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Objectives: To perform a nationwide study of quadrichorionic quadriamniotic (QCQA) quadruplet pregnancies and to compare the pregnancy outcome in those undergoing fetal reduction with non‐reduced quadruplets and dichorionic diamniotic (DCDA) twin pregnancies from the same time period. Methods: This was a retrospective Danish national register‐based study performed using data from the national Danish Fetal Medicine Database, which included all QCQA quadruplets and all non‐reduced DCDA twin pregnancies with an estimated due date between 2008 and 2018. The primary outcome measure was a composite of adverse pregnancy outcomes, including pregnancy loss or intrauterine death of one or more fetuses. Secondary outcomes included gestational age at delivery, the number of liveborn children, preterm delivery before 28, 32 and 37 gestational weeks and birth weight. Data on pregnancy complications and baseline characteristics were also recorded. Outcomes were compared between reduced and non‐reduced quadruplet pregnancies, and between DCDA pregnancies and quadruplet pregnancies reduced to twins. A systematic literature search was performed to describe and compare previous results with our findings. Results: Included in the study were 33 QCQA quadruplet pregnancies, including three (9.1%) non‐reduced pregnancies, 28 (84.8%) that were reduced to twin pregnancy and fewer than three (6.1%) that were reduced to singleton pregnancy, as well as 9563 DCDA twin pregnancies. Overall, the rate of adverse pregnancy outcome was highest in non‐reduced quadruplets (66.7%); it was 50% in quadruplets reduced to singletons and 10.7% in quadruplets reduced to twins. The proportion of liveborn infants overall was 91.1% of the total number expected to be liveborn in quadruplet pregnancies reduced to twins. This was statistically significantly different from 97.6% in non‐reduced dichorionic twins (P = 0.004), and considerably higher than 58.3% in non‐reduced quadruplets. The rates of preterm delivery < 28, < 32 and < 37 weeks were decreased in quadruplets reduced to twins compared with those in non‐reduced quadruplet pregnancies. Quadruplets reduced to twins did not achieve equivalent pregnancy outcomes to those of DCDA twins. Conclusion: This national study of QCQA quadruplets has shown that multifetal pregnancy reduction improves pregnancy outcome, including a decreased rate of preterm delivery and higher proportion of liveborn children. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Background: Biological therapies have established efficacy in psoriasis vulgaris. However, palmoplantar pustulosis (PPP) has proven difficult to treat, and data on drug survival in these patients remain scarce. Objective: To investigate drug survival of biological treatments in a nationwide cohort of patients with PPP. Methods: We included all patients treated for PPP with a biologic from a prospective Danish nationwide registry between 2007 and 2019. Descriptive statistics were reported. Drug survival was calculated for all patients and specified for the most frequently used biologics. Drug survival was reported as median time to discontinuation. Kaplan–Meier plots were used to visualize drug survival. Trajectories of Dermatology Life Quality Index (DLQI) scores were plotted by interpolating between the different visits with a dermatologist for each treatment course. Results: We identified 85 individual patients who received biological therapy for PPP across 194 treatment courses during follow‐up. Of the included treatment courses, 151 (77.8%) were discontinued. The most frequent cause of discontinuation was ineffective response to treatment (54.3%), while 18.5% of courses were discontinued due to adverse events. The median drug survival across all therapies for PPP was 9.3 (Inter quartile range (IQR), 3.9–25.6) months. Ustekinumab demonstrated the longest median time to discontinuation of 14.6 (IQR, 9.1–51.8) months. The proportion of bio‐naive patients in treatment at 12 months were according to drug 47.9% for adalimumab, 64.3% for ustekinumab and 40.0% for secukinumab. For bio‐experienced, it was 58.2% adalimumab, 54.5% for ustekinumab and 51.4% for secukinumab. Conclusions: The treatment of PPP poses significant challenges, with limited drug survival observed across all therapies regardless of prior experience with biologics. Ustekinumab demonstrated the longest median drug survival. Notably, patients discontinuing therapy due to inefficacy exhibited higher DLQI scores, highlighting the importance of personalized treatment selection and timely consideration of therapy changes when inefficacy is established. [ABSTRACT FROM AUTHOR]

Summary: We conducted a systematic review of the literature reporting phenylephrine‐induced changes in blood pressure, cardiac output, cerebral blood flow and cerebral tissue oxygen saturation as measured by near‐infrared spectroscopy in humans. We used the proportion change of the group mean values reported by the original studies in our analysis. Phenylephrine elevates blood pressure whilst concurrently inducing a reduction in cardiac output. Furthermore, despite increasing cerebral blood flow, it decreases cerebral tissue oxygen saturation. The extent of phenylephrine's influence on cardiac output (r = ‐0.54 and p = 0.09 in awake humans; r = ‐0.55 and p = 0.007 in anaesthetised humans), cerebral blood flow (r = 0.65 and p = 0.002 in awake humans; r = 0.80 and p = 0.003 in anaesthetised humans) and cerebral tissue oxygen saturation (r = ‐0.72 and p = 0.03 in awake humans; r = ‐0.24 and p = 0.48 in anaesthetised humans) appears closely linked to the magnitude of phenylephrine‐induced blood pressure changes. When comparing the effects of phenylephrine in awake and anaesthetised humans, we found no evidence of a significant difference in cardiac output, cerebral blood flow or cerebral tissue oxygen saturation. There was also no evidence of a significant difference in effect on systemic and cerebral circulations whether phenylephrine was given by bolus or infusion. We explore the underlying mechanisms driving the phenylephrine‐induced cardiac output reduction, cerebral blood flow increase and cerebral tissue oxygen saturation decrease. Individualised treatment approaches, close monitoring and consideration of potential risks and benefits remain vital to the safe and effective use of phenylephrine in acute care. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to validate the clinical quality database of the Danish Colorectal Cancer Group. The validation is meant to focus on core data regarding staging of the disease, treatment provided, patient‐related factors and key complications. Method: This was a database validation study assessing the completeness of the database and the accuracy of the data by re‐entering core variables into an online module in a blinded fashion and comparing re‐entered data with the original database data. A sample of 5% of patients from the years 2014–2017 was randomly selected. Results: The sample of 936 patients was identified and data were re‐entered. The completeness of the data retrieved was a median of 96%, 100% and 99% for preoperative, intra‐operative and postoperative variables, respectively. The overall accuracy was a median of 95%. The least accurate variable was date of diagnosis (50% perfect agreement), with agreement rising to 96% when near matches defined as correct date ± 30 days were included. Intra‐operative variables were of high quality, as were data on surgical complications including anastomotic leakage, where agreement was 97%. Conclusion: This was the first major validation of the Danish Colorectal Cancer Group's database. Overall, the completeness and quality of data were high, but the validation process also identified weaknesses, which can be crucial for future users to acknowledge and consider. [ABSTRACT FROM AUTHOR]

Aim: Although patients with Lynch syndrome have an increased risk of developing colorectal cancer, surveillance can reduce morbidity and mortality. Whether or not affected individuals benefit from lifetime surveillance depends on individual factors and patient adherence, and these may vary, complicating risk modelling. The aim of this study was to identify individual factors which influence patient adherence to surveillance programmes and whether extended surveillance interval influenced their risk of developing colorectal cancer. Method: Demographics and survival data were obtained from patients (n = 1223) with Lynch syndrome, identified by interrogating the Danish Hereditary Non‐Polyposis Colorectal Cancer Register. These data were linked to patient surveillance interval data which had been divided into three subsets (< 27 months, adherent to the recommended biennial programme; > 27 months, extended surveillance interval; and no surveillance) to estimate the cumulative risks and hazard ratios (HRs) for colorectal cancer. Results: In all, 147 colorectal cancers (99 first; 48 metachronous) were identified in 1223 patients. Factors associated with adherence to surveillance were female sex, a previous history of cancer and age < 75 years. The cumulative incidence for colorectal cancer was 38% (95% CI 27%–50%) for surveillance intervals < 27 months, 48% (95% CI 29%–67%) for intervals > 27 months and 72% (95% CI 61%–83%) with no surveillance. Adjusted HRs were 0.22 for surveillance intervals < 27 months and 0.32 for surveillance intervals > 27 months. Extended surveillance intervals > 27 months had a non‐significant benefit with an HR of 1.51 (95% CI 0.83–2.75) compared to surveillance intervals < 27 months. Conclusion: This study demonstrates that adherence to colonoscopic surveillance in Lynch syndrome varies with age, sex and cancer history and demonstrates a consistent benefit from colorectal cancer surveillance, though it might be lower for individuals with extended intervals. [ABSTRACT FROM AUTHOR]

Objective: To examine the association between mid-pregnancy dietary patterns and pregnancy-associated hypertension (PAH).Design: A prospective longitudinal cohort study.Setting: Denmark.Population: About 55 139 Danish women with single enrolments and recorded food frequency questionnaire dates with complete information on dietary intake.Methods: Women were eligible if they could speak Danish and were planning to carry to term. Diet was assessed using a validated semi-quantitative 360-item food frequency questionnaire and dietary patterns were derived using factor analysis.Main Outcome Measures: Gestational hypertension (GH) and pre-eclampsia (PE).Results: Disease prevalence was 14% for GH (5491/39 362); 2% for PE (1168/54 778), and 0.4% for severe PE (234/55 086). Seven dietary patterns were characterised in the population, of which two were associated with PAH. The Seafood diet characterised by high consumption of fish and vegetables was inversely associated with the odds of developing GH [odds ratio (OR) 0.86; 95% CI 0.77-0.95)] and PE (OR 0.79; 95% CI 0.65-0.97). The Western diet characterised by high consumption of potatoes (including French fries), mixed meat, margarine and white bread increased the odds of developing GH (OR 1.18; 95% CI 1.05-1.33) and PE (OR 1.40; 95% CI 1.11-1.76). No association was seen with severe PE.Conclusions: We found protective associations of Seafood diet and harmful associations of Western diet with PAH. Dietary interventions encouraging the reduction of Western diet may contribute to a decrease of PAH.Tweetable Abstract: Western diet increases (Seafood diet decreases) the likelihood of developing pre-eclampsia among Danish pregnant women. [ABSTRACT FROM AUTHOR]

Aim: Duchenne muscular dystrophy (DMD) is an X-linked myopathy affecting one in 3600-6000 live male births. The aim of this study was to gain further insight into how parents experience caring for boys with DMD.Methods: Using a qualitative design, parents in 12 families with boys with DMD, whereof two pairs of siblings, were interviewed in 2014 and 2015. Participants were parents of boys followed at Oslo University Hospital or other hospitals in the south-eastern health region of Norway. Mean age of the boys was 13 years, range 7-17.Results: Parents expressed the importance of obtaining good information about the diagnosis, supplied with sensitivity for them as clients, and the parents must be involved in timing of interventions. Meeting with others in the same situation was highly appreciated. Many of the parents expressed their own need for support to cope with the difficult situation. Continuity of support in the boys' transition to adulthood was pointed out as important, as well as the need for professional help to talk to the boys about their diagnosis.Conclusion: Our study suggests that professional teams should expand the parental perspective and emphasise a holistic approach in their work with patients with DMD. [ABSTRACT FROM AUTHOR]

Identification of fetal kidney anomalies invites questions about underlying causes and recurrence risk in future pregnancies. We therefore investigated the diagnostic yield of next‐generation sequencing in fetuses with bilateral kidney anomalies and the correlation between disrupted genes and fetal phenotypes. Fetuses with bilateral kidney anomalies were screened using an in‐house‐designed kidney‐gene panel. In families where candidate variants were not identified, whole‐exome sequencing was performed. Genes uncovered by this analysis were added to our kidney panel. We identified likely deleterious variants in 11 of 56 (20%) families. The kidney‐gene analysis revealed likely deleterious variants in known kidney developmental genes in 6 fetuses and TMEM67 variants in 2 unrelated fetuses. Kidney histology was similar in the latter 2 fetuses—presenting a distinct prenatal form of nephronophthisis. Exome sequencing identified ROBO1 variants in one family and a GREB1L variant in another family. GREB1L and ROBO1 were added to our kidney‐gene panel and additional variants were identified. Next‐generation sequencing substantially contributes to identifying causes of fetal kidney anomalies. Genetic causes may be supported by histological examination of the kidneys. This is the first time that SLIT‐ROBO signaling is implicated in human bilateral kidney agenesis. [ABSTRACT FROM AUTHOR]

Abstract: Laterally bent dorsal fins are rarely observed in free‐ranging populations of cetaceans, contrary to captivity, where most killer whale Orcinus orca adult males have laterally collapsed fins. This topic has been poorly explored, and data/information on its occurrence and possible causes are limited. The present study: (i) undertakes a review of the available information on bent dorsal fins in free‐ranging cetaceans, and updates it with new records, (ii) reports on the proportion of bent fins in different study populations, and (iii) discusses possible causes. An empirical approach based on bibliographic research and compilation of 52 new records collected worldwide resulted in a total of 17 species of cetaceans displaying bent dorsal fins. The species with the highest number of records (64%) and from most locations was O. orca. On average, individuals with bent dorsal fins represent < 1% of their populations, with the exception of false killer whales Pseudorca crassidens and O. orca. While line injuries associated with fisheries interactions may be the main cause for P. crassidens, and the vulnerability to health issues caused by the evolutionary enlargement of the fin may be the cause for O. orca adult males, factors contributing to this abnormality for other species are still unclear. The occurrence of bent dorsals could be influenced by a set of variables rather than by a single factor but, irrespective of the cause, it is suggested that it does not directly affect the animals' survivorship. While still rare in nature, this incident is more common (at least 101 known cases) and widespread (geographically and in species diversity) than hypothesized, and is not confined only to animals in captive environments. Investigation into the occurrence of bent fins may be an interesting avenue of research. [ABSTRACT FROM AUTHOR]

Background: The optimal method of anaesthesia for endovascular therapy (EVT) in acute ischaemic stroke (AIS) has not been identified. Nordic departments of anaesthesiology may handle EVT cases for AIS differently. The aim of this survey was to describe the current practice patterns of Nordic anaesthesia departments in anaesthetic management of EVT in AIS.Methods: A survey consisting of 13 questions was sent to one qualified individual at all Nordic departments of anaesthesiology who manage anaesthesia for EVT interventions. The individual completed the questionnaire on behalf of their department.Results: Response rate was 100%. The majority of departments (84%) managed all EVT cases at their respective centres. Most departments have institutional guidelines on anaesthetic management (84%) including blood pressure management (63%) and were able to provide a 24-h immediate response to an EVT request (63%). Conscious sedation was favoured by 68% of the departments using a variety of sedation protocols. Propofol and remifentanil was preferred for GA (58%). Emergent conversion to GA due to uncontrolled patient movements or loss of airway was experienced by 82% and 35% of the departments, respectively. Majority of the departments (89%) responded that non-specialist anaesthetists occasionally handle EVT cases.Conclusions: This survey indicates that the majority of Nordic anaesthesia departments who manage anaesthesia for EVT are able to provide immediate 24-h response to an EVT request. Most of these departments have institutional guidelines for EVT anaesthesia and haemodynamic management. Conscious sedation appears to be the preferred method of anaesthetic care. [ABSTRACT FROM AUTHOR]

Aim To determine the mortality rate in a Danish cohort of children and adolescents diagnosed with Type 1 diabetes mellitus compared with the general population. Methods In 1987 and 1989 we included 884 children and 1020 adolescents aged 20 years and under, corresponding to 75% of all Danish children and adolescents with Type 1 diabetes, in two nationwide studies in Denmark. Those who had participated in both investigations ( n = 720) were followed until 1 January 2014, using the Danish Civil Registration System on death certificates and emigration. We derived the expected number of deaths in the cohort, using population data values from Statistics Denmark to calculate the standardized mortality ratio. Survival analysis was performed using Cox proportional hazards model. Results During the 24 years of follow-up, 49 (6.8%) patients died, resulting in a standardized mortality ratio of 4.8 (95% confidence interval 3.5, 6.2) compared with the age-standardized general population. A 1% increase in baseline HbA1c (1989), available in 718 of 720 patients, was associated with all-cause mortality (hazard ratio = 1.38; 95% confidence interval 1.2, 1.6; P < 0.0001). Type 1 diabetes with multiple complications was the most common reported cause of death (36.7%). Conclusion We found an increased mortality rate in this cohort of children and adolescents with Type 1 diabetes compared with the general population. The only predictor for increased risk of death up to 24 years after inclusion was the HbA1c level in 1989. This emphasizes the importance of achieving optimal metabolic control in young people with Type 1 diabetes. [ABSTRACT FROM AUTHOR]

The objectives of this study were (a) to examine the association between various kinds of parental social support and adolescents' physical activity ( PA) and (b) to examine whether various kinds of social support from mothers and fathers were differently associated with boys' and girls' PA. Data came from the Aarhus School Survey that included 2100 schoolchildren at 11, 13, and 15 years of age. Parental social support for PA was measured by items about encouragement to do PA, doing joint PA, parents watching PA, and talking about PA. PA was measured as at least 4 h of vigorous PA per week during leisure time. We used logistic regression analyses to estimate the associations for girls and boys separately, adjusted by age group, parents' occupational social class, family structure, and migration status. There were significant and graded associations between adolescents' PA and all four dimensions of parental support for PA. The association patterns were similar for mothers' and fathers' social support and similar for girls and boys. Social processes in the family are important for adolescents' participation in PA. It is important to continue to explore these social processes in order to understand why some adolescents are physically active and others are not. [ABSTRACT FROM AUTHOR]

Bisphenol A is widely used in food contact materials and other products and is detected in human urine and blood. Bisphenol A may affect reproductive and neurological development; however, opinion of the European Food Safety Authority (EFSA) on bisphenol A (EFSA J, 13, 2015 and 3978) concluded that none of the available studies were robust enough to provide a point of departure for setting a tolerable daily intake for bisphenol A. In the present study, pregnant Wistar rats ( n = 17-21) were gavaged from gestation day 7 to pup day 22 with bisphenol A doses of 0, 25 μg, 250 μg, 5 mg or 50 mg/kg bw/day. In the offspring, growth, sexual maturation, weights and histopathology of reproductive organs, oestrus cyclicity and sperm counts were assessed. Neurobehavioural development was investigated using a behavioural testing battery including tests for motor activity, sweet preference, anxiety and spatial learning. Decreased sperm count was found at the lowest bisphenol A dose, that is 25 μg/kg/day, but not at the higher doses. Reproductive organ weight and histology were not affected and no behavioural effects were seen in male offspring. In the female offspring, exposure to 25 μg/kg bw/day bisphenol A dose resulted in increased body weight late in life and altered spatial learning in a Morris water maze, indicating masculinization of the brain. Decreased intake of sweetened water was seen in females from the highest bisphenol A dose group, also a possible sign of masculinization. The other investigated endpoints were not significantly affected. In conclusion, the present study using a robust experimental study design, has shown that developmental exposure to 25 μg/kg bw/day bisphenol A can cause adverse effects on fertility (decreased sperm count), neurodevelopment (masculinization of spatial learning in females) and lead to increased female body weight late in life. These results suggest that the new EFSA temporary tolerable daily intake of 4 μg/kg bw/day is not sufficiently protective with regard to endocrine disrupting effects of bisphenol A in humans. [ABSTRACT FROM AUTHOR]

Background Siblings have been shown to reduce the risk of childhood asthma and allergy, but the mechanism driving this association is unknown. The objective was to study whether siblings affect the airway immune response in healthy neonates, which could represent an underlying immune modulatory pathway. Methods We measured 20 immune mediators related to the Type 1, Type 2, Type 17, or regulatory immune pathways in the airway mucosa of 571 one-month-old asymptomatic neonates from the Copenhagen Prospective Studies on Asthma in Childhood2010 birth cohort ( COPSAC2010). The association between airway mediator levels and presence of siblings was investigated using conventional statistics and principle component analysis ( PCA). Results Neonates with siblings had an upregulated level of airway immune mediators, with predominance of Type 1- and Type 17-related mediators. This was supported by the PCA showing a highly significant difference between children with vs without siblings: P < 10−10, which persisted after adjustment for potential confounders including pathogenic airway bacteria and viruses: P < 0.0001. The immune priming effect was inversely associated with time since last childbirth: P = 0.0015. Conclusions Siblings mediate a Type 1/Type 17-related immune-stimulatory effect in the airways of asymptomatic neonates, also after adjustment for pathogenic bacteria and viruses, indicating that siblings exert a transferable early immune modulatory effect. These findings may represent an in utero immune priming effect of the fetal immune system caused by previous pregnancies as the effect was attenuated with time since last childbirth, or it could relate to the presence of unidentified microbes, but further studies are needed to confirm our findings. [ABSTRACT FROM AUTHOR]

Objective Patients with burning mouth syndrome (BMS) often represent a clinical challenge as available agents for symptomatic treatment are few and often ineffective. The aim was to evaluate the effect of a bupivacaine lozenge on oral mucosal pain, xerostomia, and taste alterations in patients with BMS. Methods Eighteen patients (4 men and 14 women) aged 39-71 years with BMS were included in this randomized, double-blinded, placebo-controlled, crossover trial. Lozenges (containing bupivacaine or placebo) were administrated three times a day for 2 weeks for two separate treatment periods. Assessment of oral mucosal pain, xerostomia, and taste alterations was performed in a patient diary on a visual analog scale (ranging from 0 to 100 mm) before and after the lozenge was dissolved. Results The bupivacaine lozenge significantly reduced the burning oral pain ( P < 0.001) , increased the sense of taste disturbances ( P < 0.001), and had no impact on xerostomia, when adjusted for the treatment period. Conclusions Our results indicate that the bupivacaine lozenge offers a novel therapeutic modality to patients with BMS, although without alleviating effect on the associated symptoms, taste alterations, and xerostomia. [ABSTRACT FROM AUTHOR]

Background First-born children are at higher risk of developing a range of immune-mediated diseases. The underlying mechanism of 'birth-order effects' on disease risk is largely unknown, but in utero programming of the child's immune system may play a role. Objective We studied the association between birth order and the functional response of stimulated cord blood T cells. Method Purified cord blood T cells were polyclonally activated with anti- CD3-/anti- CD28-coated beads in a subgroup of 28 children enrolled in the COPSAC2010 birth cohort. Expression levels of seven activation markers on helper and cytotoxic T cells as well as the percentage of CD4+ CD25+ T cells were assessed by flow cytometry. Production of IFN-γ, TNF-α, IL-17, IL-4, IL-5, IL-13, and IL-10 was measured in the supernatants. Results IL-10 secretion ( P = 0.007) and CD25 expression on CD4+ helper T cells ( P = 0.0003) in the activated cord blood T cells were selectively reduced in first-born children, while the percentage of circulating CD4+ CD25+ cord blood T cells was independent of birth order. Conclusion First-born infants display a reduced anti-inflammatory profile in T cells at birth. This possible in utero 'birth-order' T-cell programming may contribute to later development of immune-mediated diseases by increasing overall immune reactivity in first-born children as compared to younger siblings. [ABSTRACT FROM AUTHOR]

Background: Pain after Caesarean section is often treated with opioids with a risk of side effects. Wound infiltration with local anaesthetics is effective and has few side effects, but volume vs. dose concentration has not been examined. Methods: Ninety patients scheduled for elective Caesarean section included in a randomised, double-blinded, placebo-controlled trial receiving infiltration with 50 ml ropivacaine 0.5% or 125 ml ropivacaine 0.2% or 50 ml 0.9% saline (placebo) during surgery. Surgery was performed under lumbar spinal anaesthesia. Primary endpoint was post-operative pain. Secondary endpoints were rescue analgesic, post-operative nausea and vomiting, time spent in the postanesthesia care unit (PACU) and time to first mobilisation. Results: No difference in pain response between groups, but time until maximum pain score was prolonged in the ropivacaine 0.5% group compared with the placebo group (P = 0.0493). The administration of ketobemidone at 24 h post-operatively in the ropivacaine 0.5% group was reduced compared with the placebo group (P = 0.020), and between the ropivacaine 0.2% group and the ropivacaine 0.5% group (P = 0.044). No significant differences between groups were found concerning time spent in the PACU, to first mobilisation or in number of women with nausea/vomiting (P ≥ 0.05). No complications related to ropivacaine were observed. Conclusions: Systematic infiltration with a high concentration, low volume compared with low concentration, high volume showed no significant effect on post-operative pain intensity. However, a statistically significant, but clinically limited opioid sparing effect was demonstrated compared with placebo in the high concentration, low volume group. [ABSTRACT FROM AUTHOR]

Aims To examine the long-term incidence of vitrectomy in young people with Type 1 diabetes. Methods We prospectively studied 324 people with Type 1 diabetes who participated in baseline examinations in 1995. Surgical history was obtained from the Danish National Patient Registry in April 2012. Results During the 17-year study period, 39 people (12.0%) underwent vitrectomy at least once. The mean age and diabetes duration at first vitrectomy were 29.8 and 22.9 years, respectively, and 64.1% of the participants were men. In multivariable Cox regression analysis, baseline age (hazard ratio 0.81 per 1 year increase), BMI (hazard ratio 1.21 per 1 kg/m2 increase), HbA1c (hazard ratio 1.72 per 1% increase) and diabetic retinopathy (hazard ratio 2.85 and 6.07 for mild and moderate/severe diabetic retinopathy vs none, respectively) were independent predictors of vitrectomy ( P < 0.05 for all variables). Conclusions Vitrectomy is a relatively common procedure in young people with Type 1 diabetes, with poor glycaemic control being the strongest modifiable risk factor. [ABSTRACT FROM AUTHOR]

The human leukocyte antigen ( HLA) class Ib molecule, HLA-G, has gained increased attention because of its assumed important role in immune regulation. The HLA-G protein exists in several soluble isoforms. Most important are the actively secreted HLA-G5 full-length isoform generated by alternative splicing retaining intron 4 with a premature stop codon, and the cleavage of full-length membrane-bound HLA-G1 from the cell surface, so-called soluble HLA-G1 ( sHLA-G1). A specific and sensitive immunoassay for measurements of soluble HLA-G is mandatory for conceivable routine testing and research projects. We report a novel method, a competitive immunoassay, for measuring HLA-G5/ sHLA-G1 in biological fluids. The sHLA-G immunoassay is based upon a competitive enzyme-linked immunosorbent assay ( ELISA) principle. It includes a recombinant sHLA-G1 protein in complex with β2-microglobulin and a peptide as a standard, biotinylated recombinant sHLA-G1 as an indicator, and the MEM-G/9 anti- HLA-G monoclonal antibody ( mAb) as the capture antibody. The specificity and sensitivity of the assay were evaluated. Testing with different recombinant HLA class I proteins and different anti- HLA class I mAbs showed that the sHLA-G immunoassay was highly specific. Optimal combinations of competitor sHLA-G1 and capture mAb concentrations were determined. Two versions of the assay were tested. One with a relatively wide dynamic range from 3.1 to 100.0 ng/ml, and another more sensitive version ranging from 1.6 to 12.5 ng/ml. An intra-assay coefficient of variation ( CV) of 15.5% at 88 ng/ml and an inter-assay CV of 23.1% at 39 ng/ml were determined. An assay based on the competitive sHLA-G ELISA may be important for measurements of sHLA-G proteins in several conditions: assisted reproduction, organ transplantation, cancer, and certain pregnancy complications, both in research studies and possibly in the future also for clinical routine use. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective To explore the association between clinical training characteristics and trainees' level of confidence in performing ultrasound scans independently. Methods A cross-sectional e-survey was distributed to members of the national societies of junior obstetricians/gynecologists in Denmark, Sweden and Norway (n = 973). Multiple linear regression models were used to explore the effect that amount of time spent in specialized ultrasound units and clinical experience had on trainees' confidence in performing ultrasonography independently. Exploratory factor analysis was used to identify factors that contributed to trainees' confidence in performing ultrasonography. Trainees' ultrasound confidence was finally compared with their expected levels of performance. Results Of the 682 respondents (response rate 70.1%), 621 met the inclusion criteria. Clinical experience and time spent in specialized ultrasound units were predictors of trainees' confidence in performing ultrasonography independently (P < 0.001). Trainees required more than 24 months of clinical experience and 12-24 days of training in specialized ultrasound units in order to feel confident about performing transvaginal and transabdominal ultrasound scans independently. Three factors were related to ultrasound confidence: technical aspects, image perception and integration of scan into patient care. There were significant differences between trainees' level of confidence and their expected levels of performance (P < 0.001). Conclusions Clinical experience and time spent in specialized ultrasound units were predictors of trainees' confidence in performing ultrasonography independently. Discrepancies between trainees' confidence and their expected levels of performance raised concerns about the adequacy of current ultrasound training programs. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Clinical case reports have suggested that specific bacterial infections are associated with certain non-Hodgkin lymphoma (NHL) subtypes. Epidemiological case-control studies have been conducted using antibiotics as a proxy for bacterial infections, but with inconclusive results. The aim of this study was, in a cohort design, based on the unique nationwide Danish registers, to investigate the association between use of antibiotics and the risk of NHL subtypes. On the basis of the Civil Registration System, we established a cohort of the entire adult (≥15 years) Danish population. Information on use of antibiotics came from the Danish Drug Prescription Registry and lymphoma diagnosis from the Danish Cancer Registry. Associations were assessed by adjusted rate ratios (RRs). In total, 13,602 patients were diagnosed with one of the NHL subtypes during 51.6 million person-years of follow-up (1995-2008). We observed positive associations between use of antibiotics and plasma cell myeloma [RR = 1.11, 95% confidence intervals (CIs) = 1.00-1.24], chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (RR = 1.32, 95% CI = 1.20-1.45), mantle cell lymphoma (MCL) (RR = 1.40, 95% CI = 1.04-1.88) and anaplastic large T-cell lymphoma (ALCL) (RR = 1.83, 95% CI = 1.00-3.36). Among these, the increased risk of CLL/SLL, MCL and ALCL, respectively, did not vary by years since use, and only the risk of CLL/SLL risk differed by number of prescriptions. While causality could not be established in our study, an intriguing positive long-term association between antibiotic use and CLL/SLL risk was observed. To what extent these findings indicate a role for bacteria in lymphoma pathogenesis requires further investigation. [ABSTRACT FROM AUTHOR]

Minor histocompatibility antigens (mHags) encoded by the Y-chromosome (H-Y-mHags) are known to play a pivotal role in allogeneic haematopoietic cell transplantation (HCT) involving female donors and male recipients. We present a new H-Y-mHag, YYNAFHWAI (UTY139-147), encoded by the UTY gene and presented by HLA-A*24:02. Briefly, short peptide stretches encompassing multiple putative H-Y-mHags were designed using a bioinformatics predictor of peptide-HLA binding, NetMHCpan. These peptides were used to screen for peptide-specific HLA-restricted T cell responses in peripheral blood mononuclear cells obtained post-HCT from male recipients of female donor grafts. In one of these recipients, a CD8+ T cell response was observed against a peptide stretch encoded by the UTY gene. Another bioinformatics tool, HLArestrictor, was used to identify the optimal peptide and HLA-restriction element. Using peptide/HLA tetramers, the specificity of the CD8+ T cell response was successfully validated as being HLA-A*24:02-restricted and directed against the male UTY139-147 peptide. Functional analysis of these T cells demonstrated male UTY139-147 peptide-specific cytokine secretion (IFNγ, TNFα and MIP-1β) and cytotoxic degranulation (CD107a). In contrast, no responses were seen when the T cells were stimulated with patient tumour cells alone. CD8+ T cells specific for this new H-Y-mHag were found in three of five HLA-A*24:02-positive male recipients of female donor HCT grafts available for this study. [ABSTRACT FROM AUTHOR]

Ecosystems across the globe are threatened by climate change and human activities. New rapid survey approaches for monitoring biodiversity would greatly advance assessment and understanding of these threats. Taking advantage of next-generation DNA sequencing, we tested an approach we call metabarcoding: high-throughput and simultaneous taxa identification based on a very short (usually <100 base pairs) but informative DNA fragment. Short DNA fragments allow the use of degraded DNA from environmental samples. All analyses included amplification using plant-specific versatile primers, sequencing and estimation of taxonomic diversity. We tested in three steps whether degraded DNA from dead material in soil has the potential of efficiently assessing biodiversity in different biomes. First, soil DNA from eight boreal plant communities located in two different vegetation types (meadow and heath) was amplified. Plant diversity detected from boreal soil was highly consistent with plant taxonomic and growth form diversity estimated from conventional above-ground surveys. Second, we assessed DNA persistence using samples from formerly cultivated soils in temperate environments. We found that the number of crop DNA sequences retrieved strongly varied with years since last cultivation, and crop sequences were absent from nearby, uncultivated plots. Third, we assessed the universal applicability of DNA metabarcoding using soil samples from tropical environments: a large proportion of species and families from the study site were efficiently recovered. The results open unprecedented opportunities for large-scale DNA-based biodiversity studies across a range of taxonomic groups using standardized metabarcoding approaches. [ABSTRACT FROM AUTHOR]

Background Despite similar clinical symptoms, collagenous colitis ( CC) and lymphocytic colitis ( LC) are considered two distinct disease entities. Aim To compare pathoanatomical findings, clinical presentations, risk factors, course of diseases and response to treatment in CC and LC to establish whether they could be subtypes of the same disease, microscopic colitis ( MC). Methods The MEDLINE was searched for CC, LC and MC, and clinical studies of >20 patients were included. Pooled results with 95% confidence intervals were calculated based on the number of patients. Results An abnormal number of intraepithelial lymphocytes are found in 45% (40-50%) with CC, and an abnormal subepithelial collagen band in 16% (13-20%) with LC suggesting a histological overlap. The incidence of CC and LC has increased in parallel. Mean age ( CC 63 years; LC 60 years) and clinical presentation are indistinguishable, and females are predominant in CC (77%; 75-79%) as well as LC (68%; 66-70%). Risk factors such as nonsteroid anti-inflammatory drugs consumption CC 39% (36-42%); LC 32% (29-35%) are similar and prevalence of concomitant autoimmune diseases such as coeliac disease ( CC 5%; CI: 4-6% and LC 7%; CI: 6-9%) do not differ. Bile acid diarrhoea is highly prevalent in CC (41%; 37-45%) and LC (29%; 24-34%). The effect of budesonide is identical. Conclusions CC and LC could be considered histological subtypes of the same disease, MC. To facilitate recruitment to clinical trials, all MC patients could be included in future trials and stratified for subtypes. [ABSTRACT FROM AUTHOR]

This article gives an overview of methods concerning the detection and quantification of internal leaks through valves. It also presents comparisons of the methods using new experimental data with emphasis on the spectral information in the signals. The first method utilizes known analytical relationships between acoustic emissions and fluid flow. The second method is a data-driven comparative approach where an online signal from a leaking valve is compared with a set of saved reference signals from leaking valves. The work presents a new and improved way of leak estimation compared to what is practiced in the industry today, which will ultimately result in safer operations and reduced maintenance related costs. © 2011 American Institute of Chemical Engineers AIChE J, 2012 [ABSTRACT FROM AUTHOR]

Aim: Sulphonylureas (SUs) are often used as first-line treatments for type 2 diabetes in Japan, hence it is important to study new antidiabetic drugs in combination with SUs in Japanese patients. Methods: The efficacy and safety of the once-daily human glucagon-like peptide-1 (GLP-1) analogue liraglutide were compared in 264 Japanese subjects [mean body mass index (BMI) 24.9 kg/m2; mean glycated haemoglobin (HBA1c) 8.4%] randomized and exposed to receive liraglutide 0.6 mg/day (n = 88), 0.9 mg/day (n = 88) or placebo (n = 88) each added to SU monotherapy (glibenclamide, glicazide or glimeprimide) in a 24-week, double-blind, parallel-group trial. Results: The mean change in HBA1c from baseline to week 24 (LOCF) was −1.56 (s.d. 0.84) and −1.46 (s.d. 0.95) with liraglutide 0.9 and 0.6 mg respectively, and −0.40 (s.d. 0.93) with placebo. HBA1c decreased in the placebo group from 8.45 to 8.06%, while liraglutide reduced HBA1c from 8.60 to 7.14%, and from 8.23 to 6.67% at the 0.6 and 0.9 mg doses respectively. Mean HBA1c at week 24 of the two liraglutide groups were significantly lower than the placebo group (p < 0.0001 for both). More subjects reached HBA1c < 7.0% with liraglutide (0.6 mg: 46.5%; 0.9 mg: 71.3%) vs. placebo (14.8%). Fasting plasma glucose (FPG) levels were significantly improved with liraglutide (difference −1.47 mmol/l and −1.80 mmol/l with 0.6 and 0.9 mg vs. placebo; p < 0.0001). Overall safety was similar between treatments: no major hypoglycaemic episodes were reported, while 84/77/38 minor hypoglycaemic episodes occurred in the 0.6 mg/0.9 mg and placebo treatment groups (all in combination with SU), reflecting lower ambient glucose levels. No relevant change in mean body weight occurred in subjects receiving liraglutide (0.6 mg: 0.06 kg; 0.9 mg: −0.37 kg), while mean body weight decreased in subjects receiving placebo (−1.12 kg). Conclusions: The addition of liraglutide to SU treatment for 24 weeks dose-dependently improved glycaemic control vs. SU monotherapy, without causing major hypoglycaemia or weight gain or loss. [ABSTRACT FROM AUTHOR]

Aim: We wanted to stabilize the availability of nitric oxide (NO) at levels compatible with normal systemic haemodynamics to provide a model for studies of complex regulations in the absence of changes in NO levels. Methods: Normal volunteers (23–28 years) were infused i.v. with the nitric oxide synthase (NOS) inhibitor NG-nitro-l-arginine methyl ester (l-NAME) at 0.5 mg kg−1 h−1. One hour later, the NO donor sodium nitroprusside (SNP) was co-infused in doses eliminating the haemodynamic effects ofl-NAME. Haemodynamic measurements included blood pressure (MABP) and cardiac output (CO) by impedance cardiography. Results: l-NAME increased MABP and total peripheral resistance (TPR, 1.02 ± 0.05 to 1.36 ± 0.07 mmHg s mL−1, mean ± SEM, P < 0.001). With SNP, TPR fell to a stable value slightly below control (0.92 ± 0.05 mmHg s mL−1, P < 0.05). CO decreased withl-NAME (5.8 ± 0.3 to 4.7 ± 0.3 L min−1, P < 0.01) and returned to control when SNP was added (6.0 ± 0.3 L min−1). A decrease in plasma noradrenaline (42%, P < 0.01) duringl-NAME administration was completely reversed by SNP. Plasma renin activity decreased duringl-NAME administration and returned towards normal after addition of SNP. In contrast, plasma aldosterone was increased byl-NAME and remained elevated. Conclusions: Concomitant NOS inhibition and NO donor administration can be adjusted to maintain TPR at control level for hours. This approach may be useful in protocols in which stabilization of the peripheral supply of NO is required. However, the dissociation between renin and aldosterone secretion needs further investigation. [ABSTRACT FROM AUTHOR]

Background: Multimodal analgesia may be important for optimal postoperative pain treatment and facilitation of early mobilization and recovery. We investigated the analgesic effect of pregabalin and dexamethasone in combination with paracetamol after abdominal hysterectomy. Methods: One hundred and sixteen patients were randomly assigned to either group A (paracetamol+placebo × 2), group B (paracetamol+pregabalin+placebo) or group C (paracetamol+pregabalin+dexamethasone). According to randomization and preoperatively, patients received paracetamol 1000 mg, pregabalin 300 mg, dexamethasone 8 mg or placebo. General anaesthesia was performed. Postoperative pain treatment was paracetamol 1000 mg × 4 and patient-controlled intravenous morphine, 2.5 mg bolus. Nausea was treated with ondansetron. Morphine consumption, pain score (visual analogue scale) at rest and during mobilization, nausea, sedation, dizziness, number of vomits and consumption of ondansetron were recorded 2, 4 and 24 h after the operation. P<0.05 was considered statistically significant. Results: The 24-h morphine consumption and pain score, both at rest and during mobilization, were not significantly different between treatment groups. The mean nausea score ( P=0.002) was reduced in group C vs. A. The number of vomits was significantly reduced in both group B ( P=0.041) and C ( P=0.001) vs. A. Consumption of ondansetron was reduced in group C vs. A and B ( P<0.001). Other side effects were not different between groups. Conclusion: Combinations of paracetamol and pregabalin, or paracetamol, pregabalin and dexamethasone did not reduce morphine consumption and pain score compared with paracetamol alone for patients undergoing abdominal hysterectomy. Dexamethasone reduced nausea, vomiting and use of ondansetron. [ABSTRACT FROM AUTHOR]

Spot blotch, caused by Bipolaris sorokiniana, has become an increasingly important disease on barley in Sweden. In order to enhance our knowledge of this disease, eight Swedish B. sorokiniana isolates were assessed for their virulence pathotype on 30 barley genotypes including eight lines of mutant origin, designated B. sorokiniana tolerant ( bst). A leaf screen assay revealed the presence of virulence groups 1 and 7 in Sweden. Several mutant genotypes demonstrated enhanced resistance responses (P = 0.0001), of which bst1:3 had the lowest leaf scoring value to the most virulent isolate, Swe2 (virulence group 7). To evaluate the host root responses, two contrasting isolates Swe2 and Swe4 (virulence group 7 and 1) were used to inoculate a set of eight differential lines, including four promising mutant lines from the leaf screen. Mutant bst1:6 was significantly less susceptible (P = 0.001) compared with the other barley genotypes tested, independent of the two isolates used. Mutants bst1, bst1:3 and bst1:4, which displayed less or no spots, are also considered promising genotypes for further breeding attempts. [ABSTRACT FROM AUTHOR]

Background: Na+/K+-ATPase activity is upregulated during muscle exercise to maintain ionic homeostasis. One mechanism may involve movement of α-subunits to the outer membrane (translocation). Aim: We investigated the existence of exercise-induced translocation and phosphorylation of phospholemman (PLM, FXYD1) protein in rat skeletal muscle and exercise-induced changes in Vmax and Km for Na+ of the Na+/K+-ATPase. Methods: Two membrane fractionation methods and immunoprecipitation were used. Results: Both fractionation methods revealed a 200–350% increase in PLM in the sarcolemma after 30 min of treadmill running, while the phosphorylation of Ser-68 of PLM appeared to be unchanged. Exercise did not change Vmax or Km for Na+ of the Na+/K+-ATPase in muscle homogenate, but induced a 67% increase in Vmax in the sarcolemmal giant vesicle preparation; Km for Na+ remained constant. The main part of the increase in Vmax is related to a 36–53% increase in the level of α-subunits; the remainder may be related to increased PLM content. Similar results were obtained with another membrane purification method. In resting muscle, 29% and 32% of α1- and α2-subunits, respectively, were co-immunoprecipitated by PLM antibodies. In muscle homogenate prepared after exercise, immunoprecipitation of α1-subunits was increased to 227%, whereas the fraction of precipitated α2 remained constant. Conclusion: Exercise translocates PLM to the muscle outer membrane and increases its association with mainly the α1-subunit, which may contribute to the increased Vmax of the Na+/K+-ATPase. [ABSTRACT FROM AUTHOR]

Cereal cyst nematodes ( Heterodera avenae Woll.) are economically damaging barley parasites in most cereal growing areas of the world and the development of resistant cultivars is the best measure against the pathogen. An ISSR (inter-simple sequence repeat) marker identified as closely linked with the H. avenae race 1 and 2 resistance gene ( Ha2) has been converted into a codominant sequence characterized amplified region marker ( Ha2S18) and mapped in barley ‘SW Buddy’ × ‘SW Cecilia’ DH population at 4.3 cM from the Ha2 locus on the long arm of chromosome 2H. The potential usefulness of Ha2S18 in large scale marker assisted selection schemes has been evaluated in a broad genetic background and is an important complement to the bioassay and to other linked DNA-markers for this trait. [ABSTRACT FROM AUTHOR]

Background Irritable bowel syndrome is the most common diagnosis in gastroenterology. Trials suggest certain probiotics to be beneficial. Aim To investigate the effects of multispecies probiotic supplementation ( Lactobacillus rhamnosus GG, L. rhamnosus Lc705, Propionibacterium freudenreichii ssp. shermanii JS and Bifidobacterium animalis ssp. lactis Bb12) on abdominal symptoms, quality of life, intestinal microbiota and inflammatory markers in irritable bowel syndrome. Methods Eighty-six irritable bowel syndrome patients (Rome II criteria) participated in this randomized, placebo-controlled 5-month intervention. Patients were randomized to receive daily either multispecies probiotic supplementation or placebo. Irritable bowel syndrome symptoms, quality of life, microarray-based intestinal microbiota stability ( n = 20), serum cytokines and sensitive C-reactive protein were monitored. Results The composite irritable bowel syndrome score had at 5 months decreased 14 points (95% CI: −19 to −9) from baseline with the multispecies probiotic vs. three points (95% CI: −8 to 1) with placebo ( P = 0.0083). Especially, distension and abdominal pain were affected. A stabilization of the microbiota was observed, as the microbiota similarity index increased with the probiotic supplementation (1.9 ± 3.1), while it decreased with placebo (−2.9 ± 1.7). No differences were seen in C-reactive protein. Conclusions This multispecies probiotic seems to be an effective and safe option to alleviate symptoms of irritable bowel syndrome, and to stabilize the intestinal microbiota. [ABSTRACT FROM AUTHOR]

Background: In this study, we tested the hypothesis that escalating drug concentrations of isoflurane are associated with a significant decline in cerebral blood flow (CBF) in regions sub-serving conscious brain activity, including specifically the thalamus. Methods: Nine human volunteers received three escalating drug concentrations: 0.2, 0.4 and 1.0 MAC end-tidal inhalation. During waking, baseline and the three levels of sedation, a O PET scan was performed. Results: Isoflurane decreased the bispectral index (BIS) values dose-dependently. Cardiovascular and respiratory parameters were maintained constant over time. No significant change in global CBF was observed. Throughout all three MAC levels of sedation, isoflurane caused an increased regional cerebral blood flow (rCBF) in the anterior cingulate and decreased rCBF in the cerebellum. Initially, isoflurane (0 vs. 0.2 MAC) significantly increased relative rCBF in the medial frontal gyrus and in the nucleus accumbens. At the next level (0.2 vs. 0.4 MAC), relative rCBF was significantly increased in the caudate nucleus and decreased in the lingual gyrus and cuneus. At the last level (0.4 vs. 1 MAC), relative rCBF was significantly increased in the insula and decreased in the thalamus, the cuneus and lingual gyrus. Compared with flow distribution in awake volunteers, 1 MAC of isoflurane significantly raised relative activity in the anterior cingulate and insula regions. In contrast, a significant relative flow reduction was identified in the thalamus, the cerebellum and lingual gyrus. Conclusions: Isoflurane, like sevoflurane, induced characteristic flow redistribution at doses of 0.2–1.0 MAC. At 1 MAC of isoflurane, rCBF decreased in the thalamus. Specific areas affected by both isoflurane and sevoflurane included the anterior cingulate, insula regions, cerebellum, lingual gyrus and thalamus. [ABSTRACT FROM AUTHOR]

Indomethacin has been suggested as a therapeutic tool to manage elevated intracranial pressure in patients with severe head injury and patients undergoing craniotomy for brain tumors. Indomethacin is a non-selective cyclooxygenase inhibitor. Compared to other cyclooxygenase inhibitors indomethacin has unique effects on cerebral blood flow. Administration of indomethacin causes cerebral vasoconstriction and decreases cerebral blood flow, which elicits a decrease in intracranial pressure. The mechanism of indomethacin-induced cerebral vasoconstriction is not completely understood and controversies exist whether indomethacin causes cerebral ischemia. The primary aims of this article were to review the existing knowledge of indomethacin's influence upon cerebral hemodynamics and elevated ICP in patients with brain pathology. Furthermore, indomethacin's mechanism of action and whether it causes cerebral ischemia are discussed. [ABSTRACT FROM AUTHOR]

The incidence of thromboembolism after colorectal surgery is higher than after general surgery. The aim of this paper is to update a systematic review addressing thrombosis prophylaxis in connection with colorectal surgery.MEDLINE, EMBASE, LILACS, abstract books and reference lists from reviews were searched without language restrictions for randomized controlled trials or clinical controlled trials comparing prophylactic interventions and/or placebo up til August 2003. Five hundred and fifty-eight studies were identified of which 19 fulfilled the inclusion criterias. Data extraction was done by at least two of the authors. Outcome was deep venous thrombosis and/or pulmonary embolism diagnosed by various methods.Any kind of heparin is better than no treatment or placebo (11 studies) with a Peto Odds ratio (POR) at 0.32 (95% CI 0.20–0.53). Unfractionated heparin and low molecular weight heparin (4 studies) were equally effective POR 1.01 (95% CI 0.67–1.52). The combination of graduated compression stockings and LMWH is better than LMWH alone (2 studies) with a POR at 4.17 (95% CI 1.37–12.70).The optimal thromboprophylaxis in colorectal surgery is the combination of graduated compression stockings and low-dose unfractionated heparin or low molecular weight heparin. [ABSTRACT FROM AUTHOR]

Background: We tested the hypothesis that escalating drug concentrations of sevoflurane are associated with a significant decline of cerebral blood flow in regions subserving conscious brain activity, including specifically the thalamus. Methods: Nine healthy human volunteers received three escalating doses using 0.4%, 0.7% and 2.0% end-tidal sevoflurane inhalation. During baseline and each of the three levels of anaesthesia one PET scan was performed after injection of . Cardiovascular and respiratory parameters were monitored and electroencephalography and bispectral index (BIS) were registered. Results: Sevoflurane decreased the BIS values dose-dependently. No significant change in global cerebral blood flow (CBF) was observed. Increased regional CBF (rCBF) in the anterior cingulate (17-21%) and decreased rCBF in the cerebellum (18-35%) were identified at all three levels of sedation compared to baseline. Comparison between adjacent levels sevoflurane initially (0 vs. 0.2 MAC) decreased rCBF significantly in the inferior temporal cortex and the lingual gyrus. At the next level (0.2 MAC vs. 0.4 MAC) rCBF was increased in the middle temporal cortex and in the lingual gyrus, and decreased in the thalamus. At the last level (0.4 MAC vs. 1 MAC) the rCBF was increased in the insula and decreased in the posterior cingulate, the lingual gyrus, precuneus and in the frontal cortex. Conclusion: At sevoflurane concentrations at 0.7% and 2.0% a significant decrease in relative rCBF was detected in the thalamus. Interestingly, some of the most profound changes in rCBF were observed in structures related to pain processing (anterior cingulate and insula). [ABSTRACT FROM AUTHOR]

We tested the hypothesis that oxytocin in normal man causes natriuresis by means of nitric oxide and/or atrial natriuretic peptide. Normal male subjects were investigated after 4 days of sodium controlled diets (30 mmol sodium chloride day−1, n = 8 or 230 mmol sodium chloride day−1, n = 6). Oxytocin was infused intravenously (1 pmol kg−1 min−1 for 240 min). Mean arterial blood pressure, heart rate and glomerular filtration rate by clearance of chromium-labelled ethylenediaminetetraacetate remained stable. Plasma oxytocin increased from 2 to 3 pg mL−1 to around 50 pg mL−1. Oxytocin decreased urine flow (4.2 ± 0.2–0.75 ± 0.11 and 4.6 ± 1.3–1.4 ± 0.6 mL min−1, low- and high-salt diet, respectively). During low-salt conditions, oxytocin reduced sodium and potassium excretion (11 ± 2–4 ± 2 and 93 ± 19–42 ± 3 μmol min−1, respectively). Plasma renin, angiotensin II, aldosterone and renal excretion of metabolites of nitric oxide (nitrate and nitrite) all decreased. Plasma atrial natriuretic peptide and cyclic guanosine monophosphate were unchanged. A similar pattern was obtained during high-salt conditions but in this case the antinatriuresis was not different from that occurring during the corresponding time control series. The data reject the hypothesis. In contrast, we found significant antinatriuretic, antikaliuretic and antidiuretic effects, which were not mediated by the renin–angiotensin–aldosterone system, atrial natriuretic peptide, systemic haemodynamics, or processes increasing urinary excretion of metabolites of nitric oxide. The natriuretic effect of oxytocin found in laboratory animals is species-specific. [ABSTRACT FROM AUTHOR]

We compared the effects of indomethacin (bolus of 0.2 mg.kg−1 followed by an infusion of 0.2 mg.kg−1.h−1) and placebo on intracranial pressure and cerebral haemodynamics in 30 patients undergoing craniotomy for supratentorial brain tumours under propofol and fentanyl anaesthesia. Indomethacin was given before induction of anaesthesia and the infusion was terminated after opening of the dura. Subdural intracranial pressure was measured through the first burr hole and before opening the dura. Cerebral blood flow velocity, cerebral perfusion pressure, jugular bulb oxygen saturation, arterio-venous oxygen difference and carbon dioxide reactivity were measured; dural tension and the degree of brain swelling were estimated. Before induction of anaesthesia, indomethacin administration was associated with a significant decrease in cerebral blood flow velocity compared with placebo. After induction of anaesthesia, cerebral blood flow velocity and mean arterial blood pressure decreased significantly in both groups. Indomethacin was not associated with a decrease in intracranial pressure. There were no differences in cerebral perfusion pressure, dural tension or degree of brain swelling between the two groups. Carbon dioxide reactivity measured after induction of anaesthesia was significantly lower in the indomethacin group (p < 0.05). After removal of the bone flap, no significant difference in carbon dioxide reactivity was observed. We suggest that these findings are explained by propofol-induced cerebral vasoconstriction. [ABSTRACT FROM AUTHOR]

The glycaemic control of thrice daily treatment with premixed biphasic insulin aspart (BIAsp) without other antidiabetic therapy was tested in type 2 diabetic patients, in order to compare the glucose control of a ‘high’ mixture (BIAsp 70) or a ‘medium’ mixture (BIAsp 50) (70 or 50% soluble IAsp and 30 or 50% protamine-crystallized IAsp, respectively) administered just before dinner. To compare these regimens to conventional 30 : 70 premixture on a twice a day basis. This randomized, double-blind, two-period crossover study included 16 patients with type 2 diabetes. Twenty four-hour serum glucose and insulin profiles were obtained thrice: (1) after a one-week run-in period with biphasic human insulin (BHI) 30/70 twice daily (run-in), (2) after 4 weeks of treatment with thrice daily BIAsp 70 before breakfast, lunch and dinner (Dinner70 regimen) and (3) after 4 weeks of BIAsp 70 before breakfast and lunch and BIAsp 50 before dinner (Dinner50). Daytime average serum glucose was lower with Dinner70 compared to run-in (9.6 ± 0.39 mmol/l vs. 11.2 ± 0.61 mmol/l, p < 0.05). Postprandial glucose excursions after breakfast and lunch were lower, but fasting morning glucose was higher during the treatment periods than in the run-in period. Twenty four-hour C-peptide AUC was considerably lower during both treatment periods than in the run-in period (run-in/Dinner50 ratio 1.29 [1.08; 1.54] p < 0.01; run-in/Dinner70 ratio 1.31 [1.08;1.58], p < 0.01). Switching the dinner dose to BIAsp 50 did not alter overall glucose control significantly from that provided with BIAsp 70. Exploratory analyses between the two active treatment regimens and run-in/BHI indicate that thrice daily BIAsp 70 administration: (1) for optimization of the night-time control, the dinner dose needs adjustment or replacement by a premixed insulin with a larger proportion of basal insulin than BIAsp 50 and (2) none of the premixtures adequately provide for both the evening meal and overnight requirements. [ABSTRACT FROM AUTHOR]

Background: The mechanism behind indomethacin-induced cerebral vasoconstriction is incompletely understood. We tested the hypothesis that the mixed endothelin-1 receptor antagonist bosentan would modify or prevent indomethacin-induced reduction of CBF in the anaesthetized pig. Furthermore, we investigated the effect of bosentan on resting CBF and CMRO2.Methods: Twelve pigs were randomized in two groups of six, and received either bosentan and indomethacin (group 1), or placebo and indomethacin (group 2). Anaesthesia was induced with ketamine and midazolam and maintained with fentanyl, nitrous oxide and pancuronium. Baseline measurements of CBF and CMRO2 were performed before intravenous bolus injection of bosentan (10 mg/kg) or placebo (0.9% NaCl). The second CBF and CMRO2 measurement was performed 30 min after administration of bosentan/placebo. A 40-min infusion of indomethacin (0.05 mg/kg/min) was administered and the third CBF and CMRO2 measurement was performed 80 min after administration of bosentan/placebo. Independently, pharmacokinetic data of bosentan were generated in four pigs.Results: In group 1, baseline CBF was 55 +/- 7 ml/100 cm3/min. Administration of bosentan i.v. did not change CBF significantly. Indomethacin decreased CBF to 41 +/- 5 ml/100 cm3/min (P < 0.002). In group 2, baseline CBF was 54 +/- 10 ml/100 cm3/min. Placebo did not change CBF while indomethacin decreased CBF significantly to 41 +/- 5 ml/100 cm3/min (P < 0.002). No significant changes in CMRO2 were observed. In group 2, a significant increase in MABP was observed after administration of indomethacin. No change in MABP was observed in the bosentan-treated animals. Total plasma concentrations of bosentan at the time of the first and the second PET measurement were 3.9 and 1.4 microg/ml, respectively. The corresponding values for the pharmacologically active metabolite Ro 48-5033 were 1.2 and 0.4 microg/ml.Conclusion: These findings indicate that endothelin receptor stimulation is not involved in indomethacin-induced cerebral vasoconstriction or maintenance of cerebrovascular tone in the anaesthetized pig. However, our results suggest that the increase in MABP is mediated through endothelin receptors. [ABSTRACT FROM AUTHOR]

Background: Despite the widespread use of paracetamol for many years, the analgesic serum concentrations of paracetamol are unknown. Therefore the correlation between serum paracetamol concentrations and the analgesic effect was studied.Methods: Sixty-four women undergoing laparoscopic sterilization were included in a double-blind, placebo-controlled, randomized study. Patients were given i.v. propacetamol 40 mg kg(-1) (group H), 20 mg kg(-1) (group I), 10 mg kg(-1) (group L) or placebo after surgery. Alfentanil was available via patient-controlled analgesia (PCA) during the 4-h postoperative study period. The patients' self-reported pain was registered on the visual analog scale (VAS). A pharmacokinetic model was fitted to the paracetamol data.Results: One to 3 h after injection of propacetamol the alfentanil consumption was significantly (P = 0.01-0.04) higher in the placebo group compared with groups H, I, and L receiving propacetamol. There were no significant differences between the amounts of alfentanil consumed in groups H, I, and L. Initial VAS-scores were moderate (5.4-6.2), and declined significantly (P < 0.0001) over time, with no difference between groups. Paracetamol followed an open two-compartment model with i.v. administration and first order elimination. The estimated concentrations immediately (t = 0) after injection were 56 mg l(-1) (H), 28 mg l(-1) (I) and 14 mg l(-1) (L).Conclusion: We showed a significant opioid-sparing effect of paracetamol in the immediate postoperative period. Pharmacokinetic data were in accordance with other studies. Our results suggest that a ceiling effect of paracetamol may be present at i.v. doses of 5 mg kg(-1), i.e. a serum concentration of 14 mg l(-1), which is a lower dose than previously suggested. [ABSTRACT FROM AUTHOR]

SUMMARY Aim To evaluate the long-term effect of changes in body composition induced by weight loss on insulin sensitivity (SI ), non-insulin mediated glucose disposal, glucose effectiveness (SG ) and β-cell function. Design Glucose metabolism was evaluated before and after participation in a two-year weight loss trial of Orlistat vs. placebo, combined with an energy and fat restricted diet. Subjects Twelve obese patients (11 women, 1 man), age 45.8 ± 10.5 years, body weight (BW) 99.7 ± 13.3 kg, BMI 35.3 ± 2.8 kg/m2 . Measurements At inclusion and 2 years later an oral glucose tolerance test (OGTT) and a frequently sampled intravenous glucose tolerance test (FSIGT) were performed. Body composition was estimated by a dual-energy X-ray absorptiometry (DXA) whole body scanning. Results The patients obtained varying changes in BW ranging from a weight loss of 17.8 kg to a weight gain of 6.0 kg. Corresponding changes in fat mass (FM) varied from a 40% reduction to a 19% increase. A significant decrease in both fasting (p = 0.038) and 2 h (p = 0.047) blood glucose at OGTT was found. The improvement in insulin sensitivity (SI ) estimated by means of Bergmans Minimal Model, was significantly and linearly correlated to change in total FM (r = - 0.83, p = 0.0026). A multiple regression analysis showed that changes in truncal FM was the strongest predictor of change in SI explaining 67% of the variation. First phase insulin response (AIRg) remained unchanged whereas insulin disposition index increased significantly (p = 0.044). At inclusion five patients had impaired glucose tolerance of which four, who lost weight, were normalized at the retest 2 years later. Conclusion In obese subjects long-term minimal or moderate changes in weight were found to be linearly associated with changes in insulin sensitivity. In obese subjects with impaired glucose tolerance even a minor... [ABSTRACT FROM AUTHOR]

Background: The primary purpose of the study was to examine the absorption of acetaminophen by measuring serum and saliva concentrations produced by a standard postoperative acetaminophen dosing regimen and secondary to examine the correlation between saliva and serum concentrations of acetaminophen after rectal and oral dosing. Methods: Twenty-four women, aged 18–60 years, scheduled for minor gynaecological laparoscopic surgery were studied. Patients received acetaminophen 2000 mg suppositories after surgery and oral doses of 1000 mg at 4 and 8 h postoperatively. Alfentanil was available via patient-controlled analgesia. Saliva and blood samples were collected postoperatively. Results: At 1, 2, 3, and 4 h after rectal dosing the saliva concentrations (mean±SD) were 15.2±5.9 μmol/l, 33.7±12.5 μmol/l, 45.5±19.1 μmol/l, and 55.4±23.1 μmol/l, respectively. The serum concentrations at 2 and 4 h were 31.0±11.2 μmol/l and 54.8±23.8 μmol/l, respectively. Additional oral dosing resulted in saliva concentrations at 5, 8, and 9 h of 99.7±49.5 μmol/l, 106.9±31.7 μmol/l, and 139.3±55.4 μmol/l, respectively, with coincident serum concentrations of 100.1±50.2 μmol/l, 105.6±29.0 μmol/l, and 141.2±52.1 μmol/l. After rectal dosing the linear regression resulted in r2=0.96, P<0.001 and saliva/serum-ratio=0.99. After additional oral dosing the outcome of linear regression was: r2=0.90, P<0.001 and saliva/serum-ratio=1.00. Conclusion: The slow and ongoing absorption process resulting in no maximum concentration within 4 h after administration of 2000 mg acetaminophen suppositories makes this rectal regimen therapeutically irrational for treatment of postoperative pain. The significant ratio and linear correlation between saliva and serum concentrations of acetaminophen suggests that saliva could be used instead of blood to monitor acetaminophen administration in patients. [ABSTRACT FROM AUTHOR]