposed to type 1 diabetic serum. The presence of low voltage-gated Ca2+ currents and long neuronal dendrites indicated that this unique cell was of neuronal origin and not of glial origin.

The antidiabetogenic effect of GLP-1 is maintained during a 7-day treatment period and improves diabetic dyslipoproteinemia in NIDDM patients.

OBJECTIVE: To investigate the long-term antidiabetogenic effect of glucagon-like peptide 1 (GLP-1) and its influence on diabetic dyslipoproteinemia, patients with NIDDM were treated with GLP-1 subcutaneously for 1 week. RESEARCH DESIGN AND METHODS: Twelve patients participated in the study. The 1st week of the study, all of them were on intensive insulin treatment and from day 8, four were randomized to a control group continuing with insulin, and eight to a treatment group where GLP-1 was given at meals together with regular insulin from day 8 to 12. On days 13 and 14, they were only given GLP-1 at meals. NPH insulin at bedtime was given throughout the study. RESULTS: In the GLP-1-treated patients, the doses of regular insulin, given to keep a satisfactory blood glucose control, were reduced compared with treatment with insulin only. GLP-1 virtually inhibited the early increase in blood glucose after the meals, whereas an increase of approximately 2 mmol was seen during an optimized insulin treatment. In agreement with the short half-life of the peptide, 2-h postprandial plasma insulin levels were significantly decreased both at day 12 and 14, suggesting that there was not enough GLP-1 left to stimulate endogenous insulin release and compensate for the decrease in the dose of exogenous insulin. Therefore, the effect of GLP-1 was lost before the next meal, resulting in increased preprandial blood glucose values at lunch and dinner. The concentration of VLDL triglycerides decreased already during the 1st week. This decrease persisted during the 2nd week when GLP-1 was included in the treatment. No changes were observed in the levels of LDL and HDL cholesterol. The LDL particle diameter increased from a mean of 22.3 to 22.6 nm (P < 0.01) in response to insulin treatment. A further increment to 22.9 nm (P < 0.05) was seen after GLP-1 treatment. The LDL particle size did not change in the control group. Lipoprotein lipase activity was decreased by 27% and hepatic lipase was reduced by 13% in the GLP-1-treated group. CONCLUSIONS: We confirm the antidiabetogenic effect of GLP-1 in NIDDM patients. This effect was maintained during 7 days, which implies that the patients did not develop tolerance during this treatment period. Intensive insulin treatment, leading to normotriglyceridemia, increased the mean LDL particle diameter, which is likely to lower the risk of future coronary heart disease in patients with NIDDM. Furthermore, an additive effect of GLP-1 is indicated. Hence, this study gives additional evidence that GLP-1 may be useful as an agent for treating NIDDM.

Glucagon-like peptide I enhances the insulinotropic effect of glibenclamide in NIDDM patients and in the perfused rat pancreas.

OBJECTIVE: To investigate the acute effects of glibenclamide and glucagon-like peptide I (GLP-I) and their combination in perfused isolated rat pancreas and in patients with secondary failure to sulfonylureas. RESEARCH DESIGN AND METHODS: Rat islets were perfused with 10 nmol/l GLP-I in combination with 2 mumol/l glibenclamide. In human experiments, GLP-I (0.75 pmol. kg-1.min-1) was given as a continuous infusion during 240 min, while glibenclamide (3.5 mg) was administered orally. Eight patients participated in the study (age 57.6 +/- 2.7 years, BMI 28.7 +/- 1.5 kg/m2, mean +/- SE). In all subjects, blood glucose was first normalized by insulin infusion administered by an artificial pancreas (Biostator). RESULTS: GLP-I increased the insulinotropic effect of glibenclamide fourfold in the perfused rat pancreas. In human experiments, treatment with GLP-I alone and in combination with glibenclamide significantly decreased basal glucose levels (5.1 +/- 0.4 and 4.5 +/- 0.1 vs. 6.0 +/- 0.3 mmol/l, P < 0.01), while with only glibenclamide, glucose concentrations remained unchanged. GLP-I markedly decreased total integrated glucose response to the meal (353 +/- 60 vs. 724 +/- 91 mmol.l-1. min-1, area under the curve [AUC] [-30-180 min], P < 0.02), whereas glibenclamide had no effect (598 +/- 101 mmol.l-1. min-1, AUC [-30-180 min], NS). The combined treatment further enhanced the glucose lowering effect of GLP-I (138 +/- 24 mmol. l-1.min, AUC [-30-180 min], P < 0.001). GLP-I, glibenclamide, and combined treat-stimulated meal-induced insulin release as reflected by insulinogenic indexes (control 1.44 +/- 0.4; GLP-I 6.3 +/- 1.6, P < 0.01; glibenclamide 6.8 +/- 2.1, P < 0.01; combination 20.7 +/- 5.0, P < 0.001). GLP-I inhibited basal but not postprandial glucagon responses. Using paracetamol as a marker for gastric emptying rate of the test meal, treatment with GLP-I decreased gastric emptying at 180 min by approximately 50% compared with the control subjects (P < 0.01). CONCLUSIONS: In acute experiments on overweight patients with NIDDM, GLP-I exerted a marked antidiabetogenic action on the basal and postprandial state. The peptide stimulated insulin, suppressed basal glucagon release, and prolonged gastric emptying. The glucose-lowering effect of GLP-I was further enhanced by glibenclamide. This action may be at least partially accounted for by a synergistic effect of these two compounds on insulin release. Glibenclamide per se enhanced postprandial but not basal insulin release and exerted a less pronounced antidiabetogenic effect compared with GLP-I.

Patterns of long-term and short-term responses in adult patients with attention-deficit/hyperactivity disorder in a completer cohort of 12 weeks or more with atomoxetine.

BACKGROUND: Atomoxetine is a well-established pharmacotherapy for adult ADHD. Long-term studies show incremental reductions in symptoms over time. However, clinical experience suggests that patients differ in their response patterns. METHODS: From 13 Eli Lilly-sponsored studies, we pooled and analyzed data for adults with ADHD who completed atomoxetine treatment at long-term (24 weeks; n=1443) and/or short-term (12 weeks; n=2830) time-points, and had CAARS-Inv:SV total and CGI-S data up to or after these time-points and at Week 0 (i.e. at baseline, when patients first received atomoxetine). The goal was to identify and describe distinct trajectories of response to atomoxetine using hierarchical clustering methods and linear mixed modelling. RESULTS: Based on the homogeneity of changes in CAARS-Inv:SV total scores, 5 response clusters were identified for patients who completed long-term (24 weeks) treatment with atomoxetine, and 4 clusters were identified for patients who completed short-term (12 weeks) treatment. Four of the 5 long-term clusters (comprising 95% of completer patients) showed positive trajectories: 2 faster responding clusters (L1 and L2), and 2 more gradually responding clusters (L3 and L4). Responses (i.e.≥30% reduction in CAARS-Inv:SV total score, and CGI-S score≤3) were observed at 8 and 24 weeks in 80% and 95% of completers in Cluster L1, versus 5% and 48% in Cluster L4. CONCLUSIONS: While many adults with ADHD responded relatively rapidly to atomoxetine, others responded more gradually without a clear plateau at 24 weeks. Longer-term treatment may be associated with greater numbers of responders.

The effects of atomoxetine on emotional control in adults with ADHD: An integrated analysis of multicenter studies.

PURPOSE: To investigate the effects of atomoxetine on emotional control in adults with ADHD. METHODS: We performed an integrated analysis using individual patient data pooled from three Eli Lilly-sponsored studies. An integrated analysis can be viewed as a meta-analysis of individual patient-level data, rather than study-level summary data. RESULTS: Two populations were identified: a large sample of patients with pre-treatment baseline data (the "overall population"; n=2846); and a subset of these patients with placebo-controlled efficacy data from baseline to 10 or 12 weeks after initiating treatment (the "placebo-controlled population"; n=829). At baseline, in the overall population, ∼50% of ADHD patients had BRIEF-AS (Behavior Rating Inventory of Executive Function-Adult Version Self-Report) Emotional control subscores between 21 and 30, compared with ∼10% of normative subjects in the BRIEF-A manual. At endpoint, in the placebo-controlled population, atomoxetine led to a small (effect size 0.19) but significant (P=0.013) treatment effect for emotional control. The effect size was 0.32 in patients with BRIEF-AS Emotional control scores>20 at baseline. Improvements in emotional control correlated with improvements in the core ADHD symptoms and quality-of-life. DISCUSSION: As deficient emotional control is associated with impaired social, educational and occupational functioning over and above that explained by core ADHD symptoms alone, improvements in emotional control may be clinically relevant. CONCLUSION: At baseline, adults with ADHD were more likely to have impaired emotional control than normative subjects. In the adult ADHD patients, atomoxetine treatment was associated with improvements in emotional control, as well as in core ADHD symptoms and quality-of-life.

An endogenous peptide isolated from the gut, NK-lysin, stimulates insulin secretion without changes in cytosolic free Ca2+ concentration.

We have recently isolated and cloned a novel endogenous peptide from pig intestine, NK-lysin (NKL). In the present study we show that NKL (1-100 nM) potently and reversibly stimulates insulin secretion in rat pancreatic islets and in the beta-cell line HIT T15. This effect of NKL was not accompanied by changes in cytoplasmic free calcium concentration. The stimulatory activity of NKL on insulin release was also observed in permeabilized islets under Ca2+-clamped conditions. Preincubation of HIT T15 cells with NKL for 1 h or 24 h did not influence cell viability. Possible mechanisms of insulinotropic activity of NKL are discussed.

7beta-hydroxycholesterol induces Ca(2+) oscillations, MAP kinase activation and apoptosis in human aortic smooth muscle cells.

In the present study, we characterize the early cytotoxic effects of 7beta-hydroxycholesterol, a major cytotoxin in oxidized LDL, in human aortic smooth muscle cells. Within a few minutes after addition, 7beta-hydroxycholesterol induced Ca(2+) oscillations with a frequency of approximately 0.3-0.4 min(-1). A few hours later, thapsigargin-sensitive Ca(2+) pools were depleted, indicating that 7beta-hydroxycholesterol perturbs intracellular Ca(2+) homeostasis. The mitogen-activated protein kinases (MAPKs) ERK1 and ERK2 (but not JNK) were activated within 5 min after addition of 7beta-hydroxycholesterol. The side-chain hydroxylated oxysterols 25-hydroxycholesterol and 27-hydroxycholesterol were more potent in inducing apoptosis than 7beta-hydroxycholesterol and cholesterol-5alpha,6alpha-epoxide, as determined by TUNEL staining. Addition of TNFalpha (10 ng/ml) and IFNgamma (20 ng/ml) enhanced the cytotoxicity of oxysterols and potentiated apoptosis. The cytokines alone were not toxic to smooth muscle cells at these concentrations. 25-Hydroxycholesterol and 7beta-hydroxycholesterol but not cholesterol inhibited protein synthesis at 4-8 h as determined by [35S]methionine incorporation assay. Morphologically, oxysterol-induced cell death was characterized by disorganization of the ER and Golgi membranes. The Ca(2+) and ERK signals preceded the ultrastructural changes induced by 7beta-hydroxycholesterol.

Interleukin-1 beta-induced stimulation of insulin release in mouse pancreatic islets is related to diacylglycerol production and protein kinase C activation.

The aim of the present study was to investigate the mechanisms responsible for the acute, stimulatory effects of interleukin-1 beta (rIL-1 beta; 1 ng/ml) on insulin release from mouse pancreatic islets. For this purpose, mouse islets were exposed for 60-120 min to rIL-1 beta and their function and metabolism characterized during this period. The cytokine did not increase insulin release in the presence of 1.7 mM glucose, but both in the presence of 5.6 or 16.7 mM glucose, or 10 mM leucine + 2 mM glutamine, it induced a 60-100% increase in insulin release. Moreover, rIL-1 beta also enhanced the effects of 1 mu/ml glipizide on insulin release, but failed to increase insulin release induced by 30 mM KCl or by glucose plus phorbol ester (TPA; 100 nM). These early stimulatory effects of rIL-1 beta on insulin release were neither accompanied by major increases in glucose or amino acid metabolism, nor by modifications in islet cAMP content, and they were prevented by mannoheptulose, diazoxide or verapamil. rIL-1 beta potentiation of glucose-induced insulin release was not accompanied by modifications in [Ca2+]i, but the cytokine increased diacylglycerol production and induced protein kinase C (PKC) activation. Down-regulation of PKC completely prevented the stimulatory effects of rIL-1 beta on glucose-induced insulin release. In conclusion, rIL-1 beta induces an early stimulation of insulin release in mouse beta-cells by a mechanism independent of glucose metabolism, cAMP generation or modifications in [Ca2+]i. This effect is probably related to diacylglycerol formation and stimulation of PKC.

Withdrawal of life support--who should decide? Differences in attitudes among the general public, nurses and physicians.

OBJECTIVE: To examine the attitudes of the general public regarding who should decide about the withdrawal of life support and to compare these attitudes with those of intensive care personnel. DESIGN: Nationwide postal questionnaire survey. SETTING: Sweden. PARTICIPANTS: One thousand one hundred ninety-six randomly selected persons from the Swedish population register, 339 nurses and 121 physicians from 29 randomly selected intensive care units (ICUs). MEASUREMENTS AND RESULTS: Respondents' answers to questions related to two clinical scenarios: one with a conscious and competent patient and one with an unconscious patient. The response rates were 64 % for the general public, 86 % for the nurses and 88 % for the physicians. Concerning the competent patient, 48 % of the public, 31 % of the nurses and 8 % of the physicians were of the opinion that a decision about continued ventilator treatment should be made by the patient alone or together with the family, but without the physician. The vast majority of physicians (87 %) wanted to make the decision themselves, either alone or together with the patient or family. Concerning the incompetent patient, 73 % of the general public and 70 % of the nurses advocated a joint decision made by the family and the physician together. The majority of the physicians (61 %) regarded themselves as the sole decision-maker, a view supported by only 5 % of the public and 20 % of the nurses. CONCLUSIONS: While existing Swedish guidelines recommend that the physician should be the sole decision-maker, the general public favour more patient and family influence on the decision to withdraw life support as compared with intensive care physicians.

Response to nitric oxide inhalation in early acute lung injury.

OBJECTIVE: To evaluate the dose response of inhaled nitric oxide (NO) on gas exchange and central haemodynamics in patients with early acute lung injury (ALI). DESIGN: Prospective, multicentre clinical study. SETTING: General ICUs in university and regional hospitals. PATIENTS: 18 Patients with early ALI according to specified criteria. INTERVENTIONS: During controlled ventilation an inhalation system was used to deliver NO (1000 ppm in N2) and O2/air to the low pressure fresh gas inlet of a Siemens 900C ventilator. Haemodynamics and pulmonary gas exchange variables were measured at baseline and at stepwise increased inspiratory NO concentrations of 0.1, 0.3, 1, 3, 10, 30 and 100 ppm, each dose being maintained for 15 min. Dose testing was repeated the next day, and the response to prolonged (2 h) NO inhalation at 1 and 10 ppm was also tested. MEASUREMENTS AND RESULTS: Inhalation of NO produced a significant increase in PaO2 (P < 0.0025). The degree of response, as well as the optimal NO dose varied in individual patients and between different days. Venous admixture (QVA/QT) was reduced (P < 0.02) from 38% (31-46%) to 33% (26-41%). In our patients with early acute lung injury and only a moderate elevation in pulmonary arterial pressure NO inhalation did not reduce mean pulmonary artery pressure significantly, being 27.0 (21-30) mmHg at baseline and 26.0 (21-30) mm Hg at 100 ppm. CONCLUSIONS: This study shows that improvements in arterial oxygenation in response to inhaled NO may show great inter- as well as intraindividual variability, and that improvements in arterial oxygenation occur without any measurable lowering of the pulmonary artery pressure.

Elemental composition in the pancreatic B cell is normal in the prediabetic Chinese hamster.

To clarify whether elemental changes are present before the onset of diabetes, freeze-dried pancreas sections from young (18-19 days old), genetically prediabetic Chinese hamsters were subjected to proton bombardment and the concentrations of 15 elements (Na, Mg, Al, P, S, Cl, K, Ca, Mn, Fe, Cu, Zn, Rb, Cd, and Pb) in B cells and exocrine pancreas were calculated from the x-rays emitted. We have previously shown that islet B cells and exocrine pancreas from adult, overtly diabetic Chinese hamsters contain subnormal levels of Al (-61%, -88%) and excess levels of Cu (+92%, +59%), Rb (+13%, +13%), and Mg (+6%, +6%) in B cells and exocrine pancreas, respectively (Juntti-Berggren et al., Biosci Rep 1976;7:33-41). In the present study the prediabetic B cells contained normal levels of all 15 elements, whereas the prediabetic exocrine pancreas contained a subnormal level of Fe (-10%; p less than 0.005). Hence, the development of diabetes in the Chinese hamster does not seem to be associated with an early change in the elemental composition of the pancreatic B cells. In fact, the overt diabetic condition may cause changes in the body's handling of some elements.

X-ray microanalysis of in situ and isolated pancreatic islets.

The effect of stimulation of insulin secretion in pancreatic beta cells on the elemental composition of these cells was investigated by x-ray microanalysis. In vitro experiments on isolated islets of Langerhans from ob/ob mice were compared to in situ experiments. The only significant difference in the elemental composition of beta cells from ob/ob mice versus their lean counterparts is a lower Ca concentration in the ob/ob animals. The nucleus of the beta cells has a higher concentration of P, K, and Na than the cytoplasm, which has a higher concentration of S and Cl. No polarized ion distribution in the cytoplasm of the beta cells was observed. Isolated beta cells show a higher concentration of Na and Cl and a lower concentration of K than their in situ counterparts. Stimulation of insulin secretion with glucose both in situ and in vitro showed only very small effects on the elemental composition of the beta cells: a tendency to a decreased P content was noted. In vitro experiments using stimulation with high extracellular K+ showed, in addition, a small increase in the intracellular K concentration. In conclusion, while the elemental content of beta cells in vitro differs from that in situ, the response to glucose stimulation appears to be similar in both systems.